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El problema de la enfermedad de Alzheimer como una pista para la inmortalidad

Ruolo Fisiologico del Sale (Na-Cl +)

LATEST ARTICLES POSTED

The dark side of stress (learned helplesness)

Physiology texts and the real world

Cancer: Disorder and Energy

Mitochondria and mortality

Heart and hormones

The Cancer Matrix

Serotonin: Effects in disease, aging and inflammation

Cataracts: water, energy, light, and aging

Fatigue, aging, and recuperation

Estrogen Receptors - what do they explain?

Meat physiology, stress, and degenerative physiology

Multiple Sclerosis and other hormone related brain syndromes

Prostate Cancer

Growth hormone: Hormone of Stress, Aging, and Death?

Phosphate, activation, and aging

Rosacea, inflammation, and aging: The inefficiency of stress

Hot flashes, energy, and aging

Multiple Sclerosis and other hormone-related brain syndromes

When energy fails: Edema, heart failure, hypertension, sarcopenia, etc.

Cancer: Disorder and Energy

Fats, functions & malfunctions

Radiation and Growth: Incoherent imprinting from inappropriate irradiation (pdf file)
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Sugar issues

Glucose and sucrose for diabetes

Cascara, energy, cancer and the FDA's laxative abuse

Osteoporosis, aging, tissue renewal, and product science

Regeneration and degeneration: Types of inflammation change with aging

Pathological Science & General Electric: Threatening the paradigm

Protective CO2 and aging

Genes, Carbon Dioxide and Adaptation

Serotonin, depression, and aggression: The problem of brain energy

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Academic authoritarians, language, metaphor, animals, and science

Adaptive substance, creative regeneration: Mainstream science, repression, and creativity

Calcium and Disease: Hypertension, organ calcification, & shock, vs. respiratory energy

Cholesterol, longevity, intelligence, and health.

Estrogen, memory and heredity: Imprinting and the stress response

Estrogen, progesterone, and cancer: Conflicts of interest in regulation and product promotion

Natural Estrogens

Tissue-bound estrogen in aging

Suitable Fats, Unsuitable Fats: Issues in Nutrition

The Great Fish Oil Experiment

Gelatin, stress, longevity

Glycemia, starch, and sugar in context

How do you know? Students, patients, and discovery

Intelligence and metabolism

Intuitive knowledge and its development

Lactate vs. CO2 in wounds, sickness, and aging; the other approach to cancer

Milk in context: allergies, ecology, and some myths

Membranes, plasma membranes, and surfaces

Multiple sclerosis, protein, fats, and progesterone

Progesterone Summaries

Progesterone Deceptions

Preventing and treating cancer with progesterone.

Protective CO2 and aging

RU486, Cancer, Estrogen, and Progesterone

Salt, energy, metabolic rate, and longevity

Stem cells, cell culture, and culture: Issues in regeneration

Thyroid, insomnia, and the insanities: Commonalities in disease

TSH, temperature, pulse rate, and other indicators in hypothyroidism

Water: swelling, tension, pain, fatigue, aging

Unsaturated fatty acids: Nutritionally essential, or toxic?

Aging, estrogen, and progesterone.

Aging Eyes, Infant Eyes, and Excitable Tissues

Altitude and Mortality.

Alzheimer's: The problem of Alzheimer's disease as a clue to immortality - part 1.

Alzheimer's: The problem of Alzheimer's disease as a clue to immortality - part 2.

Aspirin, brain and cancer.

Autonomic systems.

Bleeding, clotting, cancer.

Blocking Tissue Destruction.

Bone Density: First Do No Harm.

Breast Cancer.

BSE ("mad cow"), scrapie, etc.: Stimulated amyloid degeneration and the toxic fats.

Caffeine: A vitamin-like nutrient, or adaptogen. Questions about tea and coffee, cancer and other degenerative diseases, and the hormones.

Coconut Oil.

Diabetes, scleroderma, oils and hormones.

Eclampsia in the Real Organism: A Paradigm of General Distress Applicable in Infants, Adults, Etc.

Epilepsy and Progesterone.

Estriol, DES, DDT, etc.

Estrogen - Age Stress Hormone.

Estrogen and Osteoporosis.

Fats and degeneration.

Food-junk and some mystery ailments: Fatigue, Alzheimer's, Colitis, Immunodeficiency.

Immunodeficiency, dioxins, stress, and the hormones.

Iron's Dangers.

Leakiness, aging, and cancer.

Menopause and its causes.

Oils in Context.

Osteoporosis, harmful calcification, and nerve/muscle malfunctions.

Progesterone Pregnenolone & DHEA - Three Youth-Associated Hormones.

Progesterone, not estrogen, is the coronary protection factor of women.

Thyroid: Therapies, Confusion, and Fraud.

The transparency of life: Cataracts as a model of age-related disease.

Tryptophan, serotonin, and aging.

Unsaturated Vegetable Oils: Toxic.

Vegetables, etc. - Who Defines Food?

Vitamin E: Estrogen antagonist, energy promoter, and anti-inflammatory

William Blake as biological visionary. Can art instruct science?

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A R T I C L E

El problema de la enfermedad de Alzheimer como una pista para la inmortalidad

Germán Parada Cores, nacido en ISLA DE AROUSA, Galicia, España.
Licenciado en Psicología por la U.S.C, escritor patafísico (pataphysical writer)

I. INTRODUCCIÓN

II. ELEMENTOS COMUNES DE LAS LESIONES DURANTE EL CRECIMIENTO Y EL ENVEJECIMIENTO

III. RENOVACIÓN DEL CEREBRO, ENTROPÍA

IV. FALSAS SEÑALES DEL MEDIO AMBIENTE

a. EDUCACIÓN, DIETA Y MEDICINA INTERACTIVAS

b. SEÑALES

V. DESEQUILIBRIO HORMONAL, FALLOS DE PROTECCIÓN Y LA ENFERMEDAD DE ALZHEIMER

a. LA FUNCIÓN DE LA ENERGÍA

b. EFECTOS DE LOS ESTRÓGENOS Y LOS ÁCIDOS GRASOS INSATURADOS

c. VITAMINA A Y ESTEROIDES

d. LA NATURALEZA DE LA ENFERMEDAD DE ALZHEIMER

e. UN EJEMPLO DE CÓMO LA DIETA AFECTA A HORMONAS Y ESTRUCTURAS, APARENTE AUTODESTRUCCIÓN

XIII. LA ESTRUCTURA COMO SISTEMA REGULATORIO, UNA URGENTE VISIÓN DE LA OMNIPRESENTE EPIGÉNESIS

I. INTRODUCCIÓN

La toxicidad de los estrógenos y de las grasas no saturadas ha sido conocido durante todo el siglo XX, y se ha aprendido mucho acerca de sus interacciones en el proceso de envejecimiento. El organismo, durante todo este tiempo, ha sido entendido como una interacción dinámica de las influencias *tróficas celulares que regulan la forma y función.

*TRÓFICO, CA. (Del gr. trofós, alimenticio.) adj. Perteneciente o relativo a la nutrición de los tejidos. II m. Biol. Influencia trófica directa. II Estado de la nutrición.

Mi argumento es que algunos de nuestros adaptativos y protectores procesos de regulación, son anulados por la presencia excesiva de grasas no saturadas - con el apoyo de algunas otras toxinas - en nuestra dieta, actuando como una falsa señal, y que el colesterol, Pregnenolona , y la progesterona, siendo nuestras principales defensas de largo alcance, son superadas por los efectos de las grasas no saturadas; que la cascada de reacciones ineficaces y defectuosas (con inclusión de diversos procesos del Estrógeno) lleva a bajar cada vez más la producción de energía, la reducción de la función , y en extremo la muerte.

En ciertos momentos, especialmente en la infancia y la vejez, el hierro (que también tiene importantes funciones de regulación) se acumula hasta el punto de que sus funciones de señalización pueden ser inapropiadas. También está relacionado con los estrógenos y grasas no saturadas de manera que podría pasarse de la moderación y adaptación a una repentina auto-destrucción, la denominada muerte celular apoptótica.

Si nos fijamos en el organismo humano a partir de una única-total perspectiva, parece coherente e inteligible, pero desde la perspectiva de la doctrina establecida por la actual Academia Biológica, parece terriblemente complejo, carece de cualquier principio de integración visible; como resultado de una visión mecánica, simplista, farmacéutica, o de ideas religiosas que cada vez más se ofrecen a llenar dicho vacío. Sin embargo, los datos experimentales pueden ser sacados de la confusión, y darles una coherencia. En lo que sigue, voy a actuar como si las doctrinas de determinismo genético y la regulación de las membranas fueran meras reliquias históricas.

La aparición de Sistemas de control son ahora lo suficientemente claros como para empezar a utilizarlos en la inversión de la enfermedades degenerativas: Alzheimer, demencia, epilepsia, artritis, osteoporosis, depresión, hipertensión, el endurecimiento arterial y de los vasos sanguíneos, la diabetes y algunos tipos de tumor, inmunodeficiencias, reflejo de los problemas, en especial atróficos, incluida la limpieza de depósitos de amiloide y mucoide.

Creo que muchas personas experimentan regeneración cuando muchas circunstancias actúan correctamente, en sinergia; por ejemplo, irse de viaje a las montañas en primavera con amigos puede optimizar los sistemas reguladores básicos

II. ELEMENTOS COMUNES EN LAS LESIONES CEREBRALES DURANTE EL CRECIMIENTO Y EL ENVEJECIMIENTO.

La mayoría de las personas se sorprenden por el número de células en el cerebro prenatal, así como en el encéfalo envejecido: En el feto humano en sus 6 meses de desarrollo, hay aproximadamente el doble de células que en el momento del nacimiento, y, en la vejez, el número de células cerebrales sigue aumentando, de modo que a la edad de 90 la cantidad de ADN en el cerebro (36,94 gramos) es de aproximadamente 50% mayor que a la edad de 16-20 (23,04 gramos) En un cerebro de avanzada edad, las *células gliales se multiplican mientras las neuronas mueren.

*El sistema nervioso está constituido por dos tipos celulares básicos: las neuronas y las células gliales. El conjunto de células gliales conforma la denominada neuroglía. Además de desempeñar la función de soporte de las neuronas, intervienen activamente en el procesamiento cerebral de la información.

En el feto, las células que mueren son aparentemente las células nerviosas que aún no han madurado. Los factores que se sabe que reducen el tamaño del cerebro en el momento del nacimiento son también factores que están implicados en la degeneración del cerebro en la vejez o la enfermedad de Alzheimer: la falta de oxígeno, el exceso de grasas no saturadas o deficiencia de las grasas saturadas, el exceso de estrógenos, la deficiencia de progesterona, y la falta de glucosa. La falta de dióxido de carbono es probablemente perjudicial en ambos, prenatal y anciano.

Inflamación y coágulos de sangre pueden ser factores en el envejecimiento del cerebro, y el sangrado con espasmo vascular es a veces un factor que contribuye a daño cerebral, tanto en el viejo como en el encéfalo fetal. La Endotoxemia quizás sea un importante factor en la degeneración nerviosa sólo durante la vida adulta, pero a veces se presentan durante el embarazo.

Free Press, NY, 1988. C. Finch and L. Hayflick, Handbook of the Biology of Aging. Van Nostrand Reinhold, NY, 1977.

III. UNA VISIÓN DE LA ENTROPÍA: RENOVACIÓN DEL CEREBRO

Cuando un óvulo fertilizado se está convirtiendo en una persona, de cada división celular se crea un nuevo entorno para las células hijas, que deben adaptarse. Éstas deben recorrer límites y resistencias (a veces un determinado gen no responde a la necesidad de la situación, o hay toxinas que están presentes, o los nutrientes y las hormonas no están perfectamente suministrados), pero el proceso es flexible, encontrando maneras de solventar dichas limitaciones.

El desarrollo del cerebro en el embrión es mi ejemplo favorito de los caminos por las que los genes interactúan con el medio ambiente. Podemos pensar en el "óptimo desarrollo del cerebro" de una persona, o una rata o un pollo, como algo que está claramente limitado por "los genes".

Pero si a las ratas, por ejemplo, se les da un ambiente estimulante, cada generación tiene un desarrollo un poco más grande, un poco más inteligente su encéfalo. Si las ratas son tratadas durante el embarazo para aumentar su cantidad de progesterona, las crías tienen cerebros más grandes y aprenden de manera más eficiente. Aunque podríamos pensar que éste es el restablecimiento de una condición que era natural para las ratas en ambiente técnicamente perfectos.

Con otro ejemplo, los pollos se desarrollan dentro de la cáscara de huevo, de forma que los nutrientes necesarios para su desarrollo están todos presentes cuando la gallina pone el huevo. Por todo esto, el cerebro, al igual que los otros órganos, cuando deja de crecer la oferta de alimentos se agota. Sin embargo, un experimentador (Zamenhof) abrió las cáscaras de huevo en la etapa de desarrollo cuando el encéfalo estanca su crecimiento, y les añadió glucosa, encontrando que el cerebro continuaba creciendo, desarrollando pollos con cerebros más grandes. Los "genes" de un pollo, como parte de un sistema, tienen algo que ver con el desarrollo de éste, pero estos genes, este sistema existen en un ambiente dado, y todo el organismo en sí es capaz de orientar y apoyar la forma en que el sistema se desarrolla.

El tamaño, la complejidad y la inteligencia del cerebro representa una parte muy importante de la "información" que figura en el organismo, y el experimento de Zamenhof demostró que la capacidad para hacer realidad este potencial, la creación de esta complejidad, viene del apoyo del ambiente, y que "la naturaleza genética del pollo" no constituye un límite para el desarrollo de su cerebro.

Voy a argumentar que la enfermedad de Alzheimer es análoga a la situación de confrontación en el desarrollo de embriones de pollo o de la rata o de un feto humano, cuando el entorno no es capaz de satisfacer las exigentes y sensibles células del cerebro y las células cerebrales empiezan a morir; en lugar de transformarse en estados más complejos, yendo más allá de los diversos obstáculos y limitaciones.

Hay dos estereotipos que están en conflicto con este punto de vista: (1) Que la estructura del cerebro se determina en un punto temprano de la vida, a veces explícitamente a la edad de 12 o 16 años, y (2) que la estructura del cerebro entra en un deterioro "entrópico" durante el proceso de envejecimiento. Mi postura es que las células del cerebro están en un proceso de desarrollo en todo momento, y que las mismas cosas que dañan el cerebro de un feto pueden también lesionar el cerebro de la persona que va envejeciendo.

Si una novedad aparece durante el desarrollo, entonces es difícil sostener que "la entropía aumenta" durante el desarrollo de un individuo. ¿Acaso no es un niño una organización más rica que un óvulo fertilizado? ¿No es un adulto más individualizado o independiente que un niño?.

Visto desde el interior, nuestro conocimiento del mundo se hace más rico con la experiencia. El aprendizaje es, sin duda, anti-entrópico. ¿De dónde viene la idea de "la vida aumenta la entropía"?

Muchas circunstancias contribuyen a esta visión, entre ellos la doctrina del determinismo genético, la vieja idea platónica de la imperfección de lo concreto, la irrealidad de lo existente, y la idea medieval del "cuerpo corrupto." Estas filosofías aún guían a algunos individuos en la investigación del envejecimiento.

El astrofísico, NA Kozyrev, puso de manifiesto que la idea de un "universo entrópico" deriva simplemente de las hipótesis de los Deísmos del siglo 19, aquellas cuyo axioma sostiene que "Dios configuró el universo en movimiento mecánico, y lo dejó en funcionamiento..."

A principios de este siglo, Raymond Pearl sostuvo que la "Tasa de Vida" rige la duración de esta, a fin de que "vivir rápido" significa una corta vida. Basó su argumento en las semillas de melón: el que más rápido creció, fue así mismo el primero en morir. Esto fue porque no les dio otra cosa excepto agua, por lo que estos melones tuvieron que vivir de su energía almacenada, así, si crecían rápidamente, obviamente, se quedaban sin esa energía almacenada antes.

Nunca he oído que lo haya descrito como una idea absurda, pero creo que en ocasiones la cortesía se lleva demasiado lejos.

En la analogía del reloj, o la analogía de las semillas, la energía disponible se ha agotado. El reloj con su varianza primaveral y las semillas en un plato de agua pueden ser considerados como sistemas cerrados, y podemos comprender su destino Pero si es absurdo extrapolar de una semilla olvidada en un laboratorio a los organismos en un ambiente libre, entonces , es igualmente absurdo extrapolar a partir de un reloj analógico un cosmos.

Desafortunadamente, estas inferencias acerca de los sistemas cerrados se aplican a menudo a situaciones reales que no son energéticamente cerradas.

La teoría de la edad en función de "la tasa de vida recogió la idea del envejecimiento como una propiedad física natural del tiempo, y le dio una expresión matemática, con el argumento (Hershey, "Entropía, el metabolismo basal y la esperanza de vida," Gerontología 7, 245 -- 250, 1963) que "la producción de entropía en la totalidad de la duración vital" puede ser calculada, para dar idea de "la esperanza de vida y desarrollo evolutivo". Lamentablemente, la ecuación que empleó Hershey supone que el flujo de calor externo al cuerpo es reversible. Esto sugiere la imagen del Dr. Frankenstein reviviendo a su monstruo con un relámpago, poniendo de nuevo en el calor del cuerpo.

Si el calor se va a "volver a poner en el cuerpo," será pues, necesario asegurarse de que es conveniente para dicha estructura tal como ésta existe

En realidad, es justamente el flujo de energía dirigida la que genera las estructuras. Si cualquier argumento biológico puede elaborarse a partir de la idea de la entropía, es que sería muy difícil de generar alimentos poniendo calor en una persona

En algunas situaciones, es demostrable que las estructuras vivas pueden absorber directamente el calor de su entorno (lo que provoca la caída de la temperatura)- este proceso es denominado "producción negativa de calor" - pero el significado exacto de este proceso aún no está claro.

(Abbott BC, et al., "La producción positiva y negativa de calor asociadas a un impulso nervioso", Proc. R. Soc. B, 148, 149, 1958, RD y JM Keynes Ritchie, "La producción inicial de calor en las fibras nerviosas mielinizadas de anfibios ", Proc. Physiol. Soc.., de junio de 1970, página 29p-30p: "Ahora está claro que en crustáceos y mamíferos ... (Howarth, et al., 1968) las fibras no mielinizadas hay una producción inicial de calor durante (o poco después) el potencial de acción, el 80% de los cuales es rápidamente reabsorbido. ")

Zotin AI (" Envejecimiento y rejuvenecimiento desde el punto de vista de la termodinámica de los procesos irreversibles ", Priroda, N ° 9, 49-55, 1970), citando la teoría de Prigogine-Wiame, sostuvo que el proceso de envejecimiento implica una disminución de la entropía y una disminución en la tasa de producción de calor.

La Regeneración implica una producción de entropía, como cuando se forma un huevo. (Las fluctuaciones de temperatura en el momento de la ovulación podrían contribuír a la construcción de la entropía en el huevo.) El argumento de que el envejecimiento del animal (como el envejecimiento del cosmos) se rige por "la tendencia al aumento de la entropía" ha llevado a la gente decir que el rejuvenecimiento sería como revolver un huevo. El argumento de Zotin es interesante, porque dice que un huevo es un "revuelto de animales".

Este punto de vista es muy parecido a la teoría del cáncer de Warburg y Szent-Gyorgyi en la que se considera a éste como un retorno a un estado de vida más simple.

Para esbozar lo que he sostenido en diversos contextos, digamos que el agua es la parte de la sustancia viva de la que podemos discutir más significativamente en términos de entropía. De hecho, gran parte del concepto de entropía se ha derivado del estudio del agua, dado que cambió el estado en las máquinas de vapor, etc.

Las células cancerosas, al igual que los óvulos, tienen un mayor contenido de agua que las células diferenciadas en funcionamiento en un adulto, y ésta agua está menos rígidamente ordenada por las moléculas celulares. Este diferente y más móvil estado del agua, se puede medir con la RMN (resonancia magnética nuclear) El estrógeno tiene un lugar especial en relación con el agua en el organismo, íntimamente involucrado en la formación de los óvulos, y donde éste opera, aumenta tanto la cantidad de agua y, al parecer, un desorden de éste agua. Su función, en mi opinión, es promover la regeneración, como en el sistema de Zotin , mediante el aumento de la entropía, o "la codificación del animal" .

La forma en que se potencia la regeneración es mediante el fomento de la absorción de agua, estimulando la división celular, y eliminando el estado diferenciado de un grado a otro, proporcionando un nuevo suministro de "células madre", o de células al comienzo de una determinada secuencia en su diferenciación. Estas células cada vez más numerosas deben encontrar un ambiente hospitalario en el que desarrollarse y adaptarse. Y si no pueden encontrar este apoyo, entonces las células se reciclarían, al igual que las células no alimentadas en el cerebro de un feto.

Si nos imaginamos el curso del desarrollo como un resumen de la evolución (ontogenia recopilada en la filogénesis"), entonces, el óvulo, que se " decodifica " en el desarrollo embrionario, pasa por las etapas de gusano, pez, reptil, ave, primate, etc, persistiendo en la búsqueda de energía disponible que se le permite; en efecto, como diciendo "quiero esto, no quiero que," hasta que el óvulo se perfila como un bebé humano, diciendo "Yo quiero", y comienza a alimentarse, comienza el aprendizaje, y con suerte sigue el decodificado-autoactualización, por así decirlo.

El envejecimiento degenerativo, en lugar de ser "físicamente derivado de las propiedades del tiempo", parece ser producido situacionalmente, por diversos tipos de contaminación en nuestro suministro de energía.

Las grasas no saturadas, interactúan con un exceso de hierro y una deficiencia de oxígeno o de energía útil, reorientando nuestro desarrollo. La grasas saturadas, en sí mismas, no parecen tener "funciones de señalización", y cuando, son naturalmente modificadas por nuestros enzimas desaturadoras, las sustancias que éstas producen se comportan de forma muy diferente a la derivada de las plantas "* eicosanoides".

* En bioquímica, eicosanoides o icosanoides[1] [2] es el nombre general que se le da a un grupo de moléculas de constitución lipídica obtenidas de la oxigenación de los ácidos grasos esenciales de 20 carbonos tipo omega-3 y omega-6. Cumplen amplias funciones como mediadores para el sistema nervioso central, los eventos de la inflamación y de la respuesta inmune tanto en vertebrados como en invertebrados.

Todos los eicosanoides son moléculas de 20 átomos de carbono y están agrupados en prostaglandinas, tromboxanos, leucotrienos, y ciertos hidroxiácidos precursores de los leucotrienos. Constituyen las moléculas involucradas en las redes de comunicación celular más complejas del organismo animal, incluyendo el ser humano.

En lo que respecta a estos efectos, se ha observado que son de adaptación, en lugar de desadaptativos. Todos los factores que afectan el cerebro de un feto debe examinarse en relación con el envejecimiento del cerebro.

Además de los estrógenos y grasas, hago referencia a factores como el oxígeno y el dióxido de carbono, glucosa, calcio y hierro, el colesterol, la progesterona, Pregnenolona, DHEA, las endorfinas, GABA, tiroides, y de vitamina A. Un elemento adicional, el de las endotoxinas, a la larga tiende a intervenir durante el estrés y el envejecimiento, lo que exacerba la tendencia iniciada bajo la influencia de los otros factores.

IV. FALSAS SEÑALES DEL AMBIENTE

El ambiente puede servir de apoyo, aunque también puede impedir el desarrollo de un curso óptimo.

Cogiendo de forma pasiva sea lo que sea que es dado, la historia y la naturaleza, es entrópica; pero con la elección inteligente de dietas alternativas, la selección de otros cursos de acción, se creará y reducirá este patrón de entropía.

Si la educación contiene un elemento de elección y auto-actualización, entonces los resultados observados en varios estudios de la enfermedad de Alzheimer podrían tener un significado más influyente que el que ha sido sugerido por los investigadores.

Se ha informado un sesgo de diagnóstico referente al resultado de la utilización de las Baterías de Test estandarizados basados en la evaluación del vocabulario, porque la educación aumenta el vocabulario, y tiende a cubrir la pérdida de vocabulario que se produce en la demencia.

En el estudio Framingham, se llegó a la conclusión de que había una significativa relación entre un menor nivel educativo con la demencia, pero se sugirió que ciertas conductas perjudiciales para la salud como el tabaquismo son más comunes entre pacientes con menor educación.

Un estudio de Seattle sobre los pacientes de un Centro de Salud mostraron una clara diferencia en cuanto al nivel educativo entre pacientes con demencia y sin demencia, y ambos grupos tenían similares prescripciones de Estrógenos.

Las características que a mí me parecen importantes, y no han sido discutidas por los autores de estos estudios, fueron que la mujer con Demencia tiene mucho menor tasa de uso progestágeno, y una incidencia mucho más elevada de la histerectomía, que interfiere con la producción de progesterona natural. Aunque Brenner, et al., en el estudio de Seattle llegó a la conclusión de que "este estudio no proporciona pruebas de que la terapia de reemplazo hormonal de Estrógenos tiene un efecto sobre el riesgo de la enfermedad de Alzheimer en mujeres postmenopáusicas"; Brenner e al., informó de que "el uso actual de estrógeno por vías oral o vaginal, por separado, tiene un odd ratio por debajo de 1, mientras que el empleo de ambos tipos ha dado odds ratio por encima de 1 ...."

(Estas investigaciones parecen negar el hecho que el tipo de Alzheimer en ancianos tiene unha larga historia de desarrollo, por lo que es, precisamente, su anterior uso el que es pertinente. 31% de las mujeres con demencia habían utilizado estrógeno, y sólo el 20% de el grupo de control. Dado que el estrógeno es un excitante cerebral, su uso actual crea exactamente el mismo tipo de efecto en la fluidez verbal y otros signos de la conciencia del medio ambiente que la toma de unos mg de cocaína. Cualquier persona que descuida este efecto está deliberadamente construyendo un estudio propagandístico)

Esta observación, que en el Grupo Demencia había 155% más de uso estrogénico que en el grupo normal, así como una diferencia en las tasas de uso de progestágeno (los pacientes normales tenían un 50% más que el uso de progestágeno que el grupo de pacientes con demencia) y la histerectomía ( los pacientes con demencia tenían 44,1% frente al 17% al grupo de pacientes normales, es decir, 259%, como mucho, la incidencia de histerectomía -que es un fuerte indicio de un exceso en el uso de los estrógenos naturales- después de los 55 años, en pacientes con demencia es del orden de 374% sobre la incidencia en los no dementes) , debería hacer un llamamiento para un mayor estudio aclaratorio de estos datos, que tienden a indicar que la exposición a estrógenos en la mediana edad aumenta el riesgo de la enfermedad de Alzheimer en la vejez, y que incluso el uso médico de progestágenos ofrecen cierta protección hacia la Demencia...

(Aunque este estudio podría haber sido más amplio y mejor realizado, es con todo superior a los estudios-basura promovidos por la maquinaria publicitaria farmacéutica. He visto o escuchado aproximadamente 100 menciones de los "estudios" pro -estrógeno pseudocientíficos, y ninguno citaba éste.)

De Brenner, et al: La terapia de reemplazo de estrógenos Postmenopáusicas y el riesgo de la enfermedad de Alzheimer, "Am. J. Epidemiol. 140, 262-267, 1994." Las mujeres tienden a tener mayor prevalencia e incidencia en las tasas de Alzheimer que los varones AF, Jorm. La epidemiología de la enfermedad de Alzheimer y trastornos relacionados, Chapman y Hall, Londres, 1990, y Rocca WA, et al., Ann. Neurol. 30, 381-190 , 1991.

HC Liu, et al., "Performance on a dementia screening test in relation to demographic variables--study of 5297 community residents in Taiwan,"

Liu HC, et al.,"La ejecución en una prueba de detección de la demencia en relación con las variables demográficas - estudio de 5297 residentes de la comunidad de Taiwán", Arch. Neurol. Neurol. 51(9), 910-915, 1994. 51 (9), 910-915, 1994.

" Las pruebas comunmente utilizados en la detección de la Demencia pueden estar sesgadas para las personas con bajo nivel educativo, especialmente las mujeres y los residentes de las zonas rurales".

SEÑALES, EN RESUMEN.

Cuando enseño endocrinología , molesto a mis alumnos de mente ordenada por instarlos a considerar el potencial de acción de hormonas en todo el cuerpo, y hacerlos pensar en las Capas de control, que van desde el azúcar, la sal, y el dióxido de carbono, a través de las " las hormonas oficiales ", a la complejidad de las acciones del sistema nervioso tales como la esperanza, y los biorritmos.

Ciertas sustancias que son activas en procesos fundamentales, merecen una atención especial como "señales", pero deberían ser entendidas en su contexto. En este sentido, podemos pensar en Ca2 + como una sustancia-señal, en sus múltiples contextos, estando fuertemente regulada por las células de carga energética.

- Magnesio y sodio antagonizan Ca2+ en determinadas situaciones.

- Ácido linoleico, ácido linolénico, ácido araquidónico: Su toxicidad puede ser potencialmente prevenida mediante los ácidos Mead, y sus derivados eicosanoides, que se comportan de forma muy distinta que las conocidas prostaglandinas, en la medida en que se han comparado, y éstos pueden ser reducidos drásticamente mediante cambios en la dieta.

- Prostaglandinas, prostaciclina, tromboxano: Su formación está bloqueada por la aspirina y otros antiinflamatorios.

- Adenosina: Dormir induce un efecto protector.

La Adenosina es estructuralmente muy similar a inosina, otra sustancia natural (que se encuentra en la carne, por ejemplo) que es uno de loss componentes de "Inosiplex", un fármaco antiviral ( Gordon Brown, la Reserva Federal. Proc. 29, 684, 1970, y can. J . Microbiol. 18, 1463, 1972) o inmunoestimulante del cual se han encontrado efectos contra la senilidad (Doty y Gordon, la Reserva Federal. Proc. 29).

La Adenosina es un buscador de radicales libres y protege contra el calcio y el glutamato excitotóxicos. (I. Yokoi, et al. "La Adenosina rastreó los radicales hidroxilo y previno una epilepsia postraumática," radical libre Biol.. Med. 19 (4), 473-479, 1995, GP Abbracchio, et al.

" Los receptores Adenosina A (1) en los sinaptosomas del cerebro de rata: Mecanismos trasductores, (2) Efectos sobre la liberación de glutamato, y la conservación después de la inhibición del metabolismo," Desarrollo de Drogas. Res. 35 (3), 119-129, 1995.) Asimismo, parece proteger contra la relativa hiperventilación que los residuos de dióxido de carbono, y las endotoxinas que puedan interferir con su acción protectora.

- La Guanosina, en este mismo grupo de sustancias, podría tener algunas propiedades similares.

- Timidina y citidina, basadas en la pirimidina, son análogos endógenos de los barbitúricos, y como ellos, pueden ser los reguladores de las enzimas del citocromo P450.

- Uridina, en este grupo, promueve la síntesis de glucógeno y se libera de bacterias en presencia de la penicilina.

- Hierro: Regulador de la estabilidad del mRNA, síntesis sanguínea; reacciona con agentes reductores y aceites no saturados, para producir radicales libres y peróxidos lípidos, y su absorción es incrementada por los estrógenos, hipotiroidismo, anemia o falta de oxígeno.

- Glutamato y aspartato, excitotoxinas, y GABA, un transmisor inhibitorio. Estos tienen vínculos metabólicos entre sí, con el amoníaco, y con el estrés y el metabolismo energético.

- El estrógeno y la acetilcolina, excitotoxinas; ver Savolainen, et al., 1994.

La información es abrumadoramente clara, y la publicidad que manifiesta todo lo contrario es un horrible ejemplo de la corrupción de los medios de comunicación por la industria farmacéutica

- Endorfinas: estrés inducido, especificidad lateral, involucrados en la acción de estrógenos, son antagonizados por naloxona y similares inhibidores de opiáceos.

He propuesto que las endorfinas pueden causar o mantener algunos de los síntomas del envejecimiento. La Naloxona parece ser un tratamiento útil para la senilidad.

Ann. E. Roberts,. NY Acad. Sci... 396, 165, 1982; B. Reisberg, et al., N. Engl. 396, 165, 1982; N. Engl. J. Med. 308, 721, 1983.

- Endotoxinas: Acción antimitocondrial, las causas de elevación de los estrógenos. Tienen sinergia con grasas no saturadas, y la naloxona opone algunos de sus efectos tóxicos.

- Urea, colesterol: La estabilidad estructural de las proteínas y complejos de lípido-proteínas.

- Sustancias que actúan directamente sobre la estructura del agua: Creo que todos los reguladores naturales tienen un efecto sobre la estructura del agua, pero algunos sustancias inusuales actúan principalmente en el agua. Los Gases nobles, por ejemplo, no tienen efectos químicos, en cambio tienden a formar "jaulas" de moléculas de agua a su alrededor.

- Alcanfor, adamantane, y el fármaco antiviral amantadina, probablemente tengan el mismo efecto estructurante del agua, y la amantadina, se utiliza ampliamente como una terapia en la enfermedad de Parkinson, y tiene una acción anti-excitotóxica.

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V. DESEQUILIBRIO HORMONAL, LO QUE LLEVA A LA INHIBICIÓN, FALLOS DE PROTECCIÓN Y ENFERMEDAD DE ALZHEIMER

"Toda muerte celular se caracteriza por un aumento del calcio intracelular ...."" Aumento del calcio citoplásmico libre puede ser llamado 'el último camino en común » de la enfermedad de las células y de la muerte celular. El envejecimiento como fondo de las enfermedades también se caracteriza por un aumento del calcio intracelular. enfermedades típicamente asociadas con la edad son la hipertensión, la arteriosclerosis, la diabetes mellitus y la demencia ".

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a. LA FUNCIÓN DE LA ENERGÍA

La mayoría de las personas sufrimos Demencia ligera de vez en cuando; cuando estamos muy soñolientos o cansados, enfermos o borrachos, o tenemos un desequilibrio hormonal o un estado de ansiedad extrema A veces, los médicos han descrito a las personas como Dementes, lo que implica que esta condición quizás nunca mejoraría, cuando la persona padece depresión o sufre hipotiroidismo.

Si la persona tiene una historia de la epilepsia, o es anciana, el médico tiene más probabilidades de diagnosticar demencia que si la misma pérdida de la función mental se produce en una persona joven sin antecedentes de un trastorno nervioso. Incluso las personas con un menor nivel Educativo tienen mayor riesgo de ser diagnosticadas como "Dementes".

En 1976, vi a una señora de 52 años de edad que tenía el diagnóstico de demencia epiléptica. Después de 3 o 4 días tomando progesterona, restableció su funcionamiento mental en la medida en que podía manejarse con normalidad en su ciudad, volvió a trabajar... Unos meses más tarde, regresó a la escuela de postgrado, continuó y obtuvo su título universitario... Años más tarde, un hombre de unos 80 mostró los signos estándar de la Demencia Senil, como infantilismo, confusión, egocentrismo, y la inestabilidad emocional.

A los pocos días después de tomar una mezcla de tiroides, Pregnenolona y progesterona, su mente se volvió clara, y fue capaz de trabajar en un proyecto de investigación que había planeado años antes.

Cuando la temperatura del cuerpo está muy por debajo de lo normal, el funcionamiento mental se ve seriamente limitado.

Con todo, creo que la primera cuestión que debemos preguntarnos sobre una persona que padece Demencia es: ¿ tiene el síndrome del Cerebro frío, o hay algo más involucrado en su dolencia?

Cuando podemos afirmar que un cerebro ha encogido drásticamente, se llena de placas y desarolla gliosis, sabemos que algo más que un "síndrome de cerebro frío" está involucrado, pero no sabemos cuánto, a nivel cuantitativo y cualitativo, puede ser recuperado a nivel de función mental si las hormonas son normalizadas. Cada momento de mal funcionamiento, probablemente deja señales-déficits estructurales.

Tarde o temprano, es adecuado prevenir los errores funcionales que derivan en un mayor daño, y a su vez dar la oportunidad de funcionar a los Mecanismos de Regeneración.

Antes de la "Muerte por calcio" descrita (anteriormente citado) por Fujita, hay muchas oportunidades de intervenir para detener o revertir el proceso. Para considerar lo viejo que una persona es, se debería hacer mayor hincapié en la inhibición de la protección, en lugar de aumentar inmediatamente la producción de energía.

Magnesio, dióxido de carbono, el sueño, la luz roja, y la naloxona podría ser apropiado al comienzo de la terapia. El estado de reposo de una célula es un estado altamente energético.

Para los antiguos *Paulovianos, el estado de reposo existe entre dos niveles de energía, y aplican el término "inhibición protectora" generalmente para referirse a la Depleción de estado (parabiosis) que ocurre en estados de Coma o en Agotamiento, pero estoy usando la expresión en un sentido más general, y parece razonable ahora que el concepto de "Daños Excitotoxicos" se ha convertido en un tema de actualidad. Me refiero a esto a fin de incluir todo lo que protege contra el daño Excitotoxico. Esta definición, por lo tanto, tiene la virtud de ser bioquímicamente y fisiológicamente muy específica, conservando al mismo tiempo la significación funcional y la importancia terapéutica que le daban los Paulovianos. (En mi libro, La mente y el tejido, y el capítulo "Un principio unificador" en Energía generativa, discuto sobre la idea del estado de reposo y de protección de inhibición).

El sueño saludable es un ejemplo de restauración, de inhibición protectora. La carga energética, incluidos los niveles de ATP, la creatina fosfato, y almacenamiento de glucógeno, regulan muchos sistemas de reparación enzimática.

He sugerido (1975, J. Orthomol. Psiquiatría) la manera en que la sensibilidad de la entropía o la inhibición en reposo de una enzima podría participar en el cambio cerebral hacia un estado de inhibición.

Una publicación reciente (JH Benington and HC Heller, "Restoration of brain energy metabolism as the function of sleep", Progress in Neurobiol. 45, 347-360, 1995) ha propuesto que la reducción de la carga de energía y despolarización de las células actúan a través de la secreción de adenosina para restaurar glucógeno.

El almacenamiento de glucógeno disminuye con el envejecimiento, este trabajo apoya la idea de que la inhibición protectora se debiilita con la edad.(LN Simanovskiy and Zh. A. Chotoyev, "The effect of hypoxia on glycogenolysis and glycolysis rates in the rat brain," Zhurnal Evolyutsionnoy Biokhimii i Fiziologii 6(5), 577-579, 1970.)

"... las condiciones que se han demostrado que estimulan la liberación de adenosina desde el tejido nervioso representan cualquier aumento de la demanda metabólica (... activación de los receptores excitatorios), o disminución en dicho suministro (hipoxia, isquemia, hipoglucemia )...." H Benington and HC Heller, "Restoration of brain energy metabolism as the function of sleep,", " Prog. in Neurobiology 45, 347-360, 1995.

"En el cerebro, la estimulación de adenosina aumenta la conductancia del potasio que produce hiperpolarización, reduciendo así la respuesta neuronal ...."

"La liberación de Adenosina se activa globalmente como respuesta a los cambios en la homeostasis de la energía cerebral."

"Una serie de hallazgos proporcionan apoyo indirecto a la hipótesis de que el glucógeno se va agotando y se restaura durante el despertar durante el sueño."

"La reducción de la disponibilidad de glucógeno hacia los astrocitos debe aumentar ... la liberación de la adenosina...." "Debido a que la concentración de ATP es 100 veces superior a la concentración de AMP, disminuye durante 1 minuto la carga de energía celular esto se traduce en un gran aumento proporcional de la concentración de adenosina extracelular..."

Los términos "latencia funcional" y "latencia G0(La fase G0 (G sub 0) es un período en el ciclo celular donde las células están en un estado de reposo ) son similares en el sentido de un estado de reposo; cuando las células están en el estado de "inactividad G0", en latencia celular, están a la espera de su empleo regenerativo, pero no comparto la idea que no pueden ser reconstituidas a partir de su funcionamiento, como células diferenciadas.

En las plantas, * la Desdiferenciación se activa con bastante facilidad, y en el estudio de las células animales la tendencia en esa dirección parece muy evidente, aunque mucha gente sigue diciendo que esto no es posible. * (Biol. - vuelta de las células a una condición general o primitiva).

En general, procesos tales como la peroxidación lipídica o el influjo de calcio, causan la replicación de las células en un nivel, y provocan la muerte celular en un nivel superior.

La energía para resistir el estrés hace posible la inactividad, y evita el deterioro de las células, del tipo que se produce en el envejecimiento.

O. Toussaint, et al., "Cellular aging and energetic factors", Exp.. Gerontology 30(1), 1-22, 1995.

"Los experimentos realizados con células endoteliales en el contexto de la la toxicidad de los radicales libres en una Isquemia-*Reperfusión, también ofrece buenos ejemplos de los efectos de la energía celular en las resistencia celulular a estas moléculas tóxicas." *( La Reperfusión es un procedimiento en el cual se abren las arterias bloqueadas para restablecer el flujo sanguíneo. Puede llevarse a cabo mediante un tratamiento trombolítico o una angioplastia transluminal percutánea, Medciclopedia)

"... si se dota de un suplemento de energía ... el efecto tóxico de los radicales libres es mucho menor ...." .

Los enfoques específicos de esta orientación - para dinamizar el cerebro en estado de reposo - son diametralmente opuestas a algunas de las "terapias" para la enfermedad de Alzheimer que se han promovido recientemente por la industria farmacéutica: fármacos que potencian la estimulación, sobre todo para aumentar la excitación colinérgica; incluso aminoácidos excitotóxicos y sus análogos, y los estrógenos, que son pluriexcitantes cerebrales , proconvulsivos, promotores excitotóxicos, y agentes antimemoria.

Estas publicaciones Product-centered se destacan claramente de las investigaciones actuales

Hay muchos círculos viciosos relacionados con la energía asociados al envejecimiento, pero el principal parece ser el bucle calcio-radicales libres- estrógenos-tiroides-grasa,en los que la capacidad de producir la estabilización de sustancias, incluidos el dióxido de carbono y la progesterona se pierden progresivamente, aumentando la susceptibilidad a la inestabilidad de grasas no saturadas.

b. EFECTOS DEL ESTRÓGENO Y LOS ÁCIDOS GRASOS NO SATURADOS

La producción de estrógeno se ve promocionada cuando el tejido es más frío, y cuando éste disminuye la temperatura corporal. Además, los estrógenos y las endorfinas actúan conjuntamente en muchos aspectos (incluido el comportamiento del *estro) y la naloxona (antagonista de la morfina y las endorfinas), aumenta la temperatura corporal y se opone al estrógeno. *Conducta de celo animal

La Naloxona se ha demostrado que mejora los síntomas de las personas con demencia, y yo he visto rápida y potentemente, mejorar la claridad mental de una mujer de 60 años que había utilizado estrógenos. Es, junto a la Clonidina (un fármaco anti-adrenalina), un buen candidato para los golpes de calor y otros síntomas de la menopausia.

En diversas condiciones degenerativas del cerebro, la coagulación de la sangre ha estado implicada como una causa directa o una complicación de dicha degeneración.

Many people are promoting unsaturated oils for their "anti-clotting" value, in spite of the older literature showing that they inhibit proteolytic enzymes and slow clot removal.

Muchas personas están promocionando los aceites no saturados por su valor "anti-coagulante", a pesar de que la literatura clásica muestra de que éstos inhiben las enzimas proteolíticas y la promueven una lenta eliminación del coágulo.

Varias publicaciones más recientes han puesto de manifiesto otros aspectos de su participación en la formación de trombos. AJ Honour, et al.,

"The effects of changes in diet on lipid levels and platelet thrombus formation in living blood vessels," Br. Honor AJ, et al., Pathol. 59(4), 390-394, 1978--corn oil caused platelets to be more sensitive to ADP. 59 (4)

Aunque hay mucho que hablar sobre "la fluidez de la membrana," como una cosa deseable, y la pérdida de lípidos no saturados en un cerebro envejecido, hay algunas observaciones interesantes relacionadas con la "viscosidad" en la enfermedad de Alzheimer.

Las plaquetas de pacientes con Alzheimer son menos viscosas, y los lípidos extraídos del cerebro son más fluidos, y contienen un 30% menos colesterol de lo normal (a nivel molar, en relación con los fosfolípidos). (Roth SG, et al., 1995.) En general, la peroxidación lipídica causa la viscosidad celular para aumentar, al parecer, el entrecruzamiento de las proteínas, pero creo que la significación de la disminución del colesterol se refiere a su importancia como precursor de Pregnenolona y progesterona, y la conocida asociación con la enfermedad de Alzheimer de una variante de la proteína de transporte de colesterol, apoE, que supongo es un poco menos estable que la forma molecular, más susceptibles al mal funcionamiento en situación de estrés.

La matriz extracelular es un importante factor en la función y la estabilidad de las células cerebrales.

(LF Agnati, et al., "The concept of trophic units in the central nervous system," Prog. in Neurobiol. 46, 561-574, 1995. Any factor producing edema tends to disrupt the extracellular matrix (Chan and Fishman, 1978, 1980, and L. Loeb, 1948.)

Se sabe que los Accesos nerviosos son promovidos por los estrógenos, por grasas no saturadas, y por la peroxidación lipídica, y todo ello provoca un aumento en el tamaño del depósito de ácidos grasos libres en el cerebro.

Convulsiones prolongadas causan daño a los nervios en determinadas zonas, especialmente en el hipocampo, tálamo y neocorteza (Siesjo, et al., 1989). De la Demencia se sabe que es producida por convulsiones prolongadas.

La exposición prenatal a los estrógenos, por falta de oxígeno, o de grasas no saturadas reduce el tamaño del cerebro al nacer.

(JM Bourre, N. Gozlan-Devillierre, O. Morand, and N. Baumann, "Importance of exogenous saturated fatty acids during brain development and myelination in mice," Ann. Biol. Anim., Biochim., Biophys. 19(1B), 172-180, 1979.

Hay aparentemente una exigencia de las grasas saturadas durante el desarrollo. Bajo la influencia de los estrógenos, o de grasas no saturadas, las células del cerebro se inflaman, y su forma e interacciones son alterados. La memoria se deteriora dado un exceso de estrógenos.

Los estrógenos, la grasas no saturadas y el exceso de hierro matan a las células por la peroxidación lipídica, y este proceso es promovido por la falta de oxígeno.

El feto y los ancianos tienen altos niveles de hierro en las células. El estrógeno aumenta la absorción de hierro.

La Terapia Estrogénica produce un aumento de los ácidos grasos libres en la sangre, y la peroxidación lipídica en los tejidos. Todo este proceso tiende a acelerar la acumulación de Lipofuscina, pigmento del envejecimiento.

El Ácido láctico, cuya producción es promovida por los estrógenos, reduce la disponibilidad de dióxido de carbono, lo que lleva a deficiencia de suministro de sangre al cerebro. El estrógeno estimula la división celular, pero también puede aumentar la tasa de muerte celular. Los Ácidos grasos insaturados, así mismo también pueden estimular o matar.

Ambos, promueven a su vez, la formación del pigmento del envejecimiento. Además de aumentar la concentración de ácidos grasos libres, el estrógeno posiblemente disminuye el nivel de colesterol, cambios observados en el cerebro senil.

El estrógeno causa alteraciones masivas en la matriz extracelular, y parece promover la disolución de los microtúbulos (Nemetschek-Gannsler), como hace el Calcio.

Las grasas no saturadas aumentan la absorción de calcio por lo menos en algunas células del cerebro (Katsuki H. y S. Okuda, 1995). Las grasas no saturadas , como los estrógenos, aumentan la permeabilidad de los vasos sanguíneos.

Las grasas insaturadas causan edema cerebral, inhiben la captación de colina, bloqueando la producción de acetilcolina.

La progesterona es un factor de crecimiento nervioso, producido por las células gliales (oligodendrocitos). Promueve la producción de mielina, protege contra ataques, y protege las células contra los radicales libres.

Protege antes de la concepción, durante la gestación, durante el crecimiento y la pubertad, y durante el envejecimiento. Promueve la regeneración.

Su producción está bloqueada por el estrés, la peroxidación lipídica, un exceso de estrógenos y el hierro.

La aspirina protege contra la toxicidad de hierro, la formación del coágulo, y reduce la peroxidación lipídica, mientras que bloquea la formación de prostaglandinas.

La aspirina y otros antiinflamatorios, tomadas para la artritis, han sido claramente asociadas con una menor incidencia de Alzheimer, reduciendo la formación de prostaglandinas a partir del ácido araquidónico.

Los Ácidos grasos no saturados, no los ácidos grasos saturados, son las señales que activan los sistemas de la célula. Diferentes estímulos pueden inducir la actividad celular, muerte celular, o modificar a otro tipo de células.

(J. Niquet, et al., "Glial reaction after seizure induced hippocampal lesion: Immunohistochemical characterization of proliferating glial cells)

J. Neurocytol. 23(10), 641-656, 1994

De este modo, una "deficiencia" de los ácidos grasos poliinsaturados conduce a la alteración de las tasas de regeneración celular y la diferenciación, un cerebro más grande en el nacimiento, la mejora de la función del sistema inmunitario, disminución de la inflamación, la disminución de la mortalidad por endotoxinas, menor susceptibilidad a la peroxidación lipídica, aumento de la tasa metabólica basal y la respiración, aumento de la función tiroidea, pubertad tardía y disminución de otros signos de estrógeno dominante.

Cuando en la dieta los AGPI no están disponibles, el organismo produce una pequeña cantidad de ácidos grasos no saturados (ácidos Mead), pero éstos no activan los sistemas celulares de la misma manera que las plantas derivadas de AGPI, que son los precursores de un grupo totalmente diferente de prostaglandinas.

c. VITAMINA A Y ESTEROIDES

En la variedad de tipos celulares, la vitamina A funciona como un antagonista de los estrógenos, inhibiendo la división celular y promocionando o manteniendo el Estado de Funcionamiento. Promueve la síntesis de proteínas, regula los lisosomas, y protege contra la peroxidación lipídica.

Así como el estrés y la toxicidad de estrógenos se asemejan al proceso de envejecimiento, lo hace una deficiencia de vitamina A.

Mientras que sus funciones conocidas son muy variadas, creo que el mayor uso de la vitamina A es para la producción de Pregnenolona, progesterona, y otros esteroides asociados a la juventud. Una de las más importantes funciones de la vitamina E es la de preteger la oxidación destructiva de la vitamina A

Aunque se ha prestado escasa atención a los efectos de las grasas no saturadas en vitamina A, la destrucción de la vitamina E conlleva necesariamente la destrucción de la vitamina A. El aumento de la peroxidación lipídica en la tercera edad representa un círculo vicioso, en el que la pérdida de los antioxidantes y vitamina A conduce a una mayor degeneración orgánica.

Para producir Pregnenolona, tiroides, vitamina A, y colesterol tienen que ser enviadas a la mitocondria en la proporción y cantidad suficiente.

Normalmente, el estrés es equilibrado por el aumento de la síntesis de Pregnenolona, lo que mejora la capacidad de hacer frente al estrés. La Peroxidación Lipídica, como resultado de la acumulación de ácidos grasos insaturados, hierro, y la deficiencia de energía, daña a la mitocondria en la capacidad de producir Pregnenolona. Cuando la Pregnenolona es insuficiente, se activa un exceso de cortisol.

Cuando la progesterona es deficiente, el efecto de los estrógenos no encuentra oposición alguna. Cuando tiroides y progesterona son deficientes, incluso las células grasas sintetizan estrógenos.

d. NATURALEZA DE LA ENFERMEDAD DE ALZHEIMER

Aunque dentro del Alzheimer, hasta hace poco que se hace referencia a un determinado tipo de demencia orgánica que ocurre en las personas a los treinta, cuarenta y cincuenta (demencia presenil), han sido vistas similitudes estructurales con la demencia senil que han causado que el actual término vaya perdiendo su significado original.

La arterosclerosis que aparece en el Alzheimer, e incluso la muerte de células nerviosas, a veces se descuida en favor de ideas más elegantes, haciendo hincapié en ciertas proteínas que causan obturaciones y placas. Hasta hace poco, las obturaciones se han interpretado comúnmente como desechos tras la muerte celular, más que como uno de los procesos que causan la muerte de la célula.

La Demencia tipo Alzheimer es diferente de otras demencias, pero se superpone con ellas, y con la edad y el estrés relacionados se producen cambios en otros órganos.

Los signos físicos (observados en la autopsia) de Alzheimer:

1) La muerte de las neuronas (aumento de células gliales)

2) Placas de amiloide (extracelular), asociados a una variante de la apolipoproteína E, el alelo épsilon 4

3) Obturaciones de las fibras (a nivel intracelular, o restos después de que la célula ha desaparecido),

4) Amiloide en los vasos sanguíneos.

Observaciones Funcionales y bioquímicas:

1) El problema de la energía mitocondrial, Oxidasa citocromo y su regulación, la temperatura corporal /perturbación en la tasa del pulso; la peroxidación lipídica; Defectos respiratorio; alteración de la absorción de los aminoácidos; la memoria; dominio de los sistemas excitatorios frente a la adenosina inhibitoria / GABA / progesterona. / Sistema Pregnenolona.

- Aumento en la absorción de calcio, que está asociado con la peroxidación lipídica y la muerte celular.

- Aumento de cortisol y DHEA.

2) Depósito de proteínas anormales, tales como-amiloide transtiretina; albúmina vinculante de AGPI, frente al transporte de tiroides y retinol.

- Aumento de Beta-glucuronidasa, depósito de estrógeno en las células.

(AJ Cross, et al., "Cortical neurochemistry in Alzheimer-type dementia," Chapter 10, pages 153-170 in Aging of the Brain and Alzheimer's Disease, Prog. in Brain Res. 70, edited by DF Swaab, et al., Elsevier, NY, 1986. ) .

3) Proteínas anormalmente fosforiladas (tau); asociación con la variante de Apo E; microtúbulos tau organizan las proteínas, los microtúbulos están involucrados en el transporte de colesterol; fosforilación por la quinasa, regulados a su vez por las AGPI; los filamentos intermedios están por lo general asociados al estrés.

4) ApoE, en el citoplasma, que participa en la entrega de colesterol en la síntesis de Pregnenolona, como en las suprarrenales; su expresión regulada por la tiroides. Reglamento de la cadena lateral enzimática, la regulación de la ingesta de colesterol y la conversión a Pregnenolona por el receptor de endozepine / Receptores GABA, modificada por la progesterona.

e. UN EJEMPLO DE UN PROBLEMA REGULATORIO

El aceite vegetal suprime la tiroides aumentando la producción de estrógenos.

Los estrógenos y el calcio despolimerizan los microtúbulos. Los microtúbulos transportan para la Apo E transtiretina, entonces la síntesis de Pregnenolona de la tiroides y colesterol se interrumpe.

Si la Transtiretina y Apo E no se utilizan son acumulados, y se depositan en los vasos sanguíneos, alrededor de los nervios, y en el citoplasma. La deficiencia de Pregnenolona y Progesterona (agravados por la deficiencia de la tiroides) causa la pérdida de la memoria, desestabilización de las células nerviosas, falta de formación de la mielina, y exceso en la síntesis de cortisol.

Los radicales libres y el Calcio causan lesiones múltiples en las células nerviosas, incluyendo la muerte de los nervios.El estrógeno es liberado por un nivel elevado de beta-glucuronidasa.

Los desequilibrios de otros esteroides, incluyendo el cortisol y la DHEA, se desarrollan como células para compensar la deficiencia de Pregnenolona, causando cambios en el equilibrio de las células gliales.

Hipotiroidismo, el exceso de estrógeno, grasas no saturadas causan un aumento en la permeabilidad vascular y edema cerebral, fuga de proteínas, y la alteración de la matriz .

VI: ESTRUCTURA COMO SISTEMA DE REGULACIÓN: UNA VISION DE NUEVAS EPIGÉNESIS

En la introducción he mencionado que la regulación membranosa y la Determinación genética deben ser consideradas como teorías ya extintas. Lo que he estado diciendo acerca de los sistemas de auto-actualización y los factores que los perturban se deriva de una visión de la función de la célula que se ha venido desarrollando desde la década de 1920.

Alrededor de 1940, un bioquímico ruso (Oparin, creo) propone que las enzimas de la glicólisis estaban vinculados a la estructura de la célula cuando no estaban en uso, y que eran "desorbidas" bajo condiciones que requieran de abundante glicolisis.

Tras conocer este concepto, en 1970 propuse que las células de agua llevan a cabo una transición bajo tales condiciones (que podrían incluir el aumento de la temperatura, reducción de oxígeno, estimulación hormonal o nerviosa).

La activación de la glicólisis se explica generalmente por la disponibilidad de sustancias regulatorias como el amoniaco, fosfato, y NAD, y muchos bioquímicos se satisfacen de entender las de células en términos de modelos de tubo de ensayo.

Pero en los últimos años, ha quedado claro que algunas de estas moléculas básicas de regulación dirigen los componentes estructurales de la célula.

(T. Henics, "Thoughts over cell biology: A commentary," Physiol. Chem. Phys. & Med. NMR 27, 139-140, 1995.)

Aunque los detalles no están claros, se sabe que las hormonas y otros factores estabilizan o desestabilizan el ARN, y que durante algunos de estos eventos se unen a las enzimas de la ARN. Cuando estos factores se combinan con la información que se acumule en el empalme y la modificación de ARN, la copia de ARN se convierte en ADN, entonces, el sistema hereditario se considera mucho más flexible de lo que se creía que era.

Un cambio en el estado global es capaz de dirigir cada una de las partes del proceso, continuamente. De esta manera, la célula se asemeja más a un sistema de control analógico, más que digital: cada parte está momentáneamente guiado, en lugar de esperar por una "retroalimentación".

Cuando antes, los "mecanismos de regulación celulares" se referían a determinados mecanismos de retroalimentación sobre la base de las interacciones de la difusión de moléculas al azar, la nueva comprensión de la célula se asemeja a un sistema muy estructurado en el que muy poco es al azar, y las posibilidades de adaptación de la célula, en vez de limitarse a una serie de marcadores genéticos, se moldea por todas las influencias ambientales imaginables .

La estructura de la célula, lejos de ser "una lectura del genoma", es sensiblemente modificado constantemente por los procesos que incorporan algunos de estos factores ambientales en el establecimiento de cada nueva estabilidad.

El viejo modelo-genetista se ha visto obligado a admitir que los genes no pueden especificar todo lo que está en la estructura del organismo, y la complejidad del cerebro fue la que obligó a este reconocimiento de que ciertas cosas se desarrollan "epigeneticamente." Pero este nuevo hecho que la mayoría de los biólogos se muestran renuentes a aceptar es que la estructura de la célula en sí está muy desarrollado en gran medida debido a la información recibida desde el medio ambiente, es decir, "epigeneticalmente".

La epigenética (del griego epi, en o sobre) se refiere a los cambios reversibles de ADN que hace que unos genes se expresen o no dependiendo de condiciones exteriores (polifenismo). El término fue acuñado por C. H. Waddington

Tradicionalmente, la significación del concepto epigénesis se refería a que la forma de un embrión o del organismo no preexiste, o no está completamente especificada por los genes. Es decir, que ha tenido que ver con las relaciones entre las células. Se trataba del reconocimiento que "las células son lo suficientemente hábiles como para diseñar un organismo."

Es un paso significativo más allá de que para el reconocimiento de que "las células son lo suficientemente hábiles como para rediseñarse y sintonizarse en situaciones novedosas". Los Biólogos que trabajan con bacterias y levaduras han visto a éstas adaptarse de forma no aleatoria en condiciones nuevas. "Las mutaciones dirigidas " son imposibles, de acuerdo con el "dogma central", que cuenta con el apoyo de los libros de texto y la mayoría de los profesores de biología, pero éstas se producen en los organismos unicelulares.

Barbara McClintock mostró que en el maíz los genes móviles se movilizaron debido el estrés. Aunque esta no es exactamente una " mutación dirigida ", es un ejemplo de un mecanismo para aumentar la adaptación cuando ésta es necesaria.

Hay un determinado tipo de enzima que hace cortes específicos en la cadena de ADN. Y aunque los Biotecnólogos lo encontraron conveniente para sus fines, su existencia se fundamenta en efectos fisiológicos, probablemente en todos los organismos, como las descritas por McClintock en el maíz.

En el fase final del estrés que produce un tipo especial de muerte celular denominado apoptosis, estas enzimas hacen por así decirlo, un confeti del genoma. Venenos, como los estrógenos, ácidos grasos insaturados, o incluso la radiación, producen efectos diferentes en diferentes dosis.

Las dosis bajas suelen estimular la división celular, dosis mayores producen cambios de tipo celular y estados alterados de la diferenciación y, por último, ciertas dosis producen la denominada muerte celular por apoptosis.

Hay una ideología en torno a la apoptosis, que sostiene que es "genéticamente programada", esto implica que cada vez que la apoptosis se produce en el cerebro, ella estaba destinada a suceder tarde o temprano. Pero en realidad, hay varios tipos de "factores de crecimiento" que pueden prevenirla.

Cada vez está más claro que representa un estrés excesivo y/o una deficiencia de recursos. La participación de la genética en la diferenciación y la adaptación radical adaptación sugiere que (Epigenéticamente) los recursos de las células son ilimitadas.

Los cambios que se sabe que producen los venenos a los que habitualmente estamos expuestos son exactamente los cambios que se producen durante el envejecimiento cerebral. Como he revisado cientos de estudios que definen los efectos del estrógeno, grasas no saturadas, el exceso de hierro, y la peroxidación lípida, mi argumento parece común, incluso trivial, salvo que sé que claramente se refiere a los tratamientos para la mayoría de las enfermedades degenerativas, y que la gran maquinaria de la industria publicitaria propaga una perspectiva diferente en varios puntos que son esenciales en mi argumentación.

Esta industria publicitaria presentan un mito acerca de la naturaleza humana, por lo que yo expongo una contrateoría. En aquellos tiempos los humanos con mayor crecimiento cerebral vivían en los trópicos.

Sugiero que en estos orígenes antes del desarrollo de la agricultura a base de grano, estos antepasados comieron una dieta que es relativamente libre de grasas no saturadas y baja en hierro - sobre la base de frutas tropicales.

Sugiero que el cráneo de Boskop en elMonte Kilimanjaro fue un protototipo representativo de las personas que vivían bajo esas condiciones, y que sólo debido al conocimiento actual de la relación del tamaño cerebral con la longevidad, éstos - como diversos mitos de la "Edad de Oro" sugieren - deben haber tenido una larga tasa de vida.

A medida que los humanos migraron hacia el norte y desarrollaron nuevas formas de vida, su consumo de grasas no saturadas aumentó, su cerebro se redujo de tamaño, envejeciendo más rápido

Fósiles Neanderthales muestran que la linaza es un alimento básico de su dieta.

Incluso viviendo en los trópicos, hay muchas posibilidades de dietas ricas en sustancias que alteran las señales, incluyendo el hierro, y en latitudes altas existen oportunidades para reducir nuestra exposición a ellas.

Como fuente de proteínas, la leche es especialmente baja en su contenido de hierro. Las patatas, debido a la alta calidad de sus proteínas, están probablemente libre de sustancias con señales tóxicas.

Muchas frutas tropicales, además de tener relativamente grasas saturadas, también son bajas en hierro, y, a menudo, contienen importantes cantidades de aminoácidos y proteínas. En este contexto, me viene a la mente la longeva Jeanne Calment, consumidora diaria de chocolate: Cuando ella se acercaba a su 121 cumpleaños, todavía comía chocolate, aunque hbía dejado de fumar y beber vino. Se ha encontrado que las grasas saturadas del chocolate bloquean la toxicidad de los aceites ricos en ácido linoleico, y sus extrañas proteínas parecen tener una acción anabolizante.

Si realmente nos tomamos en serio la Epigénesis tradicional, y sobre todo si aceptamos una concepción más profunda de la Epigénesis a nivel de la estructura y la función celular, tenemos que ver el organismo como una especie de "torbellino de células", compuesta por torbellinos de los átomos (tal como la describe Vernadsky), en la que nuestro estilo de vida fija los límites dentro de los que nuestras células se autoreestructuran.

El azar en la producción de radicales libres, en lugar de actuar sólo en forma de daño genético o proteínas cross-linking, también es capaz de actuar como un proceso de señalización, es decir, en un nivel estrictamente fisiológico.

Un exceso de ácidos grasos insaturados constituye en sí misma una gran distorsión de los sistemas reguladores, pero también da lugar a distorsiones en el "sistema de eicosanoides", un incremento en la producción descontrolada de radicales libres, y cambios a nivel energético, la actividad tiroidea y el equilibrio en los esteroides. El envejecimiento cuerpo, en lugar de ser como un coche que necesita más y más hasta que se avería por el uso, es más parecido a un coche que viaja por una carretera que se vuelve cada vez más complicada y fangoso, hasta convertirse en un pantano intransitable.

El tratamiento que sugiero es una corrección del proceso de señalización, en lugar de "cirugía genética", trasplante, etc, que es la implicación pesimista de la doctrina de que el daño oxidativo es simplemente una cuestión de "desgaste", "mutaciones somáticas", y "entrecruzamiento". Esos problemas son reparables, y nuestro énfasis debe estar en la producción de energía y la prevención de las condiciones que permiten la acumulación de estas señales indeseables.

La ausencia de cáncer de una dieta carente de grasas, el aumento de la tasa de metabolismo, disminución de producción de radicales libres, resistencia al estrés y la intoxicación por hierro, disminución del alcohol, endotoxinas, alloxan y Estreptozotocina, etc, mejora de la estructura y función del cerebro, disminución de la susceptibilidad de coágulos de sangre, así como de la obesidad y pigmentos de edad, uilizando aceite de coco en lugar de grasas no saturadas, indica que algo muy simple que se puede hacer para reducir el sufrimiento de las principales enfermedades degenerativas, y que es muy probable que actúen mediante la reducción de la propio proceso de envejecimiento fisiológico, en su núcleo.

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RUOLO FISIOLOGICO DEL SALE (Na-Cl +)

Dr. Giorgio Rossi -NMD - Bionutritionist

Il cloruro di sodio è il sale di sodio dell'acido cloridrico ed è il comune sale da

cucina. A temperatura ambiente si presenta come un solido cristallino incolore e

inodore, dal sapore caratteristico. I suoi cristalli hanno un reticolo cubico ai cui

vertici si alternano ioni sodio Na+ e ioni cloruro Cl- . In soluzione acquosa oppure

fuso, conduce corrente elettrica.

Gia nel 1950, quando le industrie farmaceutiche iniziavano a promuovere nuovi

prodotti con azione diuretica capaci di rimpiazzare i tradizionali composti di

mercurio, iniziò ad essere proposta sia dai media che da riviste scentifiche la dieta

a base di riso con basso tenore di sodio.

I diuretici erano offerti per trattare la pressione sanguigna alta, gli edemi polmonari,

problemi cardiaci, "edemi idiopatici", edemi ortostatici e obestià, e in altre forme di

retenzione di liquidi, includendo in questo la gravidanza; e dacchè tali diuretici

funzionano attravereso l'escrezione di sodio dalle urine, le prescrizioni erano

seguite da avvertimenti di riduzione di apporto di sale per rendere l'effetto diuretico

molto più efficace.

Era chiaro che la restrizione di sale, specialmente combinata con la perdita di sale

nelle urine, era veramente dannosa durante la gravidanza, ma la combinazione

diventò uno standard per la pratica medica per diversi anni, danneggiando così

miglioni di bambini.

A discapito di molte pubblicazioni che dimostravano che i diuretici potevano

causare problemi di edemi che gli stessi erano supposti risolvere, divennero

comunque dei rimedi molto redditizi per le case farmaceutiche.

Così facendo le diete a restrizione di sale divennero un vero e proprio clichè

culturale, instillando tra l'altro la credenza erronea che il sodio causasse edemi e

ipertensione.

La restrizione del sale, in accordo con oltre 100 studi (Alderman,2004), abbassa le

pressione sanguigna di pochissimi punti. Ma questo non è generalmetne collegato

con un migliore stato di salute. In uno studio su oltre 3000 persone per circa 4 anni

si rilevò un aumento della mortalità negli individi che utilizzavano meno sale. Un

piccolo extra di pochi grammi di sale giornaliero era associato con un 36% in meno

di "eventi coronarici" ( Alderman, et al, 1995) . In un altro studio con oltre 11.000

persone in circa 22 anni si dimostrò che vi era una relazione inversa tra l'opporto di

sale e mortalità ( Alderman , et al, 1997).

Da alcuni validi ricercatori venne rilevata l'importanza nella nutrizione prenatale di

educare verso un adeguato apporto di proteine ( specialmente quelle del latte), delle

calorie, e il sale. Infatti era ormai in uso nelle donne in gravidanza il graduale

abbandono del sale e dell'uso di diuretici.

Infatti il sodio in associazione con l'albumina sierica, è essenziale per mantenere il

volume del sangue. Senza un adeguato apporto di sodio, l'albumina sierica non è

capace di trattenere l'acqua dal lasciare il sangue e conseguentemente quindi

entrare nei tessuti.

I tessuti si gonfiano non appena il volume del sangue si riduce. Durante la

gravidanza, la riduzione del volume non nutre e non ossigena adeguatamente la

crescita del feto, e la ridotta circolazione renale causa il rilascio da parte dei reni di

una sostanza segnale ( la renina) che causa al sangue di circolare più velocemente,

sotto una grande pressione. Una dieta a basso apporto di sale è giusto una delle

cose che possono ridurre la circolazione e stimolare la produzione di renina. Le

endotossine batteriche, e altre cose che causano eccessiva permeabilità capillare,

edemi, oppure sintomi come shock, attiveranno la secrezione di renina.

Diversi studi (Shanklin and Hodin, 1979) sulla preeclampsia ( questa affezione fa

aumentare la pressione arteriosa e sono potenzialmente mortali per la madre e per il

feto. Tale aumento di pressione è accompagnato da edemi generalizzati, aumento di

peso improvviso di 1,4 kg o maggiore per settimana, cefalea frontale intensa,

visione ofuscata o doppia, riduzione della portata urinaria, proteinuria, dolore

addominale centrale, irritabilità neuromuscolare, nausea e talvolta crisi convulsive

che ci si riferisce con il termine eclampsia) oppure tossiemia nella gravidanza

dimostrano che supplementando la dieta con sale potrebbe favorire la diminuzione

della pressione nelle donne gravide, e prevenire le altre complicazioni associate con

la tossicità.

L'elasticità dei vasi sanguigni è diminuita con la diminuzione del sale nella dieta.

E' risaputo già da molti anni che la diminuzione dell'apporto di sale causa una

risposta da parte del corpo ( risposta adattiva), incrementando e quindi attivando il

sistema renina-angiotensina-aldosterone (RAAS). L'attivazione di questo sistema è

riconosciuto come fattore nell'ipertensione, nelle malattie renali, nei problemi

cardiaci, nelle fibrosi cardiaca, e in altri problemi. La restrizione di sodio fà

incrementare anche la serotonina, l'attività del sistema simpatico, e PAI-1

( plasminogen activator inhibitor type-1), il quale contribuisce all'accumulazione del

coagulo ed è associato con il cancro alla prostata e al seno. Il sistema nervoso

simpatico diviene iperattivo nella preeclampsia (Metsaars, et al., 2006).

A discapito delle conoscenze generali della relazione del sale nella dieta e il sistema

RAAS, la sua applicazione per la prevenzione della tossiemia in gravidanza, non è

comunemente applicata anche ad altri problemi, come l'invecchiamento e le malattie

degenerative collegate con lo stress.

Molte donne durante il periodo mestruale hanno desiderio di sale o zucchero.

Fisiologicamente e simile come durante la gravidanza. La retenzione di acqua

durante il perido premestruale è un problema comune, e i medici comunemente

offrono le stesse indicazioni per i ciclo mestruale che era offerto già come

trattamento standard per le donne in gravidanza: eliminazione di sale, alle volte con

un diuretico. Ma quando le donne nel ciclo premestruale incrementano l'apporto di

sale in accordo con il loro desiderio , la retenzione di acqua può essere prevenuta.

Il volume del sangue cambia durante il normale ciclo mestruale, e quando il volume

del sangue è basso, è perchè l'acqua si è mossa indirizzata nei tessuti, causando

quindi edema. Quando gli estrogeni sono alti, l'osmolarità del sangue è bassa

( Courtar, et al, 2007; Stachenfeld, et al, 1999).

L'aumento dell'adrenalina causato dalla restrizione di sale ha molti effetti dannosi,

includendo insonnia. Molte persone anziane hanno riferito che una dieta a basso

livello di sodio disturba il loro sonno, e che mangiando il loro normale livello di sale

ristabiliscono la loro abilità di sonno. L'attività del loro sistema nervoso simpatico

(adrenergica) aumenta con l'età, così la restrizione di sale esalta uno dei problemi

base dell'età. L'aumento cronico dell'attivtà del sistema nervoso simpatico

contribuisce alla permeabilità capillare, resistenza insulinica ( con incremento degli

acidi grassi liberi nel sangue) , e cambiamenti degenerativi nel cervello ( Griffth and

Sutin, 1996).

La comparsa della tossicità nella gravianza e della preenclampsia aumentano la

pressione sanguigna e la permeabilità capillare, e un aumento di prolattina. La

secrezione di prolattina è aumentata dalla serotonina, la quale è una delle sostanze

che aumentano dalla restrizione del sale, ma la prolattina di per se può promuovere

la perdita di sale nelle urine (Ibarra, et al., 2005), e contribuisce alla permeabilità

vascolare e alla ipertensione.

In gravidanza, l'eccesso estrogenico e la deficienza di progesterone è un importante

fattore negli effetti dannosi della restrizione di sodio e la deficienza di proteine. Una

deficienza di proteine contribuisce all'ipotiroidismo, il quale è responsabile per il

relativo eccesso estrogenico.

Le proteine, il sale, la tiroide, e il progesterone sono termogenici, aumentano quindi

la produzione di calore e stabilizzano quindi la temperatura corporea. La prolattina e

gli estrogeni abbassano la temperatura basale.

L'abbassamento della temperatura e il metabolismo energetico nella tossiemia

oppure nella deprivazione del sale tendono ad abbassare l'utilizzo di ossigeno,

aumentando l'uso glicolitico dello zucchero, e contribuendo alla formazione

dell'acido lattico, più di quando il biossido di carbonio ( CO2).

Nella preeclampsia, il livello sierico di lattato è aumentato, pur l'addove gli acidi

grassi liberi stanno interferendo con l'uso del glucosio.

Possiamo quindi analizzare questi fatti considerando che la restrizione di sodio

abbassa il metabolismo, abbassa la produzione di biossido di carbonio, e crea

infiammazione, stress e degenerazione. Rifrasando il tutto, il sodio stimola il

metabolismo energetico, aumenta la produzione di biossido di carbonio, e protegge

contro le infiammazioni e altre reazioni di maladattamento allo stress.

In anni recenti è sato dimostrato che intensificando la respirazione mitocondriale

diminuisce il danno cellulare, e viene quindi supportata una durata di vita maggiore.

Ad esempio molti proprietari di cani sono consapevoli che i cani più piccoli

mangiano molto di più in proporzione alle loro dimensioni in rapporto a quelli più

grandi. E infine i cani piccoli hanno una durata di vita molto più lunga dei cani di

stazza più grande, e in alcuni casi questa differenza si aggira a circa il doppio.

Organismi differenti come lieviti e roditori dimostrano simili associazioni di

intensità metabolica e durata di vita. Una varietà di criceti con un 20 % in più di

tasso metabolico vivono il 15% di più che criceti con un medio tasso metabolico.

Le capacità individuali dei topi allo sforzo era in relazione al loro tasso metabolico.

I topi con un alto tasso metabolico usavano il 30 % di energia in più dei topi a basso

tasso metabolico, oltre a vivere un 36% in più (I mitocondri di questi animali sono

"sganciati", che vale a dire , il loro uso di ossigeno non è direttamente

proporzionale alla produzione di ATP. Questo significa che essi stanno producendo

molto biossido di carbonio senza necessariamente produrre più ATP, e quando a

riposo essi usano una considerevole quantità di energia).

Una importante funzione del biossido di carbonio è di regolare il movimento della

carica positiva deglio ioni metallici alcalini, come il sodio e il calcio. Quando troppo

calcio entra nella cellula attiva molti enzimi, previene il rilassamento dei nervi e dei

muscoli, e in ultimo uccide la cellula. La costante formazione di biossido di

carbonio ( acido) nella cellula permette di rimuovere il calcio, ed una piccola

quantità di sodio dalla quale è costantemente rifornita la cellula.

Quando c' è un adeguato quantitativo di sodio nel fluido extracellulare, il continuo

movimento degli ioni sodio nella cellula a riposo attiva un enzima, il sodio-potassio

ATPase, causando la formazione da ATP di ADP e fosfato, che stimola l'utilizzo di

carburante e ossigeno per mantenere un adeguato livello di ATP. Incrementando la

concentrazione di sodio aumenta il consumo energetico e la produzione di biossido

di carbonio della cellula. Il sodio protegge contro l'eccitazione e gli effetti tossici del

calcio intracellulare.

Le soluzioni ipertoniche, contenendo molto più sodio del normale ( circa da 2 a 4-10

volte il normale) sono usate per "rinvenire " persone e animali dopo incidenti.

Piuttosto che incrementare il volume del sangue nell'intento di ristabilire la

circolazione, il fluido ipertonico di sodio ripristina la produzione di energia cellulare,

aumentando il consumo di ossigeno e la produzione di calore mentre riduce la

produzione di radicali liberi, migliora la contrazione e il rilassamento del muscolo

cardiaco, e riduce l'infiammazione , la permeabilità vascolare, e gli edemi.

L'acqua di mare, che è ipertonica per i nostri tessuti, è stata inoltre usata per curare

le ferite, e le concentrazioni salini sono state trovate molto efficaci per accellerare le

guarigioni di ferite. (Mangete, et al. 1993).

Ci sono state diverse pubblicazioni che suggerivano che un aumento di sale nella

dieta può causare cancro allo stomaco, poichè nei paesi come il Giappone con un

alta incidenza di questo tipo di cancro si ha un alto uso di sale.

Sebbene cibo preservato incrementa molte delle caratteristiche tossine , anche il

pesce fresco nella dieta è stato trovato essere associato con un incremento di

rischio di cancro ( Phukan, et al., 2006).

Quando a piccoli animali veniva dato un millilitro di una soluzione saturata di sale

con il carcinogeno, il numero dei tumori incrementava . Comunque, quando il sale

era dato con mucina , non vi erano effetti carcinogeni. Dacchè un largo ammontare

di soluzione saturata di sale distruggeva la protezione naturale dello stomaco, le

cellule dello stomaco non venivano protette dal carcinogeno. Quindi più che

dimostrare che il sale causava cancro, l'esperimento dimostrava che una tazza o

più di soluzione di sale, oppure alcuni grammi si sale puro, non dovrebbero venire

ingeriti nello stesso tempo con un forte carcinogeno.

Alcuni studi hanno trovato che la carne di maiali è associata con cancro

all'esofago (Nagai, et al., 1982), tiroide (Markaki, et al., 2003), e altri organi, ma un

esperimento con manzo, pollo, oppure una dieta con pancetta nei ratti ha rilevato

un altro ruolo in relazione al sale nel processo di carcinogenesi. Dopo aver ricevuto

un carcinogeno, i ratti erano alimentati con una dieta a base di carne, contendo dal

30% al 60% di manzo surgelato fritto, pollo e pancetta . E qui ne il manzo ne il pollo

cambiavanano l'incidenza delle lesioni precancerogene, ma l'incidenza era ridotta

del 12% negli animali con il 30% di dieta con pancetta, e del 20% in ratti con dieta a

60% di pancetta. Il sale sembrava proprio fare la differenza.

Altri effetti protettivi dell'incremento del sodio sono che migliora il sistema

immunitario( Junger, et al. 1994), riduce i danni vascolari , e allevia le

infiammazioni( Cara, et al., 1988) : tutti questi effetti dovrebbero tendere a

proteggere contro malattie degenerative, incluso tumori, ateriosclerosi, e Alzheimer.

Il sistema RAAS appare essere crucialmente interessato in tutte le specie di malattie

e degenerazioni, ma gli effetti protettivi del sale sono molto importanti più di che un

semplice aiuto di prevenzione su questo sistema.

Una leggera diminuzione di temperatura può promuore l'infiammazione ( Matsui, et

al., 2006). Le sostanze termogeniche dietetiche : proteine, sodio, saccarosio, tiroide

e progesterone sono antiinfiammazione per molte ragioni, ma di per se è veramente

importante l'aumento della temperatura .

Un bassa reazione allo stress, con incremento del cortisolo, può aumentare la

temperatura del corpo attraverso l' accellerazione della distruzione e risintesi delle

proteine, ma una resistenza adattiva per lo stress aumenta la temperatura

attraverso l'incremento del consumo di ossigeno e carburante. In presenza di un

incremento di cortisolo, il grasso addominale aumenta, insieme con acidi grassi e

calcio circolanti, dove invece la respirazione mitocondriale è soppressa.

Quando i topi vengono messi in ambiente con bassa temperatura, essi

spontaneamente preferiscono acqua leggermente salata, più di quanto fresca, e

essi aumentano la loro produzione di calore (Dejima, et al., 1996). Quando ai ratti

vengono dati 0,9% di cloruro di sodio con il loro cibo, la loro produzione di

temperatura aumenta, e il loro grasso , incluso quello addominale, diminuisce(

Bryant, et al, 1984). Questi risultati attraverso l'incremneto del sodio nella dieta

sono immediati. Parte dell'effetto del sodio comporta processi regolatori nel

cervello, i quali sono molto sensibili al rapporto tra sodio e calcio. La diminuzione

del sodio, oppure l'incremento del calcio, causa il metabolsimo corporeo di

allontanarsi sia dalla termogenesi che dall'accellerazione della respirazione.

Regolando il calcio intracelluare attraveso l'incremento della produzione di

biossido di carbonio è probabilmente un meccanismo base del sodio contro

l'infiammazione e danni eccitatori a livello celluare e degenerativi.

L'azione del cortisolo nel sopprimere la respirazione mitocondriale è associato

molto fortemente con la sua abilità di aumentare il calcio intracellualre. Il cortisolo

blocca gli effetti termogenici del sodio, permettendo al calcio intracellulare di

danneggiare le cellule. Con l'età, i tessuti sono molto suscettibili a questi processi.

Gli effetti termogenici del sodio possono essere visti su un lungo studio, come su

uno breve. Un basso sodio nella dieta accellera il decremento della produzione di

calore che normalmente avviene con l'età, abbassando il tasso metabolico delle

cellule grasse brune e la temperatura corporea, e aumentando il grasso contenuto

nel corpo, cosi come l'attività della sintesi degli enzimi dei grassi. (Xavier, et al.,

2003).

L'attivazione della produzione di calore e l'incremento della temperatura può essere

considerata come un effetto dell'incremento del sodio simile al GABA .L'aumento

del GABA nel cervello incrementa la produzione di calore dalle cellule grasse brune.

( Horton, et al., 1988). L'attivazione della produzione di calore attraverso le cellule

grasse brune incrementa con onde lente durante il sonno. (Dewasmes, et al., 2003),

la quale perdita è caratteristica dell'invecchiamento ( nell'uomo adulto, i muscoli

scheletrici hanno la funzione di produrre calore simile alle cellule grasse brune).

Ora che l'infiammazione è riconosciuta come nell 'avere un ruolo centrale nelle

malattie degenerative, il fatto che la renina, angiotensina, e aldosterone

contribuiscono tutti all'infiammazione e ad un loro aumento attraverso un

deficienza di sodio,dovrebbe destare interesse nell'esplorazione terapuetica della

supplementazione del sodio, e l'integrale uso di tutti quei fattori che normalmente

supportano la produzione di energia, specialmente la tiroide e il progesterone.

L'azione antagonista sull'aldosterone del progesterone è già risaputa da molti

anni, e le medicine sintetiche antagonizzanti l'adosterone sono povere imitazioni

del progesterone.

Ma le case farmaceutiche sono interessate a vendere il loro prodotti medicinali per

bloccare la formazione e l'azione di ogni componente del RASS, più di quando

utilizzare un metodo meno costoso ( come la nutrizione) per normalizzare il sistema.

Nota finale : dato che questo mio elaborato è stato tratto dalle personali ricerche e

dall'insegnamento del Prof. Raymond Peat, [ Ph. D in Biologia presso l'Università

dell'Oregon (USA) , con specializzazione in fisiologia ] , rivolgo a lui sempre un

grosso ringraziamento per chiarirmi molto processi biochimici , tale lavoro non può

essere pubblicato se non dopo averne creata una completa elaborazione e arrichita

con altra documentazione e ricerca personale o di gruppo e personali commenti.

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The dark side of stress (learned helplessness) 

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Acetylcholine is the "neurotransmitter" of cholinergic nerves, including the parasympathetic system.

Cholinesterase (or acetylcholinesterase) is an enzyme that destroys acetylcholine, limiting the action of the cholinergic nerves.

Attaching a phosphate group to the cholinesterase enzyme inactivates it, prolonging and intensifying the action of cholinergic stimulation.

==========================================

The autonomic nervous system has traditionally been divided into the sympathetic-adrenergic system, and the parasympathetic-cholinergic system, with approximately opposing functions, intensifying energy expenditure and limiting energy expenditure, respectively. The hormonal system and the behavioral system interact with these systems, and each is capable of disrupting the others. Disruptive factors in the environment have increased in recent decades.

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Living is development; the choices we make create our individuality. If genetically identical mice grow up in a large and varied environment, small differences in their experience will affect cell growth in their brains, leading to large differences in their exploratory behavior as they age (Freund, et al., 2013). Geneticists used to say that "genes determine our limits," but this experiment shows that an environment can provide both limitations and opportunities for expanding the inherited potential. If our environment restricts our choices, our becoming human is thwarted, the way rats' potentials weren't discovered when they were kept in the standard little laboratory boxes. An opportunity to be complexly involved in a complex environment lets us become more of what we are, more humanly differentiated.

A series of experiments that started at the University of California in 1960 found that rats that lived in larger spaces with various things to explore were better at learning and solving problems than rats that were raised in the standard little laboratory cages (Krech, et al., 1960). Studying their brains, they found that the enzyme cholinesterase, which destroys the neurotransmitter, acetylcholine, was increased. They later found that the offspring of these rats were better learners than their parents, and their brains contained more cholinesterase. Their brains were also larger, with a considerable thickening of the cortex, which is considered to be the part mainly responsible for complex behavior, learning and intelligence.

These processes aren't limited to childhood. For example, London taxi drivers who learn all the streets in the city develop a larger hippocampus, an area of the brain involved with memory.

The 1960s research into environmental enrichment coincided with political changes in the US, but it went against the dominant scientific ideas of the time. Starting in 1945, the US government had begun a series of projects to develop techniques of behavior modification or mind control, using drugs, isolation, deprivation, and torture. In the 1950s, psychiatry often used lobotomies (about 80,000, before they were generally discontinued in the 1980s) and electroconvulsive "therapy," and university psychologists tortured animals, often as part of developing techniques for controlling behavior.

The CIA officially phased out their MKultra program in 1967, but that was the year that Martin Seligman, at the University of Pennsylvania, popularized the idea of "learned helplessness." He found that when an animal was unable to escape from torture, even for a very short time, it would often fail to even try to escape the next time it was tortured. Seligman's lectures have been attended by psychologists who worked at Guantanamo, and he recently received a no-bid Pentagon grant of $31,000,000, to develop a program of "comprehensive soldier fitness," to train marines to avoid learned helplessness.

Curt Richter already in 1957 had described the "hopelessness" phenomenon in rats (“a reaction of hopelessness is shown by some wild rats very soon after being grasped in the hand and prevented from moving. They seem literally to give up,”) and even how to cure their hopelessness, by allowing them to have an experience of escaping once (Richter, 1957, 1958).  Rats which would normally be able to keep swimming in a tank for two or three days, would often give up and drown in just a few minutes, after having an experience of "inescapable stress." Richter made the important discovery that the hearts of the hopeless rats slowed down before they died, remaining relaxed and filled with blood, revealing the dominant activity of the vagal nerve, secreting acetylcholine.

The sympathetic nervous system (secreting noradrenaline) accelerates the heart, and is usually activated in stress, in the "fight or flight" reaction, but this radically different (parasympathetic) nervous activity hadn't previously been seen to occur in stressful situations. The parasympathetic, cholinergic, nervous system had been thought of as inactive during stress, and activated to regulate processes of digestion, sleep, and repair. Besides the cholinergic nerves of the parasympathetic system, many nerves of the central nervous system also secrete acetylcholine, which activates smooth muscles, skeletal muscles, glands, and other nerves, and also has some inhibitory effects. The parasympathetic nerves also secrete the enzyme, cholinesterase, which destroys acetylcholine. However, many other types of cell (red blood cells, fibroblasts, sympathetic nerves, marrow cells), maybe all cells, can secrete cholinesterase.

Because cholinergic nerves have been opposed to the sympathetic, adrenergic, nerves, there has been a tendency to neglect their nerve exciting roles, when looking at causes of excitotoxicity, or the stress-induced loss of brain cells. Excessive cholinergic stimulation, however, can contribute to excitotoxic cell death, for example when it's combined with high cortisol and/or hypoglycemia.

Drugs that block the stimulating effects of acetylcholine (the anticholinergics) as well as chemicals that mimic the effects of acetylcholine, such as the organophosphate insecticides, can impair the ability to think and learn. This suggested to some people that age-related dementia was the result of the deterioration of the cholinergic nerves in the brain. Drugs to increase the stimulating effects of acetylcholine in the brain (by inactivating cholinesterase) were promoted as treatment for Alzheimer's disease.

Although herbal inhibitors were well known, profitable new drugs, starting with Tacrine, were put into use. It was soon evident that Tacrine was causing serious liver damage, but wasn't slowing the rate of mental deterioration.

As the failure of the cholinergic drug Tacrine was becoming commonly known, another drug, amantadine (later, the similar memantine) was proposed for combined treatment. In the 1950s, the anticholinergic drug atropine was proposed a few times for treating dementia, and amantadine, which was also considered anticholinergic, was proposed for some mental conditions, including Creutzfeldt-Jacob Disease (Sanders and Dunn, 1973). It must have seemed odd to propose that an anticholinergic drug be used to treat a condition that was being so profitably treated with a pro-cholinergic drug, but memantine came to be classified as an anti-excitatory "NMDA blocker," to protect the remaining cholinergic nerves, so that both drugs could logically be prescribed simultaneously. The added drug seems to have a small beneficial effect, but there has been no suggestion that this could be the result of its previously-known anticholinergic effects.

Over the years, some people have suspected that Alzheimer's disease might be caused partly by a lack of purpose and stimulation in their life, and have found that meaningful, interesting activity could improve their mental functioning. Because the idea of a "genetically determined hard-wired" brain is no longer taught so dogmatically, there is increasing interest in this therapy for all kinds of brain impairment. The analogy to the Berkeley enrichment experience is clear, so the association of increasing cholinesterase activity with improving brain function should be of interest.

The after-effect of poisoning by nerve gas or insecticide has been compared to the dementia of old age. The anticholinergic drugs are generally recognized for protecting against those toxins. Traumatic brain injury, even with improvement in the short term, often starts a long-term degenerative process, greatly increasing the likelihood of dementia at a later age. A cholinergic excitotoxic process is known to be involved in the traumatic degeneration of nerves (Lyeth and Hayes, 1992), and the use of anticholinergic drugs has been recommended for many years to treat traumatic brain injuries (e.g., Ward, 1950: Ruge, 1954; Hayes, et al., 1986).

In 1976 there was an experiment (Rosellini, et al.) that made an important link between the enrichment experiments and the learned helplessness experiments. The control animals in the enrichment experiments were singly housed, while the others shared a larger enclosure. In the later experiment, it was found that the rats "who were reared in isolation died suddenly when placed in a stressful swimming situation," while the group-housed animals were resistant, effective swimmers. Enrichment and deprivation have very clear biological meaning, and one is the negation of the other.

The increase of cholinesterase, the enzyme that destroys acetylcholine, during enrichment, serves to inactivate cholinergic processes. If deprivation does its harm by increasing the activity of the cholinergic system, we should expect that a cholinergic drug might substitute for inescapable stress, as a cause of learned helplessness, and that an anticholinergic drug could cure learned helplessness. Those tests have been done: "Treatment with the anticholinesterase, physostigmine, successfully mimicked the effects of inescapable shock." "The centrally acting anticholinergic scopolamine hydrobromide antagonized the effects of physostigmine, and when administered prior to escape testing antagonized the disruptive effects of previously administered inescapable shock." (Anisman, et al., 1981.)

This kind of experiment would suggest that the anticholinesterase drugs still being used for Alzheimer's disease treatment aren't biologically helpful. In an earlier newsletter I discussed the changes of growth hormone, and its antagonist somatostatin, in association with dementia: Growth hormone increases, somatostatin decreases. The cholinergic nerves are a major factor in shifting those hormones in the direction of dementia, and the anticholinergic drugs tend to increase the ratio of somatostatin to growth hormone. Somatostatin and cholinesterase have been found to co-exist in single nerve cells (Delfs, et al., 1984).

Estrogen, which was promoted so intensively as prevention or treatment for Alzheimer's disease, was finally shown to contribute to its development. One of the characteristic effects of estrogen is to increase the level of growth hormone in the blood. This is just one of many ways that estrogen is associated with cholinergic activation. During pregnancy, it's important for the uterus not to contract. Cholinergic stimulation causes it to contract; too much estrogen activates that system, and causes miscarriage if it's excessive. An important function of progesterone is to keep the uterus relaxed during pregnancy. In the uterus, and in many other systems, progesterone increases the activity of cholinesterase, removing the acetylcholine which, under the influence of estrogen, would cause the uterus to contract.

Progesterone is being used to treat brain injuries, very successfully. It protects against inflammation, and in an early study, compared to placebo, lowered mortality by more than half. It's instructive to consider its anticholinergic role in the uterus, in relation to its brain protective effects. When the brain is poisoned by an organophosphate insecticide, which lowers the activity of cholinesterase, seizures are likely to occur, and treatment with progesterone can prevent those seizures, reversing the inhibition of the enzyme (and increasing the activity of cholinesterase in rats that weren't poisoned) (Joshi, et al., 2010). Similar effects of progesterone on cholinesterase occur in menstrually cycling women (Fairbrother, et al., 1989), implying that this is a general function of progesterone, not just something to protect pregnancy. Estrogen, with similar generality, decreases the activity of cholinesterase. DHEA, like progesterone, increases the activity of cholinesterase, and is brain protective (Aly, et al., 2011).

Brain trauma consistently leads to decreased activity of this enzyme (Östberg, et al., 2011; Donat, et al., 2007), causing the acetylcholine produced in the brain to accumulate, with many interesting consequences. In 1997, a group (Pike, et al.) created brain injuries in rats to test the idea that a cholinesterase inhibitor would improve their recovery and ability to move through a maze. They found instead that it reduced the cognitive ability of both the injured and normal rats. An anticholinergic drug, selegeline (deprenyl) that is used to treat Parkinson's disease and, informally, as a mood altering antiaging drug, was found by a different group (Zhu, et al., 2000) to improve cognitive recovery from brain injuries.

One of acetylcholine's important functions, in the brain as elsewhere, is the relaxation of blood vessels, and this is done by activating the synthesis of NO, nitric oxide. (Without NO, acetylcholine constricts blood vessels; Librizzi, et al., 2000.) The basic control of blood flow in the brain is the result of the relaxation of the wall of blood vessels in the presence of carbon dioxide, which is produced in proportion to the rate at which oxygen and glucose are being metabolically combined by active cells. In the inability of cells to produce CO2 at a normal rate, nitric oxide synthesis in blood vessels can cause them to dilate. The mechanism of relaxation by NO is very different, however, involving the inhibition of mitochondrial energy production (Barron, et al., 2001). Situations that favor the production and retention of a larger amount of carbon dioxide in the tissues are likely to reduce the basic "tone" of the parasympathetic nervous system, as there is less need for additional vasodilation.

Nitric oxide can diffuse away from the blood vessels, affecting the energy metabolism of nerve cells (Steinert, et al., 2010). Normally, astrocytes protect nerve cells from nitric oxide (Chen, et al., 2001), but that function can be altered, for example by bacterial endotoxin absorbed from the intestine (Solà, et al., 2002) or by amyloid-beta (Tran, 2001), causing them to produce nitric oxide themselves.

Nitric oxide is increasingly seen as an important factor in nerve degeneration (Doherty, 2011). Nitric oxide activates processes (Obukuro, et al., 2013) that can lead to cell death. Inhibiting the production of nitric oxide protects against various kinds of dementia (Sharma & Sharma, 2013; Sharma & Singh, 2013). Brain trauma causes a large increase in nitric oxide formation, and blocking its synthesis improves recovery (Hüttemann, et al., 2008; Gahm, et al., 2006). Organophosphates increase nitric oxide formation, and the protective anticholinergic drugs such as atropine reduce it (Chang, et al., 2001; Kim, et al., 1997). Stress, including fear (Campos, et al., 2013) and isolation (Zlatković & Filipović, 2013) can activate the formation of nitric oxide, and various mediators of inflammation also activate it. The nitric oxide in a person's exhaled breath can be used to diagnose some diseases, and it probably also reflects the level of their emotional well-being.

The increase of cholinesterase by enriched living serves to protect tissues against an accumulation of acetylcholine. The activation of nitric oxide synthesis by acetylcholine tends to block energy production, and to activate autolytic or catabolic processes, which are probably involved in the development of a thinner cerebral cortex in isolated or stressed animals. Breaking down acetylcholine rapidly, the tissue renewal processes are able to predominate in the enriched animals.

Environmental conditions that are favorable for respiratory energy production are protective against learned helplessness and neurodegeneration, and other biological problems that involve the same mechanisms. Adaptation to high altitude, which stimulates the formation of new mitochondria and increased thyroid (T3) activity, has been used for many years to treat neurological problems, and the effect has been demonstrated in animal experiments (Manukhina, et al., 2010). Bright light can reverse the cholinergic effects of inescapable stress (Flemmer, et al., 1990).

During the development of learned helplessness, the T3 level in the blood decreases (Helmreich, et al., 2006), and removal of the thyroid gland creates the "escape deficit," while supplementing with thyroid hormone before exposing the animal to inescapable shock prevents its development (Levine, et al., 1990). After learned helplessness has been created in rats, supplementing with T3 reverses it (Massol, et al., 1987, 1988).

Hypothyroidism and excess cholinergic tone have many similarities, including increased formation of nitric oxide, so that similar symptoms, such as muscle inflammation, can be produced by cholinesterase inhibitors such as Tacrine, by increased nitric oxide, or by simple hypothyroidism (Jeyarasasingam, et al., 2000; Franco, et al., 2006).

Insecticide exposure has been suspected to be a factor in the increased incidence of Alzheimer's disease (Zaganas, et al., 2013), but it could be contributing to many other problems, involving inflammation, edema, and degeneration. Another important source of organophosphate poisoning is the air used to pressurize airliners, which can be contaminated with organophosphate fumes coming from the engine used to compress it.

Possibly the most toxic component of our environment is the way the society has been designed, to eliminate meaningful choices for most people. In the experiment of Freund, et al., some mice became more exploratory because of the choices they made, while others' lives became more routinized and limited. Our culture reinforces routinized living. In the absence of opportunities to vary the way you work and live to accord with new knowledge that you gain, the nutritional, hormonal and physical factors have special importance.

Supplements of thyroid and progesterone are proven to be generally protective against the cholinergic threats, but there are many other factors that can be adjusted according to particular needs. Niacinamide, like progesterone, inhibits the production of nitric oxide, and also like progesterone, it improves recovery from brain injury (Hoane, et al., 2008). In genetically altered mice with an Alzheimer's trait, niacinamide corrects the defect (Green, et al., 2008). Drugs such as atropine and antihistamines can be used in crisis situations. Bright light, without excess ultraviolet, should be available every day.

The cholinergic system is much more than a part of the nervous system, and is involved in cell metabolism and tissue renewal. Most people can benefit from reducing intake of phosphate, iron, and polyunsaturated fats (which can inhibit cholinesterase; Willis, et al., 2009), and from choosing foods that reduce production and absorption of endotoxin. And, obviously, drugs that are intended to increase the effects of nitric oxide (asparagine, zildenafil/Viagra, minoxidil/Rogaine) and acetylcholine (bethanechol, benzpyrinium, etc.) should be avoided.

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Neuroreport. 2000 Apr 27;11(6):1173-6. Tacrine, a reversible acetylcholinesterase inhibitor, induces myopathy. Jeyarasasingam G, Yeluashvili M, Quik M.

J Pharmacol Exp Ther. 2000 Oct;295(1):314-20. Nitric oxide is involved in acetylcholinesterase inhibitor-induced myopathy in rats. Jeyarasasingam G, Yeluashvili M, Quik M.

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1. Eur J Neurosci. 2013 Jan;37(2):181-9. Regulation of acetylcholinesterase activity by nitric oxide in rat neuromuscular junction via N-methyl-D-aspartate receptor activation. Petrov KA, Malomouzh AI, Kovyazina IV, Krejci E, Nikitashina AD, Proskurina SE, Zobov VV, Nikolsky EE.

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WARD A Jr.

Toxicol Appl Pharmacol. 2013 Aug 3. pii: S0041-008X(13)00326-8. Arsenic toxicity induced endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible nitric oxide synthase inhibitors. Sharma B, Sharma PM.

Pharmacol Biochem Behav. 2013 Feb;103(4):821-30.  Pharmacological inhibition of inducible nitric oxide synthase (iNOS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, convalesce behavior and biochemistry of hypertension induced vascular dementia in rats. Sharma B, Singh N.

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FASEB J. 2001 Jun;15(8):1407-9. Amyloid beta-peptide induces nitric oxide production in rat hippocampus: association with cholinergic dysfunction and amelioration by inducible nitric oxide synthase inhibitors. Tran MH, Yamada K, Olariu A, Mizuno M, Ren XH, Nabeshima T.

Genes Nutr. 2009 December; 4(4): 309–314. Dietary polyunsaturated fatty acids improve cholinergic transmission in the aged brain Willis LM, Shukitt-Hale B, Joseph JA.

Toxicology. 2013 May 10;307:3-11. Linking pesticide exposure and dementia: what is the evidence? Zaganas I, Kapetanaki S, Mastorodemos V, Kanavouras K, Colosio C, Wilks MF, Tsatsakis AM.

Exp Neurol. 2000 Nov;166(1):136-52. Postinjury administration of L-deprenyl improves cognitive function and enhances neuroplasticity after traumatic brain injury. Zhu J, Hamm RJ, Reeves TM, Povlishock JT, Phillips LL.

Neurochem Int. 2013 Sep;63(3):172-9. Chronic social isolation induces NF-κB activation and upregulation of iNOS protein expression in rat prefrontal cortex. Zlatković J, Filipović D.

J Biol Chem. 2006 Feb 24;281(8):4779-86. Hypothyroid phenotype is contributed by mitochondrial complex I inactivation due to translocated neuronal nitric-oxide synthase. Franco MC, Antico Arciuch VG, Peralta JG, Galli S, Levisman D, López LM, Romorini L, Poderoso JJ, Carreras MC.

Laboratory of Oxygen Metabolism, University Hospital, Facultad de Medicina,

University of Buenos Aires, 1120-Buenos Aires, Argentina.

Although transcriptional effects of thyroid hormones have substantial influence

on oxidative metabolism, how thyroid sets basal metabolic rate remains obscure.

Compartmental localization of nitric-oxide synthases is important for nitric

oxide signaling. We therefore examined liver neuronal nitric-oxide synthase-alpha

(nNOS) subcellular distribution as a putative mechanism for thyroid effects on

rat metabolic rate. At low 3,3',5-triiodo-L-thyronine levels, nNOS mRNA increased

by 3-fold, protein expression by one-fold, and nNOS was selectively translocated 

to mitochondria without changes in other isoforms. In contrast, under thyroid

hormone administration, mRNA level did not change and nNOS remained predominantly

localized in cytosol. In hypothyroidism, nNOS translocation resulted in enhanced 

mitochondrial nitric-oxide synthase activity with low O2 uptake. In this context,

NO utilization increased active O2 species and peroxynitrite yields and tyrosine 

nitration of complex I proteins that reduced complex activity. Hypothyroidism was

also associated to high phospho-p38 mitogen-activated protein kinase and

decreased phospho-extracellular signal-regulated kinase 1/2 and cyclin D1 levels.

Similarly to thyroid hormones, but without changing thyroid status, nitric-oxide 

synthase inhibitor N(omega)-nitro-L-arginine methyl ester increased basal

metabolic rate, prevented mitochondrial nitration and complex I derangement, and 

turned mitogen-activated protein kinase signaling and cyclin D1 expression back

to control pattern. We surmise that nNOS spatial confinement in mitochondria is a

significant downstream effector of thyroid hormone and hypothyroid phenotype.

 Toxicology. 2013 May 10;307:3-11. Linking pesticide exposure and dementia: what is the evidence? Zaganas I, Kapetanaki S, Mastorodemos V, Kanavouras K, Colosio C, Wilks MF, Tsatsakis AM.

J Pharmacol Exp Ther. 2000 Oct;295(1):314-20. Nitric oxide is involved in acetylcholinesterase inhibitor-induced myopathy in rats. Jeyarasasingam G, Yeluashvili M, Quik M.

Neuroreport. 2000 Apr 27;11(6):1173-6. Tacrine, a reversible acetylcholinesterase inhibitor, induces myopathy. Jeyarasasingam G, Yeluashvili M, Quik M.

Biochem Biophys Res Commun. 2002 Jan 11;290(1):97-104.

NO synthesis, unlike respiration, influences intracellular oxygen tension.

Coste J, Vial JC, Faury G, Deronzier A, Usson Y, Robert-Nicoud M, Verdetti J.

We have developed a new phosphorescent probe, PdTCPPNa(4), whose luminescence properties are affected by local variations of intracellular oxygen tension (PO(2)). Spectrofluorometric measurements on living human umbilical venous endothelial cells loaded with this molecule show that a decrease in extracellular oxygen tension induces a decrease of PO(2), illustrating the phenomenon of oxygen diffusion and validating the use of this probe in living cells. Moreover, KCN- or 2,4-dinitrophenol-induced modifications of respiration do not lead to detectable PO(2) variations, probably because O(2) diffusion is sufficient to allow oxygen supply. On the contrary, activation by acetylcholine or endothelial nitric oxide synthase (eNOS), which produces NO while consuming oxygen, induces a significant decrease in PO(2), whose amplitude is dependent on the acetylcholine dose, i.e., the eNOS activity level. Hence, activated cytosolic enzymes could consume high levels of oxygen which cannot be supplied by diffusion, leading to PO(2) decrease. Other cell physiology mechanisms leading to PO(2) variations can now be studied in living cells with this probe.

Science. 1984 Jan 6;223(4631):61-3. Coexistence of acetylcholinesterase and somatostatin-immunoreactivity in neurons cultured from rat cerebrum. Delfs JR, Zhu CH, Dichter MA.

Genes Nutr. 2009 December; 4(4): 309–314. Dietary polyunsaturated fatty acids improve cholinergic transmission in the aged brain Willis LM, Shukitt-Hale B, Joseph JA.

Toxicology. 2013 May 10;307:3-11. Linking pesticide exposure and dementia: what is the evidence? Zaganas I, Kapetanaki S, Mastorodemos V, Kanavouras K, Colosio C, Wilks MF,

Tsatsakis AM.

s sufficient for oxidative phosphorylation (references in ref. 1). These findings indicate that, in execution of these tasks, the involved brain tissue switches to aerobic glycolysis.

Acta Neurochir Suppl. 1997;70:130-3. Topical application of insulin like growth factor-1 reduces edema and upregulation of neuronal nitric oxide synthase following trauma to the rat spinal cord. Sharma HS, Nyberg F, Gordh T, Alm P, Westman J.

 Toxicol Appl Pharmacol. 2013 Aug 3. pii: S0041-008X(13)00326-8. Arsenic toxicity induced endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible nitric oxide synthase inhibitors. Sharma B, Sharma PM.

2. Pharmacol Biochem Behav. 2013 Feb;103(4):821-30.  Pharmacological inhibition of inducible nitric oxide synthase (iNOS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, convalesce behavior and biochemistry of hypertension induced vascular dementia in rats. Sharma B, Singh N.

CNS and CVS Research Lab., Pharmacology Division, Department of Pharmaceutical

Sciences and Drug Research, Faculty of Medicine, Punjabi University, Patiala

147002, Punjab, India. bhupeshresearch@gmail.com

Cognitive disorders are likely to increase over the coming years (5-10). Vascular

dementia (VaD) has heterogeneous pathology and is a challenge for clinicians.

Current Alzheimer's disease drugs have had limited clinical efficacy in treating 

VaD and none have been approved by major regulatory authorities specifically for 

this disease. Role of iNOS and NADPH-oxidase has been reported in various

pathological conditions but there role in hypertension (Hypt) induced VaD is

still unclear. This research work investigates the salutiferous effect of

aminoguanidine (AG), an iNOS inhibitor and 4'-hydroxy-3'-methoxyacetophenone

(HMAP), a NADPH oxidase inhibitor in Hypt induced VaD in rats.

Deoxycorticosterone acetate-salt (DOCA-S) hypertension has been used for

development of VaD in rats. Morris water-maze was used for testing learning and

memory. Vascular system assessment was done by testing endothelial function. Mean

arterial blood pressure (MABP), oxidative stress [aortic superoxide anion, serum 

and brain thiobarbituric acid reactive species (TBARS) and brain glutathione

(GSH)], nitric oxide levels (serum nitrite/nitrate) and cholinergic activity

(brain acetyl cholinesterase activity-AChE) were also measured. DOCA-S treated

rats have shown increased MABP with impairment of endothelial function, learning 

and memory, reduction in serum nitrite/nitrate & brain GSH levels along with

increase in serum & brain TBARS, and brain AChE activity. AG as well as HMAP

significantly convalesce Hypt induced impairment of learning, memory, endothelial

function, and alterations in various biochemical parameters. It may be concluded 

that AG, an iNOS inhibitor and HMAP, a NADPH-oxidase inhibitor may be considered 

as potential agents for the management of Hypt induced VaD.

Copyright © 2012 Elsevier Inc. All rights reserved.

[Curr Pharm Des. 2010;16(25):2837-50. Nitric oxide: target for therapeutic strategies in Alzheimer's disease. Fernandez AP, Pozo-Rodrigalvarez A, Serrano J, Martinez-Murillo R. "data implicating nitric oxide (NO) in the progression of the disease. The three isoforms of the NO-synthesizing enzyme (NOS) operate as central mediators of amyloid beta-peptide (Aβ) action, giving rise to elevated levels of NO that contributes to the maintenance, self-perpetuation and progression of the disease. "]

J Neuropathol Exp Neurol. 2007 Apr;66(4):272-83. Nitric oxide synthase 3-mediated neurodegeneration after intracerebral gene delivery. de la Monte SM, Jhaveri A, Maron BA, Wands JR. "increased nitric oxide synthase 3 (NOS3) expression correlates with apoptosis in cortical neurons and colocalizes with amyloid precursor protein (APP)-amyloid beta (Abeta) deposits in the brain."

Neuroscience. 2000;101(2):283-7. Nitric oxide synthase inhibitors unmask acetylcholine-mediated constriction of cerebral vessels in the in vitro isolated guinea-pig brain. Librizzi L, Folco G, de Curtis M.

Pharmacology. 2000 Feb;60(2):82-9. Choline is a full agonist in inducing activation of neuronal nitric oxide synthase via the muscarinic M1 receptor. Carriere JL, El-Fakahany EE.

Glia. 2003 Jan 15;41(2):207-11. Alzheimer's disease is associated with a selective increase in alpha7 nicotinic acetylcholine receptor immunoreactivity in astrocytes. Teaktong T, Graham A, Court J, Perry R, Jaros E, Johnson M, Hall R, Perry E.

16. Neuroscientist. 2010 Aug;16(4):435-52. 

Nitric oxide signaling in brain function, dysfunction, and dementia.

Steinert JR, Chernova T, Forsythe ID.

Neurotoxicity at the Synaptic Interface, MRC Toxicology Unit, University of

Leicester, Leicester, UK.

Nitric oxide (NO) is an important signaling molecule that is widely used in the

nervous system. With recognition of its roles in synaptic plasticity (long-term

potentiation, LTP; long-term depression, LTD) and elucidation of

calcium-dependent, NMDAR-mediated activation of neuronal nitric oxide synthase

(nNOS), numerous molecular and pharmacological tools have been used to explore

the physiology and pathological consequences for nitrergic signaling. In this

review, the authors summarize the current understanding of this subtle signaling 

pathway, discuss the evidence for nitrergic modulation of ion channels and

homeostatic modulation of intrinsic excitability, and speculate about the

pathological consequences of spillover between different nitrergic compartments

in contributing to aberrant signaling in neurodegenerative disorders.

Accumulating evidence points to various ion channels and particularly

voltage-gated potassium channels as signaling targets, whereby NO mediates

activity-dependent control of intrinsic neuronal excitability; such changes could

underlie broader mechanisms of synaptic plasticity across neuronal networks. In

addition, the inability to constrain NO diffusion suggests that spillover from

endothelium (eNOS) and/or immune compartments (iNOS) into the nervous system

provides potential pathological sources of NO and where control failure in these 

other systems could have broader neurological implications. Abnormal NO signaling

could therefore contribute to a variety of neurodegenerative pathologies such as 

stroke/excitotoxicity, Alzheimer's disease, multiple sclerosis, and Parkinson's

disease.

Neurosci Bull. 2011 Dec;27(6):366-82. Nitric oxide in neurodegeneration: potential benefits of non-steroidal anti-inflammatories. Doherty GH.18. 

Neuroscience. 2010 Dec 15;171(3):859-68. Low energy laser light (632.8 nm) suppresses amyloid-β peptide-induced oxidative and inflammatory responses in astrocytes.

Yang X, Askarova S, Sheng W, Chen JK, Sun AY, Sun GY, Yao G, Lee JC.

Neurosci Behav Physiol. 2010 Sep;40(7):737-43. Prevention of neurodegenerative damage to the brain in rats in experimental Alzheimer's disease by adaptation to hypoxia. Manukhina EB, Goryacheva AV, Barskov IV, Viktorov IV, Guseva AA, Pshennikova MG, Khomenko IP, Mashina SY, Pokidyshev DA, Malyshev IY.

 Physiol Behav. 1990 Jul;48(1):165-7.

Thyroparathyroidectomy produces a progressive escape deficit in rats.

Levine JD, Strauss LR, Muenz LR, Dratman MB, Stewart KT, Adler NT.

Department of Anatomy, University of Pennsylvania, Philadelphia.

Abnormal thyroid status and affective disorders have been associated in the human

clinical literature. It has recently been shown that pretreatment with thyroid

hormone can prevent escape deficits produced by inescapable shock in an animal

analogue of depression. In this report we provide evidence that hypothyroid

status can produce an escape deficit in rats. While sham-operated rats improved

their performance on a simple escape task over three days of testing,

thyroparathyroidectomized rats showed a pronounced decrease in their responses.

Markov transition analysis was used to obtain conditional probabilities of

escaping given a prior escape or failure to escape for the two groups. This

analysis shows that the structure of the data set may be similar for the two

groups. These results suggest that if intact rats learn to escape, then

hypothyroid rats may learn not to escape.

1. Pharmacol Biochem Behav. 1990 Aug;36(4):775-8.

Bright light blocks the capacity of inescapable swim stress to supersensitize a

central muscarinic mechanism.

Flemmer DD, Dilsaver SC, Peck JA.

Department of Psychiatry, Ohio State University.

Clinical and basic researchers have proposed that muscarinic cholinergic

mechanisms mediate some effects of chronic stress. Chronic inescapable (forced)

swim stress depletes brain biogenic amines and is used to produce learned

helplessness in rats. Behavioral and biochemical characteristics of animals in

the state of learned helplessness lead some investigators to believe this

condition provides a useful animal model of depression. Inescapable swim stress

also produces supersensitivity to the hypothermic effect of the muscarinic

agonist oxotremorine in the rat. The authors previously demonstrated that bright 

light potently induces subsensitivity of a central muscarinic mechanism involved 

in the regulation of core temperature under a variety of circumstances. They now 

report using a repeated measures design that inescapable swim stress of five days

duration produces supersensitivity to oxotremorine (increase in thermic response 

of 405%). This supersensitivity is reversed within five days by treatment with

bright light, despite continuation of daily swim stress. Daily inescapable swim

stress was continued beyond cessation of treatment with bright light. Five days

later, supersensitivity to the hypothermic effect of oxotremorine was once again 

evident.

Pharmacol Biochem Behav. 1986 Aug;25(2):415-21. 

Neurochemical and behavioral consequences of mild, uncontrollable shock: effects 

of PCPA. 

Edwards E, Johnson J, Anderson D, Turano P, Henn FA. 

The present experiments examined the role of the serotonergic system in the 

behavioral deficit produced by uncontrollable shock. In Experiment 1: 

Establishment of model, the behavioral potential of the Sprague-Dawley rat was 

defined. When exposed to mild uncontrollable stress such as a 0.8 mA electric 

footshock, a significant percentage of rats developed a shock escape deficit 

which was evident when subsequently placed in a shock escape paradigm. Serotonin 

depletion was produced by chronic treatment with p-chlorophenylalanine. Biogenic 

amine levels and 5-HT levels were monitored in various brain areas using HPLC. 

Following chronic treatment with PCPA, the shock escape capability of the 

Sprague-Dawley rat was assessed. The severe depletion of 5-HT in various brain 

regions was highly correlated with a dramatic improvement in the shock escape 

scores. Thus, the detrimental effects of exposure to a mild course of inescapable 

shock can be prevented by chronic treatment with PCPA. These experiments 

implicate the serotonergic system as a possible mediator of the "learned 

helplessness" phenomenon. 

Biol Psychiatry. 1985 Sep;20(9):1023-5. 

Triiodothyronine-induced reversal of learned helplessness in rats. 

Martin P, Brochet D, Soubrie P, Simon P. 

Pharmacol Biochem Behav. 1982 Nov;17(5):877-83. 

Evidence for a serotonergic mechanism of the learned helplessness phenomenon. 

Brown L, Rosellini RA, Samuels OB, Riley EP. 

The present experiments examined the role of the serotonergic system in the 

learned helplessness phenomenon. In Experiment 1, a 200 mg/kg dose of 

1-tryptophan injected 30 min prior to testing disrupted acquisition of Fixed 

Ratio 2 shuttle escape behavior. In Experiment 2, a 100 mg/kg dose of 5-HTP 

produced interference with the acquisition of the escape response. Furthermore, 

this interference was prevented by treatment with the serotonergic antagonist 

methysergide. In Experiment 3, animals were pretreated with a subeffective dose 

of 1-tryptophan in combination with subeffective exposure to inescapable shock. 

These animals showed a deficit in the acquisition of FR-2 shuttle escape. In 

Experiment 4, combined exposure to a subeffective dose of 5-HTP and inescapable 

shock (40 trials) resulted in an acquisition deficit. This deficit was reversed 

by methysergide. Experiment 5 showed that the detrimental effects of exposure to 

prolonged (80 trials) of inescapable shock can be prevented by treatment with 

methysergide. These studies implicate the serotonergic system as a possible 

mediator of the learned helplessness phenomenon. 

45. Med Hypotheses. 2004;63(2):308-21. Brain cholinesterases: II. The molecular and cellular basis of Alzheimer's disease. Shen ZX.

2436 Rhode Island Avenue #3, Golden valley, MN 55427-5011, USA.

zhengxshen@yahoo.com

Currently available evidence demonstrates that cholinesterases (ChEs), owing to

their powerful enzymatic and non-catalytic actions, unusually strong

electrostatics, and exceptionally ubiquitous presence and redundancy in their

capacity as the connector, the organizer and the safeguard of the brain, play

fundamental role(s) in the well-being of cells, tissues, animal and human lives, 

while they present themselves adequately in quality and quantity. The widespread 

intracellular and extracellular membrane networks of ChEs in the brain are also

subject to various insults, such as aging, gene anomalies, environmental hazards,

head trauma, excessive oxidative stress, imbalances and/or deficits of organic

constituents. The loss and the alteration of ChEs on the outer surface membranous

network may initiate the formation of extracellular senile plaques and induce an 

outside-in cascade of Alzheimer's disease (AD). The alteration in ChEs on the

intracellular compartments membranous network may give rise to the development of

intracellular neurofibrillary tangles and induce an inside-out cascade of AD. The

abnormal patterns of glycosylation and configuration changes in ChEs may be

reflecting their impaired metabolism at the molecular and cellular level and

causing the enzymatic and pharmacodynamical modifications and neurotoxicity

detected in brain tissue and/or CSF of patients with AD and in specimens in

laboratory experiments. The inflammatory reactions mainly arising from

ChEs-containing neuroglial cells may facilitate the pathophysiologic process of

AD. It is proposed that brain ChEs may serve as a central point rallying various 

hypotheses regarding the etio-pathogenesis of AD.

3. Neurology. 2011 Mar 22;76(12):1046-50. doi: 10.1212/WNL.0b013e318211c1c4.

Cholinergic dysfunction after traumatic brain injury: preliminary findings from a

PET study.

Östberg A, Virta J, Rinne JO, Oikonen V, Luoto P, Någren K, Arponen E, Tenovuo O.

Department of Neurology, University of Turku and Turku University Central

Hospital, Turku, Finland.

OBJECTIVE: There is evidence that the cholinergic system is frequently involved

in the cognitive consequences of traumatic brain injury (TBI). We studied whether

the brain cholinergic function is altered after TBI in vivo using PET.

METHODS: Cholinergic function was assessed with

[methyl-(11)C]N-methylpiperidyl-4-acetate, which reflects the

acetylcholinesterase (AChE) activity, in 17 subjects more than 1 year after a TBI

and in 12 healthy controls. All subjects had been without any centrally acting

drugs for at least 4 weeks.

RESULTS: The AChE activity was significantly lower in subjects with TBI compared 

to controls in several areas of the neocortex (-5.9% to -10.8%, p=0.053 to

0.004).

CONCLUSIONS: Patients with chronic cognitive symptoms after TBI show widely

lowered AChE activity across the neocortex.

© 2011 by AAN Enterprises, Inc.

9. Brain Inj. 2007 Sep;21(10):1031-7.

Alterations of acetylcholinesterase activity after traumatic brain injury in

rats.

Donat CK, Schuhmann MU, Voigt C, Nieber K, Schliebs R, Brust P.

Institute of Interdisciplinary Isotope Research, Permoserstasse 15, 04318

Leipzig, Germany. donat@iif-leipzig.de

OBJECTIVE: The cholinergic system is highly vulnerable to traumatic brain injury 

(TBI). However, limited information is available to what extent the degrading

enzyme acetylcholinesterase (AChE) is involved. The present study addresses this 

question.

METHOD: Thirty-six anaesthetized Sprague-Dawley rats were subjected to sham

operation or to TBI using controlled cortical impact (CCI). The AChE activity was

histochemically determined in frozen brain slices at 2, 24 and 72 hours after

TBI.

RESULTS: High enzyme activity was observed in regions rich in cholinergic

innervation such as the olfactory tubercle, basal forebrain, putamen and superior

colliculi. Low activity was found in the cortex, cerebellum and particularly in

the white matter. A decrease of AchE activity (20-35%) was found in the

hippocampus and hypothalamus already at 2 hours after TBI. An increase of

approximately 30% was found in the basal forebrain at 2 and 24 hours. No changes 

occurred at 72 hours.

CONCLUSION: The findings are consistent with impairment of the cholinergic

neurotransmission after TBI and suggest the involvement of the AChE in short-term

regulatory mechanisms.

35. Res Commun Chem Pathol Pharmacol. 1990 Jun;68(3):391-4.

Increase of muscarinic receptor following kainic acid lesions of the nucleus

basalis magnocellularis in rat brain: an autoradiographic study.

Katayama S, Kito S, Yamamura Y.

Third Department of Internal Medicine, Hiroshima University School of Medicine,

Japan.

We observed changes in cholinergic markers in rat brain seven days after

lesioning the nucleus basalis magnocellularis (nbm) with kainic acid. In

histochemical preparations stained for acetylcholinesterase (AChE), there was a

marked loss of large AChE reactive neurons within and beneath the nbm on the

injected side, and the AChE positive fibers were greatly decreased particularly

in the IV-VI layers of the frontal and parietal cortices ipsilateral to the

kainate lesion. Using in vitro receptor autoradiography, we found a significant

increase (about 25%) in 3H-QNB binding sites in the I-IV layers of the

ipsilateral frontal and parietal cortices (p 0.05, Student's t-test). The area

with decreased AChE activity and increased density in 3H-QNB binding sites

corresponded to the innervation of the cholinergic system arising from the nbm.

The increase of density in 3H-QNB binding sites was considered to reflect the

postsynaptic denervation supersensitivity.

36. Hum Exp Toxicol. 1992 Nov;11(6):517-23.

Long-term study of brain lesions following soman, in comparison to DFP and

metrazol poisoning.

Kadar T, Cohen G, Sahar R, Alkalai D, Shapira S.

Department of Pharmacology, Israel Institute for Biological Research, Ness-Ziona,

Israel.

The long-term histopathological effects of acute lethal (95 micrograms kg-1) and 

sublethal (56 micrograms kg-1) doses of soman were studied in rats and were

compared to lesions caused by equipotent doses of either another cholinesterase

(ChE) inhibitor, DFP (1.8 mg kg-1), or a non-organophosphorus convulsant,

metrazol (100 mg kg-1). Severe toxic signs were noted following one LD50 dose

administration of all the compounds, yet only soman induced brain lesions.

Moreover, even when administered at a sublethal dose (0.5 LD50), soman induced

some histological changes without any clinical signs of intoxication.

Soman-induced brain lesions were assessed quantitatively using a computerized

image analyser. The analysis was carried out for up to 3 months following

administration, and a dynamic pattern of pathology was shown. The cortical

thickness and area of CA1 and CA3 cells declined significantly as early as 1 week

post-exposure. No pathological findings were detected following DFP and metrazol 

administration. It is therefore suggested that brain lesions are not common for

all ChE inhibitors and that convulsions per se are not the only factor leading to

brain damage following the administration of soman. The degenerative process

(found also with the sublethal dose of soman) might be due to a secondary effect,

unrelated to soman's clinical toxicity, but leading to long-term brain injuries.

42. J Neurotrauma. 1997 Dec;14(12):897-905. Effect of tetrahydroaminoacridine, a cholinesterase inhibitor, on cognitive performance following experimental brain injury. Pike BR, Hamm RJ, Temple MD, Buck DL, Lyeth BG.

Department of Psychology, Virginia Commonwealth University, Medical College of

Virginia, Richmond 23284-2018, USA.

An emerging literature exists in support of deficits in cholinergic

neurotransmission days to weeks following experimental traumatic brain injury

(TBI). In addition, novel cholinomimetic therapeutics have been demonstrated to

improve cognitive outcome following TBI in rats. We examined the effects of

repeated postinjury administration of a cholinesterase inhibitor,

tetrahydroaminoacridine (THA), on cognitive performance following experimental

TBI. Rats were either injured at a moderate level of central fluid percussion TBI

(2.1+/-0.1 atm) or were surgically prepared but not delivered a fluid pulse (sham

injury). Beginning 24 h after TBI or sham injury, rats were injected (IP) daily

for 15 days with an equal volume (1.0 ml/kg) of either 0.0, 1.0, 3.0, or 9.0

mg/kg THA (TBI: n = 8, 8, 10, and 7, respectively, and Sham: n = 5, 7, 8, 7,

respectively). Cognitive performance was assessed on Days 11-15 after injury in a

Morris water maze (MWM). Analysis of maze latencies over days indicated that

chronic administration of THA produced a dose-related impairment in MWM

performance in both the injured and sham groups, with the 9.0 mg/kg dose

producing the largest deficit. The 1.0 and 3.0 mg/kg doses of THA impaired MWM

performance without affecting swimming speeds. Thus, the results of this

investigation do not support the use of THA as a cholinomimetic therapeutic for

the treatment of cognitive deficits following TBI.

43. Toxicol Lett. 1998 Dec 28;102-103:527-33.

Chronic effects of low level exposure to anticholinesterases--a mechanistic

review.

Ray DE.

Medical Research Council Toxicology Unit, Leicester, UK. der2@le.ac.uk

High dose exposure to anticholinesterases which results in symptomatic poisoning 

can have lasting consequences due to the trauma of intoxication, excitotoxicity, 

secondary hypoxic damage, and (for some agents) a delayed onset polyneuropathy

(OPIDN). The potential effects of low level exposure are less well defined. The

most reliable data comes from controlled clinical trials with specific agents. A 

single dose of sarin or repeated doses of metrifonate or mevinphos, have produced

only transient adverse effects at doses causing substantial acetylcholinesterase 

inhibition. Other data comes from epidemiological surveys. These have often used 

more sensitive indices than the clinical studies, but are less reliable due to

the difficulty of defining exposure and matching control and exposed populations.

Subtle, mainly cognitive, differences between exposed and non-exposed populations

are sometimes seen. Low level exposure can cause a reversible down-regulation of 

cholinergic systems, and a range of non-cholinesterase effects that are

structure-specific, and do not always parallel acute toxicity. Novel protein

targets sensitive to low level exposure to some organophosphates are known to

exist in the brain, but their functional significance is not yet understood.

44. Exp Neurol. 2000 Nov;166(1):136-52.

Postinjury administration of L-deprenyl improves cognitive function and enhances 

neuroplasticity after traumatic brain injury.

Zhu J, Hamm RJ, Reeves TM, Povlishock JT, Phillips LL.

Department of Anatomy, Medical College of Virginia, Richmond, Virginia

23298-0709, USA.

The rat model of combined central fluid percussion traumatic brain injury (TBI)

and bilateral entorhinal cortical lesion (BEC) produces profound, persistent

cognitive deficits, sequelae associated with human TBI. In contrast to percussive

TBI alone, this combined injury induces maladaptive hippocampal plasticity.

Recent reports suggest a potential role for dopamine in CNS plasticity after

trauma. We have examined the effect of the dopamine enhancer l-deprenyl on

cognitive function and neuroplasticity following TBI. Rats received fluid

percussion TBI, BEC alone, or combined TBI + BEC lesion and were treated once

daily for 7 days with l-deprenyl, beginning 24 h after TBI alone and 15 min after

BEC or TBI + BEC. Postinjury motor assessment showed no effect of l-deprenyl

treatment. Cognitive performance was assessed on days 11-15 postinjury and brains

from the same cases examined for dopamine beta-hydroxylase immunoreactivity

(DBH-IR) and acetylcholinesterase (AChE) histochemistry. Significant cognitive

improvement relative to untreated injured cases was observed in both TBI groups

following l-deprenyl treatment; however, no drug effects were seen with BEC

alone. l-Deprenyl attenuated injury-induced loss in DBH-IR over CA1 and CA3 after

TBI alone. However, after combined TBI + BEC, l-deprenyl was only effective in

protecting CA1 DBH-IR. AChE histostaining in CA3 was significantly elevated with 

l-deprenyl in both injury models. After TBI + BEC, l-deprenyl also increased AChE

in the dentate molecular layer relative to untreated injured cases. These results

suggest that dopaminergic/noradrenergic enhancement facilitates cognitive

recovery after brain injury and that noradrenergic fiber integrity is correlated 

with enhanced synaptic plasticity in the injured hippocampus.

Copyright 2000 Academic Press.

J Neurotrauma. 1992 May;9 Suppl 2:S463-74. Cholinergic and opioid mediation of traumatic brain injury. Lyeth BG, Hayes RL.

Psychosom Med. 1976 Jan-Feb;38(1):55-8. Sudden death in the laboratory rat. Rosellini RA, Binik YM, Seligman MP.

Vulnerability to sudden death was produced in laboratory rats by manipulating

their developmental history. Rats who were reared in isolation died suddenly when

placed in a stressful swimming situation. Handling of these singly-housed rats

from 25 to 100 days of age potentiated the phenomenon. However, animals who were 

group housed did not die even when they had been previously handled.

J Neurol Neurosurg Psychiatry. 1973 Aug;36(4):581-4.

Creutzfeldt-Jakob disease treated with amantidine. A report of two cases.

Sanders WL, Dunn TL.

The treatment of two cases of Creutzfeldt-Jakob disease with amantidine is described. The first case made a remarkable initial improvement which was sustained for two months, but then deteriorated and died. Histological examination of the brain showed changes consistent with early Creutzfeldt-Jakob disease. The second case which was clinically one of Creutzfeldt-Jakob disease has now been followed for 30 months since the start of treatment and appears to be cured. It is considered that amantidine has a definite effect in this disease and it is suggested that its mode of action, though unknown, is more likely to be metabolic than antiviral.

Free PMC Article

Arch Int Pharmacodyn Ther. 1986 Mar;280(1):136-44. Effect of stress and glucocorticoids on the gastrointestinal cholinergic enzymes. Oriaku ET, Soliman KF. (Glucocorticoids lower AChE)

Cardiovasc Res. 1990 Apr;24(4):335-9. Sympathectomy alters acetylcholinesterase expression in adult rat heart. Nyquist Battie C, Moran N.

  Harris LW, Garry VF, Jr, Moore RD. Biosynthesis of cholinesterase in rabbit bone marrow cells in culture. Biochem Pharmacol. 1974 Aug;23(15):2155–2163.  

    Heller M, Hanahan DJ. Human erythrocyte membrane bound enzyme acetylcholinesterase. Biochim Biophys Acta. 1972 Jan 17;255(1):251–272. 

J Cell Biol. 1976 June 1; 69(3): 638–646. Bartos EM. Properties of growth-related acetylcholinesterase in a cell line of fibroblastic origin

Behav Brain Res  2000 Jul;112(1-2):33-41

Impaired escape performance and enhanced conditioned fear in rats following

exposure to an uncontrollable stressor are mediated by glutamate and nitric

oxide in the dorsal raphe nucleus.

Grahn RE, Watkins LR, Maier SF.

Department of Psychology, Connecticut College, Box 5275, 270 Mohegan Avenue,

06320-4196, New London, CT 06320-4196, USA. regra@conncoll.edu

Exposure to uncontrollable aversive events produces a variety of behavioral

consequences that do not occur if the aversive event is controllable.

Accumulating evidence suggests that exaggerated excitation of serotonin (5-HT)

neurons in the dorsal raphe nucleus (DRN) is sufficient to cause these same

behaviors, such as poor shuttlebox escape performance and enhanced conditioned

fear that occur 24 h after exposure to inescapable tailshock (IS). The aim of

the present studies was to explore the possibility that N-methyl-D-aspartate

(NMDA) receptor activation and nitric oxide (NO) formation within the DRN might

be involved in mediating the behavioral consequences of IS. To this end, either

the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (APV) or the nitric

oxide synthase inhibitor Nw-nitro-L-arginine methyl ester (L-NAME), was

microinjected into the DRN before IS or before testing 24 h later. Blocking NMDA

receptors with APV in the DRN during IS prevented the usual impact of IS on

escape responding and conditioned fear. However, injection of APV at the time of

testing only reduced these effects. The DRN was shown to be the critical site

mediating blockade of these behavioral changes since injection of APV lateral to

the DRN did not alter the behavioral consequences of IS. Conversely, L-NAME was

most effective in reversing the effects of IS when administered at the time of

testing. These results suggest that there is glutamatergic input to the DRN at

the time of IS that produces long-lasting changes in DRN sensitivity. This

plasticity in the DRN is discussed as a possible mechanism by which IS leads to

changes in escape performance and conditioned fear responding.

and prolonged depression causes shrinkage of this area. The high cortisol associated with depression is undoubtedly one of the factors causing brain shrinkage during stress. Cushing's disease, in which the adrenal glands produce far too much cortisol, causes shrinkage of the brain, and when the disease is cured by normalizing the level of cortisol, the brain size is restored.

There are two very different kinds of stress reaction. The best known "fight or flight reaction" could be called more accurately "struggle to adapt." Another, less discussed kind, might appear to be a "give up and die or get depressed" reaction, but it involves many processes that are protective and adaptive in certain circumstances.

 tone and heart rate;

drown easily. The role of acetylcholine, (Anisman, et al., 1981).

A situation of extreme restraint causes very rapid damage to the tissues, with bleeding ulcers of the stomach and intestine, shrinking of the thymus gland, and, if the animal survives for a while, atrophy of the brain. (Doi, et al., 1991; Gatón, et al., 1993)

LH, somatotropin, GH, Ach. caffeine progest

Behav Brain Res. 2012 Mar 17;228(2):294-8. doi: 10.1016/j.bbr.2011.11.036. Epub

2011 Dec 8.

Parental enrichment and offspring development: modifications to brain, behavior

and the epigenome.

Mychasiuk R, Zahir S, Schmold N, Ilnytskyy S, Kovalchuk O, Gibb R.

University of Lethbridge, Canadian Centre for Behavioural Neuroscience, Canada.

r.mychasiuk@uleth.ca

4. Biomed Pharmacother. 2012 Jun;66(4):249-55. doi: 10.1016/j.biopha.2011.11.005.

Epub 2011 Dec 21.

Cholinesterase activities and biochemical determinations in patients with

prostate cancer: influence of Gleason score, treatment and bone metastasis.

Battisti V, Bagatini MD, Maders LD, Chiesa J, Santos KF, Gonçalves JF, Abdalla

FH, Battisti IE, Schetinger MR, Morsch VM.

Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade

Federal de Santa Maria, Campus Universitário, 97105-900 Santa Maria, RS, Brazil. 

battistivanessa@gmail.com

Prostate cancer (PCa) is the sixth most common type of cancer worldwide.

Cholinesterase is well known as having non-cholinergic functions such as cellular

proliferation and differentiation, suggesting a possible influence of

cholinesterase in tumorogenesis. Thus, the aim of this study was to investigate

the whole blood acetylcholinesterase (AChE) and plasma butyrylcholinesterase

(BChE) activities and some biochemical parameters in PCa patients. This study was

performed in 66 PCa patients and 40 control subjects. AChE and BChE activities

were determined in PCa patients and the influence of the Gleason score; bone

metastasis and treatment in the enzyme activities were also verified.

Furthermore, we also analyzed possible biochemical alterations in these patients.

AChE and BChE activities decreased in PCa patients in relation to the control

group and various biochemical changes were observed in these patients. Moreover, 

Gleason score, metastasis and treatment influenced cholinesterase activities and 

biochemical determinations. Our results suggest that cholinesterases activities

and biochemical parameters are altered in PCa. These facts support the idea that 

the drop in the cholinesterase activity and the consequent increased amount of

acetylcholine could lead to a cholinergic overstimulation and increase the cell

proliferation in PCa.

Copyright © 2011 Elsevier Masson SAS. All rights reserved.

4. Biomed Pharmacother. 2012 Jun;66(4):249-55. doi: 10.1016/j.biopha.2011.11.005.

Epub 2011 Dec 21.

Cholinesterase activities and biochemical determinations in patients with

prostate cancer: influence of Gleason score, treatment and bone metastasis.

Battisti V, Bagatini MD, Maders LD, Chiesa J, Santos KF, Gonçalves JF, Abdalla

FH, Battisti IE, Schetinger MR, Morsch VM.

Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade

Federal de Santa Maria, Campus Universitário, 97105-900 Santa Maria, RS, Brazil. 

battistivanessa@gmail.com

Prostate cancer (PCa) is the sixth most common type of cancer worldwide.

Cholinesterase is well known as having non-cholinergic functions such as cellular

proliferation and differentiation, suggesting a possible influence of

cholinesterase in tumorogenesis. Thus, the aim of this study was to investigate

the whole blood acetylcholinesterase (AChE) and plasma butyrylcholinesterase

(BChE) activities and some biochemical parameters in PCa patients. This study was

performed in 66 PCa patients and 40 control subjects. AChE and BChE activities

were determined in PCa patients and the influence of the Gleason score; bone

metastasis and treatment in the enzyme activities were also verified.

Furthermore, we also analyzed possible biochemical alterations in these patients.

AChE and BChE activities decreased in PCa patients in relation to the control

group and various biochemical changes were observed in these patients. Moreover, 

Gleason score, metastasis and treatment influenced cholinesterase activities and 

biochemical determinations. Our results suggest that cholinesterases activities

and biochemical parameters are altered in PCa. These facts support the idea that 

the drop in the cholinesterase activity and the consequent increased amount of

acetylcholine could lead to a cholinergic overstimulation and increase the cell

proliferation in PCa.

Copyright © 2011 Elsevier Masson SAS. All rights reserved.

1. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2012 May;28(3):253-4, 262.

[Progesterone exerts neuroprotective effect on hypoxic-ischemic

encephalopathy-induced brain damage via inhibition expression of inducible nitric

oxide synthase and nitric oxide production].

[Article in Chinese]

Wang XY, Li XJ, Li DL, Wang CR, Guo XP.

wxyinwxyin@163.com

2. Mol Reprod Dev. 2012 Oct;79(10):689-96. doi: 10.1002/mrd.22075. Epub 2012 Sep 11.

Roles of cytokines and progesterone in the regulation of the nitric oxide

generating system in bovine luteal endothelial cells.

Yoshioka S, Acosta TJ, Okuda K.

Laboratory of Reproductive Physiology, Graduate School of Natural Science and

Technology, Okayama University, Okayama, Japan.

Nitric oxide (NO) produced by luteal endothelial cells (LECs) plays important

roles in regulating corpus luteum (CL) function, yet the local mechanism

regulating NO generation in bovine CL remains unclear. The purpose of the present

study was to elucidate if tumor necrosis factor-α (TNF), interferon γ (IFNG),

and/or progesterone (P4) play roles in regulating NO generating system in LECs.

Cultured bovine LECs obtained from the CL at the mid-luteal stage (Days 8-12 of

the cycle) were treated for 24 hr with TNF (2.9 nM), IFNG (2.5 nM), or P4

(0.032-32 µM). NO production was increased by TNF and IFNG, but decreased by P4

(P < 0.05). TNF and IFNG stimulated the relative steady-state amounts of

inducible nitric oxide synthase (iNOS) mRNA and iNOS protein expression

(P < 0.05), whereas P4 inhibited relative steady-state amounts of iNOS mRNA and

iNOS protein expression (P < 0.05). In contrast, endothelial nitric oxide

synthase (eNOS) expression was not affected by any treatment. TNF and IFNG

stimulated NOS activity (P < 0.05) and 1400W, a specific inhibitor of iNOS,

reduced NO production stimulated by TNF and IFNG in LECs (P < 0.05). Onapristone,

a specific P4 receptor antagonist, blocked the inhibitory effect of P4 on NO

production in LECs (P < 0.05). The overall findings suggest that TNF and IFNG

accelerate luteolysis by increasing NO production via stimulation of iNOS

expression and NOS activity in bovine LECs. P4, on the other hand, may act in

maintaining CL function by suppressing iNOS expression in bovine LECs. Mol.

Reprod. Dev. 79: 689-696, 2012. © 2012 Wiley Periodicals, Inc.

Copyright © 2012 Wiley Periodicals, Inc.

3. J Neurochem. 2012 Jul;122(1):185-95. doi: 10.1111/j.1471-4159.2012.07753.x.

Progesterone prevents mitochondrial dysfunction in the spinal cord of wobbler

mice.

Deniselle MC, Carreras MC, Garay L, Gargiulo-Monachelli G, Meyer M, Poderoso JJ, 

De Nicola AF.

Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina

Experimental-CONICET, Buenos Aires, Argentina.

In the Wobbler mouse, a mutation of the Vps54 protein increases oxidative stress 

in spinal motoneurons, associated to toxic levels of nitric oxide and

hyperactivity of nitric oxide synthase (NOS). Progesterone neuroprotection has

been reported for several CNS diseases, including the Wobbler mouse

neurodegeneration. In the present study, we analyzed progesterone effects on

mitochondrial-associated parameters of symptomatic Wobbler mice. The activities

of mitochondrial respiratory chain complexes I, II-III and IV and protein levels 

of mitochondrial and cytosolic NOS were determined in cervical and lumbar cords

from control, Wobbler and Wobbler mice receiving a progesterone implant for 18

days. We found a significant reduction of complex I and II-III activities in

mitochondria and increased protein levels of mitochondrial, but not cytosolic

nNOS, in the cervical cord of Wobbler mice. Progesterone treatment prevented the 

reduction of complex I in the cervical region and the increased level of

mitochondrial nNOS. Wobbler motoneurons also showed accumulation of amyloid

precursor protein immunoreactivity and decreased activity and immunostaining of

MnSOD. Progesterone treatment avoided these abnormalities. Therefore,

administration of progesterone to clinically afflicted Wobblers (i) prevented the

abnormal increase of mitochondrial nNOS and normalized respiratory complex I;

(ii) decreased amyloid precursor protein accumulation, a sign of axonal

degeneration, and (iii) increased superoxide dismutation. Thus, progesterone

neuroprotection decreases mitochondriopathy of Wobbler mouse cervical spinal

cord.

© 2012 The Authors. Journal of Neurochemistry © 2012 International Society for

Neurochemistry.

Comp Biochem Physiol C. 1993 Sep;106(1):125-9. The role of the neurotransmitters acetylcholine and noradrenaline in the pathogenesis of stress ulcers. Gatón J, Fernández de la Gándara F, Velasco A.

People with Cloninger's "harm avoidance" personality trait, which is closely associated with serotonin (Hansenne, et al., 1999), are more likely to develop dementia (Clément, et al., 2010). These observations are consistent with the stress-susceptibility of people with high serotonin exposure, and to the effects of cortisol on nerves and glucose-derived energy production.

Jpn J Surg. 1991 Jan;21(1):43-9.

Participation of the parasympathetic nervous system in the development of

activity-stress ulcers.

Doi K, Iwahashi K, Tsunekawa K.17. J Auton Nerv Syst. 1987 Oct;20(3):265-8.

Adrenergic modulation of gastric stress pathology in rats: a cholinergic link.

Ray A, Sullivan RM, Henke PG.

Department of Psychology, St. Francis Xavier University, Antigonish, Nova Scotia,

Canada.

The effects of some adrenergic drugs were evaluated on cold restraint-induced

gastric ulcers in rats. The beta-adrenergic antagonist, (+/-)-propranolol (1 and 

10 mg/kg), as well as the beta-agonist, isoproterenol (0.05 and 0.5 mg/kg)

potentiated the gastric pathology. On the other hand, the alpha-agonist,

clonidine (0.5 mg/kg) attenuated and the alpha-antagonist, yohimbine (1 mg/kg)

aggravated stress ulcer development. The anticholinergic agent, atropine

methylnitrate (1 mg/kg), reduced both the frequency and severity of stress ulcers

and also antagonized the potentiating effects of (+/-)-propranolol, isoproterenol

and yohimbine. The results suggest a cholinergic role in the adrenergic

modulation of gastric stress pathology.

Psychopharmacology (Berl). 1981;74(1):81-7.

Cholinergic influences on escape deficits produced by uncontrollable stress.

Anisman H, Glazier SJ, Sklar LS.

A series of experiments assessed the potential role of acetylcholine (ACh) in the

escape interference produced by inescapable shock. Treatment with the

anticholinesterase, physostigmine, successfully mimicked the effects of

inescapable shock. That is, the drug disrupted performance when escape was

prevented for 6 s on any given trial, thereby necessitating sustained active

responding. When escape was possible upon shock onset, the drug treatment did not

influence performance. The centrally acting anticholinergic scopolamine

hydrobromide antagonized the effects of physostigmine, and when administered

prior to escape testing antagonized the disruptive effects of previously

administered inescapable shock. In contrast, the peripherally acting agent

scopolamine methylbromide did not influence the effects of these treatments,

suggesting that the effects of physostigmine and inescapable shock involved

central ACh changes. Scopolamine hydrobromide administered prior to inescapable

shock did not prevent the escape interference from subsequently appearing, but

this effect could not be attributed to state dependence. It was argued that the

interference of escape following uncontrollable stress was due to non-associative

motor deficits. Alterations of the escape deficits by scopolamine were due to

elimination of the motor disruption.

Curr Opin Oncol. 2005 Jan;17(1):55-60.

DNA methylation and cancer therapy: new developments and expectations.

Esteller M.

Cancer Epigenetics Laboratory, Spanish National Cancer Centre (CNIO) Madrid,

Spain. mesteller@cnio.es

PURPOSE OF REVIEW: In addition to having genetic causes, cancer can also be

considered an epigenetic disease. The main epigenetic modification is DNA

methylation, and patterns of aberrant DNA methylation are now recognized to be a 

common hallmark of human tumors. One of the most characteristic features is the

inactivation of tumor-suppressor genes by CpG-island hypermethylation of the CpG 

islands located in their promoter regions. These sites, among others, are the

targets of DNA-demethylating agents, the promising chemotherapeutic drugs that

are the focus of this article.

RECENT FINDINGS: Four exciting aspects have recently arisen at the forefront of

the advancements in this field: first, the development of new compounds with

DNA-demethylating capacity that are less toxic (for example, procaine) and may be

administered orally (for example, zebularine); 

Science. 2013 May 10;340(6133):756-9.  

Emergence of individuality in genetically identical mice.

Freund J, Brandmaier AM, Lewejohann L, Kirste I, Kritzler M, Krüger A, Sachser N,

Lindenberger U, Kempermann G.

CRTD-DFG Research Center for Regenerative Therapies Dresden, Technische

Universität Dresden, Dresden, Germany.

Comment in

    Science. 2013 May 10;340(6133):695-6.

Brain plasticity as a neurobiological reflection of individuality is difficult to

capture in animal models. Inspired by behavioral-genetic investigations of human 

monozygotic twins reared together, we obtained dense longitudinal activity data

on 40 inbred mice living in one large enriched environment. The exploratory

activity of the mice diverged over time, resulting in increasing individual

differences with advancing age. Individual differences in cumulative roaming

entropy, indicating the active coverage of territory, correlated positively with 

individual differences in adult hippocampal neurogenesis. Our results show that

factors unfolding or emerging during development contribute to individual

differences in structural brain plasticity and behavior. The paradigm introduced 

here serves as an animal model for identifying mechanisms of plasticity

underlying nonshared environmental contributions to individual differences in

behavior.

Neurobiol Aging. 1995 Jul-Aug;16(4):523-30.

Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and

histamine H2 blocking drugs.

Breitner JC, Welsh KA, Helms MJ, Gaskell PC, Gau BA, Roses AD, Pericak-Vance MA, 

Saunders AM.

If each opportunity we have to choose expands our curiosity, 

we go beyond our inheritance to become something unique but also universal, that is, more fully human.

J Neurobiol. 1976 Jan;7(1):75-85. Effects of environment on morphology of rat cerebral cortex and hippocampus. Diamond MC, Ingham CA, Johnson RE, Bennett EL, Rosenzweig MR.

…

strains of rats. KRECH D, ROSENZWEIG MR, BENNETT EL.…

19. Pharmacol Biochem Behav. 1986 Sep;25(3):521-6.

Cholinergic function and memory: extensive inhibition of choline

acetyltransferase fails to impair radial maze performance in rats.

Wenk G, Sweeney J, Hughey D, Carson J, Olton D.

The present study investigated the effects of a potent inhibitor of choline

acetyltransferase (ChAT), BW813U, on the choice accuracy of rats in the radial

arm maze. BW813U (100 mg/kg, IP) produced a rapid (within 1 hour) and substantial

decrease in ChAT activity throughout the brain, ranging from 66% (hippocampus) to

80% (caudate nucleus) that lasted up to 5 days. A single injection (50 mg/kg, IP)

into rats with lesions (using ibotenic acid) in the nucleus basalis

magnocellularis and medial septal area, decreased ChAT activity by 75% and 60% in

the cortex and hippocampus, respectively. Lesioned and unlesioned rats were

trained on the radial arm maze until they reached a criterion level of

performance. Each rat then received an injection of BW813U (50 or 100 mg/kg, IP).

Choice accuracy was not impaired at any time following the injection. The lack of

effect on performance may be due to 2 possible factors: The radial maze retention

paradigm chosen may not be sufficiently difficult, or the decrease in

acetylcholine production was not sufficient to affect behavior. Compensation by

non-cholinergic neural systems might account for the insensitivity of the rats to

significant cholinergic depletion.

Psychol Aging. 1988 Dec;3(4):399-406.

Genotype-environment interaction in personality development: identical twins reared apart.

Bergeman CS, Plomin R, McClearn GE, Pedersen NL, Friberg LT.

Center for Developmental and Health Genetics, Pennsylvania State University, University Park 16802.

The focus of this study is to identify specific genotype-environment (GE) interactions as they contribute to individual differences in personality in later life. In behavioral genetics, GE interaction refers to the possibility that individuals of different genotypes may respond differently to specific environments. A sample of 99 pairs of identical twins reared apart, whose average age is 59 years, has been studied as part of the Swedish Adoption/Twin Study of Aging (SATSA). Hierarchical multiple regression was used to detect interactions between personality and environmental measures after the main effects of genotype and environment were removed. Analyses yield evidence for 11 significant interactions that provide the first evidence for GE interaction in human development using specific environmental measures. Thus, in addition to the main-effect contributions of heredity and environment, GE interactions contribute to individual differences in personality as measured in the second half of the life course.

Wikipedia:Excitability and inhibition[edit source | editbeta]

Acetylcholine also has other effects on neurons. One effect is to cause a slow depolarization[citation needed] by blocking a tonically active K+
 current, which increases neuronal excitability. Alternatively, acetylcholine can activate non-specific cation conductances to directly excite neurons.[10] An effect upon postsynaptic M4-muscarinic ACh receptors is to open inward-rectifier potassium ion channel (Kir) and cause inhibition.[11] The influence of acetylcholine on specific neuron types can be dependent upon the duration of cholinergic stimulation. For instance, transient exposure to acetylcholine (up to several seconds) can inhibit cortical pyramidal neurons via M1 type muscarinic receptors that are linked to Gq-type G-protein alpha subunits. M1 receptor activation can induce calcium-release from intracellular stores, which then activate a calcium-activated potassium conductance which inhibits pyramidal neuron firing.[12] On the other hand, tonic M1 receptor activation is strongly excitatory. Thus, ACh acting at one type of receptor can have multiple effects on the same postsynaptic neuron, depending on the duration of receptor activation.[13] Recent experiments in behaving animals have demonstrated that cortical neurons indeed experience both transient and persistent changes in local acetylcholine levels during cue-detection behaviors.[14]

In the cerebral cortex, tonic ACh inhibits layer 4 medium spiny neurons, the main targets of thalamocortical inputs while excitingpyramidal cells in layers 2/3 and layer 5.[11] This filters out weak sensory inputs in layer 4 and amplifies inputs that reach the layers 2/3 and layer L5 excitatory microcircuits. As a result, these layer-specific effects of ACh might function to improve the signal noise ratio of cortical processing.[11] At the same time, acetylcholine acts through nicotinic receptors to excite certain groups of inhibitory interneurons in the cortex, which further dampen down cortical activity.[15]

Role in decision making[edit source | editbeta]

One well-supported function of acetylcholine (ACh) in cortex is increased responsiveness to sensory stimuli, a form of attention.Phasic increases of ACh during visual,[16] auditory [17] and somatosensory [18] stimulus presentations have been found to increase the firing rate of neurons in the corresponding primary sensory cortices. When cholinergic neurons in the basal forebrain are lesioned, animals' ability to detect visual signals was robustly and persistently impaired.[19] In that same study, animals' ability to correctly reject non-target trials was not impaired, further supporting the interpretation that phasic ACh facilitates responsiveness to stimuli. Looking at ACh's effect on thalamocortical connections, a known pathway of sensory information, in vitro application of cholinergic agonist carbachol to mouse auditory cortex enhanced thalamocortical activity.[20] In addition, Gil et al. (1997) applied a different cholinergic agonist, nicotine, and found that activity was enhanced at thalamocortical synapses.[21]This finding provides further evidence for a facilitative role of ACh in transmission of sensory information from the thalamus to selective regions of cortex.

An additional suggested function of ACh in cortex is suppression of intracortical information transmission. Gil et al. (1997) applied the cholinergic agonist muscarine to neocortical layers and found that excitatory post-synaptic potentials between intracortical synapses were depressed.[21] In vitro application of cholinergic agonist carbachol to mouse auditory cortex suppressed intracortical activity as well.[20] Optical recording with a voltage-sensitive dye in rat visual cortical slices demonstrated significant suppression in intracortical spread of excitement in the presence of ACh.[22]

Some forms of learning and plasticity in cortex appear dependent on the presence of acetylcholine. Bear et al. (1986) found that the typical synaptic remapping in striate cortex that occurs during monocular deprivation is reduced when there is a depletion of cholinergic projections to that region of cortex.[23] Kilgard et al. (1998) found that repeated stimulation of the basal forebrain, a primary source of ACh neurons, paired with presentation of a tone at a specific frequency, resulted in remapping of the auditory cortex to better suit processing of that tone.[24]Baskerville et al. (1996) investigated the role of ACh in experience-dependent plasticity by depleting cholinergic inputs to the barrel cortex of rats.[25] The cholinergic depleted animals had a significantly reduced amount of whisker-pairing plasticity. Apart from the cortical areas, Crespo et al. (2006) found that the activation of nicotinic and muscarinic receptors in the nucleus accumbens is necessary for the acquisition of an appetitive task.[26]

ACh has been implicated in the reporting of expected uncertainty in the environment [27] based both on the suggested functions listed above and results recorded while subjects perform a behavioral cuing task. Reaction time difference between correctly cued trials and incorrectly cued trials, called the cue validity, was found to vary inversely with ACh levels in primates with pharmacologically (e.g. Witte et al., 1997) and surgically (e.g. Voytko et al., 1994) altered levels of ACh.[28][29] The result was also found in Alzheimer's disease patients (Parasuraman et al., 1992) and smokers after nicotine (an ACh agonist) consumption.[30][31] The inverse covariance is consistent with the interpretation of ACh as representing expected uncertainty in the environment, further supporting this claim.

12•.^ Gulledge, AT; Stuart, GJ (2005). "Cholinergic inhibition of neocortical pyramidal neurons". Journal of Neuroscience 25 (44): 10308–20. doi:10.1523/JNEUROSCI.2697-05.2005. PMID 16267239.

^ Gulledge, AT; Bucci, DJ; Zhang, SS; Matsui, M; Yeh, HH (2009). "M1 Receptors Mediate Cholinergic Modulation of Excitability in Neocortical Pyramidal Neurons". Journal of Neuroscience 29 (31): 9888–902. doi:10.1523/JNEUROSCI.1366-09.2009.PMC 2745329. PMID 19657040.

^ Parikh, V; Kozak, R; Martinez, V; Sarter, M (2007). "Prefrontal acetylcholine release controls cue detection on multiple time scales". Neuron 56 (1): 141–54. doi:10.1016/j.neuron.2007.08.025.PMC 2084212. PMID 17920021.

^ Gulledge, AT; Park, SB; Kawaguchi, Y; Stuart, GJ (2007). "Heterogeneity of phasic cholinergic signaling in neocortical neurons".Journal of neurophysiology 97 (3): 2215–29. doi:10.1152/jn.00493.2006.PMID 17122323.

^ Spehlmann R, Daniels JC, Smathers CC (1971). "Acetylcholine and the synaptic transmission of specific impulses to the visual cortex". Brain 94 (1): 125–38. doi:10.1093/brain/94.1.125. PMID 4324030.

^ Foote SL, Freedman R, Oliver AP (March 1975). "Effects of putative neurotransmitters on neuronal activity in monkey auditory cortex". Brain Res. 86 (2): 229–42. doi:10.1016/0006-8993(75)90699-X.PMID 234774.

^ Stone TW (September 1972). "Cholinergic mechanisms in the rat somatosensory cerebral cortex". J. Physiol. (Lond.) 225 (2): 485–99. PMC 1331117. PMID 5074408.

^ McGaughy J, Kaiser T, Sarter M (April 1996). "Behavioral vigilance following infusions of 192 IgG-saporin into the basal forebrain: selectivity of the behavioral impairment and relation to cortical AChE-positive fiber density". Behav. Neurosci. 110 (2): 247–65.doi:10.1037/0735-7044.110.2.247. PMID 8731052.

^ a b Hsieh CY, Cruikshank SJ, Metherate R (October 2000). "Differential modulation of auditory thalamocortical and intracortical synaptic transmission by cholinergic agonist". Brain Res. 880 (1–2): 51–64.doi:10.1016/S0006-8993(00)02766-9.PMID 11032989.

^ a b Gil Z, Connors BW, Amitai Y (September 1997). "Differential regulation of neocortical synapses by neuromodulators and activity". Neuron 19 (3): 679–86. doi:10.1016/S0896-6273(00)80380-3.PMID 9331357.

^ Kimura F, Fukuda M, Tsumoto T (October 1999). "Acetylcholine suppresses the spread of excitation in the visual cortex revealed by optical recording: possible differential effect depending on the source of input". Eur. J. Neurosci. 11 (10): 3597–609.doi:10.1046/j.1460-9568.1999.00779.x. PMID 10564367.

^ Bear MF, Singer W (1986). "Modulation of visual cortical plasticity by acetylcholine and noradrenaline". Nature 320 (6058): 172–6.doi:10.1038/320172a0. PMID 3005879.

^ Kilgard MP, Merzenich MM (March 1998). "Cortical map reorganization enabled by nucleus basalis activity". Science 279 (5357): 1714–8. doi:10.1126/science.279.5357.1714. PMID 9497289.

^ Baskerville KA, Schweitzer JB, Herron P (October 1997). "Effects of cholinergic depletion on experience-dependent plasticity in the cortex of the rat". Neuroscience 80 (4): 1159–69. doi:10.1016/S0306-4522(97)00064-X. PMID 9284068.

^ Crespo JA, Sturm K, Saria A, Zernig G (May 2006). "Activation of muscarinic and nicotinic acetylcholine receptors in the nucleus accumbens core is necessary for the acquisition of drug reinforcement".J. Neurosci. 26 (22): 6004–10.doi:10.1523/JNEUROSCI.4494-05.2006. PMID 16738243.

^ Yu & Dayan 2005

^ Witte EA, Marrocco RT (August 1997). "Alteration of brain noradrenergic activity in rhesus monkeys affects the alerting component of covert orienting". Psychopharmacology (Berl.) 132 (4): 315–23.doi:10.1007/s002130050351. PMID 9298508.

^ Voytko ML, Olton DS, Richardson RT, Gorman LK, Tobin JR, Price DL (January 1994). "Basal forebrain lesions in monkeys disrupt attention but not learning and memory". J. Neurosci. 14 (1): 167–86.PMID 8283232.

1. Pharmacol Res. 2011 Jun;63(6):525-31. 

Endothelin receptor antagonists: potential in Alzheimer's disease.

Palmer J, Love S.

Dementia Research Group, Institute of Clinical Neurosciences, School of Clinical 

Sciences, University of Bristol, Frenchay Hospital, Bristol BS16 1LE, United

Kingdom. jen.palmer@bristol.ac.uk

Alzheimer's disease (AD) is believed to be initiated by the accumulation of

neurotoxic forms of Aβ peptide within the brain. AD patients show reduction of

cerebral blood flow (CBF), the extent of the reduction correlating with the

impairment of cognition. There is evidence that cerebral hypoperfusion precedes

and may even trigger the onset of dementia in AD. Cerebral hypoperfusion impairs 

neuronal function, reduces the clearance of Aβ peptide and other toxic

metabolites from the brain, and upregulates Aβ production. Studies in animal

models of AD have shown the reduction in CBF to be more than would be expected

for the reduction in neuronal metabolic activity. Aβ may contribute to the

reduction in CBF in AD, as both Aβ₁₋₄₀ and Aβ₁₋₄₂ induce cerebrovascular

dysfunction. Aβ₁₋₄₀ acts directly on cerebral arteries to cause cerebral smooth

muscle cell contraction. Aβ₁₋₄₂ causes increased neuronal production and release 

of endothelin-1 (ET-1), a potent vasoconstrictor, and upregulation of

endothelin-converting enzyme-2 (ECE-2), the enzyme which cleaves ET-1 from its

inactive precursor. ET-1 and ECE-2 are also elevated in AD, making it likely that

upregulation of the ECE-2-ET-1 axis by Aβ₁₋₄₂ contributes to the chronic

reduction of CBF in AD. At present, only a few symptomatic treatment options

exist for AD. The involvement of ET-1 in the pathogenesis of endothelial

dysfunction associated with elevated Aβ indicates the potential for endothelin

receptor antagonists in the treatment of AD. It has already been demonstrated

that the endothelin receptor antagonist bosentan, preserves aortic and carotid

endothelial function in Tg2576 mice, and our findings suggest that endothelin

receptor antagonists may be beneficial in maintaining CBF in AD.

Copyright © 2011 Elsevier Ltd. All rights reserved.

Fiziol Zh SSSR Im I M Sechenova. 1975 Oct;61(10):1466-72.

[Amine receptors in brain vessels].

[Article in Russian]

Edvinsson L, Owman Ch.

Isolated middle cerebral arteries from cats and pial arteries from humans

(obtained during lobe resection) were studied in a sensitive in vitro system

allowing a detailed pharmacological characterization of various amine receptors

and related dissociation constants. It was found that the adrenergic receptors

comprise contractile (alpha) and dilatory (beta) receptors. Acetylcholine induced

dilation (at low doses) as well as constriction (at high doses) both responses

being inhibited in a comparative way by atropine. Experiments with selective

inhibitors showed the presence of specific histamine H2 (dilatory) receptors; at 

high doses histamine contracted the vessels in a non-specific way.

5-Hydroxytryptamine was the most efficient vasoconstrictor agent, and the

response could be blocked by the serotonin-antagonist, methysergide.

Behav Neurosci. 2007 Jun;121(3):491-500.

Exposure to enriched environment improves spatial learning performances and enhances cell density but not choline acetyltransferase activity in the hippocampus of ventral subicular-lesioned rats.

Dhanushkodi A, Bindu B, Raju TR, Kutty BM.

Department of NeurophysiologyNational Institute of Mental Health and Neuro Sciences (NIMHANS Deemed University), Bangalore, India.

The authors demonstrated the efficacy of enriched housing conditions in promoting the behavioral recovery and neuronal survival following subicular lesion in rats. Chemical lesioning of the ventral subiculum impaired the spatial learning performances in rats. The lesion also induced a significant degree of neurodegeneration in the CA1 and CA3 areas of the hippocampus and entorhinal cortex. Exposure to enriched housing conditions improved the behavioral performance and partially attenuated the neurodegeneration in the hippocampus. The choline acetyl transferase (ChAT) activity in the hippocampus remained unchanged following ventral subicular lesion and also following exposure to an enriched environment. The study implicates the effectiveness of activity-dependent neuronal plasticity induced by environmental enrichment in adulthood following brain insult.

Copyright (c) 2007 APA, all rights reserved.

Horm Behav. 2013 Jul 27. pii: S0018-506X(13)00139-6.

Progesterone and vitamin D: Improvement after traumatic brain injury in middle-aged rats.

Tang H, Hua F, Wang J, Sayeed I, Wang X, Chen Z, Yousuf S, Atif F, Stein DG.

Department of Emergency Medicine, Emory University, Atlanta, GA 30322, USA.

Progesterone (PROG) and vitamin D hormone (VDH) have both shown promise in treating traumatic brain injury (TBI). Both modulate apoptosis, inflammation, oxidative stress, andexcitotoxicity. We investigated whether 21days of VDH deficiency would alter cognitive behavior after TBI and whether combined PROG and VDH would improve behavioral and morphological outcomes more than either hormone alone in VDH-deficient middle-aged rats given bilateral contusions of the medial frontal cortex. PROG (16mg/kg) and VDH (5μg/kg) were injected intraperitoneally 1h post-injury. Eight additional doses of PROG were injected subcutaneously over 7days post-injury. VDH deficiency itself did not significantly reduce baseline behavioral functions or aggravate impaired cognitive outcomes. Combination therapy showed moderate improvement in preserving spatial and reference memory but was not significantly better than PROG monotherapy. However, combination therapy significantly reduced neuronal loss and the proliferation of reactive astrocytes, and showed better efficacy compared to VDH or PROG alone in preventing MAP-2 degradation. VDH+PROG combination therapy may attenuate some of the potential long-term, subtle, pathophysiological consequences of brain injury in older subjects.

© 2013.

KEYWORDS:

Yang, glutamate stimulates DNA repair; methylation of dna during stress, hydrophobic

Life Sci 1998;62(17-18):1717-21 

Induction of inducible nitric oxide synthase and heme oxygenase-1 in

rat glial cells.

Kitamura Y, Matsuoka Y, Nomura Y, Taniguchi T

Department of Neurobiology, Kyoto Pharmaceutical University, Japan. 

Recent observations suggest a possible interaction between the nitric oxide (NO)/NO synthases and carbon monoxide (CO)/heme oxygenases systems. We examined the effects of lipopolysaccharide (LPS), interferon-gamma (IFN-gamma), and NO donor such as S-nitroso-N-acetylpenicillamine (SNAP) on induction of inducible NO synthase (iNOS) and heme oxygenase-1 (HO-1) in mixed glial cells and in rat hippocampus. In in vitro glial cells, treatment with LPS induced the expression of 130-kDa iNOS after 6

h, and NO2- accumulation and enhancement of the protein level of 33-kDa HO-1 after 12 h. In addition, treatment with SNAP induced HO-1 expression after 6 h. Although a NOS inhibitor, such as N(G)-nitro-L-arginine (NNA), did not change LPS-induced iNOS expression, the inhibitor suppressed both NO2- accumulation and the enhancement of HO-1. Immunocytochemistry showed that LPS-treatment induced iNOS-immunoreactivity predominantly in microglia, while this treatment induced HO-1-immunoreactivity in both microglia and astrocytes. These results suggest that endogenous NO production by iNOS in microglia causes autocrine- and paracrine-induction of HO-1 protein in microglia

and astrocytes in rat brain. 

4. Proc Soc Exp Biol Med. 1994 Oct;207(1):43-7.

Dietary restriction modulates the norepinephrine content and uptake of the heart 

and cardiac synaptosomes.

Kim SW, Yu BP, Sanderford M, Herlihy JT.

Department of Physiology, University of Texas Health Science Center at San

Antonio 78284.

The present study was designed to examine the effects of long-term dietary

restriction on cardiac sympathetic nerves and neurotransmitter. The food intake

of male, 6-week-old Fischer 344 rats was reduced to 60% of the intake of control 

rats fed ad libitum. The body and heart weights of rats diet restricted for 4.5

months were less than those of the ad libitum fed animals, while the heart weight

to body weight ratios were higher. The norepinephrine (NE) content of hearts from

restricted rats (1073 +/- 84 ng/g wet wt) was higher than controls (774 +/- 38

ng/g wet wt), although the total amount of NE per heart was unchanged. Similarly,

the cardiac synaptosomal P2 fraction from restricted rats possessed a higher NE

content (24.1 +/- 2.4 ng/mg protein) than the P2 fraction of ad libitum fed

controls (13.7 +/- 1.3 ng/mg protein). The desmethylimipramine-sensitive

norepinephrine uptake of the P2 fraction from restricted rats was significantly

higher than that of control rats (9.44 +/- 1.33 vs 4.75 +/- 0.35 ng/mg

protein/hr). The NE uptakes of the two groups were similar when uptake was

normalized to endogenous NE levels. These results demonstrate that long-term

dietary restriction affects cardiac sympathetic nerve endings and suggest that

part of the beneficial action of life-long dietary restriction on the age-related

decline in cardiovascular regulation may be related to changes in cardiac

sympathetic nerves.

Int J Cancer. 1985 Apr 15;35(4):493-7.

Muscarinic cholinergic receptors in pancreatic acinar carcinoma of rat.

Taton G, Delhaye M, Swillens S, Morisset J, Larose L, Longnecker DS, Poirier GG.

The active enantiomer of tritiated quinuclidinyl benzilate (3H(-)QNB) was used as

a ligand to evaluate the muscarinic receptors. The 3H(-)QNB binding

characteristics of muscarinic cholinergic receptors obtained from normal and

neoplastic tissues were studied to determine changes in receptor properties

during neoplastic transformation. Saturable and stereospecific binding sites for 

3H(-)QNB are present in homogenates of rat pancreatic adenocarcinoma. The

proportions of high- and low-affinity agonist binding sites are similar for

neoplastic and normal tissues. The density of muscarinic receptors is higher in

neoplastic (200 femtomoles/mg protein) than in normal pancreatic homogenates (80 

femtomoles/mg protein). The muscarinic binding sites of the neoplastic and fetal 

pancreas show similar KD values which are higher than those observed for normal

pancreas.

17: Cancer Res. 1986 Nov;46(11):5706-14.

Muscarinic receptor coupling to intracellular calcium release in rat pancreatic

acinar carcinoma.

Chien JL, Warren JR.

Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of

cholinergic receptor protein affinity labeled with the muscarinic antagonist

[3H]propylbenzilylcholine mustard revealed a major polypeptide with molecular

weight of 80,000-83,000 in both acinar carcinoma and normal acinar cells of rat

pancreas. Muscarinic receptor protein is therefore conserved in pancreatic acinar

carcinoma. A small but significant difference was detected in the affinity of

carcinoma cell receptors (Kd approximately 0.6 nM) and normal cell receptors (Kd 

approximately 0.3 nM) for reversible binding of the muscarinic antagonist drug,

N-methylscopolamine. In addition, carcinoma cell muscarinic receptors displayed

homogeneous binding of the agonist drugs carbamylcholine (Kd approximately 31

microM) and oxotremorine (Kd approximately 4 microM), whereas normal cell

receptors demonstrated heterogeneous binding, with a minor receptor population

showing high affinity binding for carbamylcholine (Kd approximately 3 microM) and

oxotremorine (Kd approximately 160 nM), and a major population showing low

affinity binding for carbamylcholine (Kd approximately 110 microM) and

oxotremorine (Kd approximately 18 microM). Both carcinoma and normal cells

exhibited concentration-dependent carbamylcholine-stimulated increases in

cytosolic free Ca2+, as measured by 45Ca2+ outflux assay and intracellular quin 2

fluorescence. However, carcinoma cells were observed to be more sensitive to Ca2+

mobilizing actions of submaximal carbamylcholine concentrations, demonstrating

50% maximal stimulation of intracellular Ca2+ release at a carbamylcholine

concentration (approximately 0.4 microM) approximately one order of magnitude

below that seen for normal cells. These results indicate altered muscarinic

receptor coupling to intracellular Ca2+ release in acinar carcinoma cells, which 

manifests as a single activated receptor state for agonist binding, and increased

sensitivity of Ca2+ release in response to muscarinic receptor stimulation.

1: Anticancer Drugs. 2008 Aug;19(7):655-71.

Neurotransmission and cancer: implications for prevention and therapy.

Schuller HM.

Experimental Oncology Laboratory, Department of Pathobiology, College of

Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN

37996, USA. hmsch@utk.edu

Published evidence compiled in this review supports the hypothesis that the

development, progression, and responsiveness to prevention and therapy of the

most common human cancers is strongly influenced, if not entirely orchestrated,

by an imbalance in stimulatory and inhibitory neurotransmission. The

neurotransmitters acetylcholine, adrenaline, and noradrenaline of the autonomic

nervous system act as powerful upstream regulators that orchestrate numerous cell

and tissue functions, by releasing growth factors, angiogenesis factors and

metastasis factors, arachidonic acid, proinflammatory cytokines, and local

neurotransmitters from cancer cells and their microenvironment. In addition, they

modulate proliferation, apoptosis, angiogenesis, and metastasis of cancer

directly by intracellular signaling downstream of neurotransmitter receptors.

Nicotine and the tobacco-specific nitrosamines have the documented ability to

hyperstimulate neurotransmission by both branches of the autonomic nervous

system. The expression and function of these neurotransmitter pathways are cell

type specific. Lifestyle, diet, diseases, stress, and pharmacological treatments 

modulate the expression and responsiveness of neurotransmitter pathways. Current 

preclinical testing systems fail to incorporate the modulating effects of

neurotransmission on the responsiveness to anticancer agents and should be

amended accordingly. The neurotransmitter gamma-aminobutyric acid has a strong

inhibitory function on sympathicus-driven cancers whereas stimulators of cyclic

adenosine monophosphate/protein kinase A signaling have strong inhibitory

function on parasympathicus-driven cancers. Marker-guided restoration of the

physiological balance in stimulatory and inhibitory neurotransmission represents 

a promising and hitherto neglected strategy for the prevention and therapy of

neurotransmitter-responsive cancers.

Psychological stress in IBD: new insights into pathogenic and ...

www.ncbi.nlm.nih.gov › Journal List › Gut › v.54(10); Oct 2005

by JE Mawdsley - ‎2005 - ‎Cited by 255 - ‎Related articles

Psychological stress has long been reported anecdotally to increase disease ..... atropine and was more marked in cholinesterase deficient Wistar-Kyoto rats.

Neuropsychopharmacology. 2002 May;26(5):672-81. 

Sexual diergism of hypothalamo-pituitary-adrenal cortical responses to low-dose

physotigmine in elderly vs. young women and men.

Rubin RT, Rhodes ME, O'Toole S, Czambel RK.

Center for Neurosciences Research, MCP Hahnemann University School of Medicine,

Allegheny General Hospital, Pittsburgh, PA 15212, USA. rubin@wpahs.org

We previously demonstrated that the reversible cholinesterase inhibitor,

physostigmine (PHYSO), administered to normal young adult women and men (average

age 35 years) at a dose that produced few or no side effects, resulted in a sex

difference (sexual diergism) in hypothalamo-pituitary-adrenal cortical (HPA)

axis responses: Plasma ACTH(1-39), cortisol, and arginine vasopressin (AVP)

concentrations increased to a significantly greater extent in the men than in

the women. To explore the effect of age on these sexually diergic hormone

responses, in the present study we used the same dose of PHYSO (8 microg/kg IV)

to stimulate ACTH(1-39), cortisol, and AVP secretion in normal elderly,

non-estrogen-replaced women and elderly men (average ages 73 years and 70 years,

respectively). The subjects underwent three test sessions 5-7 days apart: PHYSO,

saline control, and a second session of PHYSO. Serial blood samples were taken

for hormone analyses before and after pharmacologic challenge.As with the

previously studied younger subjects, PHYSO administration produced no side

effects in about half the elderly subjects and mild side effects in the other

half, with no significant female-male differences. The hormone responses were

2-5 fold greater in the elderly subjects than in the younger subjects, but in

contrast to the younger subjects, the elderly men did not have significantly

greater hormone responses to PHYSO administration than did the elderly women.

The ACTH(1-39) and AVP responses to PHYSO for the two sessions were

significantly positively correlated in the men (+0.96, +0.91) but not in the

women. None of the hormone responses was significantly correlated with the

presence or absence of side effects in either group of subjects.These results

indicate a greater sensitivity of the HPA axis to low-dose PHYSO, and a loss of

overall sex differences in hormone responses, in elderly compared with younger

subjects. The lack of a difference in side effects between the elderly women and

men and the lack of significant correlations between presence or absence of side

effects and hormone responses suggest that the increase in hormone responses

with aging is due to correspondingly increased responsiveness of central

cholinergic systems and/or the HPA axis, and not to a nonspecific stress

response.

Horm Behav. 2013 Feb;63(2):284-90. 

Progesterone and neuroprotection.

Singh M, Su C.

Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, Center FOR HER, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107, USA. meharvan.singh@unthsc.edu

Numerous studies aimed at identifying the role of estrogen on the brain have used the ovariectomized rodent as the experimental model. And while estrogen intervention in these animals has, at least partially, restored cholinergic, neurotrophin and cognitive deficits seen in the ovariectomized animal, it is worth considering that the removal of the ovaries results in the loss of not only circulating estrogen but of circulating progesterone as well. As such, the various deficits associated with ovariectomy may be attributed to the loss of progesterone as well. Similarly, one must also consider the fact that the human menopause results in the precipitous decline of not just circulating estrogens, but in circulating progesterone as well and as such, the increased risk for diseases such as Alzheimer's disease during the postmenopausal period could also be contributed by this loss of progesterone. In fact, progesterone has been shown to exert neuroprotective effects, both in cell models, animal models and in humans. Here, we review the evidence that supports the neuroprotective effects of progesterone and discuss the various mechanisms that are thought to mediate these protective effects. We also discuss the receptor pharmacology of progesterone's neuroprotective effects and present a conceptual model of progesterone action that supports the complementary effects of membrane-associated and classical intracellular progesterone receptors. In addition, we discuss fundamental differences in the neurobiology of progesterone and the clinically used, synthetic progestin, medroxyprogesterone acetate that may offer an explanation for the negative findings of the combined estrogen/progestin arm of the Women's Health Initiative-Memory Study (WHIMS) and suggest that the type of progestin used may dictate the outcome of either pre-clinical or clinical studies that addresses brain function.

Brain Res. 2005 Jul 5;1049(1):112-9. Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury. Pettus EH, Wright DW, Stein DG, Hoffman SW.

Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.

Progesterone given after traumatic brain injury (TBI) has been shown to reduce

the initial cytotoxic surge of inflammatory factors. We used Western blot

techniques to analyze how progesterone might affect three inflammation-related

factors common to TBI: complement factor C3 (C3), glial fibrillary acidic

protein (GFAP), and nuclear factor kappa beta (NFkappaB). One hour after

bilateral injury to the medial frontal cortex, adult male rats were given

injections of progesterone (16 mg/kg) for 2 days. Brains were harvested 48 h

post-TBI, proteins were extracted from samples, each of which contained tissue

from both the contused and peri-contused areas, then measured by Western blot

densitometry. Complete C3, GFAP, and NFkappaB p65 were increased in all injured

animals. However, in animals given progesterone post-TBI, NFkappaB p65 and the

inflammatory metabolites of C3 (9 kDa and 75 kDa) were decreased in comparison

to vehicle-treated animals.

J Leukoc Biol 1996 Mar;59(3):442-50 

Progesterone inhibits inducible nitric oxide synthase gene

expression and nitric oxide production in murine

macrophages.

Miller L, Alley EW, Murphy WJ, Russell SW, Hunt JS

Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, USA. 

The purpose of this study was to determine whether the female hormones estradiol-l7 beta (E2) and progesterone (P4) influence inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) by interferon-gamma(IFN-gamma)-and lipopolysaccharide (LPS)-activated mouse macrophages. Treatment with P4 alone caused a time- and dose-dependent inhibition of NO production by macrophage cell lines (RAW 264.7, J774) and mouse bone marrow culture-derived macrophages as assessed by nitrite accumulation. RAW 264.7 cells transiently transfected with an iNOS gene promoter/luciferase reporter-gene construct that were stimulated with IFN-gamma/LPS in the presence of P4 displayed reduced luciferase activity and NO production. Analysis of RAW 264.7 cells by Northern blot hybridization revealed concurrent P4-mediated reduction in iNOS mRNA. These observations suggest that P4-mediated inhibition of NO may be an important gender-based difference within females and males that relates to macrophage-mediated host defense. 

J Reprod Immunol 1997 Nov 15;35(2):87-99 

Female steroid hormones regulate production of

pro-inflammatory molecules in uterine leukocytes.

Hunt JS, Miller L, Roby KF, Huang J, Platt JS, DeBrot BL

Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City 66160-7400, USA. jhunt@kumc.edu 

Estrogens and progesterone could be among the environmental signals that govern uterine immune cell synthesis of pro-inflammatory substances. In order to investigate this possibility, we first mapped expression of the inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) genes in the leukocytes of cycling and pregnant mouse uteri, then tested the ability of estradiol-17 beta (E2) and progesterone to influence gene expression. Immunohistochemistry, in situ hybridization, and other experimental approaches, revealed that the iNOS and TNF-alpha genes are expressed in mouse uterine mast cells, macrophages and natural killer cells (uNK). Gene expression in each cell type was noted to be dependent upon stage of the cycle or stage of gestation, implying potential relationships with levels of female hormones and state of cell differentiation or activation. Further in vivo and in vitro experiments showed that individual hormones have cell type-specific effects on synthesis of iNOS and TNF-alpha that are exerted at the level of transcription. In uterine mast cells, iNOS and TNF-alpha are promoted by E2 whereas preliminary studies in macrophages suggest that transcription and translation

of the two genes are unaffected by E2 but are inhibited by progesterone. 

Hypothyroidism increases NO; T3, vs helpless; hypothyroid, escape deficit, Levine, et 1990.

choline is increased in AD CSF Elble R;, Carriere;

Genes Nutr. 2009 December; 4(4): 309–314. Dietary polyunsaturated fatty acids improve cholinergic transmission in the aged brain Willis LM, Shukitt-Hale B, Joseph JA.

28. Bloj B, Morero RD, Farias RN, Trucco RE (1973) Membrane lipid fatty acids and regulation of membrane-bound enzymes. Allosteric behaviour of erythrocyte Mg 2+-ATPase (Na++ K+)-ATPase and acetylcholinesterase from rats fed different fat-supplemented diets. Biochim Biophys Acta 311:67–79. [PubMed]

29. Vajreswari A, Narayanareddy K (1992) Effect of dietary fats on erythrocyte membrane lipid composition and membrane-bound enzyme activities. Metabolism 41:352–358. [PubMed]

30. Vajreswari A, Rupalatha M, Rao PS (2002) Effect of altered dietary n-6-to-n-3 fatty acid ratio on erythrocyte lipid composition and membrane-bound enzymes. J Nutr Sci Vitaminol 48:365–370. [PubMed]

31. Foot M, Cruz TF, Clandinin MT (1983) Effect of dietary lipid on synaptosomal acetylcholinesterase activity. Biochem J 211:507–509. [PMC free article] [PubMed]

33. Srinivasarao P, Narayanareddy K, Vajreswari A, Rupalatha M, Prakash PS, Rao P (1997) Influence of dietary fat on the activities of subcellular membrane-bound enzymes from different regions of the brain. Neuochem Int 31:789–794. [PubMed]

The protective effect of anticholinergic drugs, such as atropine or scopolamine, against various degenerative brain processes might lead a person to wonder whether the Berkeley enrichment experiments might not have been neurologically exactly the opposite of the stress experiments of Richter and Seligman, that is, reducing cholinergic processes with enrichment, increasing them with impoverishment of choices and experience.  A drug, pilocarpine, 

USING THE BRAIN FOR LIFE

Living is development; the choices we make create our individuality. If genetically identical mice grow up in a large and varied environment, small differences in their experience will affect cell growth in their brains, leading to large differences in their exploratory behavior as they age (Freund, et al., 2013). Geneticists used to say that "genes determine our limits," but this experiment shows that an environment can provide both limitations and opportunities for expanding the inherited potential. If our environment restricts our choices, our becoming human is thwarted, the way rats' potentials weren't discovered when they were kept in the standard little laboratory boxes. An opportunity to be complexly involved in a complex environment lets us become more of what we are, more humanly differentiated.

A series of experiments that started at the University of California in 1960 found that rats that lived in larger spaces with various things to explore were better at learning and solving problems than rats that were raised in the standard little laboratory cages (Rosenzweig, 1960). Studying their brains, they found that the enzyme cholinesterase, which destroys the neurotransmitter, acetylcholine, was increased. They later found that the offspring of these rats were better learners than their parents, and their brains contained more cholinesterase. Their brains were also larger, with a considerable thickening of the cortex, which is considered to be the part mainly responsible for complex behavior, learning and intelligence. 

These processes aren't limited to childhood. For example, London taxi drivers who learn all the streets in the city develop a larger hippocampus, an area of the brain involved with memory. 

The 1960s research into environmental enrichment coincided with political changes in the US, but it went against the dominant scientific ideas of the time. Starting in 1945, the US government had begun a series of projects to develop techniques of behavior modification or mind control, using drugs, isolation, deprivation, and torture. In the 1950s, psychiatry often used lobotomies (about 80,000, before they were generally discontinued in the 1980s) and electroconvulsive "therapy," and university psychologists tortured animals, often as part of developing techniques for controlling behavior. 

The CIA officially phased out their MKultra program in 1967, but that was the year that Martin Seligman, at the University of Pennsylvania, popularized the idea of "learned helplessness." He found that when an animal was unable to escape from torture, even for a very short time, it would often fail to even try to escape the next time it was tortured. 

Seligman's lectures have been attended by psychologists who worked at Guantanamo, and he recently received a no-bid Pentagon grant of $31,000,000, to develop a program of "comprehensive soldier fitness," to train marines to avoid learned helplessness. 

Curt Richter already in 1957 had described the "hopelessness" phenomenon in rats (“a reaction of hopelessness is shown by some wild rats very soon after being grasped in the hand and prevented from moving. They seem literally to give up,”) and even how to cure their hopelessness, by allowing them to have an experience of escaping once (Richter, 1957).  Rats which would normally be able to keep swimming in a tank for two or three days, would often give up and drown in just a few minutes, after having an experience of "inescapable stress." Richter made the important discovery that the hearts of the hopeless rats slowed down before they died, remaining relaxed and filled with blood, revealing the dominant activity of the vagal nerve, secreting acetylcholine. 

The sympathetic nervous system (secreting noradrenaline) accelerates the heart, and is usually activated in stress, in the "fight or flight" reaction, but this radically different (parasympathetic) nervous activity hadn't previously been seen to occur in stressful situations. The parasympathetic, cholinergic, nervous system had been thought of as inactive during stress, and activated to regulate processes of digestion, sleep, and repair. Besides the cholinergic nerves of the parasympathetic system, many nerves of the central nervous system also secrete acetylcholine, which activates smooth muscles, skeletal muscles, glands, and other nerves, and also has some inhibitory effects. The parasympathetic nerves also secrete the enzyme, cholinesterase, which destroys acetylcholine. However, many other types of cell (red blood cells, fibroblasts, sympathetic nerves, marrow cells), maybe all cells, can secrete acetylcholine.

Because cholinergic nerves have been opposed to the sympathetic, adrenergic, nerves, there has been a tendency to neglect their nerve exciting roles, when looking at causes of excitotoxicity, or the stress-induced loss of brain cells. Excessive cholinergic stimulation, however, can contribute to excitotoxic cell death, for example when it's combined with high cortisol and/or hypoglycemia.

Drugs that block the stimulating effects of acetylcholine (the anticholinergics) as well as chemicals that mimic them, such as the organophosphate insecticides, can impair the ability to think and learn. This suggested to some people that age-related dementia was the result of the deterioration of the cholinergic nerves in the brain. Drugs to increase the stimulating effects of acetylcholine in the brain (by inactivating cholinesterase) were promoted as treatment for Alzheimer's disease. 

Although herbal inhibitors were well known, profitable new drugs, starting with Tacrine, were put into use. It was soon evident that Tacrine was causing serious liver damage, but wasn't slowing the rate of mental deterioration.

As the failure of the cholinergic drug Tacrine was becoming commonly known, another drug, amantadine (later, the similar memantine) was proposed for combined treatment. In the 1950s, the anticholinergic drug atropine was proposed a few times for treating dementia, 

and amantadine, which was also considered anticholinergic, was proposed for some mental conditions, including Creutzfeldt-Jacob Disease (Sanders and Dunn, 1973). It must have seemed odd to propose that an anticholinergic drug be used to treat a condition that was being so profitably treated with a pro-cholinergic drug, but memantine came to be classified as an anti-excitatory "NMDA blocker," to protect the remaining cholinergic nerves, so that both drugs could be prescribed simultaneously. The added drug seems to have a small beneficial effect, but there has been no suggestion that this could be the result of its previously-known anticholinergic effects.

Over the years, some people have suspected that Alzheimer's disease might be caused partly by a lack of purpose and stimulation in their life, and have found that meaningful, interesting activity could improve their mental functioning. Because the idea of a "genetically determined hard-wired" brain is no longer taught so dogmatically, there is increasing interest in this therapy for all kinds of brain impairment. The analogy to the Berkeley enrichment experience is clear, so the association of increasing cholinesterase activity with improving brain function should be of interest.

The after-effect of poisoning by nerve gas or insecticide has been compared to the dementia of old age. The anticholinergic drugs are generally recognized for protecting against those toxins. Traumatic brain injury, even with improvement in the short term, often starts a long-term degenerative process, greatly increasing the likelihood of dementia at a later age. A cholinergic excitotoxic process is known to be involved in the traumatic degeneration of nerves (Lyeth and Hayes, 1992), and the use of anticholinergic drugs has been recommended for many years to treat traumatic brain injuries (e.g., Ward, 1950: Ruge, 1954; Hayes, et al., 1986).

In 1976 there was an experiment (Rosellini, et al.) that made an important link between the enrichment experiments and the learned helplessness experiments. The control animals in the enrichment experiments were singly housed, while the others shared a larger enclosure. In the later experiment, it was found that the rats "who were reared in isolation died suddenly when placed in a stressful swimming situation," while the group-housed animals were resistant, effective swimmers. Enrichment and deprivation have very clear biological meaning, and one is the negation of the other. 

The increase of acetylcholinesterase, the enzyme that destroys acetylcholine, during enrichment, serves to inactivate cholinergic processes. If deprivation does its harm by increasing the activity of the cholinergic system, we should expect that a cholinergic drug might substitute for inescapable stress, as a cause of learned helplessness, and that an anticholinergic drug could cure learned helplessness. Those tests have been done: "Treatment with the anticholinesterase, physostigmine, successfully mimicked the effects of

inescapable shock." "The centrally acting anticholinergic scopolamine hydrobromide antagonized the effects of physostigmine, and when administered prior to escape testing antagonized the disruptive effects of previously administered inescapable shock." (Anisman, et al., 1981.)

This kind of experiment would suggest that the anticholinesterase drugs still being used for Alzheimer's disease treatment aren't biologically helpful. In an earlier newsletter I discussed the changes of growth hormone, and its antagonist somatostatin, in association with dementia: Growth hormone increases, somatostatin decreases. The cholinergic nerves are a major factor in shifting those hormones in the direction of dementia, and the anticholinergic drugs tend to increase the ratio of somatostatin to growth hormone. Somatostatin and cholinesterase have been found to co-exist in single nerve cells (Delfs, et al., 1984).

Estrogen, which was promoted so intensively as prevention or treatment for Alzheimer's disease, was finally shown to contribute to its development. One of the characteristic effects of estrogen is to increase the level of growth hormone in the blood. This is just one of many ways that estrogen is associated with cholinergic activation. During pregnancy, it's important for the uterus not to contract. Cholinergic stimulation causes it to contract; too much estrogen activates that system, and causes miscarriage if it's excessive. An important function of progesterone is to keep the uterus relaxed during pregnancy. In the uterus, and in many other systems, progesterone increases the activity of cholinesterase, removing the acetylcholine which, under the influence of estrogen, would cause the uterus to contract.

Progesterone is being used to treat brain injuries, very successfully. It protects against inflammation, and in an early study, compared to placebo, lowered mortality by more than half. It's instructive to consider its anticholinergic role in the uterus, in relation to its brain protective effects. When the brain is poisoned by an organophosphate insecticide, which lowers the activity of cholinesterase, seizures are likely to occur, and treatment with progesterone can prevent those seizures, reversing the inhibition of the enzyme (and increasing the activity of cholinesterase in rats that weren't poisoned) (Joshi, et al., 2010). Similar effects of progesterone on cholinesterase occur in women (Fairbrother, et al., 1989), implying that this is a general function of progesterone, not just something to protect pregnancy. Estrogen, with similar generality, decreases the activity of cholinesterase. DHEA, like progesterone, increases the activity of cholinesterase, and is brain protective (Aly, et al., 2011).

Brain trauma consistently leads to decreased activity of this enzyme (Östberg, et al., 2011; Donat, et al., 2007), causing the acetylcholine produced in the brain to accumulate, with many interesting consequences. In 1997, a group (Pike, et al.) created brain injuries in rats to test the idea that a cholinesterase inhibitor would improve their recovery and ability to move through a maze. They found instead that it reduced the cognitive ability of both the injured and normal rats. An anticholinergic drug, selegeline (deprenyl) that is used to treat Parkinson's disease and, informally, as a mood altering antiaging drug, was found by a different group (Zhu, et al., 2000) to improve cognitive recovery from brain injuries.

One of acetylcholine's important functions, in the brain as elsewhere, is the relaxation of blood vessels, and this is done by activating the synthesis of NO, nitric oxide. (Without NO, acetylcholine constricts blood vessels; Librizzi, et al., 2000.) The basic control of blood flow in the brain is the result of the relaxation of the wall of blood vessels in the presence of carbon dioxide, which is produced in proportion to the rate at which oxygen and glucose are being metabolically combined by active cells. In the inability of cells to produce CO2 at a normal rate, nitric oxide synthesis in blood vessels can cause them to dilate. The mechanism of relaxation by NO is very different, however, involving the inhibition of mitochondrial energy production (Barron, et al., 2001). Situations that favor the production and retention of a larger amount of carbon dioxide in the tissues are likely to reduce the basic "tone" of the parasympathetic nervous system, as there is less need for additional vasodilation.

Nitric oxide can diffuse away from the blood vessels, affecting the energy metabolism of nerve cells (Steinert, et al., 2010). Normally, astrocytes protect nerve cells from nitric oxide (Chen, et al., 2001), but that function can be altered, for example by bacterial endotoxin absorbed from the intestine (Solà, et al., 2002) or by amyloid-beta (Tran, 2001), causing them to produce nitric oxide themselves.

Nitric oxide is increasingly seen as an important factor in nerve degeneration (Doherty, 2011). Nitric oxide activates processes (Obukuro, et al., 2013) that can lead to cell death. Inhibiting the production of nitric oxide protects against various kinds of dementia (Sharma & Sharma, 2013; Sharma & Singh, 2013). Brain trauma causes a large increase in nitric oxide formation, and blocking its synthesis improves recovery (Hüttemann, et al., 2008; Gahm, et al., 2006). Organophosphates increase nitric oxide formation, and the protective anticholinergic drugs such as atropine reduce it (Chang, et al., 2001; Kim, et al., 1997). Stress, including fear (Campos, et al., 2013) and isolation (Zlatković and Filipović, 2013) can activate the formation of nitric oxide, and various mediators of inflammation also activate it. The nitric oxide in a person's exhaled breath can be used to diagnose some diseases, and it probably also reflects the level of their emotional well-being.

The increase of cholinesterase by enriched living serves to protect tissues against an accumulation of acetylcholine. The activation of nitric oxide synthesis by acetylcholine tends to block energy production, and to activate autolytic or catabolic processes, which are probably involved in the development of a thinner cerebral cortex in isolated or stressed animals. Breaking down acetylcholine rapidly, the tissue renewal processes are able to predominate in the enriched animals.

Environmental conditions that are favorable for respiratory energy production are protective against learned helplessness and neurodegeneration, and other biological problems that involve the same mechanisms. Adaptation to high altitude, which stimulates the formation of new mitochondria and increased thyroid (T3) activity, has been used for many years to treat neurological problems, and the effect has been demonstrated in animal experiments (Manukhina, et al., 2010). Bright light can reverse the cholinergic effects of inescapable stress (Flemmer, et al., 1990).

During the development of learned helplessness, the T3 level in the blood decreases (Helmreich, et al., 2006), and removal of the thyroid gland creates the "escape deficit," while supplementing with thyroid hormone before exposing the animal inescapable shock prevents its development (Levine, et al., 1990). After learned helplessness has been created in rats, supplementing with T3 reverses it (Massol, et al., 1987, 1988). 

Hypothyroidism and excess cholinergic tone have many similarities, including increased formation of nitric oxide, so that similar symptoms, such as muscle inflammation, can be produced by cholinesterase inhibitors such as Tacrine, by increased nitric oxide, or by simple hypothyroidism (Jeyarasasingam, et al., 2000; Franco, et al., 2006).

Insecticide exposure has been suspected to be a factor in the increased incidence of Alzheimer's disease (Zaganas, et al., 2013), but it could be contributing to many other problems, involving inflammation, edema, and degeneration. Another important source of organophosphate poisoning is the air used to pressurize airliners, which can be contaminated with organophosphate fumes coming from the engine used to compress it. 

Possibly the most toxic component of our environment is the way the society has been designed, to eliminate meaningful choices for most people. In the experiment of Freund, et al., some mice became more exploratory because of the choices they made, while others' lives became more routinized and limited. Our culture reinforces routinized living. In the absence of opportunities to vary the way you work and live to accord with new knowledge that you gain, the nutritional, hormonal and physical factors have special importance.

Supplements of thyroid and progesterone are proven to be generally protective against the cholinergic threats, but there are many other factors that can be adjusted according to particular needs. Niacinamide, like progesterone, inhibits the production of nitric oxide, and also like progesterone, it improves recovery from brain injury (Hoane, et al., 2008). In genetically altered mice with an Alzheimer's trait, niacinamide corrects the defect (Green, et al., 2008). Drugs such as atropine and antihistamines can be used in crisis situations. Bright light, without excess ultraviolet, should be available every day. 

The cholinergic system is much more than a part of the nervous system, and is involved in cell metabolism and tissue renewal. Most people can benefit from reducing intake of phosphate, iron, and polyunsaturated fats (which can inhibit cholinesterase; Willis, et al., 2009), and from choosing foods that reduce production and absorption of endotoxin. And, obviously, drugs that are intended to increase the effects of nitric oxide and acetylcholine should be avoided.

© Ray Peat Ph.D. 2016. All Rights Reserved. www.RayPeat.com

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Physiology texts and the real world

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Hospital accidents kill more people than highway accidents. But when people die while they are receiving standard, but irrational and antiscientific treatments and “support,” the deaths aren’t counted as accidents. The numbers are large.

Medical training and medical textbooks bear great responsibility for those unnecessary deaths. Most medical research is done under the influence of mistaken assumptions, and so fails to correct the myths of medical training. If the “consumers” or victims of medicine are willing to demand concrete justifications before accepting “standard procedures,” they will create an atmosphere in which medical mythology will be a little harder to sustain.

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A sentence taken out of context is likely to be misleading. A chemical equation that is concerned only with the reactants, catalyst, and product, can be misleading, and its industrial application is likely to produce devastation and pollution along with the intended product. In nature and industry, the reactants, products, and energy changes are linked to the ecology and to the economy. In physiological chemistry, events in the organism are linked to the environment so closely that food, water, air, soil, and pollution form a firmly linked functional system.

But “medical physiology” has evolved as a separate thing, in which formulas that describe specific situations are linked to each other by fragmentary schemes, terminology, and computer models. This jerrybuilt scheme is even more roughly set into a hypothetical environment of “the origin of life,” “evolution,” “inheritance,” “society,” and a few other perfunctory contextualizations that have no more relevance to the subject than do the literary epigraphs that are often used at the beginning of chapters in medical books, to signify that the author isn’t just a technical hack.

This physiological mythology has made possible a practice of medicine in which “genes” and “a virus” are regularly invoked to explain things that can’t be remedied, and in which any fleshy body is described as “well nourished,” and in which malnutrition and poisoning by pollutants are systematically dismissed as explanations for sicknesses, while thousands of different drugs are administered according to instructions given by their salesmen. It is also deeply linked to attitudes that have turned the practice of medicine into the surest way for an individual to get rich and retire early. It creates a sense of confidence that the physician is doing the right thing, because there is a little physiological rationale for everything. When a practice is replaced by its opposite, there is also a rationale for that. In fact, medical textbooks are written to rationalize the highly arbitrary practices of the industry. If, for some reason, perpetual motion machines had been as successful economically as steam engines were, laws of thermodynamics would have been written to describe them, just as thermodynamic laws were invented to describe the theory of steam engines.

It was odd and interesting when a vice presidential candidate stepped to the podium several years ago and asked “who am I? What am I doing here?” But those questions are really of the greatest importance and interest, and physiology should be an attempt to understand more fully what we are, what we are doing, and how we are doing it. When we have comprehensive answers to those questions, then we will be in a position to create systematically valid solutions for our problems.

For physiology, the equivalent of medicine’s “first do no harm” would be “first, don’t believe unfounded doctrines.” Accepting that principle puts a person into a critical attitude, and experiments can become actually “empirical,” an extension of experience that allows you to perceive new things, rather than “testing hypotheses.” Unless a hypothesis is a generalization from real experience, rather than a deduction from a doctrine, progress is likely to be very slow. A first step in developing a critical attitude is to identify the idols that stand in the way of real understanding.

Immunity, intelligence, appetites, tumor growth, aging, the proper development of organs—everything that we think of as the biological foundations of health and sickness—will be misinterpreted if there are fundamental misconceptions about physiology.

Physiology is the study of the vital functions of organisms, but especially when talking about “pathologic physiology,” great emphasis in physiology textbooks is given to the processes that maintain homeostasis of the milieu interieur, or the constancy of composition of the “fluid in which tissue cells are bathed.” Since cells are embedded in a gel-like matrix, “connective tissue,” the connective tissue should have some serious attention in physiology courses, but in practice its composition is described, and then the rest of physiology treats it as the “extracellular space.” Only specialists in the extracellular matrix are likely to take it seriously as a factor in physiology.

If medical physiologists are likely to think of cells as being “bathed in fluid” which fills the empty spaces around the cells, they are also likely to think of the cell’s interior as a watery solution which “fills the space enclosed by the cell membrane.” It is this image of the organism that has made traditional biochemistry possible, since enzymes extracted from cells and dissolved in water had been thought to function the way they function in the living state. But the living cell isn’t like a tiny water-filled test-tube.

Some of the points that should be considered in a realistic (and therefore coherent) physiology text:

Connective tissues, ground substance— making a multicell organism--secreting the right amount, modifying/maintaining it, responding to the scaffolding--where the crucial milieu interieur is.

Cellular energy, a structural idea—a finely organized catalyst, a readiness for work, and conditions that determine the equilibrium of reactions.

The dimensions of the organism range from cellular fields to organismic intentions, via functional systems.

Physiology should be understood in terms of its geochemical setting, because otherwise basic definitions will be built up in the belief that life is discontinuous from its physical environment, separated by membranes, and maintained by the expense of energy mainly to preserve gradients across those membranes; while in actuality the chemical energy released by living substance is spent in renewing structures, and the gradients are mainly passive physical-chemical consequences of structure. The spontaneous polymerization that occurs under volcanic conditions creates substances with intrinsic functions. The living state is a substance that is always being renewed as it interacts with its environment, and from the larger persepective, it is an evolving catalyst that modifies the environment so that the whole system approaches equilibrium with the energy that flows through it. Since the evolving system stores energy in its structure, the cosmic energy sources and sinks are at the boundaries of the system, and are the only questions that (so far) transcend the issue of life in its environment. The chemistry of the planet is tied up with cosmic energy, but the nature of the system as a whole is still relatively unexplored. If plants are bracketed by the sun, carbon dioxide and water, animals are bracketed by sugar and oxygen.

Acid-base regulation--selectivity; physical chemistry of coral, bone; kidney, lung; roles of oxygen, carbon dioxide and protein.

An Arrhenius base is something which produces hydroxide ions when it’s dissolved in water.

Metal, an element that forms a base by combining with a hydroxyl group (or groups).

Base, an electropositive element (cation) that combines with an anion to form a salt; a compound ionizing to yield hydroxyl ion.

Electropositive atoms tend to lose electrons.

Electronegative atoms, such as oxygen, chlorine, and fluorine, tend to take up an electron and to become negatively ionized. 

Definitions of Arrhenius and Lewis for acids and bases. It’s important to keep both sides of an ionizable compound in mind, and to pay more attention to electrons than to protons.

A Lewis acid is an electron acceptor.

Alkali reserve, (Stedman’s phrase:) “the basic ions, mainly the bicarbonates” (bicarbonates of this or that; there is no abstract “bicarbonate.”)

Carbon dioxide is a neutral Lewis acid, that associates with the hydroxide ion. (This observation may be shocking to people who have thought too long in terms of abstract “bicarbonate.”)

Carbon dioxide regulates water, minerals, energy and cellular stability, excitation, and efficiency.

Cellular respiration regulates both energy and substance disposition.

Respiration regulates osmotic/oncotic pressure, including the hydration (and dehydration) of the extracellular matrix.

Electrons, positive charges, electronegativity, and induction: The unity of metabolism and signalling interactions; hormones are physical-chemical agents, not information carriers. Electrets, piezoelectricity, and crystal/bond stresses are relevant to physiology; the behavior of ionic materials in bulk water provides misleading images for physiology. Space charges are more relevant to physiology than fluxes in ion channels.

Inductive effect: an electronic effect transmitted through bonds in an organic compound due to the electronegativity of substituents. 

Cooperative adsorption interacts with inductive effects producing coherent, systemic changes and stabilities.

Steroids, peptides, biogenic amines, and other things considered as hormones and transmitters, are active as modifiers of adsorption, induction, and metabolic pathways. Their structural effects create, or inhibit, phase transitions in cells. Synergies of radiation, estrogen, and hypoxia are intelligible in terms of phase instability.

Alkaloids: organic substances occurring naturally, which are basic, forming salts with acids. The basic group is usually an amino function.

The disposition of electrons in cells and tissues is a global phenomenon, integrating metabolism, pH, osmolarity, and sensitivity. Excitation creates a field of alkalinity.

Cellular differentiation; developmental fields, polarities.

Regulation of water; electroosmosis; edema in relation to cellular energy.

Vicinal water, all water near surfaces, most of the water in cells, has special properties.

Needs on the cellular level guide the organism’s adaptations.

Functional systems, multilevel adaptive integrations, in which many “systems” and cell types are organized according to activity and needs, leading to anatomical and functional changes.

Energy and relaxation, cellular inhibition, a structural state involving the entire cell substance. High energy phosphate bonds explain nothing about the cell’s energy.

Multilevel self-regulation; cell intelligence, organic compensations (function producing structure, organ regeneration, vascular neogenesis, stem cell functions, immunity/morphogenesis, tubercles/tumors, fat/fiber/muscle/phagocytosis) permits highly organized and novel adaptive responses, which are goal-directed rather than mechanistically “programmed” from the genes.

Sensitivity and motility—plants and animals, subtle cues, rhythms, motivations.

Adaptation—learning, intention, and stress.

Light, energy, motion; pigments and electron donor-acceptor bonds.

Acceptor of action, innate and learned models of reality. Intentionality is involved in “reflexes.”

Digestion—bowel and liver; immune system and nervous system; need and intepretation, analysis; approximation and assimilation. Intestinal flora and detoxifying. Detoxifying fatty acids, estrogen, insulin, nerve chemicals, etc.  

Nutrition—appetite and satisfaction. 

Reproduction, puberty, menopause; how they are affected by the environment.

Humor, curiosity, exploratory and inventive potentials and need. 

Growth and aging; energy, individualization and generalization; mitosis and meiosis, germ cells.

Nurse cells, their interactions in various organs.

Chalones, wound hormones, phagocytes, regeneration, nerve products; inhibition of growth by nerves. Frog extracts in development. Anatomy is a dynamic system, whose integration is part of physiology.

Inflammations and tumors are systemic events, in causes and effects.

Inflammation, edema, fibrosis, calcification, and atrophy--the basic pathology.

Organisms relate to the biosphere as factors in the creation of new equilibria.

Between 1947 and 1956, Arthur C. Guyton, of Ole Miss, wrote a textbook of medical physiology, and one of his students, J. E. Hall, has added chapters to it. It is the most widely used physiology textbook in the world. It may be more influential than the bible, since it has shaped the behavior of millions of doctors, affecting billions of people. Its success probably has something to do with Guyton’s unusual personal experience. After graduating from Harvard Medical School and, along with others from Harvard, working in germ warfare,* he contracted polio, and returned to Mississippi. As someone moving from the centers of excellence and power to the most backward state in the nation, instead of using textbooks he wrote handouts for the classes he taught there, devising what he thought were plausible explanations for everything in physiology. A personalized perspective and desire to keep things simple made the book, based on those handouts, readable and popular. 

The circulatory system, and the movement of fluids in the body, are at the center of physiology, so it is of interest that Guyton believed that, in the “spaces around cells,” there is a negative pressure, a partial vacuum, that sucks fluid out of the capillaries. He believed that this suction would balance a column of 5 or 10 mm of mercury. The rib cage, and the force of the diaphragm muscle, can maintain a negative pressure around the lungs, preventing their elastic collapse, but there is no such shell around the rest of the body; if elastic fibers of connective tissue could be anchored to such a shell, then such a suction/vacuum would be conceivable. 

Hydrostatic and osmotic pressures interact in tissues, but even the hydrostatic forces produced by the heartbeat are known only approximately, as estimates, on the microscopic level. The belief in subatmospheric interstitial pressure is unreasonable on its face, and measurements are so inaccurate in the microcirculation that its disproof would be somewhat like proving that fairies aren’t responsible for the Brownian motions seen under a microscope.

The oncotic/osmotic behavior of proteins in the blood and extracellular (the term interstitial implies the presence of empty spaces which aren’t really there) fluid is usually, in medical physiology, assumed to be a fixed quantity determined by the nature of the polymer. Swelling and syneresis (contraction) of gels, with the absorption or release of water, are strongly influenced by the electrical properties of the system, which includes solvent water, bound water, and small solutes and ions as well as the polymers. Changes in pH and ionic strength and temperature, and the presence of solutes modifying the polymer’s affinity for water, affect the osmotic behavior of the polymer, and of gels formed by such polymers. Since the extracellular spaces are mainly filled with solid gels, Guyton’s image of simple fluids entering and leaving these “spaces” reveals a major conceptual error, and that error has been widely propagated by medical professors. If a person imagines open spaces, interstices, between cells, then the question of the fluid pressure in these chambers seems reasonable, and the factors that produce edema will be thought of mechanically. But if we call the material between cells the “extracellular matrix,” and recognize its relatively solid gel nature, we will see the problem of edema in physical-chemical terms, rather than as a problem of simple hydraulics.

[*Biographical side-lights: Guyton graduated from Ole Miss in 1939, got his medical degree from Harvard in 1943, where the department of bacteriology had a grant to study the polio virus, and where he worked with people “involved in the war effort,” and then from 1944 to 1946 was involved in germ warfare research, mainly at Camp Detrick. Camp Detrick had been established as the center for chemical and biological warfare research, and a test site was established in Mississippi in 1943. Guyton’s first paper was on aerosol research (published in 1946), and studies at that time were being done to improve the spreading of germs in aerosols. Bacterial aerosols were tested on the public in San Francisco, in 1950. Guyton’s Harvard colleagues established a polio research lab at Children’s Hospital Medical Center. When he left the navy, after working at Camp Detrick, Guyton resumed work at Mass General, and contracted polio before he finished his residency.] 

Idols of medical physiology, foundations and cornerstones for the landfill, some things you shouldn’t know about physiology:

Genes control the cell, the organism is its genome, the nucleus regulates the cytoplasm. Information flowing from the genes produces and maintains the organism.

Acquired traits aren’t passed on; mutations are random, the genome doesn’t acquire information from the organism or environment, the germ-line is isolated.

Physiology is bounded by the informational function of genes.

The cell is a drop of water containing dissolved chemicals enclosed in a membrane. 

Random diffusion governs energy metabolism, gene induction, and other intracellular events.

Enzyme reactions occur when dissolved molecules randomly diffusing come into contact with a suitable enzyme, as described by the Michaelis-Menton equation.

The Donnan equilibrium explains cellular electrical behavior, and since ions are distributed across the membrane by active transport, the membrane potential is maintained by the expense of metabolic energy.

Water is just a peculiar solvent.

Water structure changes only at extremes of temperature.

Cells are perfect osmometers.

There are empty spaces between cells.

The membrane regulates the composition of the cytoplasm, with pumps and pores and channels. Cells must produce enough energy to keep the pumps running.

Membrane receptors regulate cell responses.

Cells are activated by receptors, and physical forces for which there are no receptors have no effect on cells except when they are above a threshold at which they cause discrete chemical changes.

The nervous system is hard-wired.

Brain and heart cells don’t regenerate.

There is an immune system, whose function is to destroy pathogens, with inflammation as one of its functions, and its specific reactions are determined by the selection of clones which were generated by random mutations; an autonomic nervous system, which regulates visceral reflexes by innervating, via receptors, smooth muscle, heart muscle, and glands; an endocrine system, regulated mainly by negative feedback, that produces hormone molecules that carry messages to the receptors in certain target tissues.

Inflammation is produced by germs, and is a defensive reaction of the immune system, and so is good. (Sterile inflammation is too confusing to include within the ambit of medical physiology, since it is associated with serious harm to the organism. The roles in inflammation of the nervous and endocrine systems and kidneys and membrane pumps and osmoregulation aren’t discussed in polite books.)

During development, cells are organized into systems, and they don’t change their type. In the case of germ cells, their type is determined before they exist. Cells are able to undergo only about 50 divisions, and most of those divisions are used up in producing an adult organism.

The committed nature of the organism’s cells and anatomy make radical functional adaptation impossible.

Hormones and transmitter substances act only through specific receptor molecules.

High energy phosphate bonds in compounds such as ATP provide energy to molecular pumps and motors. 

Molecular forces act only locally.

Pathologies are primarily local: Inflammations and tumors have local causes, and their effects are local. Specific and local treatments are ideal. Circulation is treated as a plumbing problem, tumors as clones of defective cells.

Consciousness is produced by nervous signals that transmit information, and can be compared with the handling of information by computers.

Excitation and inhibition are functions of cell membranes.

Artificial intelligence research into computational and nerve net systems is as much a part of research into the physiology of consciousness as computer modeling of feedback systems is a form of research into endocrine physiology and immunology.

Estrogen, testosterone, thyroid, prolactin, serotonin, adrenalin, prostaglandins, etc., are carriers of information in an informational system.

Cyclic functions and behaviors are governed by genes.

The existence of hard-wired informational receptor systems and gene-induction systems is necessary because of the random diffusional nature of the other cellular processes and materials.

Essentially, an organism consists of random inert matter given form and activity by the imposition of genetic information accumulated through random mutations.

(There are really people who still believe those things.)

A NOTE ON SCIENTIFIC REVOLUTIONS:

If scientific revolutions depended on "the authorities," then the Copernican revolution would be dated from the Pope's apology. The fact that the major journals are controlled by antiscientific dimwits helps to define where science exists. Gilbert Ling's revolution in cell physiology has been moved along by the existence of the journal, Physiological Chemistry and Physics (and medical NMR).

Michael Polanyi, in Personal Knowledge, maybe even more than Thomas Kuhn did in his famous book (Structure of Scientific Revolutions), helped to solidify the belief that there is a real international monolithic "community of science." Even though Polanyi, working "in isolation" in Hungary created his general and elegant adsorption isotherm, he didn't teach it to his own students, because of his belief in that community of science, which ridiculed his work because it wasn't based on their (false) assumptions about the electrical nature of matter.  

The linguistic and cultural isolation of Hungary and Russia from Europe has permitted them to evolve distinctive scientific cultures. C.C. Lindegren, in Cold War in Biology, showed that political forces in the U.S. and England suppressed anti-Mendelian ideas by identifying them as subversive, imposing the Central Dogma of genetics.  But even within an authoritarian national tradition, there are little communities of science, where the real development of thought can take place.

Perceptions that are clear and useful are the real revolutions in science, and the rest of it has to do with social and financial commitments.

Even in the short time since Kuhn wrote his book, the status of medicine has changed significantly, putting it right up with militarism and the energy industry as a source of political and economic power. The authoritarian monolith that has been known as the community of science has become increasingly (even in areas such as astronomy, where commercial interests aren't so crudely involved) a structure of cultural propaganda maintained by bullying and fraud. Since the "normal science" in these authoritarian settings is dedicated to evading the truth, it becomes almost a guide to where to look for the truth. It's sort of analogous to the "mystery" of why breast cancer mortality is lowest in the poorest part of the U.S., Appalachia, and highest in the richest regions: the medical industry goes where the money is, taking death with it. Science, like health, thrives on the neglect of the corrupt industry. 

I have always felt that the cybernetic definition of communication as the transfer of something that makes a difference should be applied to speech and writing. As a student and teacher, I saw that information which made a difference was the essence of intellectual excitement and growth. But making a difference is exactly what university administrators and journal editors don't want. 

© Ray Peat Ph.D. 2014. All Rights Reserved. www.RayPeat.com

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For every thing that lives is holy, life delights in life.... W. Blake

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Kurt Goldstein: "Life is a condition alternating between excitation, destruction

and unbalance, and reorganization, equilibrium and rest."

===========================

Oncological pathologists, looking at slices of a tumor, believe they can guess

when the cells have an evil intention. However, biologists studying living cells find that

cells can do only what they are allowed to do by their environment.

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Cancer: Disorder and Energy

According to the World Health Organization, cancer is now the leading cause of death in

the world. Although many "causes" are known, and despite the "War on Cancer,"

nothing practical has been done to reduce the incidence of cancer. Since Nixon started

that war, the number of people dying annually in the US has increased faster than the

population. In ancient Rome and Egypt, cancer was rare; cancer has been identified in

only one Egyptian mummy. In the US and several other countries, between 2002 and

2005 there was an unprecedented decline (7% in the US) in the incidence of breast

cancer, when the medical use of estrogen decreased following the Women's Health

Initiative report showing that estrogen caused cancer, dementia, strokes and heart

attacks. However, when the public was reassured about estrogen's safety, breast

cancer incidence began increasing again each year.

The cancer industry has been flexible and imaginative in ways of presenting "age

standardized" death rates to show that they are making progress against cancer, but

there are philosophical and scientific problems in "oncology" (i.e., the study or treatment

of lumps) that should be considered by anyone who plans to do business with that

profession.

In the 19th century (in Johannes Muller's lab), cancers, like other animal tissues, were

found to be made up of cells, and by 1858, all diseases were said to be caused by

disturbances in cells (Rudolph Virchow). The atomic and molecular theory of matter was

becoming accepted at the time that animals were found to be made up of cells, and in

both cases the "elementary particles" seemed to have a special power to explain things.

This idea of a cellular basis of disease gradually displaced the old idea that diseases

were caused by an imbalance of the body fluids, or humors. In 1863, Virchow

recognized that inflammation, involving leukocytes, was a common feature of cancer,

but that aspect of his work was neglected for a long time.

Recent medical textbooks reveal no major change in the understanding of cancer since

Virchow's time, except that "genes" (which weren't known during Virchow's life)

gradually became the most important aspect of cells. The typical modern textbook

describes the cellular disturbance of cancer as the result of an "initiating" mutation in a

gene, which gives it the potential to develop into a cancer, if it subsequently is exposed

to a "promoter," which causes it to multiply. In some versions of the theory, a promoter is

a second mutation that causes proliferation, but in other versions the promotion is

caused by chemicals binding to receptors the way hormones do, to stimulate

proliferation. Typically, textbooks (and reports of continuing research) describe

subsequent changes in the genes that cause a cancer to progress from a simple excess

of cells through stages of increasing malignancy: hyperplasia, dysplasia, carcinoma in

situ, invasive cancer.

One of the reasons that the medical understanding of cancer hasn't changed

significantly since Virchow's time is that blaming misbehaving cells for causing a tumor

fits into the older medical tradition, that has existed at least since the time of

Hippocrates, 400 BC, which treated tumors either by cutting them out, or by burning

them off with caustics. Virchow's identification of misbehaving cells provided a clear

mental image of exactly what the physician must try to destroy. And it's probably hard to

get interested in something which could seriously limit your professional activities if it

turned out to be true.

The "cellular basis of cancer" was developed simultaneously with the germ theory of

disease, and in the case of cancer, the deviant cells came to be considered an alien

substance, "not-self," analogous to infective germs. Paul Ehrlich's search for poisons

that were specific for bacterial pathogens was quickly extended to the idea of finding

poisons that would distinguish between cancer cells and the patient's cells.

Hippocrates' therapeutic approach to cancer may have survived for 2400 years, but the

ideas of his younger contemporary, Plato, about order and causation have probably had

a greater effect on medicine. Plato believed that the world of experience is inferior and

accidental, and that there are timeless "Forms" that are the real substances. In the

atomic theory of matter, eternal, unchanging atoms took the place of platonic forms, and

there are still molecular biologists who insist that life can only be explained in terms of

its constituent atoms ("What else is there but atoms?"). This philosophy of timeless

forms was a deep commitment of people like Gregor Mendel and August Weismann,

whose ideas dominated the thinking of early 20th century geneticists. Genes were the

immutable essence of organisms, and the cells, tissues, and organs that form the

organism are merely temporal and accidental. Weismann's "germ plasm" or germ line

contained the immortal genes, the rest of the body lacked them, and was essentially

mortal.

For most of the 20th century, the official doctrine was that most of the cells of the adult

body became stationary once the body reached its adult size, and that aging consisted

of the "wearing out" of those mortal cells. When a tumor, containing new cells, would

appear and grow, these cells were called "immortal," because they didn't follow the rule

for normal, stationary, mortal cells. Their "immortality" is often demonstrated by growing

them endlessly in culture dishes. Normal cells, if they can be made to survive in a

culture dish, are likely to be "transformed" into cancer, demonstrated by their ability to

replicate in dishes.

This is an important ideological point, that developed as biologists were experiencing

the extreme difficulty of getting cells to replicate, or even to survive, in culture dishes. It

has only recently been realized that cells need more than nutritional and hormonal

signals to survive in culture; they require certain textural, structural, even rhythmically

repeating conditions that mimic their surroundings in the living body.

Applied to cancer, the gene theory made it seem clear that the changes occurring in

tumor cells were irrevocable, and it has seemed self-evident to oncologists that the only

hope the cancer patient has is for the physician to destroy every bit of the alien

substance. The recurrence of a cancer that has been removed has been evidence to

them that fragments had remained, or that the cancer had distributed its seeds into

other parts of the body. This seems to be the necessary conclusion if cancer is "caused"

by defective genes.

New ideas of causality have grown up in science beside, or within, the science culture

that is committed to platonism, reductionism, and genetic determinism. A few biologists,

including Ana Soto and Carlos Sonnenschein, are applying more realistic ideas of

causality to ecological, developmental, and cancer research. They have said (Soto, et

al., 2009) "The ecological developmental biology (eco-devo) movement rejects the

notion that development is merely the unfolding of a genetic program." If events such as

cancer aren't "caused by genes," understanding the causes of cancer and the

appropriate ways to treat it will require more holistic ways of looking at the tumor's

relation to the organism, and the organism's relation to the environment.

It has been more than 40 years since experimenters demonstrated that cancer cells

could be caused to revert to normal, by changing their environment. Harry Rubin (2006)

has observed that cells can accumulate hundreds of mutations, and still function

normally in the organism, but when separated and grown in a culture dish their

differences become obvious. The surrounding cells in the body are causing the

defective cells to remain normal in appearance, function, and growth behavior, instead

of acting like cancer cells, and can also cause "stem-like" cells to differentiate

appropriately.. He says "Intimate contact between the interacting cells is required to

induce these changes." When stem cells enter a tumor, they don't find that regulatory,

normalizing interaction with normal cells.

Work like Rubin's shows that even "myriad" mutations don't necessarily cause cancer,

and another line of research shows that things which don't cause mutations can cause

cancer--the "non-mutagenic carcinogens." The presence of mutations is neither

sufficient nor necessary for causing cancer, but tumors do eventually accumulate

serious damage, which causes most of the tumor cells to die quickly. Biological stress,

or excitotoxic energy deprivation, destabilizes the genome; genetic changes develop as

a result of prolonged destructive influences. The "non-genotoxic" carcinogens first

cause inflammation, excitation, and energy impairment, leading to fibrosis, and atrophy.

Cycles of cell injury, death, and repair cause chromosomes to deteriorate as the tissue

loses its organization.

When a cell is stimulated, it responds, and the response requires energy. The stronger

and more continuous the stimulus, the more energy the cell needs to continue

responding. In some conditions, cells can desensitize themselves, to survive in the

presence of continuous stimulation or irritation, but otherwise they are killed when they

don't have enough energy to keep responding.

When a nerve is stimulated and responds, a wave of negative electrical charge passes

through it; the electrical field accompanies a structural change in the cytoplasm of the

nerve; similar changes occur in other types of cell. Stimulation of a nerve with negative

(cathodal) polarity causes swelling, stimulation with the opposite polarity causes the

opposite behavior; when nerve cells are inhibited, they shrink (Tasaki and Byrne,

1980; Tasaki, et al., 1988; Tasaki, 1999).

Swelling, an increase of the water content of an area of tissue, is a general feature of

inflammation (Weiss, et al., 1951), whether it's in a lump caused by a bee sting, a

bruise, or hives, or a cancer. Besides the instantaneous uptake of water described by

Tasaki, there are increases that continue because of metabolic and chemical changes in

the irritated cell. Tasaki has used gels of synthetic polymers to demonstrate that an

electrical field can cause these changes, without the need for the "chemical osmotic"

changes that are customarily assumed to account for the swelling changes caused by

stress (Tasaki, 2002). When the pH of a protein gel becomes more alkaline, it swells.

The electrical activation of a nerve causes a quick shift towards internal alkalinity

(Endres, et al., 1986), followed by a sudden increase in lactic acid production. Although

increased lactic acid causes acidity of an irritated or inflamed region, the conversion of

pyruvic acid to lactic acid causes the interior of the stressed cell to become more

alkaline, causing it to swell. This is the same process that causes the familiar swelling of

tired muscles.

If blood vessels swell, the delivery of oxygen may be restricted, and hypoxia causes

more intense swelling, because more lactic acid is produced, and less oxidized. This

swelling pressure resembles an increase of osmolarity. For over 100 years, it has been

customary to treat shock with "isotonic" fluids, which are in balance with well

oxygenated tissues, with approximately 290 milliosmoles per liter, but this usually

causes edema, swelling, and weight gain. Stressed tissues have been found to be in

balance with fluids of much higher osmolarity, for example 372 mOsm/L (Tranum-

Jensen, et al., 1981), and sometimes much higher.

Apart from its acidity, lactic acid acts as an excitatory signal. A very slight increase

above the normal amount of lactic acid in the body fluids excites sensitive cells, and the

amounts reached in inflamed tissues and in cancers will excite even stable cells such as

myelinated nerves (Uchida and Murao, 1975).

Cancer cells show all the signs of being intensely stimulated, and this includes a high

rate of oxygen consumption (deGroof, et al., 2009). The stimulation increases the

energy requirements beyond the ability of the mitochondria's capacity to meet them,

leading to the production of lactate even when a normal amount of oxygen is present.

Even when both glucose and oxygen are supplied (which they usually aren't), the tumor

cells will consume amino acids as fuel, as well as using them as material for growth.

Tumors have been called "nitrogen traps" or "glutamine traps," but this has meaning

beyond the use of the nitrogen for growth; it is involved in the energetic inefficiency of

this process, and the reorganizing effects this wasteful flow of energy has on the tissue

structure (Medina, 2001). When glutamine enters the Krebs cycle to be used as fuel,

this interferes with the ability to oxidize glucose, causing more lactic acid to be formed,

contributing to the excitation and increased energy requirement.

Lactic acid activates the other major mediators of inflammation, including prostaglandins

(made from PUFA), free fatty acids (including arachidonate, that forms

prostaglandins; Schoonderwoerd, et al., 1989), nitric oxide, carbon monoxide,

proteolytic enzymes that degrade the extracellular matrix, TNF (Jensen, et al., 1990),

hypoxia inducible factor (Lu, et al., 2002; McFate, et al., 2008), interferon, and

interleukins. Arachidonic acid itself can increase lactate production (Meroni, et al.,

2003). TNFalpha and interferon gamma activate lactic acid production by increasing

prostaglandins (Taylor, et al., 1992).

Most of the present information about cancer cells' behavior, such as reactions to

radiation and chemical toxins, has been based on the study of cells in culture dishes.

For more than 70 years, it was generally believed that radiation caused mutations and

cancer by directly modifying the cells' genetic material. Then, it was discovered that

fresh cells that were added to a dish of irradiated cells also developed mutations. The

radiation causes cells to emit excitatory, inflammatory, substances such as serotonin

and nitric oxide, which injure the cells that are later put near them.

Applying this information to the existing knowledge that radiation induces cancer in

animals, the doctrine of genetic determinism inferred that the radiation "bystander

effect" is just another mechanism by which radiation produces the "mutant cancer cell"

or clone of cancer cells. But the difference between events in vitro and in vivo is that

cells which are injured in the organism immediately initiate a process of healing, and in

that situation each of the substances emitted by injured cells is acting both locally and

systemically to activate repair or regeneration of the damaged tissue. Cells isolated in a

culture dish can't call on the organism for the necessary materials, so the responses of

the "bystander" cells, leading to mutations and death, seem meaningless. The injured

cells are merely toxic, rather than potentially being a stimulus to healing.

When any part of a living organism is injured, for example by x-rays or surgery, the

emitted substances affect the endocrine and nervous systems, activating processes that

change metabolism and behavior. The injured tissue takes on new functions, for

example by locally synthesizing estrogen, cortisol (Vukelic, et al., 2011), and other

hormones, as well as stimulating the normal endocrine glands to secrete them. These

interactions have been generally disregarded in cancer treatment, because of the gene centered

theory of cancer, but they are essential for understanding the "malignancy" of

tumors, that property that makes them likely to return after the tumor has been

destroyed, and to spread to other tissues. Has anyone ever heard of a radiologist or

surgeon who measured estrogen or the various mediators of inflammation before,

during, and after their treatments? Long range survival after breast cancer surgery is

affected by the time in the menstrual cycle when the surgery is done (Lemon, et al.,

1996).

All sorts of stress, inflammation, and tissue injury increase the concentration of

estrogen, both locally and systemically. Estrogen in turn produces hypoxia, swelling,

lactic acid formation, and stimulates cell multiplication. Even a brief period of hypoxia

will cause the secretion of lactate and other chemoattractants (Neumann, et al., 1993),

which will cause cells to move into the hypoxic area from the blood stream. Although

lactic acid attracts immune cells, it probably reduces their anticancer functions, and it

stimulates the formation of new blood vessels, supporting continued growth and

expansion of the multiplying cells (Hirschhaeuer, et al., 2011). When a tissue is being

repaired normally, the new cells sense a quorum, and stop multiplying. The return of

nerves to the damaged area is part of the regenerative process; nerves have inductive

and stabilizing effects on differentiating cells.

These complex interactions between tumor cells and the rest of the organism are not

considered by the ideology of medical oncologists. The ruling belief is that the

malignancy of cells can be determined by examining them microscopically, and that

their rate of growth can be determined, and that the tumor's approximate time of origin

can be estimated. After surgically removing a tumor, the administration of chemotherapy

and/or radiation is governed by mathematical descriptions of the expected behavior of

cancer cells.

The mathematical relation of mortality to aging was described by Benjamin Gompertz,

an actuary, in 1825, based on the understanding that people become less able to resist

dying as they get older. This Gompertzian growth curve, which is realistic when applied

to a population of people, flies, or rabbits, was applied to tumor growth (A.K. Laird, in

1964). Gompertz' reasoning that the probability of a person's dying increases with age

has nothing to do with cancer cells, and there is very little evidence that his law of

growth is useful for describing tumors. Laird's evidence consisted of 19 tumor samples,

taken from 10 mice, 8 rats, and a rabbit. Her suggestion that the continuing deceleration

of the growth rate might represent a natural growth regulating process wasn't influential,

but her use of an actuarial formula, suggesting certain properties of cancer cells, has

been extremely influential. It seems to be the profession's great need for justification

that has made a Law of Tumor Growth so important to them.

At the time Laird did the tumor growth study, there was considerable interest in the idea

that the immune system could be induced to prevent tumor growth. In 1951, Chester

Southam, of the Sloan-Kettering Institute, tested his theory of cancer immunity on

hundreds of patients and prisoners, and his results were widely reported. He found that

pieces of tumor implanted in healthy people caused a local intense inflammation, which

healed completely after two or three weeks. In sick people, the rejection of the cancer

implant took about twice as long, and in people who already had cancer, the implant

was very slow to be destroyed, and sometimes it was still present when they died.

In 1889, Stephen Paget had noticed that cancers metastasize only into certain organs,

and compared the cancer cells to seeds that "can only live and grow if they fall on

congenial soil." While many people, like Southam, saw a failing "immune system" as

part of the congenial soil, and suggested vaccination to activate an immune rejection of

the tumor, others have suggested "reducing the soil to dust," making growth impossible

in a more general way. Recently, this attitude has taken the form of different ways of

"starving" cancer, by reducing sugar in the diet, or by blocking cells' ability to use sugar.

The idea of making the "soil" inhospitable to cancer is a variation on the theme of killing

the unwanted tissue.

As long as the lump is defined as an alien material, killing it by any means seems

reasonable, but if it is seen as the body's attempt to repair itself, then killing it is no more

reasonable than it would be to cut the spots out of someone with smallpox.

When a cell is dying, it emits growth stimulating signals (Huang, et al., 2011). That's a

normal part of tissue renewal. Some of its substance guides the differentiation of new

cells, as demonstrated long ago by Polezhaev (discussed in my previous article, "Stem

cells, cell culture, and culture: Issues in regeneration"). Anything that injures a tissue

enough to require cells to be replaced causes the activation of a regulatory protein,

hypoxia-inducible factor, HIF, which inhibits mitochondrial respiration, causing a shift

toward glycolytic metabolism, increasing substances needed for growth. HIF is essential

to the healing of any wound. Even glucose deprivation can cause the induction of HIF.

Prostaglandins, made from polyunsaturated fatty acids released by stimulation, can

cause HIF to increase, but HIF also causes prostaglandins to increase. Lactic acid

increases the expression of HIF, while HIF causes cells to shift metabolically to depend

on converting glucose to lactic acid, that is, to adopt the "cancer metabolism." HIF is

recognized as a fundamental problem in "cancer therapy," since HIF allows the cancer

to resist the treatment, but the treatment increases HIF.

Radiation, chemotherapy, and surgery all activate these processes of cell replacement,

and unless something has changed to improve the organism's recuperative ability, it

isn't clear why the cells which replace the missing part should be more able to

satisfactorily complete the recovery process than the original cells were. Even the

amount of radiation in a single dental x-ray is enough to activate the excitatory-inflammatory

processes, and a "therapeutic" x-ray to any part of the body excites similar, but much greater, processes throughout the body. But the ideology of "the cancer cell," and the Gompertz Growth Law, guide the practice of cancer treatment.

Many years ago, Harry Rubin was impressed by hearing from a pathologist that he had

been able to find diagnosable cancer somewhere in the body of every person over the

age of 50 that he had autopsied. If everyone has cancer by the age of 50, that means

that cancer is harmless for most people, and that small cancers might frequently

appear, and be spontaneously removed as part of the body's regular house-cleaning.

One of the reasons that spontaneous regression of tumors seems so rare is

undoubtedly that most tumors are quickly cut out by surgeons.

Preventing injury should be a basic consideration, but the medical slogan, "first do no

harm," just doesn't apply to the cancer treatment industry, and this results from the

doctrine of "the cancer cell," which is something to be destroyed or kept from

multiplying. In the process of diagnosing a cancer, and during the course of treating it,

the patient is usually subjected to multiple x-ray examinations, sometimes given

radioactive drugs that supposedly concentrate in hidden tumors to emit positrons, and

often has toxic contrast agents injected even for MRI examinations. These procedures,

even before the destructive "therapies" begin, are adding to the body's inflammatory

burden, interfering with the body's ability to complete a healing process. Decisions

about pain control usually disregard the effects of the drugs on tumor growth and

general vitality--for example, the opiates stimulate histamine release, which increases

inflammation and tumor growth.

In 1927, Bernstein and Elias found that rats eating a fat free diet had almost no

spontaneous cancer, and many studies since then in animals and people have shown a

close association between polyunsaturated fatty acids and cancer. The polyunsaturated

fatty acids in themselves, and their breakdown products, are excitatory and destabilizing

to normal cells, but by modifying the sensitivity and energy production of cells, they limit

cells' ability to respond to stimulation and destabilizing influences. Although they aren't

essential for wound healing (Porras-Reyes, et al., 1992), they and their metabolites, the

prostaglandins, are very conspicuous in wounds and tumors, and their proportion

generally increases with aging. The prostaglandins are involved in several vicious

cycles, including that with HIF mentioned above. This makes the PUFA and

prostaglandins important to consider in relation to optimizing wound healing, and

decreasing cancerization. Aspirin's protective and therapeutic effects in cancer are

starting to be recognized, but there are several other things that can synergize with

aspirin to reduce the circulation of free fatty acids and their conversion to

prostaglandins. Niacinamide, progesterone, sugar, carbon dioxide, and red light protect

against both free fatty acids and prostaglandins.

Since excitation leads to intracellular alkalinity and swelling, reducing the excitation

seems reasonable, and many things which protect cells against excitation also have

demonstrated anticancer effects. Local anesthetics, antihistamines, and antiinflammatory

substances and some anesthetics such as xenon (Weigt, et al., 2009) are safe. Inhibitory substances related to GABA are being investigated for their ability to stop tumor growth. Simply stopping excessive excitation tends to restore the dominance of oxidative respiration over glycolysis.

To restore the supply of oxygen, sugar, and nutrients, swelling must be stopped.

Hyperosmotic fluids act directly on swollen cells, removing water. Stopping excitation

allows a return to efficient metabolism and reduces the injury potential, allowing the pH

to decrease; with lower pH, the cell releases some of its water.

Increasing carbon dioxide lowers the intracellular pH, as well as inhibiting lactic acid

formation, and restoring the oxidation of glucose increases CO2. Inhibiting carbonic

anhydrase, to allow more CO2 to stay in the cell, contributes to intracellular acidification,

and by systemically increasing carbon dioxide this inhibition has a broad range of

protective anti-excitatory effects. The drug industry is now looking for chemicals that will

specifically inhibit the carbonic anhydrase enzymes that are active in tumors. Existing

carbonic anhydrase inhibitors, such as acetazolamide, will inhibit those enzymes,

without harming other tissues. Aspirin has some effect as an inhibitor of carbonic

anhydrase (Bayram, et al., 2008). Since histamine, serotonin (Vullo, et al., 2007), and

estrogen (Barnett, et al., 2008; Garg, 1975) are carbonic anhydrase activators, their

antagonists would help to acidify the hypoxic cells. Testosterone (Suzuki, et al., 1996)

and progesterone are estrogen antagonists that inhibit carbonic anhydrase.

With aging, cells have less ability to produce energy, and are often more easily

stimulated. The accumulation of polyunsaturated fats is one of the factors that reduce

the ability of mitochondria to produce energy (Zhang, et al., 2006, 2009; Yazbeck, et al.,

1989). Increased estrogen exposure, decreased thyroid hormone, an increased ratio of

iron to copper, and lack of light, are other factors that impair the cytochrome oxidase

enzyme.

The increased intracellular alkalinity and intracellular calcium that result from the

combination of those factors increase the tendency of cells to be overstimulated,

leading to aerobic glycolysis, the cancer metabolism. Improving any part of the system

tends to increase carbon dioxide and decrease lactate, permitting differentiated

functioning.

There are many people currently recommending fish oil (or other highly unsaturated

oils) for preventing or treating cancer, and it has become almost as common to

recommend a sugar free diet, "because sugar feeds cancer." This is often, incorrectly,

said to be the meaning of Warburg's demonstration that cancer cells have a respiratory

defect that causes them to produce lactic acid from glucose even in the presence of

oxygen. Cancer cells use glucose and the amino acid glutamine primarily for synthetic

purposes, and use fats as their energy source;the growth stimulating effect of the

"essential fatty acids" (Sueyoshi and Nagao, 1962a; Holley, et al., 1974) shows that

depriving a tumor of those fats retards its growth. The great energetic inefficiency of the

cancer metabolism, which causes it to produce a large amount of heat and to cause

systemic stress, failure of immunity, and weight loss, is because it synthesizes fat from

glucose and amino acids, and then oxidizes the fat as if it were diabetic.

Estrogen, which is responsible for the fact that women burn fatty acids more easily than

men, is centrally involved in this metabolic inefficiency. When a tissue is exposed to

estrogen, within minutes it takes up water, and begins to synthesize fat, with a tendency

to produce lactic acid at the same time. The alkalizing effect of lactic acid production is

apparently what accounts for the uptake of water. Since it takes longer, at least 30

minutes, to produce a significant amount of new enzymes, these early changes are

explained by the activation of existing enzymes by estrogen.

The transhydrogenases, or the transhydrogenase function of the steroid

dehydrogenases, which shift metabolic energy between glycolytic and oxidative

systems, have been shown to explain these effects of estrogen, but the

transhydrogenases can be activated by many stressors. The biological function of the

transhydrogenases seems to be to allow cells to continue growth and repair processes

in a hypoxic environment. Estrogen can start the process by creating new pathways for

electrons, and will promote processes that are started by something else, and

progesterone is estrogen's natural antagonist, terminating the process.

Recently, a group at Johns Hopkins University (Le, et al., 2012) has been working out

the implications of this ability to change the metabolism under hypoxia: Using an

isotope-labeled amino acid, ". . . glutamine import and metabolism through the TCA

cycle persisted under hypoxia, and glutamine contributed significantly to citrate

carbons. Under glucose deprivation, glutamine-derived fumarate, malate, and

citrate were significantly increased." The implication of this is that if the tumor isn't

supplied with sugar, it will increase the rate at which it consumes the host's proteins.

Forty years ago the work of Shapot and Blinov was showing the same effect, except

that they demonstrated the involvement of the whole organism, especially the liver, in

interaction with the tumor (Blinov and Shapot, 1975).

The alkaline cancer cell surrounds itself by the acid that it emits, and this extracellular

acidity increases the ability of fatty acids to enter the cell (Spector, 1969); cancer cells,

although they are synthesizing fat, also avidly take it up from their environment

(Sueyoshi and Nagao, 1962b). This fat avidity is so extreme that cancer cells in vitro will

eat enough polyunsaturated fat to kill themselves. This has been offered as proof that

fish oil kills cancer. Saturated fats, however, have a calming effect on cancer cells,

inhibiting their aerobic glycolysis (Marchut, et al., 1986) while permitting them to resume

the respiratory production of energy.

The foods that nourish the patient well enough to support healing while permitting

energy reserves to be built up are also the foods that don't interfere with the hormones,

that don't cause spurious excitation of the tissues. The polyunsaturated fats directly

stimulate the stress hormones, activate the excitatory amino acid signals, and directly

excite cells, while the saturated fats have opposite effects, and are anti-inflammatory,

and also don't interfere with mitochondrial function. When we eat more carbohydrate

than can be oxidized, some of it will be turned into saturated fats and omega-9 fats, and

these will support mitochondrial energy production. Carbohydrates in the diet also help

to decrease the mobilization of fatty acids from storage; niacinamide and aspirin support

that effect. Sugars are probably more favorable than starches for the immune system

(Harris, et al., 1999), and failure of the immune system is a common feature of cancer.

Polyunsaturated fats are generally known to suppress the immune system. Foods that

provide generous amounts of sodium, calcium, magnesium, and potassium, help to

minimize stress. Trace minerals and vitamins are important, but can be harmful if used

excessively--iron excess is important to avoid.

Emodin, an anti-inflammatory substance found in cascara sagrada bark and other

plants, is similar to other molecules that have been used for treating cancer, and one of

its effects is to lower HIF: "Consistently, emodin attenuated the expression of

cyclooxygenase 2 (COX-2), VEGF, hypoxia inducible factor 1 alpha (HIF-1!), MMP-1

and MMP-13 at mRNA level in IL-1" and LPS-treated synoviocytes under hypoxia" (Ha,

et al., 2011). MMP-1 and MMP-13 are collagenase enzymes involved in metastasis.

When cells are fully nourished, supplied with protective hormones, and properly

illuminated, their ability to communicate should be able to govern their movements,

preventing--and possibly reversing--metastatic migration.

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A R T I C L E

Mitonchondria and mortality:

Diet, exercise, and medicine, damaging or repairing respiratory metabolism

MAIN IDEAS AND CONTEXTS

Lactic acid and carbon dioxide have opposing effects.

Intense exercise damages cells in ways that cumulatively impair metabolism. There is clear evidence that glycolysis, producing lactic acid from glucose, has toxic effects, suppressing respiration and killing cells.   Within five minutes, exercise lowers the activity of enzymes that oxidize glucose. Diabetes, Alzheimer's disease, and general aging involve increased lactic acid production    and    accumulated    metabolic (mitochondrial) damage.

The products of glycolysis, lactic acid and pyruvic acid, suppress oxidation of glucose.

 Adaptation to hypoxia or increased carbon dioxide limits the formation of lactic acid. Muscles are 50% more efficient in the adapted state; glucose, which forms more carbon dioxide than fat does when oxidized,, is metabolized more efficiently than fats, requiring less oxygen.

Lactic acidosis, by suppressing oxidation of glucose, increases oxidation of fats, further suppressing glucose oxidation. 

Estrogen is harmful to mitochondria, progesterone is beneficial.

Progesterone's brain-protective and restorative effects involve mitochondrial actions.

Thyroid hormone, palmitic acid, and light activate a crucial respiratory enzyme, suppressing the formation of lactic acid. Palmitic acid occurs in coconut oit, and is formed naturally in animal tissues. Unsaturated oils have the opposite effect.

Heart failure, shock, and other problems involving excess lactic acid can be treated "successfully" by poisoning glycolysis with dichloroacetic acid, reducing the production of lactic acid, increasing the oxidation of glucose, and increasing cellular ATP concentration. Thyroid, vitamin B1, biotin, etc., do the same.

SOME DEFINITIONS

Glycolysis: The conversion of glucose to lactic acid, providing some usable energy, but many times less than oxidation provides.

Lactic acid, produced by splitting glucose to pyruvic acid followed by its reduction, is associated with calcium uptake and nitric oxide production, depletes energy, contributing to cell death. 

Crabtree effect: Inhibition of cellular respiration by an excess of glucose; excess of glucose promotes calcium uptake by cells.

Pasteur effect: Inhibition of glycolysis (fermentation) by oxygen.

Randle effect: The inhibition of the oxidation of glucose by an excess of fatty acids.  This lowers metabolic efficiency. Estrogen promotes this effect.

 Lactated Ringer's solution: A salt solution that has\ been used to increase blood volume in treating shock; the lactate was apparently chosen as a buffer in place of bicarbonate, as a matter of convenience rather than physiology. This solution is toxic, partly because it contains the form of lactate produced by bacteria, but our own lactate, at higher concentrations, produces the same sorts of toxic effect, damaging mitochondria,

Estrogenic phytotoxins damage mitochondria, kill brain cells; tofu is associated with dementia.

===============

Since reading Warburg's publications in the late 1960s and early 70s, and doing my own research on tissue respiration, I have been convinced that Warbug was on the right track in seeing mitochondrial respiration as the controlling influence in cell differentiation, and in seeing cancer as a reversion to a primitive form of life based on a "respiratory defect." Harry Rubin's studies of cells in culture have expanded Warburg's picture of the process of cancerization, showing that genetic changes occur only after the cells have been transformed into cancer.

It is now well recognized that defective mitochondrial respiration is a central factor in diseases of muscles, brain, liver, kidneys, and other organs. The common view has been that the mitochondrial defects are produced by genetic defects, that are either inherited or acquired, and are irreversible.

Mitochondria depend on some genes in the nuclear chromosomes, but they also contain some genes, and mutations in these specific mitochondrial genes have been associated with various diseases, and with aging. Although these aren't the genes that the cancer establishment has focussed on as "the cause" of cancer, for people interested in the achievements of Warburg and Rubin, it is important to know whether mutations in these mitochondrial genes are the cause of respiratory defects, or whether a respiratory defect causes the mutations. Recent research seems to show that physiological problems precede and cause the mutations.

Warburg believed that mitochondria supported specialized cell functions by concentrating themselves in the places where energy is needed. This idea has some interesting implications. For example, when the amount of thyroid hormone is increased, or when the organism adapts to a high altitude, the number of mitochondria increases. But in energy deficient states such as diabetes, they don't. How are these crucial organelles called into existence by the hormone that increases respiration and energy, and also by the hypoxic conditions of high altitudes?   In both of these conditions, the availability of oxygen is limiting the ability to produce energy. In both conditions, carbon dioxide concentration in tissue is higher, in one  case,   because  thyroid  stimulates  its production, in the other, because the Haldane effect limits its loss from the lungs.

Could carbon dioxide, a major product of mitochondria, help to call mitochondria into existence? My answer to this is "yes," and it will help to briefly explain how I see mitochondria. Although I have no hesitancy in accepting that organelles can be exchanged between species, and that it is conceivable that mitochondria might have been derived from symbiotic bacteria, I am reluctant to believe that something happens just because it could happen.   For example, Francis Crick proposed that life on earth originated when genes arrived here on space dust from some other world. That's a theoretical possibility, but what's the point?  It just avoids explaining how the highly organized material came into existence somewhere else, and it probably seriously interfered with the consideration of the ways life could arise here. Similarly, some people like to think that mitochondria and chloroplasts were originally bacteria, that came into symbiosis with another kind of living material, consisting of nucleus and cytoplasm. Like Crick's "space germs," it can be argued that it's possible, but the problem is that this explanation can stop people from thinking freshly about the nature of the various organelles, and how they came to exist. (How did cells originate?   How did mitochondria originate?   "Germs.")

Since I have a view of how cells came to exist, under conditions that exist on earth, I should consider whether that view doesn't also reasonably account for their various components. Sidney Fox's proteinoid microspheres provide a good model for the spontaneous formation of primitive cells; variations of that idea can account for the formation of organelles (such as mitochondria and nuclei within cells, and chromosomes within nuclei). The value of this idea, of a self-stimulating process in mitochondrial generation, is that it suggests many ways to test the idea experimentally, and it suggests explanations for developmental and pathological processes that otherwise would have no coherent explanation.

Proteinoid microspheres and coacervates form by acquiring molecules from solution, condensing them into a separate phase, with its own physical properties. At every phase boundary, there are numerous physical forces, especially electronic properties, that make each kind of interface different from other kinds.   Small changes of pH, temperature, of salts and other solutes can alter the interfacial forces, causing particles to dissolve, or grow, or fragment, or to move. In the way that carbon dioxide alters the shapes and electrical affinities of hemoglobin and other proteins, I propose that it increases the stability of the mitochondrial coacervate, causing it to "recruit" additional proteins from its external environment, as well as from its own synthetic machinery, to enlarge both its structure and its functions.

In the relative absence of carbon dioxide, or excess of alternative solutes and adsorbents, such as lactic acid, the stability of the mitochondrial phase would be decreased, and the mitochondria would be degraded in both structure and function. As the back side of the idea that carbon dioxide stabilizes and activates mitochondria, the idea that lactic acid is involved in the degrading of mitochondria can also be tested experimentally, and it is already supported by a considerable amount of circumstantial evidence.

This combination of sensitivity to the environment, with a kind of positive feedback or inertia either upward or downward, corresponds to what we actually see in mitochondrial physiology and pathology.

The Crabtree effect, which is the suppression of respiration by glycolysis, is often described as the simple opposite of the Pasteur effect, in which respiration limits glycolysis to the rate that allows its product to be consumed oxidatively. But the Pasteur effect is a normal sort of control system; when the Pasteur effect fails, as in cancer, there is glycolysis which is relatively independent of respiration, causing sugar to be consumed inefficiently. Embryonic tissues sometimes behave in this manner, leading to the suggestion that glycolysis is closely related to growth.   Unlike the logical Pasteur effect, the Crabtree effect tends to lower cellular energy and adaptability. Looking at many situations in which increasing the glucose supply increases lactic acid production and suppresses respiration, leading to maladaptive decrease in cellular energy, I have begun thinking of lactic acid as a toxin.   The use of Ringer's lactate solution in medicine has led many people to assume that lactate must be beneficial, or they wouldn't put it in the salt solution that is often used in emergiencies; however, I think its use here, as a buffer, is simply a convenience, because of the instability of some bicarbonate solutions.

On the organismic level, it is clear that lactic acid is "the essence of hyperventilation," and that it produces edema and malfunction on a grand scale: The panic reaction, shock lung, vascular leakiness, brain swelling, and finally multiple organ failure, all can be traced to an excess of lactic acid, and the related features of hyperventilated physiology.

Otto Warburg apparently thought of lactate as simply a sign of the respiratory defect that characterizes cancer. V. S. Shapot at least hinted at its possible role in turning on the catabolic reactions leading to cancer cachexia (wasting). I think a good case can be made for lactate as the cause of the respiratory defect in cancer, just as it is usually the immediate cause of the respiratory derangement of hyperventilation on the organismic level.

The Crabtree effect is usually thought of as just something that happens in tumors, and some tissues that are very active glycolytically, and some bacteria, when they are given large amounts of glucose. But when we consider lactate, which is produced by normal tissues when they are deprived of oxygen or are disturbed by a stress reaction, the Crabtree effect becomes a very general thing. The "respiratory defect" that we can see on the organismic level during hyperventilation, is very similar to the "systemic Crabtree effect" that happens during stress, in which respiration is shut down while glycolysis is activated. Since oxidative metabolism is many times more efficient for producing energy than glycolysis is, it is maladaptive to shut it down during stress.

Since the presence of lactate is so commonly considered to be a normal and adaptive response to stress, the shut-down of respiration in the presence of lactate is generally considered to be caused by something else, with lactate being seen as an effect rather than a cause. Nitric oxide and calcium excess have been identified as the main endogenous antirespiratory factors in stress, though free unsaturated fatty acids are clearly involved, too.   However, glycolysis, and the products of glycolysis, lactate and pyruvate, have been found to have a causal role in the suppression of respiration; it is both a cause and a consequence of the respiratory shutdown, though nitric oxide, calcium, and fatty acids are closely involved,

Since lactic acid is produced by the breakdown of glucose, a high level of lactate in the blood means that a large amount of sugar is being consumed; in response, the body mobilizes free fatty acids as an additional source of energy. An increase of free fatty acids suppresses the oxidation of glucose. (This is called the Randle effect, glucose-fatty acid cycle, substrate-competition cycle, etc.) Women, with higher estrogen and growth hormone, usually have more free fatty acids than men, and during exercise oxidize a higher proportion of fatty acids than men do. This fatty acid exposure "decreases glucose tolerance," and undoubtedly  explains  women's  higher incidence of diabetes.  While most fatty acids inhibit the oxidation of glucose without immediately inhibiting glycolysis, palmitic acid is unusual, in its inhibition of glycolysis and lactate production without inhibitng oxidation. I assume that this largely has to do with its important function in cardiolipin and cytochrome oxidase.

Exercise, like aging, obesity, and diabetes, increases the levels of circulating free fatty acids and lactate. But ordinary activity of an integral sort, activates the systems in an organized way, increasing carbon dioxide and circulation and efficiency. Different types of exercise have been identified as destructive or reparative to the mitochondria; "concentric" muscular work is said to be restorative to the mitochondria. As I understand it, this means contraction with a load, and relaxation without a load. The heart's contraction follows this principle, and this could explain the observation that heart mitochondria don't change in the course of ordinary aging.

When a person has an accident, or surgery, and goes into shock, the degree of lactic acidema is recognized as an indicator of the severity of the problem.   Lactated Ringer's solution has been commonly used to treat these people, to restore their blood pressure. But when prompt treatment with lactated Ringer's solution has been compared with no early treatment at all, the patients who are not "rescuscitated" do better than those who got the early treatment. And when Ringer's lactate has been compared with various other solutions, synthetic starch solutions, synthetic hemoglobin polymer solution, or simply a concentrated solution of sodium chloride, those who received the lactate solution did least well. For example, of 8 animals treated with another solution, 8 survived, while among 8 treated with Ringer's lactate, 6 died.

Mitochondrial metabolism is now being seen as the basic problem in aging and several degenerative diseases. The tendency has been to see random genetic deterioration as the driving force behind mitochondrial aging.  Genetic repair in mitochondria was assumed not to occur. However, recently two kinds of genetic repair have been demonstrated. One in which the DNA strand is repaired, and another, in which sound mitochondria are "recruited" to replace the defective, mutated, "old" mitochondria.

In ordinary nuclear chromosomal genes, DNA repair is well known. The other kind of repair, in which unmutated cells replace the. genetically damaged cells, has been commonly observed in the skin of the face: During intense sun exposure, mutant cells accumulate; but after a period in which the skin hasn't been exposed to the damaging radiation, the skin is made up of healthy "young" cells.

In the way that the skin can be seen to recover from genetic damage, that had been considered to be permanent and cumulative, simply by avoiding the damaging factor, mitochondrial aging is coming to be seen as both avoidable and repairable.

The stressful conditions that physiologically harm mitochondria are now being seen as the probable cause for the mitochondrial genetic defects that accumulate with aging.   Stressful exercise, which has been known to cause breakage of the nuclear chromosomes, is now seen to damage mitochondrial genes, too.   Providing energy, while reducing stress, seems to be all it takes to reverse the accumulated mitochondrial genetic damage.

Fewer mitochondrial problems will be considered to be inherited, as we develop an integral view of the ways in which mitochondrial physiology is disrupted. Palmitic acid, which is a major component of the cardiolipin which regulates the main respiratory enzyme, becomes displaced by polyunsaturated fats as aging progresses. Copper tends to be lost from this same enzyme system, and the state of the water is altered as the energetic processes change.

While the flow of carbon dioxide moves from the mitochondrion to the cytoplasm and beyond, tending to remove calcium from the mitochondrion and cell, the flow of lactate and other organic ions into the mitochondrion can produce calcium accumulation in the mitochondrion, during conditions in which carbon dioxide synthesis,  and consequently urea synthesis,  are depressed, and other synthetic processes are changed.

Glycolysis produces both pyruvate and lactate, and excessive pyruvate produces almost the same inhibitory effect as lactate; since the Crabtree effect involves nitric oxide and fatty acids as well as calcium, I think it is reasonable to look for the simplest sort of explanation, instead of trying to experimentally trace all the possible interactions of these substances; a simple physical competition between the products of glycolysis and carbon dioxide, for the binding sites, such as lysine, that would amount to a phase change in the mitochondrion.  Glucose, and apparently glycolysis, are required for the production of nitric oxide, as for the accumulation of calcium, at least in some types of cell, and these coordinated changes, which lower energy production,  could be produced by a reduction in carbon dioxide, in a physical change even more basic than the energy level represented by ATP. The use of Krebs cycle substances in the synthesis of amino acids, and other products, would decrease the formation of C02, creating a situation in which the system would have two possible states, one, the glycolytic stress state, and the other, the carbon dioxide producing energy-efficient state.

Besides the frequently discussed interactions of excessively accumulated iron with the unsaturated fatty acids, producing lipid peroxides and other toxins, the accumulated calcium very probably forms some insoluble soaps with the free fatty acids which are released even from intracellular fats during stress.     The growth of new mitochondria probably occasionally leaves behind such useless materials, combining soaps, iron, and porphyrins remaining from damaged respiratory enzymes.

When the background of carbon dioxide is high, circulation and oxygenation tend to prevent the anaerobic glycolysis that produces toxic lactic acid, so that a given level of activity will be harmful or helpful, depending on the level of carbon dioxide being produced at rest.

Preventively, avoiding foods containing lactic acid, such as yogurt and sauerkraut, would be helpful, since bacterial lactic acid is much more toxic than the type that we form under stress. Avoiding the stress-promoting antithyroid unsaturated oils is extremely important. Their role in diabetes, cancer, and other age-related and degenerative diseases (and I think this includes the estrogen-promoted autoimmune diseases) is well established. Avoiding phytoestrogens and other things that increase estrogen exposure, such as protein deficiency, is important, because estrogen causes increased levels of free fatty acids, increases the tendency to metabolize them at the expense of glucose metabolism, increases the tissue content of unsaturated fatty acids, and inhibits thyroid functions.

Light promotes glucose oxidation, and is known to activate the key respiratory enzyme. Winter sickness (including lethargy and weight gain), and night stress, have to be included within the idea of the "respiratory defect," shifting to the antirespiratory production of lactic acid, and damaging the mitochondria.

Therapeutically, even powerful toxins that block the glycolytic enzymes can improve functions in a variety of organic disturbances "associated with" (caused by) excessive production of lactic acid. Unfortunately, the toxin that has become standard treatment for lactic acidosis—dichloroacetic acid—is a carcinogen, and eventually produces liver damage and acidosis. But several nontoxic therapies can do the same things: Palmitate (formed from sugar under the influence of thyroid hormone, and found in coconut oil), vitamin Bl, biotin, lipoic acid, carbon dioxide, thyroid, naloxone, acetazolamide, for example. Progesterone, by blocking estrogen's disruptive effects on the mitochondria, ranks along with thyroid and a diet free of polyunsaturate fats, for importance in mitochondrial maintenance.

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Am J Physiol 1998 Jun;274(6 Pt 1):G978-83. Neural injury, repair and adaptation in the GI tract. I. New insights into neuronal injury: a cautionary tale. Hall KE, Wiley JW.

Proc Nati Acad Sci U S A 1999 Dec 21;96(26): 14706-14711. Structural details of an interaction between cardiolipin and an integral membrane protein. McAuley KE, Fyfe PK, Ridge JP, Isaacs NW, Cogdell RJ, Jones MR.

J. Appi Physiol 1991 Apr;70(4): 1720-30.. .Metabolic and work efficiencies during exercise in Andean natives. Hochachka PW, Stanley C, Matheson GO, McKenzie DC, Allen PS, Parkhouse WS.

JDev Physiol 1990 Sep;14(3): 139-46. Effect of lactate and beta-hydroxybutyrate infusions on brain metabolism in the fetal sheep. Harding JE, Charlton VE.

J Trauma 1999 Feb;46(2):286-91, The effects of diaspirin cross-linked hemoglobin on hemodynamics, metabolic acidosis, and survival in burned rats.: Soltero RG; Hansbrough JF.

J Trauma 1999 Apr;46(4):582-8; discussion 588-9, Resuscitation with lactated Ringer's solution in rats with hemorrhagic shock induces immediate apoptosis. Deb S; Martin B; Sun L; Ruff P; Burris D; Rich N; DeBreux S; Austin B; Rhee P.

Am J Physiol 1996 Oct;271(4 Pt 1):C1244-9, Glucose and pyruvate regulate cytokine-induced nitric oxide production by cardiac myocytes. Oddis CV; Finkel MS.

Biochim Biophys Acta 1999 Feb 9;1410(2):171-82. Mitochondrial involvement in Alzheimer's disease. Bonilla E, Tanji K, Hirano M, Vu TH, DiMauro S, Schon EA.

Adv Exp Med Biol 1995,384:185-94. Metabolic correlates of fatigue from different types of exercise in man. Vollestad NK.

J Biol Chem 1995 Jun 23;270(25): 14855-8. Nitric oxide activates the glucose-dependent mobilization of arachidonic acid in a macrophage-like cell line (RAW 264.7) that is largely mediated by calcium-independent phospholipase A2. GrossRW; Rudolph AE; Wang J; Sommers CD; Wolf MJ.

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Heart and hormones  

  The heart's unique behavior has given cardiologists a particularly mechanical perspective on biology. If a cardiologist and an oncologist have anything to talk about, it's likely to be about why cancer treatments cause heart failure; a cardiologist and an endocrinologist might share an interest in "cardioprotective estrogen" and "cardiotoxic obesity." Cell physiology and bioenergetics aren't likely to be their common interest. Each specialty has its close involvement with the pharmaceutical industry, shaping its thinking.

   The drug industry has been lowering the numbers for cholesterol, blood pressure, and blood glucose that are considered to be the upper limit of normal, increasing the number of customers for their prescription drugs. Recently, publications have been claiming that the upper limit of the normal range of heart rates should be lower than 100 beats per minute; this would encourage doctors to prescribe more drugs to slow hearts, but the way the evidence is being presented, invoking the discredited "wear and tear" theory of aging, could have many unexpected harmful consequences. It would reinforce existing misconceptions about heart functions.   

   A few decades ago, diuretics to lower blood pressure and digitalis/digoxin to increase the heart's strength of contraction were the main treatments for heart disease. In 1968, the annual number of deaths in the US from congestive heart failure (in which the heart beats more weakly, pumping less blood) was 10,000. By 1993 the number had increased to 42,000 per year. More recently, the annual number of deaths in which heart failure is the primary cause was more than 55,000. During these decades, many new drugs for treating heart disease were introduced, and the use of digoxin has decreased slightly. People with heart failure usually live with the condition for several years; at present about 5.7 million people in the US live with heart failure. The prevalence of, and mortality from, other cardiovascular diseases (such as hypertension and abnormalities of the coronary arteries) are higher, but congestive heart failure is especially important to understand, because it involves defective function of the heart muscle itself.

    Although Albert Szent-Gyorgyi is known mostly for his discovery of vitamin C and his contribution to understanding the tricarboxylic acid or Krebs cycle, his main interest was in understanding the nature of life itself, and he focused mainly on muscle contraction and cancer growth regulation. In one of his experiments, he compared the effects of estrogen and progesterone on rabbit hearts. A basic property of the heart muscle is that when it beats more frequently, it beats more strongly. This is called the staircase effect, from the way a tracing of its motion rises, beat by beat, as the rate of stimulation is increased. This is a logical way to behave, but sometimes it fails to occur: In shock, and in heart failure, the pulse rate increases, without increasing the volume of blood pumped in each contraction.

   Szent-Gyorgyi found that estrogen treatment decreased the staircase effect, while progesterone treatment increased the staircase. He described the staircase as a situation in which function (the rate of contraction) builds structure (the size of the contraction). Progesterone allowed "structure" to be built by the contraction, and estrogen prevented that.
(It's interesting to compare these effects of the hormones to the more general idea of anabolic and catabolic hormones, in which more permanent structures in cells are affected.)

   The rapid and extensive alternation of contraction and relaxation made possible by progesterone is also produced by testosterone (Tsang, et al., 2009). Things that increase the force of contraction are called inotropic, and the things that promote relaxation are called lusitropic; progesterone and testosterone are both positively inotropic and lusitropic, improving contraction and relaxation. Estrogen is a negative lusitropic hormone (Filice, et al., 2011), and also a negative inotropic hormone (Sitzler, et al., 1996), that is, it impairs both relaxation and contraction. 

   Another standard term describing heart function is chronotropy, referring to the frequency of contraction. Because of the staircase interaction of frequency and force, there has been some confusion in classifying drugs according to chronotropism. In a state of shock or estrogen dominance, an inotropic drug will slow the heart rate by increasing the amount of blood pumped. This relationship caused digitalis' effect to be thought of as primarily slowing the rate of contraction (Willins and Keys, 1941), though its main effect is positively inotropic. It was traditionally used to treat edema, by stimulating diuresis, which is largely the result of its inotropic action. Progesterone and testosterone's inotropic action can also slow the heart beat by strengthening it.

   I think it was a little before Szent-Gyorgyi's heart experiment that Hans Selye had discovered that a large dose of estrogen created a shock-like state. Shock and stress cause estrogen to increase, and decrease progesterone and testosterone.

   About 30 years after Szent-Gyorgyi's work, people began to realize that digoxin and other heart stimulating molecules can be found in animals and humans, as metabolites of progesterone and possibly DHEA (Somogyi, et al., 2004). 

   The regulatory proteins that are involved in estrogen's negative lusi- and inotropic actions (decreasing pumping action) have been known for over 20 years to be regulated by the thyroid hormone to produce positive lusi- and inotropic actions on the heart (increasing its pumping action), and thyroid's beneficial effects on heart and skeletal muscle have been known empirically for 100 years. However, drug centered cardiologists, reviewing the currently available drugs approved by the FDA, have typically concluded that "drugs targeted to achieve these objectives are not available" (Chatterjee, 2002).

    When a muscle or nerve is fatigued, it swells, retaining water. When the swelling is extreme, its ability to contract is limited. Excess water content resembles a partly excited state, in which increased amounts of sodium and calcium are free in the cytoplasm. Energy is needed to eliminate the sodium and calcium, or to bind calcium, allowing the cell to extrude excess water and return to the resting state. Thyroid hormone allows cells' mitochondria to efficiently produce energy, and it also regulates the synthesis of the proteins (phospholamban and calcisequestrin) that control the binding of calcium. When the cell is energized, by the mitochondria working with thyroid, oxygen, and sugar, these proteins rapidly change their form, binding calcium and removing it from the contractile system, allowing the cell to relax, to be fully prepared for the next contraction. If the calcium isn't fully and quickly bound, the cell retains extra water and sodium, and isn't able to fully relax.

   Heart failure is described as "diastolic failure" when the muscle isn't able to fully relax. In an early stage, this is just a waterlogged (Iseri, et al., 1952), fatigued condition, but when continued, the metabolic changes lead to fibrosis and even to calcification of the heart muscle.

   Many children approaching puberty, as estrogen is increasing and interfering with thyroid function, have "growing pains," in which muscles become tense and sore after prolonged activity. When hypothyroidism is severe, it can cause myopathy, in which the painful swollen condition involves the leakage of muscle proteins (especially myoglobin) into the blood stream, allowing it to be diagnosed by a blood test. The combination of hypothyroidism with fatigue and stress can lead to the breakdown and death of muscle cells, rhabdomyolysis. 

   The blood lipid lowering drugs, statins and fibrates, impair mitochondrial respiration (Satoh, et al., 1995, 1994; Brunmair, et al., 2004), and increase the incidence of rhabdomyolysis (Barker, et al., 2003; Wu, et al., 2009; Fallah, et al., 2013). Interference with coenzyme Q10 is not the only mechanism by which they can cause myopathy (Nakahara, et al., 1998). The harmful effect of lowering cholesterol seems to be relevant to heart failure: "In light of the association between high cholesterol levels and improved survival in HF, statin or other lipid-lowering therapy in HF remains controversial (Horwich, 2009).

   Heart muscle and skeletal muscle are similar in their structural responses to interference with mitochondrial functions, namely, swelling, reduced contractile ability, and dissolution. When myoglobin has been found in the blood and urine, it has been assumed to come from skeletal muscles, but the heart's myoglobin has been found to be depleted in a patient with myoglobinuria (Lewin and Moscarello, 1966). When heart failure is known to exist, similar changes can be found in the skeletal muscles (van der Ent, et al., 1998).

   Stress, in the form of pressure-overload (Zhabyeyev, et al., 2013), or overactivity of the renin-angiotensin system (Mori, et al., 2013) and sympathetic nervous system or adrenergic chemicals (Mori, et al., 2012), or a failure of energy caused by diabetes, insulin deficiency, or hypothyroidism, causes a shift of energy production from the oxidation of glucose to the oxidation of fatty acids, with the release, rather than oxidation, of the lactic acid produced from glucose. This sequence, from reduced efficiency of energy production to heart failure, can be opposed by agents that reduce the availability of fatty acids and promote the oxidation of glucose. Niacinamide inhibits the release of free fatty acids from the tissues, and thyroid sustains the oxidation of glucose. This principle is now widely recognized, and the FDA has approved a drug that inhibits the oxidation of fatty acids (raloxazine, 2006), but which has serious side effects. Glucose oxidation apparently is necessary for preventing the intracellular accumulation of free calcium and fatty acids (Jeremy, et al., 1992; Burton, et al., 1986; Ivanics, et al., 2001). The calcium binding protein which is activated by thyroid and inhibited by estrogen seems to be activated by glucose and inhibited by fatty acids (Zarain-Herzberg and Rupp, 1999). 

   Diabetes or fasting increases free fatty acids, and forces cells to shift from oxidation of glucose to oxidation of fatty acids, inhibiting the binding of calcium (McKnight, et al., 1999). Providing a small amount of sugar (0.8% sucrose in their drinking water) restored the calcium binding and heart function, without increasing either thyroid hormone or insulin (Rupp, et al., 1988, 1999, 1994). Serum glucose was lowered, as the ability to oxidize sugar was restored by lowering free fatty acids. Activity of the sympathetic nervous system is lowered as efficiency is increased. 

   Digoxin stimulates mitochondrial energy production in skeletal and heart muscle (Tsyganil, et al., 1982), increasing the oxidation of glucose, rather than fatty acids, supporting the effect of thyroid hormone. The statins have the opposite effect, decreasing the oxidation of glucose. 

   One of estrogen's effects is to chronically increase the circulation of free fatty acids, and to favor the long chain polyunsaturated fatty acids, such as EPA and DHA. These fatty acids, which slow the heart rate (Kang and Leaf, 1994), extend the excited state (action potential: Li, et al., 2011), and are negatively inotropic (Dhein, et al., 2005; Macleod, et al., 1998; Negretti, et al., 2000), are being proposed as heart protective drugs. (EPA and alpha-linoleic acid also prolong the QT interval: Dhein, et al., 2005). 

   Many publications still promote estrogen as a cardioprotective drug, but there is now increased recognition of its role in heart failure and sudden cardiac death. A prolonged excited state (action potential) and delayed relaxation (QT interval) are known to increase the risk of arrhythmia and sudden death, and estrogen, which causes those changes in humans, causes sudden cardiac death in susceptible rabbits, with an adrenergic stimulant increasing the arrhythmias, and progesterone and androgen preventing them (Odening et al., 2012). Progesterone's protective effect seems to be the result of accelerating recovery of the resting state (Cheng, et al., 2012). 

   Estrogen's interactions with adrenalin in promoting blood vessel constriction has been known for many years (for example, Cheng and Gruetter, 1992). Progesterone blocks that effect of estrogen (Moura and Marcondes, 2001). Environmental estrogens such as BPA can exacerbate ventricular arrhythmia caused by estrogen (Yan, et al., 2013). The hearts of mice genetically engineered to lack aromatase, the enzyme that synthesizes estrogen, were more resistant to damage by being deprived of blood for 25 minutes (Bell, et al., 2011), leading the authors to suggest that aromatase inhibition might be helpful for heart disease. 

   In the stressed, energy depleted failing heart, muscle cells die and are replaced by connective tissue cells. The growth produced by over-exposure to adrenergic stimulation leads to stiffening and reduced functioning. However, under the influence of thyroid hormone a high work load leads to functional enlargement, which simply increases the pumping ability. Because of the traditional belief that heart cells can't replicate, this functional growth was believed to be produced purely by the enlargement of cells, but in recent years the existence of stem cells able to create new heart muscle has been recognized. Thyroid is likely to be one of the hormones responsible for allowing stem cells to differentiate into cardiomyocytes.

   In this context, of cellular differentiation as a life-long process, we can see the changes of a failing heart as a differentiation which is forced to take an inappropriate course. The calcification of blood vessels caused by phosphate excess and vitamin K deficiency involves the expression of a protein which has its proper place in the skeleton. The replacement of heart muscle by fibrous connective tissue and even bone is a basic biological problem of differentiation, and the responsible factors--stress, increased estrogen, deficient thyroid hormone, suppression of glucose oxidation by fatty acids, etc.--are involved in the problems of differentiation that occur in other degenerative processes, such as sarcopenia, dementia, and cancer.

   There have been arguments about the nature of wound healing and regeneration, regarding the origin of the new cells--whether they are from the dedifferentiation of local cells, or the migration of stem cells. The evidence is that both can occur, depending on the tissue and the situation. The deterioration of an organ is probably not a question of a lack of stem cells, but of changed conditions causing them to differentiate into something inappropriate for the full functioning of that organ. 

   Various stresses can cause cells to dedifferentiate, but hypoxia is probably a common denominator. In the absence of estrogen, hypoxia can activate the "estrogen receptor."  Estrogen is in some situations a hormone of dedifferentiation, facilitating the formation of new cells in stressed tissues, as aromatase is induced. However, the presence of polyunsaturated fats, tending to increase in concentration with age, causes the processes of renewal to produce exaggerated inflammation, with prostaglandins participating in the processes of development and differentiation. Estrogen, by increasing the concentration of free fatty acids, especially polyunsaturated fatty acids, contributes to the metabolic shift away from glucose oxidation, toward the formation of lactic acid, and away from the full organ-specific differentiation.

   This perspective puts heart failure, cancer, and the other degenerative diseases onto the same biological basis, and shows why certain conditions and therapies can be appropriate for all of them.

   Problems that seem relatively trivial become more meaningful when they are seen in terms of these mechanisms. Some problems that become very common by middle age are "palpitations," orthostatic hypotension, orthostatic tachycardia, and varicose veins. The negative inotropic effect of estrogen in the heart has a parallel in the smooth muscle of veins, in which the muscles are weakened, and their distensibility increased, when estrogen isn't sufficiently opposed by progesterone. This allows the veins in the lower part of the body to be distended abnormally when standing, reducing the amount of blood returning to the heart, so that the volume pumped with each stroke is small, requiring faster beating. The reduced blood volume reaching the brain can cause fainting. When it becomes chronic, it can lead to the progressive distortion of the veins. An excess of estrogen is associated with varicose veins in men, as well as women. (Raj, 2006; Ciardullo, et al., 2000; Kendler, et al., 2009; Asciutto, et al., 2010; Raffetto, et al., 2010).

   The simplicity of things such as supplementing thyroid, progesterone, and sugar, avoiding an excess of phosphate in relation to calcium, and avoiding polyunsaturated fats, makes it possible for people to take action themselves, without having to depend on the medical system. Most physicians still warn their patients of the dangers of thyroid supplements, especially the active T3 hormone, for their heart, but in at least one specialty, its value is recognized. Heart transplant surgeons have discovered that administering T3 to the brain-dead heart donor before removing the heart improves its viability and function in the recipient (Novitzky, 1996). Around this time, the manufacturers of Cytomel conceived the idea of marketing it as a "heart drug," which would make it much more profitable.

   Another technique that is easy to use to lower blood pressure and improve heart rhythm is to breathe into a paper bag for a minute or two at a time, to increase the carbon dioxide content of the blood. This has a vasodilating effect, reducing the force required to circulate the blood, and reduces anxiety. Rhubarb and emodin (a chemical found in rhubarb and cascara) have been found to have heart protective actions. A considerable amount of research showed that vitamin K is effective for treating hypertension, but again, most doctors warn against its use, because of its reputation as a clot forming vitamin. Recently, the value of the "blood thinner" warfarin, a vitamin K antagonist, has been questioned for people with heart failure (An, et al., 2013; Lee, et al., 2013). There have been several recent warnings about the production of arrhythmia by drugs that increase serotonin's effects (e.g., Stillman, et al., 2013).

    Measuring the speed of relaxation of the Achilles tendon reflex twitch is a traditional method for judging thyroid function, because in hypothyroidism the relaxation is visibly delayed. This same retardation can be seen in the electrocardiogram, as a prolonged QT interval, which is associated with arrhythmia and sudden death. Insomnia, mania, and asthma are other conditions in which defective relaxation is seen, under the influence of low thyroid function, and an insufficiently opposed influence of estrogen.

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The Cancer Matrix  

   It isn't hard to understand that in heart failure the heart is undergoing changes in a unitary way, with all parts of the organ affected, and that parallel changes are happening in the rest of the body, interacting with and contributing to the changes in the heart, so that heart failure is now considered to be a systemic disease. (Most doctors see the systemic nature of heart disease, at least to the extent of warning their patients to lower cholesterol and avoid thyroid hormone.) But if someone tells a cancer patient or an oncologist that cancer is a systemic disease, the thought will be flatly rejected as untrue. They have been taught that cancer is a disease of bad, mutated, cells, which have to be completely eradicated, and that the patient's general health is a separate issue.

   The US government (NIH, CDC) provides a cancer curriculum to schools. For high school, grades 9-12, they explain that a series of gene mutations causes it. In grade school, the basic idea of the cancer curriculum is just to teach them to fear cancer and the sunlight which, according to the curriculum, seems to be a very important mutagen.

   The gene mutation theory of cancer is sustained by a broader mystique of "genetics" in our culture. Over 100 years ago, an ideology of chance and random changes in organisms was superimposed onto the theory of evolution. After 1944, when Avery, MacLeod and McCarty showed that strands of DNA carry hereditary information, the doctrine of random change took on a specific chemical meaning--changes in the sequence of bases in the DNA molecule. This made it easier to disregard the evidence of the inheritance of acquired changes, since chemical, even biochemical, reactions are usually interpreted statistically, with an assumption of randomness. If the changes in the DNA code are random, and not influenced by the organism's physiology and biochemistry, then the four nucleotides that make up DNA (abbreviated G, C, A, and T) should show a random composition, but in fact the ratio of GC pairs to AT pairs varies in different types of organism, and in mitochondrial DNA, the GC (guanine-cytosine) content corresponds closely to the rate of oxidative metabolism and longevity (Lehmann, et al., 2008). 

   The official (government and American Cancer Society) view of cancer is that a tumor consists of the descendants of a single mutated cell. A current "proof" of this is that in a given tumor, all of the X chromosomes which are active have the same genetic composition, while in the rest of the organism, the X chromosome which remains active is a matter of chance. That shows, they argue, that the tumor must have developed from a cell in which that chromosome was active, not from a group of cells. However, non-random inactivation of X chromosomes is now known to occur, and that it involves epigenetic imprinting processes, such as methylation (Falconer, et al., 1982; Heard, 2004). Mary Lyon, the person who discovered that females inactivate one of their X chromosomes, has recognized the complexity of the process (Lyon, 2004). In arguing against the idea that the development of cancer is an epigenetic process, the cancer-gene people have invoked a process that responds to epigenetic influences.

   The assumption of randomness, and the assertions of the cancer doctors who subscribe to the doctrine, have had terrible effects on biology and medicine. Following the doctrine, their treatments must concentrate on eliminating every single cell of the cancer clone. Since surgery can't eliminate defective cells that have entered the blood stream, radiation and chemical toxins are logical necessities. Since mutations are random events, the person's general health is of little importance to the oncologist. Typically, they will tell the patient that their diet doesn't matter, except that they should avoid antioxidants if they are going to have radiation therapy. 

    For centuries, the definition of a malignant tumor has been that it's one which will return after it has been cut out. In recent years, the definition has been extended to those that return after the original tumor has been eliminated by radiation or chemotherapy. The idea of a "cancer stem cell," an especially tough type of cell from the mutated clone, has been invoked to explain the reason for the regrowth of a tumor in an area that was treated with intense radiation. However, it's now clear that normal cells are attracted to an irradiated area (Klopp, et al., 2007; Kidd, et al., 2009). The recognition of a "bystander effect," in which radiation (or other--Mothersill and Seymour, 2009) injury to one cell injures near-by cells by signals from the injured cell, has led to the recognition that ordinary stem cells or repair cells entering an area where a tumor has been destroyed will be modified by the residual damage of cells in the area. The ability to recruit normal cells into a damaged area, the "cancer field," the way normal organs do, shows that tumors can be thought of as organ-like structures, and that knowledge of the organizing principles of normal organs might improve our knowledge of tumors. The idea that cancer is primarily a problem of organization isn't new: Johannes Muller, in the 19th century, and J.W. Orr, and D.W. Smithers, in the 1940s and 1950s, and many others, have suggested that something outside of the individual cell could cause the disorganization.  

    Once it is accepted that cancer is a systemic disease, and that a tumor, or the place in the body where a tumor has been removed, is something more than a collection of defective cells, very different therapeutic approaches can be considered. Looking at the events in a failing heart, we can see that the potential repair cells recruited by the stressed heart are diverted by the conditions that they encounter there, and either die or become connective tissue cells, secreting collagen, rather than becoming new muscle cells. 

    Something that everyone knows about tumors is that they are harder than the normal tissues in which they appear--they can be identified as lumps. Like the failing heart, they become harder than normal, and like the failing heart, the hardening can proceed to calcification. There has been general recognition that inflammation has a role in both heart disease and cancer, but the fact that chronic inflammation leads to fibrosis, and that fibrosis often leads to calcification, is still usually considered not to be relevant to understanding and treating cancer. The tissue hardness that allows oncologists to diagnose cancer (Huang and Ingber, 2005) is ignored when choosing treatments, which isn't surprising, since treatments that destroy cancer cells increase the production of collagen.

   Aspirin is commonly recommended for preventing heart attacks, because it helps to prevent abnormal blood clots, but it has other effects that are beneficial in heart disease, for example reducing the generalized fibrosis of the heart that develops after a heart attack (Kalkman, et al., 1995; Wu, et al., 2012). It also protects against fibrosis in other organs, by a variety of mechanisms, and this effect on the extracellular matrix seems to be one of ways in which it protects against cancer. DCA, dichloroacetate, the drug that has been in the news in recent years because it can stop cancer growth, by restoring the oxidation of glucose and stopping the aerobic production of lactic acid, has been found to reduce the fibrosis of a failing heart, by the same mechanism, restoring glucose oxidation. In general, substances that increase collagen production are promoters of cancer and contribute to the progression of heart failure, and other degenerative changes.

   The incidence of cancer increases exponentially with age, but when random mutations are seen as the cause of cancer, aging as an essential cause of cancer is disregarded. The total collagen content of the body increases with aging, and the stiffness of that collagen also increases. The total collagen content in cancer patients is higher than in people without cancer (Zimin, et al., 2010). This suggests that the processes in the body that produce aging are acting more intensely in those who develop cancer. As the collagen accumulates in the extracellular matrix, the whole body becomes more favorable for the appearance of cancer. 

   Plastic surgeons have promoted the idea of injecting collagen into tissues with the argument that they are "replacing collagen lost with aging," but in fact collagen accumulates with aging. It is the greater compactness and stiffness of collagen in old skin that produces noticeable changes such as wrinkling. The difference between calf skin leather, used for soft gloves and purses, and cow hide, used for shoe soles and boots, illustrates the changes that occur with aging. Supermarkets used to categorize chickens as fryers and stewers, or stewing hens. The difference was the age and toughness, very young chickens could be cooked quickly, old laying hens had accumulated more collagen, and especially the cross-linked hardened collagen, and required long cooking to reduce the toughness. Old beef animals are usually sold as cheaper stew meat or hamburger, because the age-hardened collagen can make a steak too rubbery to chew if it's quickly cooked. 

   In a healthy young organism, tissue injuries are repaired by processes reminiscent of Metchnikov's experiment in which he put a thorn into a jelly fish, and found that wandering cells, phagocytes, converged on the foreign object, surrounding it. If they couldn't eat it, they caused it to be expelled. The importance of that experiment was that it showed that injured tissues emit signals that attract certain types of cell. The process of removing damaged tissues by phagocytosis guides the formation of new tissue, starting with the secretion of collagen, which guides the maturation of the new cells. 

   Around the middle of the last century, Hans Selye experimented with the antiseptic implantation of a short piece of a narrow glass tube under the skin of rats. The irritation from the glass object caused a collagenous capsule to be formed around it, in the well known "foreign body reaction." He found that a filament of tissue formed in the center of the tube, connecting the two ends of the capsule. The isolated tissue of the filament quickly underwent the degenerative changes seen in aged connective tissues, but if he periodically removed the fluid around it, and allowed fresh lymph fluid to fill the capsule, the filament retained a youthful elasticity, even as the rat aged. Isolation from the organism caused age-like degeneration to develop rapidly. When the organism can't remove a foreign object, the collagenous capsule that encloses it has a high probability of forming a cancer. This "foreign body carcinogenesis" has been studied for many years.    

   Foreign body carcinogenesis is closely related to chemical carcinogenesis, radiation carcinogenesis, and hormonal carcinogenesis. Chemical carcinogens such as methylcholanthrene are irritating when injected, and stimulate collagen production. Neither type of carcinogenesis is always effective, because this collagen reaction can be protective, by isolating the irritant toxin (Zhang, et al., 2013). Radiation stimulates the secretion of collagen, and causes cross-linking that makes it stiffer, and slows its removal, leading to its accumulation (Sassi, et al., 2001). Some types of cross-linking block the ability of macrophages to remove it, creating something like a diffuse foreign body reaction. Estrogen, for example in the process of causing breast cancer, causes increased collagen synthesis. This is widely recognized, in the association of "breast density" (a high collagen content) with the risk of cancer. Estrogen also causes the formation of the enzymes that cross-link and stiffen the collagen, lysyl oxidase and transglutaminase(Sanada, et al., 1978; Campisi, et al., 2008; Balestrieri, et al., 2012).

   Although ultraviolet and ionizing radiation can act directly on collagen, to stiffen it, the greatest effect of the radiation is probably by reaction with relatively unstable components of tissues, such as polyunsaturated fatty acids, which then react with the collagen, cross-linking it (Igarashi, et al., 1989). Even in the absence of radiation, a deficiency of vitamin E accelerates the spontaneous decomposition of the unsaturated fats, accelerating the aging of collagen (Sundholm and Visapää, 1978 ). Many observations suggest that all of the collagen-aging carcinogenic factors interact synergistically.

   When cells are placed on a glass slide coated with collagen, they move to parts of the collagen that have been cross-linked, and they move from slightly cross-linked collagen to stiffer, more thoroughly cross-linked areas (Vincent, et al., 2013). When they are on stiffer collagen, they pull themselves more tightly toward it, continuously expending energy in the process. The muscle-like contraction of the cell causes it to become more rigid (Huang and Ingber, 2005). The increased hardness of even small tumors makes it possible to identify lymph node metastases from a breast cancer by touch, without removing them (Miyaji, et al., 1997).

   The increased energy cost of this "isotonic contraction" of the cell filaments requires more energy to sustain, and will tend to create lactic acid, the way intense muscle contraction does, while consuming oxygen at a higher rate. The increased lactic acid and decreased oxygen availability stimulate the synthesis of more collagen, the growth of new blood vessels, expression of enzymes for increasing the stiffness of the collagen, and other processes associated with inflammation, aging, and cancer. Blocking even one of these processes, the lysyl oxidase cross-linking enzyme, can reduce the invasiveness of a cancer (Lee, et al., 2011). Some observations (Tan, et al., 2010) show that the circulating cells of metastatic cancer are more rigid than other cells, which would increase the likelihood that they will block capillaries, creating oxygen-deprived nests of collagen-secreting cells.

  One of the substances produced by stressed cells that's involved in tumor induction, growth, and metastasis (Tanaka, et al., 2003; Datta, et al., 2010; Was, et al., 2010) is the enzyme heme oxygenase, which breaks down the essential component of respiratory enzymes, heme, producing carbon monoxide as a product, which inhibits cell respiration, increasing reliance on the glycolysis which produces lactic acid. If metastatic cells continue to produce this enzyme, this is likely to contribute to reconstituting the "cancer field," with increased HIF, hypoxia inducible factor, and a variety of other regulatory agents, each of which has its protective functions elsewhere, but which in combination can worsen the tumor.

   Substances that inhibit inflammation are likely to also inhibit excessive collagen synthesis, serotonin secretion, and the formation of estrogen. Besides aspirin, some effective substances are apigenin and naringenin, found in oranges and guavas. These flavonoids also inhibit the formation of nitric oxide and prostaglandins, which are important for inflammation and carcinogenesis (Liang, et al., 1999). Increased CO2, which has a variety of anti-inflammatory effects, can decrease collagen formation and tissue collagen content significantly (Ryu, et al., 2010).

   Deprivation of glucose and oxygen, which can be the local result of a cellular environment of condensed, stiffened collagen and the cellular tension and activation produced in response, combined with systemic stress that causes free fatty acids to interfere with the oxidation of sugar, activates enzymes that can dissolve collagen (MMP-2 and MMP-9). These enzymes are involved in metastasis, allowing cells to escape from the condensed collagen, but although they are normally thought of as enzymes that act outside of cells, they can also enter the cell's nucleus, where they degrade the DNA, causing the mutations and chromosomal abnormalities that are so characteristic of cancer (Hill, et al., 2012). Like glucose deprivation, exposure to 2-deoxyglucose, often used in tumor imaging, promotes metastasis (Schlappack, et al., 1991).

   The fact that cancer cells are stressed and damaged, and accumulate DNA damage, means that in a typical tumor there is a high rate of cell death. The number of apoptotic (disintegrating) cells in a tumor corresponds to the aggressiveness of the tumor (Vakkala, et al, 1999). In the 1940s and 1950s, Polezhaev demonstrated that dying cells stimulate cell renewal, and this is true in young and healthy organs, as well as in tumors. 

   In 36% of women who had had a breast removed, from 7 to 22 years previously, identifiable (by the same tests used to diagnose breast cancer) cancer cells could be found circulating in their blood stream (Meng, et al., 2004). Tissue biopsies would be able to find the sources of those circulating cells, nests of similar cells throughout the body, which were dying about as fast as they were replicating. In 1969, Harry Rubin described an autopsy study which found that everyone over the age of 50 had at least one diagnosable cancer in some tissue. "Occult microscopic cancers are exceedingly common in the general population and are held in a dormant state by a balance between cell proliferation and cell death and also an intact host immune surveillance"(Goldstein and Mascitelli, 2011). These authors observed that the stress of surgery stimulates tumor growth, by various mechanisms, and that surgery increases the risk of developing cancer in apparently cancer-free patients.

   In 1956, Hardin Jones wrote "If one has cancer and opts to do nothing at all, he will live longer and feel better than if he undergoes radiation, chemotherapy or surgery, other than when used in immediate life-threatening situations." In the 1990s, a group of cancer specialists were asked what they would do if they were diagnosed with prostate cancer, and most of them said they would do nothing. 

   The radical mastectomy, which removed massive amounts of apparently normal tissue as well as the breast tumor, was practiced for hundreds of years, and was the standard treatment for breast cancer until the 1980s, after G.W. Crile, Jr., had publicized the evidence showing that simply removing the tumor lump itself didn't cause a higher mortality rate, and that the surgery produced much less disability. 

   Although the lumpectomy was eventually accepted by the profession, the evidence that the long term survival rate was higher when the surgery was done during the luteal phase in premenopausal women has been generally ignored, because the cancer ideology maintains that the fate of the cancer is in the cells, rather than in the patient's hormone balance. 

   Because of the continual indoctrination about the importance of "early diagnosis to increase the chance of a cure," and the widely publicized "cure rates," it's easy for doctors to rush people into treatment, before they have time to study the issue. Dean Burk, who was a collaborator of Otto Warburg's for many years, was quoted in regard to the claims of the American Cancer Society that "They lie like scoundrels."

    In the 1970s, I noticed that the definitions of the features of uterine cancer had been changed recently, including as "cancer" things that had previously been classified as merely abnormal or precancerous.  Reading more about the grading of cancer, I saw that other cancers had been defined more inclusively since the 1940s. Things that had previously not been called cancer were now being counted among the cancers that were cured by the various treatments, so, necessarily, the rate of cure had increased. The true situation could be seen by the age-specific mortality rate for each type of cancer. During the period when the "cure rates" were increasing, the age-specific death rates had increased. I think that's the sort of thing that Dean Burk had in mind. 

    Nearly all of the studies of "cure rates" are comparisons of one ideologically-based and lucrative treatment against another ideologically-based and more or less lucrative treatment. When the cure rate, for example for breast cancer surgery, varies with the amount of progesterone in the body, there is very little interest in investigating the processes involved, because lucrative products aren't involved.

   When abnormal "metastatic" cells circulate in the blood or lymph, most of them die spontaneously when they stick in a place that doesn't support their growth. Many of the nests of cells that have started to grow probably regress spontaneously when conditions in the body change. Even large, clearly diagnosed tumors occasionally regress spontaneously. Aging and sickness tend to support the vicious cycles that lead to the progressive deterioration of the collagenous matrix. Stress (even anxiety-induced hyperventilation) produces alkalosis, and alkalosis favors increased collagen synthesis, while lower pH inhibits it (Frick, et al., 1997). For example, within a minute or two of hyperventilating, platelets release serotonin, and serotonin is a major promoter of collagen synthesis and fibrosis. 

   The vicious cycles that promote cancer can be interrupted to some extent simply by reducing exposure to things that promote stress and inflammation--endotoxin, polyunsaturated fats, amino acid imbalance, nutritional deficiencies, ionizing radiation, estrogens--and maintaining optimal levels of things that protect against those--carbon dioxide, vitamin E, progesterone, light, aspirin, sugars, and thyroid hormone, for example.

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A R T I C L E

Serotonin: Effects in disease, aging and inflammation

Interpreting medical publications requires some skills that aren't needed for understanding more strictly scientific reports, because medical writing often takes into account the fact that physicians spend most of their time interacting with the public, rather than studying. The public's understanding of medicine is shaped by "public relations," by the introduction of words and concepts that frame the argument. (The linguist George Lakoff summarized the essence of public relations by observing that people reject facts that are outside their view of reality, their mental framework.) Television and public schools now frame the worldview of the affluent cultures, according to the needs of the ruling powers. Long before specific prescription drugs could be advertised directly to consumers, the medical and pharmaceutical industries were creating a favorable frame for their products.

Many years ago, public relations experts used expensive opinion polls to judge the effectiveness of their efforts, but now there is a convenient way to see how the general public is thinking: Wikipedia, the internet encyclopedia. The success of corporate advertising can be seen in their recent article on serotonin, which says "It is a well-known contributor to feelings of well-being; therefore it is also known as a 'happiness hormone' despite not being a hormone."

The culture that has happy and unhappy hormones was a culture in which each hormone had a receptor, a substance in a cell which, when its ligand was bound to it, made the cell do something. Although that culture still has influence in the 21st century, discoveries made between 1940 and 1970 showed that those mechanical ideas of receptors didn't reflect biological reality. Albert Szent-Gyorgi and the Pullmans showed that the electronic qualities of molecules determined their functions, and Szent-Gyorgyi showed that the state of the cell, tissue, and organism governed the effect of hormones and drugs. In the 1960s, substances with very different biological effects, such as acetylcholine and adrenaline, were shown to be selectively bound to the same cellular site in some cells. It was primarily the drug industry that created and sustained the specific receptor doctrine. That doctrine suited the recognition of their public relations- marketing experts, that successful advertising had to be directed at the sixth-grade educational level. The ideas of bioelectronics and context-sensitive molecules, like morphogenetic fields, were just too complicated to sell well.

Although metaphorical thinking can be creative and productive, metaphors mustn't be taken literally. The identification of multiple types of receptor for a given natural substance involves the use of different substances as metaphors or similes for the natural substance. That type of pharmacology is slowly being replaced by an attempt to understand state-dependent sensitivities. The energetic state of a cell, and of the whole organism, determines the meaning of events and conditions, such as the presence of the "regulatory substances."

The receptor culture can be tentatively disregarded when thinking about the history of serotonin. In the 1930s Vittorio Erspamer identified an amine in the intestine, that caused the intestine to contract. Then a group in England extracted an amine from serum that caused blood vessels to contract, and identified its chemical nature. Later, Erspamer showed that the intestinal amine and the vascular amine were chemically the same. The English group who had identified the substance by extracting tons of beef blood, wanted to find sensitive ways to assay it for further studies, and in 1951 they gave a sample to a pharmacologist, John Gaddum, who tested its effects on tissues including blood vessels and rat uteruses.

Gaddum tested the serotonin in combination with a variety of other drugs, including ergot derivatives, that he knew acted on smooth muscles, and very soon observed that LSD blocked the effects of serotonin. Since he knew that LSD produced mental effects (Sandoz had distributed samples of it to researchers in 1947), he reasoned that the brain might also contain serotonin, and by 1952 was able to demonstrate that it does contain small amounts of it. A couple of years later he suggested "that the mental effects of lysergic acid diethylamide are due to interference with the normal action of this HT [5- hydroxytryptamine, serotonin]." At the Rockefeller Institute in New York, Woolley and Shaw also saw the antagonistic effects on smooth muscle, and drew similar conclusions about the brain. Erspamer (Renic. sc. farmital. 1, 1, 1954) showed that LSD was a highly effective antagonist against the antidiuresis caused by serotonin (enteramine).

Around the same time, in the early 1950s, several people recognized that the symptoms produced by administering an excess of serotonin were similar to those experienced by people with intestinal tumors called argentaffinomas or carcinoid tumors, which are usually in the small intestine or appendix. The normal intestine contains about 95% of the serotonin in the body (and the brain normally contains only about 1%), and in the normal person only about 1% of the dietary tryptophan is converted to serotonin. But in an advanced case of carcinoid, 60% of the tryptophan can be turned into serotonin. Especially if the tumor has invaded the liver, the serotonin won't be destroyed by the liver in the usual way, and will circulate in the bloodstream at high levels, producing symptoms of flushing, sweating (sometimes dark-colored), diarrhea (serotonin stimulates small intestine smooth muscle, but inhibits the large [Bennett & Whitney, 1966]), nausea, anxiety, reduced urination, muscle and joint pains, and, in late stages, very often cardiovascular disease (especially inflammation, fibroma and calcification of the valves in the right side of the heart) and aggressive behavior (Russo, et al., 2004) and psychosis.

Testing Gaddum's idea of antagonism between LSD and serotonin in humans, Montanari and Tonini found that intramuscular injections of serotonin antagonized the psychological effects of LSD. Other drugs, especially other ergot derivatives, were more successful than LSD in blocking the effects of serotonin (Dubach and Gsell, 1962). There have been suggestions that pregnancy hormones could control serotonin excess (McCullough and Myers, 1965). Since estrogen promotes serotonin, progesterone is likely to be the protective factor (Donner & Handa, 2009; Hiroi, et al., 2006; Berman, et al., 2006; Bethea, et al., 2000).

More recently (Spigset, et al., 2004), it was found that LSD binding to a presumed serotonin receptor was low in carcinoid patients, supporting the idea of antagonism between the substances, but in the older studies symptoms, rather than competition for binding to certain proteins, were the focus of attention. The effects produced by injections and oral doses of synthetic serotonin, and of substances that block the synthesis of serotonin, were studied in both animals and humans. When a symptom such as clotting, flushing, or diarrhea is produced by serotonin itself, or prevented by a blocker of serotonin synthesis, "receptors" aren't an issue.

Aldous Huxley was one of the first people to think about the general biological meaning of drugs such as LSD. Referring to the ideas of Henri Bergson and William Blake, he suggested that the brain usually acts as a filter, or "reducing valve," to make us disregard most of the information we are receiving through our senses, and that the psychedelic drugs temporarily remove the filter, or open the sensory reducing valve. Bergson had suggested that the filter was a practical measure needed to allow us to focus on practical survival needs; Blake had suggested that the doors of perception were kept closed for cultural reasons.

Some recent reviews have discussed the evidence supporting the serotonin system as primarily inhibitory and protective (Anne Frederickson, 1998, Neil Goodman, 2002). Goodman describes the serotonergic system as one of our "diffuse neuroregulatory systems," and suggests that drugs such as LSD weaken its inhibitory, filtering effect. (Jacobs, 1983, 1987: by changes in the effects of serotonin in the brain, produced by things that affect its synthesis, release, catabolism, or receptor action.) LSD depresses the rate of firing of serotonergic nerves in the raphe nuclei (Trulson and Jacobs, 1979) causing arousal similar to stimulation of the reticular formation, as if by facilitating sensory input into the reticular formation (Bowman and Rand, 1980).

In European culture, some people--e.g., Plato, Descarte, Locke, Eccles, probably even B.F. Skinner--have believed that mind and body are essentially different things (analogous to computer hardware and its programs), while another tradition--Blake, Lamarck, Darwin, C.L. Morgan, Pavlov, Reich, C.R. Cloninger, for example--has emphasized the continuity of consciousness and character with the body.

Understanding the authoritarian personality has been an important issue in the 20th century. Wilhelm Reich used some old ideas about the nervous system that were current near the beginning of the century, and Cloninger (1995) and others (Netter, et al., 1996, Ruegg, et al., 1997, Gerra, 2000), toward the end of the century, were able to incorporate the newer information about the serotonergic-dopaminergic antagonisms. In this newer view, high serotonin production causes behavioral inhibition and harm avoidance, which are traits of the authoritarian personality, while anti-authorians tend to have "novelty seeking" personalities, with high dopamine and low serotonin functions.

In the 1960s, experimenters put electrodes into a chicken's optic nerve, and when the chicken saw a checkerboard pattern, they could measure a patterned electrical activity in the nerve. Without the light stimulating the retina, the nerve was quiet. But when they gave the chicken LSD or similar chemicals, they recorded patterned electrical activity in the nerve, in the absence of external stimulation. Around the same time, other experimenters showed that retinal fatigue quickly desensitized the retina, preventing the transmission of impulses to the brain, except when the light pattern corresponded to something familiar, showing that impulses from the brain are always involved in renewing, in patterned ways, the sensitivity of the retina.

The latter experiment shows that everyone's perception involves an outward-directed activity of the brain, and the experiments using the chemical stimulants suggested that the intensity of the outward- directed action can vary.

The inhibitory serotonergic "harm avoidance" system, and the opposing excitatory activating "novelty seeking" systems are constantly being influenced by many factors, including nutrition, hormones, environmental challenges and opportunities, social interactions, seasons, and the rhythm of night and day alternation.

Several kinds of research are now showing that the effects of the environment on the serotonergic system and its antagonists can influence every aspect of health, not just the personality.

For example, there have been suggestions that early life isolation of an animal can affect its serotonergic activity and increase its anxiety, aggression, or susceptibility to stress (Malick and Barnett, 1976, Malick, 1979, dos Santos, et al, 2010), and these effects are associated with increased risk of becoming depressed, and developing organic problems. Animals kept in darkness (or with blurring lenses) become nearsighted, as the eyeball grows longer under the influence of increased serotonin, and the eyes are protected against myopia by serotonin antagonists (George, et al., 2005). The incidence of myopia is increasing, at least in countries with industrialized economies, and is more common in females.

Migraine headaches are also increasing in incidence. By the end of the 1950s, it was widely accepted that migraine headaches and associated symptoms including nausea and visual disturbances were caused by an excess of serotonin, and antiserotonin drugs of various types were being used for treatment. In one of the early studies of the use of LSD in psychotherapy, some of the patients noticed that their chronic headaches had stopped. Cluster headaches have also responded well to LSD and similar drugs (Sewell, et al., 2006).

Women have migraines more often than men do, and they tend to occur in association with ovulation or menstruation. Estrogen inhibits monoamino oxidase, MAO, especially the A form that is most active in detoxifying serotonin, and it increases the enzymes that control the rate of serotonin synthesis. During serotonin excess, the veins and capillaries of the pia mater are engorged with blood, while circulation to the brain generally is depressed. Visual symptoms are probably produced by contriction of arterioles, while the pain is associated with engorged veins. Progesterone activates the MAO-A, and has other antiserotonin effects on blood vessels and nerves.

Recently (Shansky, et al., 2010; Figueiredo, et al., 2007), females have been found to be more susceptible to stress, and to have reduced uptake of serotonin (prolonging its effects), which increases glucocorticoids and ACTH. Kendler, et al. (2005) have found that people with reduced serotonin uptake are more susceptible to stress-induced depression.

The increase of inhibitory serotonin with stress and depression is probably biologically related to the role of serotonin in hibernation, which is an extreme example of "harm avoidance" by withdrawal. A diet high in polyunsaturated fat increases the tendency to go into hibernation, probably by increasing the brain's uptake of tryptophan. When this is combined with an increasingly cold environment, the form of MAO that removes serotonin decreases its activity, while the form that removes norepinephrine increases its activity. The metabolite of serotonin, 5-HIAA, decreases, as the effect of serotonin increases.

In experiments to investigate the mechanism of hibernation, animals were injected with serotonin, at different environmental temperatures. In a cool environment, the serotonin caused their temperature to fall, by decreasing their heat production, and increasing their loss of heat (by causing vasodilation in the skin, "flushing"). In a hot environment, serotonin can cause the animal's temperature to rise.

Serotonin can reduce the production of energy by inhibiting mitochondrial respiratory enzymes (Medvedev, 1990, 1991), and by reduction of oxygen delivery to tissues by vasoconstriction. It also appears to interfere with the use of glucose (de Leiva, et al., 1978, Moore, et al., 2004).

The brains of people with Alzheimer's disease have a decreased ability to metabolize glucose, and high cortisol contributes to the altered glucose metabolism, and to the destruction of nerve cells. People with Cloninger's "harm avoidance" personality trait, which is closely associated with serotonin (Hansenne, et al., 1999), are more likely to develop dementia (Clément, et al., 2010). These observations are consistent with the stress-susceptibility of people with high serotonin exposure, and to the effects of cortisol on nerves and glucose-derived energy production.

Researchers in Brasil have suggested that the serotonergic system facilitates conditioned fear, while inhibiting the fight or flight reaction, and that this can protectively limit the stress response (Graeff, et al., 1996). "5HT systems reduce the impact of impending or actual aversive events. Anticipation of an aversive event is associated with anxiety and this motivates avoidance behaviour" (Deakin, 1990). In a stressful situation, the serotonergic nerves can prevent ulcers. In other contexts, though, increased serotonin can cause ulcers.

The protective, defensive reactions involving serotonin's blocking of certain types of reaction to ordinary stresses, are similar to the effects of serotonin in hibernation and in Alzheimer's disease (Mamelak, 1997; Heininger, 2000; Perry, et al., 2002). In those extreme conditions, serotonin reduces energy expenditure, eliminating all brain functions except those needed for simple survival. These parallels suggest that improving energy production, for example by providing ketones as an alternative energy source, while reducing the stress hormones, might be able to replace the defensive reactions with restorative adaptive nerve processes, preventing or reversing Alzheimer's disease.

One of the factors promoting excess cortisol production is intestinal irritation, causing absorption of endotoxin and serotonin. Fermentable fibers (including pectins and fructooligosaccharides) support the formation of bacterial toxins, and can cause animals to become anxious and aggressive. Fed to horses, some types of fiber increase the amount of serotonin circulating in the blood. Grains, beans, and other seeds contain fermentable fibers that can promote intestinal irritation.

The liver has several ways to detoxify endotoxin and serotonin, but these can fail as a result of poor nutrition and hypothyroidism.

The lung can bind and destroy any excess serotonin that reaches it. A lack of carbon dioxide makes platelets release their stored serotonin, and it probably has the same effect in the lung endothelial cells. Without being able to bind the serotonin, the enzyme (indoleamine 2,3-dioxygenase) would be unable to destroy it.

An excess of tryptophan in the diet, especially with deficiencies of other nutrients, can combine with inflammation to increase serotonin. Polyunsaturated fatty acids promote the absorption of tryptophan by the brain, and its conversion to serotonin. (A "deficiency" of polyunsaturated fat decreases the expression of the enzyme that synthesizes serotonin [McNamara, et al., 2009).

Some fruits, including bananas, pineapples, and tomatoes, contain enough serotonin to produce physiological effects in susceptible people.

Besides avoiding foods containing fermentable fibers and starches that resist quick digestion, eating fibrous foods that contain antibacterial chemicals, such as bamboo shoots or raw carrots, helps to reduce endotoxin and serotonin. Activated charcoal can absorb many toxins, including bacterial endotoxin, so it is likely to reduce serotonin absorption from the intestine. Since it can also bind or destroy vitamins, it should be used only intermittently. Frolkis, et al. (1989, 1984) found that it extended median and average lifespan of rats, beginning in old age (28 months) by 43% and 34%, respectively, when given in large quantities (equivalent to about a cup per day for humans) for ten days of each month.

The amino acid theanine, found in tea, has been reported to decrease the amount of serotonin in the brain, probably by decreasing its synthesis and increasing its degradation. 

This seems to be the opposite of the processes in hibernation. Progesterone, thyroid, and niacinamide (not nicotinic acid or inositol hexanicotinate) are other safe substances that help to reduce serotonin formation, and/or accelerate its elimination. (Niacinamide seems to increase serotonin uptake.)

To provide usable energy to the over-stressed brain (and heart), R.L. Veech has advocated the use of ketones, but the pure chemicals are expensive to make. An easily available and inexpensive source of ketones (in the form of ketoacids, which can be converted to amino acids if they aren't needed for energy) is the juice extracted (with a centrifugal juicer) from raw potatoes, which also contains proteins and other nutrients. The juice can be scrambled like eggs, and is usually tolerated even by very debilitated people.

Hypothyroidism is a very common cause of increased serotonin (e.g., Henley, et al., 1998), and if the thyroid hormone is supplemented until symptoms are resolved, it's likely that the serotonin will have been normalized.

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Cataracts: water, energy, light, and aging 

Because of the baby boom population bulge, the market for cataract surgery and the little plastic intraocular lenses is growing wonderfully. According to the World Health Organization, there were about 20 million cataract surgeries performed in 2010, with 32 million expected in 2020. In the US, about 3 million cataract surgeries are performed annually. Revenue from sale of the intraocular lenses in the US alone was $775,000,000 in 2010, and is expected to reach $965,000,000 by 2017. In 2010, the Alcon company earned $1,200,000,000 from one type of intraocular lens. (Market Research.com) To promote the sale of the "premium'" lenses, which cost thousands of dollars, patients are told that the more expensive lenses will save them money in the long run, by making ordinary glasses unnecessary (sometimes). 

The lens replacement surgery is now sometimes recommended when a cataract has caused only a slight decrease in visual acuity, or even a suspected decrease in acuity. I haven't known anyone who had the surgery who had been informed of the incidence of complications of the surgery, which result in permanent blindness for thousands of the patients every year. 

Some of the causes of cataracts have been known for many years, but the knowledge is usually ignored by the medical profession. Medical myths about the causes of disease support present practices. Myths about the causes of cancer, heart failure, hypertension, menopause, osteoporosis, sarcopenia, depression, dementia, and cataracts are designed to reinforce each other, forming an interlocking system, an ideology of the organism. 

The conventional ideology identifies pathological cells and defective proteins and bad genes as the causes of organ failure and disease, and "aging" is seen as a dimension in which entropy tends to increase those defects.  

This ideology discourages thoughts of "field" effects in which the function of a molecule, a cell, or an organ affects, and is affected by, things that aren't in direct contact with it. This is why the removal of a lens is treated so casually. There is some knowledge about the effects of systemic disease on the eye, but very little about the effects of particular parts of the eye on systemic physiology, and relatively few physicians are aware of the effects of one part of the eye on the other parts of the eye. A few of these physiological interactions within the eye are very interesting. For example, injury to the lens powerfully stimulates regeneration of nerves in the retina (Fischer, et al., 2000). Things which injure the lens enough to cause cataracts to develop might also be injuring the retina, but the emission of stimulating substances from the lens must be a compensating influence. 

Every normal tissue of the eye is emitting substances that affect other parts of the eye, and probably other parts of the body. Until the 1970s, the literature was dominated by the view that the lens was a lifeless material, like hair and toenails, and even in 2013 there is great reluctance of researchers to recognize its vital cellular activity.

After an artificial lens has been implanted, there are great changes in the vitreous humor (which fills the space between the retina and the lens), with a reversal of the gradient of viscosity, and with changes in many proteins, including transthyretin, alpha antitrypsin, retinoic acid binding protein, antioxidant proteins, and the enzymes carbonic anhydrase and triosephosphate isomererase (Neal, et al., 2005). 

I haven't seen any recent studies of the effects of lens removal on the nervous system, but a 1953 study of 21 patients reported a high percentage of behavioral disturbances following the surgery: "Following the operation 20 patients showed some alteration in behavior including changes in mood, psychomotor disturbances, paranoid and somatic delusions, hallucinations, disorientation and confabulations. In 3 cases the disturbance was characterized as severe." "It is concluded that disturbed behavior is an integral part of the reaction of almost all cataract patients because of a complex interaction of a number of factors" (Linn, et al., 1953). 

In animal studies, when the lens capsule is closed after removal of the lens, within a few weeks a well formed lens has regenerated (Gwon, et al., 1993); cell division is stimulated in the cells remaining attached to the capsule, similar to the regeneration of the adrenal cortex after its removal. 

Artificial replacement lenses are designed (with an ultrasharp edge) to block the regenerative migration of cells within the capsule, because the cells can quickly form a new cataract behind the plastic lens; those cataracts commonly form in reaction to the lens. The use of arsenic to kill these cells has been proposed, and probably used (Zhang, et al., 2010). 

The easy money in lens surgery has obviously discouraged professional interest in preventing cataracts, or curing them, or stimulating the regeneration of new lenses. Research in the prevention of cataracts has encountered serious barriers to performing the clinical trials that would be necessary for approval.   "… Clinicians have even developed the opinion that lens and cataract research is no longer necessary to overcome cataract blindness." (Sasaki, et al., 2000.) However, it isn't inconceivable that someone could find a way to make prevention, cure, or regeneration significantly remunerative. 

Although the lens has no blood supply, fluid carrying nutrients and oxygen is constantly flowing through it, providing the cells with glucose, amino acids, and ATP, that it uses for maintaining its structure. Its proteins are being renewed continually, broken down and synthesized (Ozaki, et al., 1985). There is clear evidence that some of the core cells retain a nucleus, and that large molecules can move between cells (Lieska, et al., 1992; Shestopalov and Bassnett, 2000; Stewart, 2008; Mathias and Rae, 2004). Despite this evidence, prominent researchers are still promoting the paradigm of inertness, the lens as analogous to a toenail. As in other cells, ATP maintains the proper water content in the cells. Besides providing energy and amino acids, the circulating fluid carries minerals and many hormones and regulatory substances. 

The absence of a blood supply to the lens has kept people from thinking of its pathology in terms of the inflammatory processes that are now recognized in other conditions, for example in dementia, heart disease, and cancer, but the same basic processes can be seen in the development of cataracts. Improved knowledge of lens physiology is very likely to lead to major improvements in therapies for the other conditions. In the lens, the state of water changes before there is any other evidence that a cataract is developing (Mori, 1993); detecting similar water changes in other tissues might improve diagnosis and treatment of other problems. Things that acutely lower the ATP content of cells increase their water content, and in the process, the water functions differently, becoming more randomly arranged. 

The idea that the properties of water change as cell functions change contradicts the common reductionist assumption that water is just the medium in which molecular interactions occur. Since Kelvin's 1858 demonstration that the heat capacity of water changes with its shape, and Drost-Hansen's demonstrations that its density decreases near surfaces, attention to the physical properties of water has made it possible to understand many biological mysteries, such as the decrease of volume (Abbott and Baskin, 1962) when a nerve or muscle cell is excited. Although the invention of the MRI grew directly from Damadian's understanding of water's centrality to biology's most important issues, the technology's most important contributions, related to changes in water structure, haven't been recognized, understood, or assimilated by medicine. 

The electrical properties of the protein framework of a cell interact with the state of the water in the cell, and with the things dissolved in the water, including phosphate, calcium, sodium, and potassium. Actin, one of the major muscle proteins, forms a meshwork in the cytoplasm of lens fiber cells, and myosin, the other major muscle protein, has been found in association with the actin (Al-Ghoul, et al., 2010). ATP (alternating with ADP+inorganic phosphate) is involved in muscle contraction and relaxation, and it is involved in the conversion of actin from a filament into a globular form. Changes in the amount of ATP and ADP are important for influencing the interactions of water and proteins. 

The actin skeleton is involved in the fiber cell's elongation as it develops from a roundish epithelial cell, and it's probably responsible for the ability of lens cells to contract when stimulated (Oppitz, et al., 2003; Andjelica, et al., 2011). These muscle-like effects of actin are believed to be responsible for the movement of organelles and other cell motion, such as cytoplasmic streaming. But, as a major part of the cell's structure, it could also be expected to act as the framework for electroosmotic flow of water, accounting for the circulation that maintains the cell's energy. The observed static electrical properties of lens cell fragments could account for a complete daily renewal of the fluid (Pasquale, et al., 1990), but the metabolic gradients in whole cells would probably cause faster flow. 

With oxidative energy production occurring in the surface cells, an electrical gradient will be created, causing water to flow away from the site of respiration. (Electroosmosis probably also accounts for the somewhat mysterious exit of water from the eyeball and brain, in perivascular flow.) The flow of water through these cells is very fast, but Ichiji Tasaki has demonstrated similarly fast movement of water in nerves and artificial polymers in association with electrical activity (2002; Tasaki and Iwasa, 1981, 1982; Iwasa, et al., 1980). 

At least since Gullstrand's unfounded assertions in his 1911 Nobel lecture, it has been assumed that the lens, like a water-filled balloon, keeps the same volume when it flattens, for distant focus. Zamudio, et al. (2008), have shown that "…the lens volume decreases as the lens flattens during unaccommodation." "The lens volume always decreases as the lens flattens." They determined that "…the changes in lens volume, as reflected by the speed of the equatorial diameter recovery in in vitro cow and rabbit lenses during simulated accommodation, occurred within a physiologically relevant time frame (200 ms), implying a rapid movement of fluid to and from the lens during accommodation." This is the duration of the action potential of healthy heart muscle, though it's probably not as fast as the very superficial changes that Tasaki saw in nerves. It's the sort of change rate that could be expected in an organ whose change of shape is the result of stimulation. Accommodation, with this immediate hydration, is produced by cholinergic stimulation, and in the healthy lens this hydration is rapidly reversible, as the stimulating acetylcholine disappears and the lens flattens. 

The failing heart muscle, unable to relax fully, becomes harder as its water content increases, and cancer cells, locked into a contracted excited state, become stiffer as their water content increases. Similarly, cataracts have been described as more rigid than normal lens tissue (Heys and Truscott, 2008; Hu, et al., 2000), yet their water content is higher (Racz, et al., 2000). Along with the increased water, the stressed cells take up very large amounts of calcium, and sodium increases while potassium decreases. Inorganic phosphate increases in the stressed cells, some of it entering with the circulating fluid, but some of it produced from the ATP which is decreasing. Serotonin, iron, lipid peroxidation products, nitric oxide, and prostaglandin are also increased. The increased calcium activates proteolytic enzymes that break down protein. 

In the failing heart and growing tumors, there is an increase in the quantity and the cross-linking of collagen in the extracellular matrix, contributing to the overall hardness, besides the contracted state of the cells themselves. In the cataract, cross-linking of various proteins, including collagen, also seems to be involved in the problem, along with the altered state of the water (Mishra, et al., 1997; Eldred, et al., 2011). The cross-linking enzyme transglutaminase is induced by stressors such as ultraviolet light which produce cataracts. 

When the available energy doesn't meet the cell's energy requirements, if the cell isn't quickly killed by the stress it will use some adaptive mechanisms, stopping some repair processes to reduce energy expenditure, possibly stopping specialized functions to reduce energy needs. Fibrotic changes occur as a result of defensive reactions in stressed cells, usually following long periods of fatigue and inflammation. Cortisol generally protects cells by blocking over-stimulation and providing increased material for energy and repair, but it can kill cells (nerve cells and thymus cells) that depend on glucose oxidation, leading to immunodeficiency and excitotoxic brain damage. The glucose-dependent lens fiber cells express the same glucose transporters, GLUT1 and GLUT3, as the brain, and the "nerve specific" GLUT3 is concentrated in the dense nucleus of the lens (Donaldson, et al., 2003). Exposure to excessive cortisol or hypoglycemia is able to quickly produce cataracts, showing the basic importance of glucose metabolism for lens health. 

Oxidative metabolism in the surface cells is probably largely responsible for the streaming of fluid through the fiber cells, providing some ATP and the nutrients that allow the fiber cells to maintain and repair their structure, but I suspect that local metabolism of glucose by the fiber cells provides most of the energy for keeping the protein-water system in its orderly relaxed state. 

The aging lens, like all normal tissues, is drier, has a lower water content, than younger tissues, but when a cataract begins to develop, there is a sharp increase in the water content in that area, something that happens in any excited or fatigued tissue. (In a stimulated nerve or muscle, for example, although in a closed system there would be a slight decrease in volume as its water becomes relatively randomized, there is normally a sudden absorption of water from the extracellular space, where the water has the same random organization.) With the decreasing energy charge of the cell, represented by decreasing ATP and increasing ADP and inorganic phosphate, the long range order of the water decreases, changing the activity of enzymes in a variety of ways, for example by the exchange of a high magnesium content for a high calcium content. While the renewal of proteins decreases because of an energy deficit, the activation of proteolytic enzymes by calcium degrades the cell architecture and the crystallin that makes up about 90% of the cell's protein, and these damaged proteins become progressively cross-linked, in a process analogous to the cross-linking of collagen in sun-damaged skin, or in cancer or a fibrotic failing heart. 

The diffusion of water in these congested cataract areas becomes random, more like ordinary bulk water, and it's likely that this randomization of the water, along with the architectural disorganization of proteins and changing electrical fields, impedes the longitudinal flow of nourishing fluid through the lens. MRI studies show relatively free diffusion of water longitudinally in the lens fiber cells from front to back, but not transversely (Moffat and Pope, 2002). Water that's highly ordered by nearby surfaces can still be very mobile parallel to the surface. 

The parasympathetic nerve transmitter acetylcholine is formed in the lens, as well as its receptor and the enzyme which destroys it, cholinesterase. Chemicals that inhibit cholinesterase, and drugs that mimic the action of acetylcholine on the receptor, cause cataracts. These drugs (Michon and Kinoshita, 1968; Harkonen and Tarkkanen, 1976) cause the lens to take up water, sodium, and calcium, and to lose potassium, and by increasing the cells' energy expenditure, they accelerate the consumption of glucose while blocking other metabolism. Since these are known effects of stimulation by acetylcholine, it's reasonable to assume that acetylcholine is involved in the natural formation of cataracts. 

Besides the direct excitatory effects of acetylcholine, the increase of intracellular calcium and decrease of magnesium (Agarwal, et al., 2012) caused by it promote the synthesis of nitric oxide (which, for example, blocks the function of cytochrome oxidase, reducing the production of ATP), and the interference with glucose metabolism in itself is cataractogenic (Greiner, et al., 1981). 

Ultraviolet light powerfully stimulates the formation of nitric oxide (Chaudhry, et al., 1993), and is one of the known causes of cataracts. Since the cornea is more directly exposed than the lens to the ultraviolet rays of sunlight, the effects of injury can be seen more quickly. Exposure of the cornea to ultraviolet light causes swelling, reduced transparency, and the formation of nitric oxide, which enters the aqueous humor (Cejka, et al., 2012; Cejkova, et al., 2005). Swelling in itself, regardless of the cause, decreases the transparency of the cornea (Stevenson, et al., 1983); anything interfering with its energy metabolism causes swelling. 

The blue color of ordinary water is caused by its absorption of red light, possibly by its hydrogen bonds (Braun and Smirnov, 1993), but there haven't been many studies of the physical effects of red light on water itself. Since water absorbs much more strongly in the infrared wavelengths, there is a tendency to explain the benefits of sunlight by its infrared rays. Red and orange wavelengths penetrate tissue very effectively, because of their weaker absorption by water, allowing them to react with pigments in the cell, such as cytochrome oxidase, which is activated (or re-activated) by red light, increasing the production of ATP. This effect counteracts the toxic effects of ultraviolet light, but there are probably other mechanisms involved in the many beneficial effects of red light. 

Recent work by a group at the University of Ulm in Germany (Andrei Sommer, et al., 2011) has revealed an effect of red light (670 nm) on water that I think helps to explain some of its protective and restorative actions. Shining laser light onto layers of water adsorbed on a solid surface, they were able to show "a breathing-like volume expansion of the topmost sheets of water molecules." They explain this as the result of a stabilization of a more ordered state of the hydrogen bonds of the water. They are applying this to chemotherapy, since the expansion of water in the cell where much of the water is in adsorbed layers similar to their experimental set-up, alternating with its volume contraction as the light is pulsed, causes water to move in and out of the cell quickly, taking some of the drug with it. They have also proposed that degenerative changes in the connective tissues involve a loss of ordered water, and have experimented with light treatments to restore elasticity and flexibility. 

Since the water in cataracts is in a less ordered state than in the transparent lens, the re-ordering effect of red light could be valuable, and if the effects are the same as in their experiments with cancer cells, the increased volume of the re-ordered water would cause a movement of water out of the cataract, as it does in cancer cells in their experiment. And the known restorative effect of red light on oxidative production of ATP would almost certainly be helpful. 

Among the popular medical treatments that are likely to contribute to the development of cataract are glucocorticoids, and drugs that increase serotonin (Dietze and Tilgner, 1973; Korsakova and Sergeeva, 2010), and drugs that increase nitric oxide. Free fatty acids are toxic to the lens, which contains the enzymes for synthesizing prostaglandins and related promoters of inflammation; the products of lipid peroxidation are increased in people with cataracts. Endotoxin from the intestine increases the formation of nitric oxide, so it's essential to minimize intestinal inflammation. 

High altitude very strongly protects against cataracts (Brilliant, et al., 1983). Low oxygen tension itself protects the lens's clarity (Akoyev, et al., 2009), possibly by the protective effect of increased carbon dioxide against glycation of protein amino groups. Aspirin's known anticataract effect apparently involves a similar protection of crystallin against glycation, but aspirin has several other protective effects, including prevention of protein cross-linking, and the inhibition of the synthesis of nitric oxide and prostaglandins and other disruptive materials (Crabbe, 1998; Beachy, et al., 1987; Lonchampt, et al., 1983). Progesterone's inhibition of nitric oxide production is probably protective for the lens, paralleling its effects in other organs. Inhibitors of nitric oxide, such as aminoguanidine, are protective. Anticholinergics, including atropine, inhibit over-hydration of the lens and prevent cataracts caused by excessive cholinergic stimulation (e.g., Kaufman, et al., 1977). Caffeine, in animal experiments, prevents cataracts. Uric acid, which inhibits nitric oxide formation, is reduced in people with cataracts. The factors that prevent or promote other degenerative diseases are similarly protective or harmful for the lens.

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Clin Exp Pharmacol Physiol. 2004 Dec;31(12):890-5. Functional imaging: new views on lens structure and function. Donaldson PJ, Grey AC, Merriman-Smith BR, Sisley AM, Soeller C, Cannell MB, Jacobs MD.
Physiol Res. 2012 Jul 20;61(3):299-306. Central corneal thickness considered an index of corneal hydration of the UVB irradiated rabbit cornea as influenced by UVB absorber. Cejka C, Luyckx J, Cejkova J.
Histol Histopathol. 2005 Apr;20(2):467-73. Irradiation of the rabbit cornea with UVB rays stimulates the expression of nitric oxide synthases-generated nitric oxide and the formation of cytotoxic nitrogen-related oxidants. Cejkova J, Ardan T, Cejka C, Kovaceva J, Zidek Z.
Photochem Photobiol. 1993 Nov;58(5):661-9. Relaxation of vascular smooth muscle induced by low-power laser radiation. Chaudhry H, Lynch M, Schomacker K, Birngruber R, Gregory K, Kochevar I.
Ophthalmologica. 1973;166(1):76-80. [Reversible lens opacity in Wistar rats following single administration of serotonin]. [Article in German] Dietze U, Tilgner S.
Philos Trans R Soc Lond B Biol Sci. 2011 Apr 27;366(1568):1301-19. The lens as a model for fibrotic disease. Eldred JA, Dawes LJ, Wormstone IM.
Invest Ophthalmol Vis Sci. 2000 Nov;41(12):3943-54. Cataractogenic lens injury prevents traumatic ganglion cell death and promotes axonal regeneration both in vivo and in culture. Fischer D, Pavlidis M, Thanos S.
Invest Ophthalmol Vis Sci. 1981 Nov;21(5):700-13. Organophosphates of the crystalline lens: a nuclear magnetic resonance spectroscopic study. Greiner JV, Kopp SJ, Sanders DR, Glonek T.
Acta Ophthalmol (Copenh). 1976 Aug;54(4):445-55. Effects of phospholine iodide on the metabolites of the glycolytic, pentose phosphate and sorbitol pathways in the rabbit lens. Harkonen M, Tarkkanen A.
Exp Eye Res. 2008 Apr;86(4):701-3. The stiffness of human cataract lenses is a function of both age and the type of cataract. Heys KR, Truscott RJ.
Arch Ophthalmol. 1977 Jul;95(7):1262-8. Atropine inhibition of echothiophate cataractogenesis in monkeys. Kaufman PL, Axelsson U, Barany EH.
Vestn Oftalmol. 2010 Jan-Feb;126(1):32-5. [The bioamine profile of the lens during the development of different types of human age-related cataract].[Article in Russian]Korsakova NV, Sergeeva VE.
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Indian J Ophthalmol. 1997 Dec;45(4):227-31. Possible role of lens collagen in cataractogenesis. Mishra G, Das GB, Behera HN.
Nihon Ganka Gakkai Zasshi. 1993 Oct;97(10):1157-64. [Magnetic resonance imaging study on rat sugar cataract]. Mori K.
Toxicology. 2007 Dec 5;242(1-3):7-15. Adverse effects of excessive nitric oxide on cytochrome c oxidase in lenses of hereditary cataract UPL rats. Nagai N, Ito Y.
Invest Ophthalmol Vis Sci. 2003 Nov;44(11):4813-9. Ca2+-mobilization and cell contraction after muscarinic cholinergic stimulation of the chick embryo lens. Oppitz M, Mack A, Drews U.
Exp Eye Res. 1992 May;54(5):807-11. A reassessment of protein synthesis by lens nuclear fiber cells. Lieska N, Krotzer K, Yang HY.
Exp Eye Res. 2004 Mar;78(3):689-98. The lens: local transport and global transparency. Mathias RT, Rae JL.
Exp Eye Res. 2002 Jun;74(6):677-87. Anisotropic water transport in the human eye lens studied by diffusion tensor NMR micro-imaging. Moffat BA, Pope JM.
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Biophys J. 1990 Oct;58(4):939-45. Electrostatic properties of fiber cell membranes from the frog lens. Pasquale LR, Mathias RT, Austin LR, Brink PR, Ciunga M.
Exp Eye Res. 2000 Apr;70(4):529-36. 1H spin-spin relaxation in normal and cataractous human, normal fish and bird eye lenses. Racz P, Hargitai C, Alfoldy B, Banki P, Tompa K.
Ophthalmologica. 2000;214(6):390-8. High hurdle of clinical trials to demonstrate efficacy of anticataractogenic drugs. Sasaki K, Hockwin O, Sakamoto Y, Sasaki H, Kojima M.
J Cell Sci. 2000 Jun;113 ( Pt 11):1913-21. Expression of autofluorescent proteins reveals a novel protein permeable pathway between cells in the lens core. Shestopalov VI, Bassnett S.
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D.N.Stewart, 2008 dissertation UC Davis, Existence of protein turnover in adult human nuclear fiber cells.
J Theor Biol 218(4): 497-505, Oct 2002.  Spread of discrete structural changes in synthetic polyanionic gel: a model of propagation of a nerve impulse. Tasaki I. 
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Ups J Med Sci. 1980;85(3):211-5. Swelling of nerve fibers during action potentials. Tasaki I, Iwasa K. 
Science 210: 338-339, 1980. Swelling of nerve fibers associated with action potentials. Iwasa K, Tasaki, I, and Gibbons RC.
Am J Physiol Cell Physiol. 2008 Jun;294(6):C1430-5. Surface change of the mammalian lens during accommodation. Zamudio AC, Candia OA, Kong CW, Wu B, Gerometta R.
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A R T I C L E

Fatigue, aging, and recuperation

        ===================================
- Old people and sick people tire easily. Surprisingly, little is known to explain that common fact.
- Myths about lactic acid and oxygen debt have misdirected most fatigue research.
- The cellular processes involved in fatigue overlap with those of aging.
- Knowledge about the mechanisms of fatigue should be useful in preventing some tissue swelling disorders, organ failure, degenerative calcification, and other energy-related problems. 

        ===================================

GLOSSARY:
* Uncoupling--In cellular respiration, oxidation of "fuel" in the mitochondrion is coupled to the phosphorylation of ADP, forming ATP. Uncouplers are chemicals that allow oxidation to proceed without producing the usual amount of ATP.
* DNP--Dinitrophenol, an uncoupler that was once popular as a weight-loss drug.
* NAD+ and NADH--Nicotinamide adenine dinucleotide, and its reduced form are coenzymes for many oxidation and reduction reactions in cells.
* Hyperammonemia--The presence of too much ammonia in the blood.
* Vicinal water--water near surfaces, especially hydrophobic surfaces, that is physically and chemically different from ordinary water.
* Hydrophobic--insoluble in water, a nonpolar oil-like molecule that repels water.

        ===================================

Unlike the somewhat technical medical concept of "stress," the idea of fatigue is something everyone understands, to some extent. Hans Selye's studies of stress weren't widely accepted until about 40 years after their publication, but some of the main investigators of the fatigue phenomenon are still practically unknown in the universities, many years after they published their work. 

Several things have kept fatigue research from advancing, including the common feeling that fatigue is already sufficiently understood, and that it is somehow trivial, compared to problems such as growth, reproduction, and disease.

Fatigue is usually described as decreased responsiveness resulting from over-exertion: For example, a muscle's decreased strength or speed of contraction, or a nerve's decreased speed of conduction, or a sense organ's decreased ability to detect or to discriminate. Another meaning of fatigue, a decreased resistance or strength, can be applied to materials, as well as to some biological functions, for example when fatigue leads to sickness or infections. 

"Responsiveness" implies sensitivity, and decreased sensitivity to stimulation can be seen in fatigued sense organs, nerves, muscles, and many other types of cell--immune cells, secretory cells, etc. Even plant cells have very similar processes of excitability that can be depleted by repetition.

In a series of lectures to the Royal Society in England (1895-1901), the physicist Jagadis Chandra Bose described work that at first excited, and then disturbed, many physicists and biologists. He had invented devices for both producing and detecting electromagnetic waves, and he had been the first to produce millimeter length radio waves (microwaves). In Marconi's first transatlantic radio transmission Bose's signal detecting device was used. This device was based on the fact that two pieces of metal in superficial contact became electrically fused (cohered) in the presence of an electrical or electromagnetic field. After they cohered, a mechanical shock would separate them, breaking the electrical fusion.

When Bose was experimenting with his "self-restoring coherer," a semiconducting device that spontaneously broke the connection without being mechanically shaken, he observed that it became insensitive after prolonged use, that is, it lost its self-restoring capacity, but that after a rest, it recovered its sensitivity. He recognized the complex behavior of his instrument as being very similar to the electrical physiology of living cells.

He then began a series of experiments on plants, animals, and minerals, that showed similar responses to all kinds of stimulation, including mechanical and thermal and electromagnetic.

The idea of metal fatigue wasn't new, but Bose was able to think far beyond the ideas of the metallurgists. Biologists were thinking of electrical responsiveness as a defining feature of life, and Bose demonstrated that plants had electrical responsiveness very similar to that of animals, but also that similar reactions could be demonstrated in minerals.

This was what disturbed the English scientists. Sensitivity, irritability, fatigue, and memory were supposed to be special properties related to life, and maybe to consciousness. For the Englishmen, there were religious implications in this Hindu's research.

There were several reasons that European and American scientists couldn't accept the universal nature of the electrical properties that they were studying in animals. One of their motives was to see life as something immaterial, or of an absolutely different nature than inorganic matter. Another problem had to do with the developing belief that the special properties of life were enclosed in the hereditary substance of each cell, and that the electrical functions of cells were produced entirely by the presence of a membrane, surrounding a drop of water containing randomly moving dissolved chemicals.  For the membrane electricity theory, it was essential to believe in the random behavior of things dissolved in the cell water.

So they considered the electrical-mechanical reactions and interactions of minerals to be so unlike the processes of life that it was inappropriate to see analogies between them. Minerals were composed of atoms, and, according to the doctrine of the time, they could have no "physiological" functions except on the atomic scale. It was more than 20 years before mainstream physicists began thinking about "delocalized" forces and fields in minerals. 

Between 1915 and 1934, Michael Polanyi made many observations that made it clear that the old kind of electrical atomism was completely unfounded. The behavior of mineral crystals, and the interactions between different phases of material, such as gas or liquid with a solid, could be understood only in terms of relatively long-range forces. Polanyi's experiments showed, for example, that events on the surface of a crystal modified the strength and deformability of the crystal. 

Many others between 1900 and 1940-- Lepeschkin, Nasonov, Bungenberg de Jong, and Solco Tromp, for example--argued that the sensitivity of protoplasm had to be understood in terms of long range order, something like a liquid crystalline state of matter that would require some of the kinds of knowledge of matter that were being developed by physicists, metallurgists, and a variety of others investigating the condensed states of matter.

But the mainstream biologists preferred to describe cells in terms that would make impossible any of the responsivities or sensitivities seen in the "simple" solid state of minerals. To defend their ideology of the immateriality of life, they denied that the subtlest features of matter had anything to do with life, reducing life to a debased set of special, merely theoretical, mechanisms. The now defunct physical theory of merely localized atomic electrical forces became the paradigm for the new biology. The many demonstrations of coherent, ordered physical behavior of the cytoplasm, for example Gurwitch's mitogenic radiation, were dismissed with prejudice. 

During G. W. Crile's long career (1889-1941), understanding shock, biological energy, and fatigue were his main concerns. He believed that shock was the result of brain exhaustion, and in one of his last publications he showed that the brains from exhausted animals produced less bioluminescence than those from rested animals. His importance was in demonstrating that fatigue and shock are systemic conditions of the organism, rather than isolated events in muscles and nerves. Recent publications are showing the validity of this view. Crile's approach to the prevention and treatment of shock was based on isolating the damaged area with local anesthetics. Blocking the nerves from one injured part of the body, for example the sciatic nerve in the leg, could preserve energy production (and normal cell functions) throughout the rest of the body.

About 30 years earlier (1901), Vvedensky had demonstrated that some types of fatigue appear to be a defensive blocking of responsiveness, such that intense stimulation would produce no response, while weak stimulation could sometimes produce a response. These changes affected cell functions in a variety of ways, that he called narcosis and parabiosis.

There have been two popular ways to "explain" fatigue, one by saying that the cell's energy (usually thought of as ATP or glycogen) is used up, the other saying that the accumulation of a metabolic product (usually lactic acid) prevents further functioning. The obvious problem with these explanations is that the fatigue response is quite independent of those metabolic changes. Another problem is that those ideas don't explain the real changes that occur in cells that are demonstrating fatigue.

Fatigued cells take up water, and become heavier. They also become more permeable, and leak. When more oxygen is made available, they are less resistant to fatigue, and when the organism is made slightly hypoxic, as at high altitude, muscles have more endurance, and are stronger, and nerves conduct more quickly. These facts don't fit with the standard model of the cell, in which its sensitivity is strictly governed by the behavior of its "membrane." (For example, how can a membrane leak large molecules at the same time that it is intact and causing the cell to swell osmotically?) They are consistent with the model of the cell that treats protoplasm as a special phase of matter.

Another feature of fatigue (and often of aging, stress, and sickness) is that the relaxation of muscles is retarded and impaired.

Hypothyroidism causes muscle relaxation to be slowed, both in skeletal muscles and in the heart. F/Z. Meerson showed that stress causes heart muscles to be exposed to increased calcium, followed by breakdown of fats and proteins, and that these changes keep the injured heart in a continuous state of partial contraction, making it stiff, and resistant to complete contractile shortening. When many cardiologists talk about the heart's stiffness, they are thinking of muscular thickening and fibrosis, but those are late consequences of the kind of contractile, unrelaxed stiffness that Meerson described.

The hypothyroid heart does eventually become fibrotic, but before that, it is just unable to relax properly, and unable to contract fully. This failure to empty fully with each contraction is a kind of "heart failure," but it can be corrected very quickly by supplementing thyroid. Even the fibrotic heart can recover under the influence of adequate thyroid.

The analogy of the "coherer" would suggest that the overstimulated muscle isn't able to decohere itself, until it has had a rest. It responds to stimulation, lets the energy flow, but then can't turn it off, and the energy keeps flowing, because of a change in physical state. 

Albert Szent-Gyorgyi was probably the first person to seriously investigate the semiconducting properties of living material. Since he was aware of W.F. Koch's idea of a free radical catalyst to support oxidative metabolism, his suggestion in 1941 that cellular proteins could function as electrical conductors (or semiconductors) was very likely based on his research in cellular respiration, as well as on his work with muscle proteins. He had observed that ATP lowers the viscosity of a solution of the muscle protein myosin, and that it would cause a filament formed by precipitating myosin to contract. The polymerization and contraction of proteins under the influence of free radicals was at the heart of F.W. Koch's therapeutic ideas, but Koch's work was about 100 years too early, by medical standards.

Szent-Gyorgyi observed that, although ATP was involved in the contraction of muscles, its post-mortem disappearance caused the contraction and hardening of muscles known as rigor mortis. When he put hardened dead muscles into a solution of ATP, they relaxed and softened. The relaxed state is a state with adequate energy reserves.

After Szent-Gyorgyi moved to the U.S., in 1947, he demonstrated the effect of muscle cytoplasm on the behavior of fluorescent substances, which was analogous to that of ice, until the muscle was stimulated. During contraction, the fluorescent material behaved as it would in ordinary liquid water. This effect involved the stabilization of the excited state of electrons. This single demonstration should have caused biologists to abandon the membrane theory of cellular excitation, and to return to basic physics for their understanding of cell behavior. The implications of Szent-Gyorgyi's work were enormous for biology and medicine, and even for the understanding of semiconductors, but most of the world was hypnotized by a simple textbook model of cell membranes.

Szent-Gyorgyi also demonstrated that the combination of properly balanced electron donors and electron acceptors (D-A pairs) would cause a muscle to contract. He compared this to "doping" an inorganic superconductor, to regulate its electronic behavior. Although these experiments were done half a century after Koch's application of free radical chemistry to medicine, they still didn't rouse the pharmaceutical industry from its toxic slumber.

I suspect that it was Szent-Gyorgyi's research with those interesting electronic properties of cellular water and proteins that in 1960 gave Linus Pauling the idea to explain anesthesia, specifically noble gas anesthesia, in terms of water clathrate formation, the restructuring of cellular water by the hydrophobic atom or molecule of an anesthetic. His suggestion caused a reaction among biologists that discouraged research into the subject for about 40 years.

Gilbert Ling's view of cytoplasmic structure gives a different emphasis to the function of electrons, which I think is an essential complement to Szent-Gyorgyi's view. Ling's emphasis is on how the inductive effect of adsorbed substances (for example, ATP and progesterone has powerful adsorptive effects) on proteins changes the charge concentration on ionizable groups. When the charge concentration is in one configuration (more acidic), the preferred counterion is potassium, and in another (less acidic) configuration, it is sodium. 

Gilbert Ling's biophysical calculations were useful to physical chemists, and were soon put to practical use for understanding ion exchange resins, such as water softeners. Many sorts of evidence showed their validity for cell physiology, but nearly all biologists rejected them, preferring to talk about membranes, pumps, and channels, despite the evidence showing that the properties ascribed to those are simply impossible. NMR imaging (MRI) was developed by Raymond Damadian specifically as an application of Ling's description of cell physiology.

Although metals are conductors, the function of the coherers of Bose and others shows that the surface is a semiconductor, that requires the slight excitation of an electromagnetic wave to become conductive, at which point the conduction band of electrons in the metal becomes coherent and extends from one particle into the others. The surface of any phase of a substance has electronic properties distinct from those of the bulk phase, and in a sense the interface constitutes a special phase of matter.  When the electrons of the interface lose their special properties, the structure of the whole system changes.

When a muscle cell is stimulated enough to cause a contraction, the interruption of its resting phase causes a shift in the charge concentration on the proteins, potassium ions are exchanged for sodium ions, calcium ions enter, and phosphate ions separate from ATP, and are replaced by the transfer of phosphate to ADP from creatine phosphate. 

Since the quantum physicist E. Schroedinger wrote his book, Time's Arrow, people have often thought of life in terms of negentropy, going against the general tendency of entropy to increase, except for aging and death, which are seen as obeying a law of increasing entropy. But A. Zotin investigated organisms, rather than abstractions about electrons, and shows that aging involves a decrease in entropy, and a slowing of metabolism. The decrease of entropy with aging, according to his view, would be analogous to crystallization, a sort of progressive freezing.

When a nerve is stimulated, it releases energy suddenly, and much of this heat seems to be the result of a change of structure in the cytoplasm, since (in crustaceans' nerves, which can function at low temperature) during the resting recovery of the nerve, its temperature goes slightly below the ambient temperature, despite the release of some heat from the chemical changes of metabolism, stimulated by the nerve's activity. 

When a physical change is endothermic, as the nerve's recovery is, that can be interpreted as an increase in overall entropy, as when a rubber band spontaneously contracts, and becomes cooler.

Bose's rested coherer, which, with time, spontaneously recovered its semiconductive (i.e., relatively insulating) property, wasn't being powered by metabolism. As the particles returned to their relatively isolated state, there was a decrease of order, and the change was probably somewhat like the spontaneous energy change in the stimulated crustacean nerve. I assume the change would result from the absorption of environmental heat, possibly with infrared resonance with electron conduction bands.

Seeing the structure of the cytoplasm as something like a spring-driven mechanism, able to bounce between two states or "phases," makes it easier to see cellular fatigue as something different from the various metabolic energy sources, ATP, glycogen, and oxygen, which--contrary to conventional assumptions--aren't closely tied to the functional losses occurring in fatigue.

The role of metabolism, then, becomes analogous to the role of the "tapper" in the early forms of the coherer.
Water in its normal state is a dielectric. But when it is polarized by an electrical charge, or by the presence of a phase boundary, its normal state is altered. This is the special interfacial water, or vicinal water. With the movement of ions (mainly potassium, sodium, calcium, and magnesium) during excitation, the state of the cellular water is necessarily changed by the presence of different substances. In the excited state, cell water is less hydrophobic, more hydrophilic than in the relaxed state. A network of "hydrophobic" interactions extends through the relaxed cell. One of the properties of a dielectric is that it tends to move into the space between charges, with a force similar in principle to that involved in dielectrophoresis. 

In the resting state, potassium is the main inorganic ion, and it is associated with acidic groups, such as aspartic and glutamic acid. During excitation, potassium is partly exchanged for sodium, which becomes the preferred counter-ion for the acid groups, and calcium enters the cell along with the sodium. Potassium's interaction with water is very weak (its hydration has been called negative), allowing water to form the structures that are stable in the presence of hydrophobic surfaces. Sodium and especially calcium (smaller atoms, with higher surface charge concentration) powerfully interact with water molecules, more strongly than water interacts with itself, disrupting the delicate somewhat hydrophobic structures of the intracellular water.

(Calcium, with its two charges, has important binding and stabilizing functions in the resting cell. In the excited cell, these internal calcium ions are released, while extracellular calcium ions enter the cell.)

With the increased movement of charged particles during the stimulation of a nerve or muscle, as one kind of counterion is exchanged for another, and the destruction of some of the water's structure, there are more opportunities for bulk dielectric water to enter cells, interfering with the arrangement of proteins, and tending to cause swelling and separation of the structural elements of the cell. Electron micrographs of fatigued muscle show a remarkable separation of the actin and myosin proteins.

In the excited state, NMR studies show that cell water behaves more like bulk water, that is, its molecular movements are relatively free, indicating the momentary loss of the interfacial state. In this state, the uptake of water, and the fatigue-related swelling of nerves and muscles, would be driven at least partly by the principle that a dielectric tends to be pulled into the spaces separating charges. The bulk water that enters a cell during the breakdown of vicinal water functions as an extraneous material somewhat beyond the cell's control.

These bulk-like high dielectric properties of water in the excited cellular state can explain many changes of enzyme activity. Previously nonpolar lipids would develop a negative surface charge (from accumulating hydroxyl groups: Marinova, et al., 1996), which would tend to increase their oxidation and degradation. With the loss of the interfacial water, the cell's high energy resting state is replaced by an active mobilization of its resources, to maintain and restore the cell's structure. Metabolic energy begins to flow into the processes of restoration, serving the function of the tapper in the earliest coherers.

Looking at fatigability, muscle contraction, and nerve conduction in a variety of situations, we can test some of the traditional explanations, and see how well the newer "bioelectronic" explanations fits the facts. Osmotic pressure, hydrostatic pressure, atmospheric pressure, and the degree of metabolic stimulation by thyroid hormone affect fatigue in ways that aren't consistent with the membrane-electrical doctrine.

The production of lactic acid during intense muscle activity led some people to suggest that fatigue occurred when the muscle wasn't getting enough oxygen, but experiments show that fatigue sets in while adequate oxygen is being delivered to the muscle. Underwater divers sometimes get an excess of oxygen, and that often causes muscle fatigue and soreness. At high altitudes, where there is relatively little oxygen, strength and endurance can increase.

An excess of oxygen can slow nerve conduction, while hypoxia can accelerate it. (Increasing the delivery of oxygen at higher pressure doesn't increase the cellular use of oxygen or decrease lactic acid production in the exercising muscle [Kohzuki, et al., 2000], but it will increase lipid peroxidation.)

High hydrostatic pressure causes muscles to contract, though for many years the membrane-doctrinaires couldn't accept that. Underwater divers experience brain excitation under very high pressure. Since vicinal water has a larger volume than ordinary water (analogous to the expansion when ice is formed, though the volume increase in cell water is slightly less, about 4%, than in ice, which is 11% more voluminous than liquid water), compression under high pressure converts vicinal cell water to the state that occurs in the excited cell, the way ice melts under pressure. The excited state exists as long as water remains in that state.

These changes of state under pressure are reminiscent of Bose's use of pressure in some of his coherers, and of the fact that pressure alters the sensitivity of electrons in a semiconductor, by altering their "band gap," the amount of energy needed to make them enter the conductive zone.

One of the early demonstrations that cell water undergoes a phase change during muscle contraction involved simply measuring the volume of an isolated muscle. With stimulation and contraction, the volume of the muscle decreases slightly. (The muscle was immersed in water in a sealed chamber, and the volume decrease in the whole chamber was measured.)  This corresponds to the conversion of vicinal water to bulk-like (dielectric) water.  (The threatening implications of those experiments with spontaneous volume change were very annoying to many biologists of my professors' generation.)

In the stimulated state, the cell's uptake of water from its environment coincides closely with its electrical and thermal activity, and its expulsion of water coincides with its recovery. In a small nerve fiber, or near the surface of a larger fiber, these changes are very fast, and in a large muscle the uptake of water is faster than the flow of water from capillaries can match, but it will become massive if stimulation is continued for several minutes. For example, two minutes of stimulation can cause a muscle's overall weight to increase by 6%, but its extracellular compartment loses 4%, so the muscle cells gain much more than 6% of their weight in that short time (Ward, et al., 1996). The water that is taken up by cells is taken from the blood, which becomes relatively dehydrated and thicker in the process.

The belief in "semipermeable membranes" (which hasn't been a viable explanation of cell physiology for a very long time) forces people to explain cell swelling osmotically, which means that they simply assume that the number of solute particles inside the cell has drastically increased in a very short time. In Tasaki's experiments (1980, 1981, 1982), the swelling in a nerve coincides with the electrical action potential, which, according to the osmotic explanation, means that a very large increase in internal osmolarity happened in essentially no time. The action potential comes and goes in about 2 milliseconds. The swelling also coincides with heat production and shortening of the nerve fiber. The shrinkage of the nerve fiber after the end of the action potential may be just as rapid, and the membrane theory offers no explanation for that, either. (But the restoration of the unswollen state can be very prolonged, depending on conditions extrinsic to the particular muscle or cell.) Troshin's survey of the theory of osmotic regulation of cell volume showed that the idea of the cell as a membrane osmometer was false, but very few biologists read his book.

Since the excited or fatigued muscle or nerve swells and gains weight, it's interesting to see what happens to their sensitivity and strength when they are exposed to hypotonic solutions that tend to promote swelling, or to hypertonic solutions, that help to prevent swelling.

In a hypotonic solution, cells are excited (Lang, et al., 1995: "Exposure of aortic strips from guinea-pigs to hypotonic extracellular fluid is followed by marked vasoconstriction..."), but the early excitation is followed by decreased responsiveness (Ohba, et al., 1984: "Exposure of muscle to hypotonic solutions [70% of normal solution] produced initially a transient increase in twitch after which twitch declined below the control level"). Hypertonic solutions tend to produce relaxation in normal muscles, including the aorta (Tabrizchi, 1999), but when muscle function is impaired (especially in the circulatory system, as in shock) they improve contractile function (Elgjo, et al., 1998: "The maximum contraction force measured in isolated right papillary muscles ex vivo was significantly greater in HSD-treated than normal saline-treated animals"). Athletes can lose 4% of their weight by dehydration without decreasing their muscular strength.

Hypothyroidism tends to cause loss of sodium from the blood, and the hyponatremia sometimes leads to a generalized hypotonicity of the body fluids. The thyroid hormone itself functions as an antioxidant, but much of its protective effect against cell damage is probably the result of preventing cell swelling and accelerating the removal of calcium from the cell. (Swelling, like fatigue, causes intracellular calcium to increase.)

The electrical surface charging of lipids in bulk water probably accounts for the increased lipid peroxidation that occurs in fatigue, edema, and hypothyroidism, when water loses its normal partial hydrophobicity. Increased carbon dioxide is known to decrease lipid peroxidation, and its production requires adequate thyroid function.

Thyroid stimulation of oxygen consumption tends to prevent lactic acid production, because it keeps the cytoplasm in a state of relative oxidation, i.e., it keeps the concentration of NAD+ hundreds of times higher than that of NADH. NADH is required for the conversion of pyruvate to lactate. It is also the source of reducing potential in many kinds of toxic redox cycling, that generate lipid peroxides, and it maintains the sulfhydryl system, involving the balance of reduced glutathione with the sulfhydryl-disulfide system of protein bonds, which governs the cell's electronic state and affects its balance of hydrophobicity and hydrophilicity.

The harmful lipid oxidation interferes with energy production and regulatory processes, and is responsible for some of the prolonged effects of fatigue, swelling, and hypothyroidism. These lingering effects of lipid oxidation are undoubtedly amplified by the presence of larger amounts of unstable polyunsaturated fats, as the energy demands of the fatigued state mobilize free fatty acids from the tissues. 

One of the oldest tests for hypothyroidism was the Achilles tendon reflex test, in which the rate of relaxation of the calf muscle corresponded to thyroid function--the relaxation is slow in hypothyroid people. Water, sodium and calcium are more slowly expelled by the hypothyroid muscle. Exactly the same slow relaxation occurs in the hypothyroid heart muscle, contributing to congestive heart failure, because the semi-contracted heart can't receive as much blood as the normally relaxed heart. The hypothyroid blood vessels are unable to relax properly, contributing to hypertension. Hypothyroid nerves don't easily return to their energized relaxed state, leading to insomnia, paresthesias, movement disorders, and nerves that are swollen and very susceptible to pressure damage. 

With aging, hypothyroidism, stress, and fatigue, the amount of estrogen in the body typically rises. Estrogen is catabolic for muscle, and causes systemic edema, and nerve excitation. It weakens muscle contraction in the bladder, although it lowers the threshold for stimulation of sensation and contraction (Dambros, et al., 2004). This is the pattern that causes people to wake up frequently, to pass a small amount of urine. (Progesterone has the opposite effect in the urinary bladder, raising the threshold of response, but strengthening contraction, as it does in the gallbladder.) Estrogen lowers stimulation threshold in the gallbladder, as it does in the brain. Part of its excitatory action might be the result of increased hypotonic tissue water, but its effects on nerve thresholds are practically instantaneous. 

In 1971 and '72, I gave some of the reasons for thinking that estrogen's biological effects result from its direct effects on cell water, causing it to become more like bulk (high dielectric) water. For example, NMR (spin echo) of estrogen treated uterus and of the uterus from an old animal were closer to bulk water than that of a young animal. Estrogen, like fatigue or excessive oxygen, slows nerve conduction.
Lactic acid production increases with fatigue, aging, hypothyroidism, estrogen excess, and other inefficient biological states. Its presence, when oxygen is available, indicates that something is interfering with efficient oxidative energy metabolism. Ammonia, free fatty acids, and various inflammatory cytokines are also likely to increase in those stress states.

A dangerously high level of ammonia in the blood (hyperammonemia) can be produced by exhaustive exercise, but also by hyperbaric oxygen (or a high concentration of oxygen), by high estrogen, and by hypothyroidism. It tends to be associated with an excess of lactic acid, probably because ammonia stimulates glycolysis. Excess oxygen, like hypothyroidism, is equivalent to "hyperventilation," in producing an abnormally low level of carbon dioxide in the blood. The Krebs cycle, during stress, is limited by the unavailability of carbon dioxide. These factors result in the waste of glucose, turning it into lactic acid, rather than carbon dioxide and energy. In these ways, the metabolism of fatigued muscle (or any cell under stress) is similar to tumor metabolism.

Hyperammonemia disturbs excitatory processes, and can cause seizures, as well as stupor, and is probably involved in mania and depression. Lithium happens to complex electronically with ammonia, and I think that accounts for some of its therapeutic effects, but carbon dioxide is the main physiological factor in the elimination of ammonia, since it combines with it to form urea. The changes in cell water in the excited/fatigued state represent an increase in the water's "structural temperature," and that would imply that less carbon dioxide could remain dissolved during excitation.

Eating sugar and using caffeine, which increases the oxidation of sugar (Yeo, et al., 2005), can reduce fatigue, both subjectively and objectively. Metabolically, they increase the production of carbon dioxide. Increasing sugar decreases the liberation and use of fatty acids, and by a variety of mechanisms, helps to lower the production of ammonia, lactate, and inflammatory cytokines. (Lactic acid, in combination with acidosis and free phospholipids, can interfere with efficient cell functions [Pacini and Kane, 1991; Boachie-Ansah, et al., 1992].) Free fatty acids release tryptophan from albumin, contributing to the formation of serotonin, which increases the sense of fatigue.

Aspirin and niacin help to prevent fatigue symptoms, and to prevent many of the harmful systemic oxidative after-effects. (Both are antilipolytic; aspirin uncouples mitochondria.)

Uncoupling of mitochondrial oxidative metabolism from ATP production helps to consume the sugar which otherwise would be diverted into lactic acid, and converts it into carbon dioxide instead. Mild hypoxia, as at high altitude, suppresses lactic acid production ("the lactate paradox"), and increases the amount of carbon dioxide in tissues. 

Aspirin and thyroid (T3) increase uncoupling. A drug that used to be used for weight reduction, DNP, also uncouples mitochondrial metabolism, and, surprisingly, it has some of the beneficial effects of thyroid and aspirin. It stimulates the consumption of lactic acid and the formation of carbon dioxide.

The squirrel monkey, which on average weighs about 2 or 3 pounds as an adult, lives much longer than other mammals of its size, usually about 20 years, as long as 27. It has an extremely high rate of oxygen consumption. This is probably the result of natural uncoupling of the mitochondria, similar to that seen in long-lived mice. Mice with 17% higher resting oxygen consumption lived 36% longer than slow respiring mice of a related strain (Speakman, et al., 2004).

Living at a high altitude, people tend to eat more and stay leaner than when they live near sea level. Apparently, their mitochondria are relatively uncoupled, and they have more mitochondria, which would partly account for their lower production of lactic acid during muscular exertion. Increased thyroid activity, too, tends to increase mitochondrial mass, as well as their uncoupling.

Most of the things that we think of as fatigue result from disturbances of the hydration of cells, whose sensitivity, composition, and structure change according to the extent of the disturbance. The hydration is governed by the cells' "electrical" properties, which are regulated by internal metabolic processes and by systemic processes. When cellular fatigue reaches a certain point, only the interactions of all the organs can restore stable cellular structure and functions. The liver eliminates lactic acid and ammonia, the adrenals and gonads provide stabilizing steroids, and the brain alters activity and behavior, in ways that can reverse most of the effects of fatigue.

But, when the tissues contain large amounts of polyunsaturated fats, every episode of fatigue and prolonged excitation leaves a residue of oxidative damage, and the adaptive mechanisms become progressively less effective. When the most powerful adaptive mechanisms, such as the timely synthesis of progesterone, pregnenolone, DHEA, T3, and the inhibitory transmitters, GABA and glycine, fail, then some of the primitive defense mechanisms will become chronically activated, and even sleep may fail to restore normal cellular water and metabolism. Hyperventilation often becomes a problem, making capillary leakiness worse.

Water in the body occupies three major compartments--blood vessels, extracellular matrix, and the moist cell substance itself--and its condition in each compartment is a little different, and subject to variation. There are no textbooks in use in the U.S. that treat intracellular water scientifically, and the result is that physicians are confused when they see patients with edema or with disturbances in blood volume. It rarely occurs to physicians to consider disturbances of water distribution in problems such as chronic fatigue, fibromyalgia, sleep disturbances, frequent urination, slow bladder emptying, anxiety, paresthesia, movement disorders, the tunnel syndromes, or even slowed thinking, but "intracellular fatigue" leading to over-hydration is probably the central problem in these, and many other degenerative and inflammatory problems. 

The improvements in cell functions and water distribution that are inversely related to oxygen pressure, and directly related to carbon dioxide, won't be discussed in medical textbooks until they have given up the idea of membrane-regulated cells. 

The "treatment" for intracellular fatigue consists of normalizing thyroid and steroid metabolism, and eating a diet including fruit juice, milk, some eggs or liver, and gelatin, assuring adequate calcium, potassium sodium, and magnesium, and using supplements of niacin-amide, aspirin, and carbon dioxide when necessary. Simply increasing carbon dioxide decreases lactic acid and ammonia, increases GABA (the sleep improving nerve inhibitor), and regulates mineral and water disposition.

One of the outcomes of the study of the physiology of fatigue is that it leads to a better understanding of cells in general, and offers some new insights into aging, inflammation, and a variety of stress-related diseases.

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Clin Investig. 1993 Dec;71(12):999-1001. Exercise-induced myalgia in hypothyroidism. Lochmuller H, Reimers CD, Fischer P, Heuss D, Muller-Hocker J, Pongratz DE.
Pflugers Arch. 1995 Dec;431(2):253-8. Ca2+ entry and vasoconstriction during osmotic swelling of vascular smooth muscle cells. Lang F, Busch GL, Zempel G, Ditlevsen J, Hoch M, Emerich U, Axel D, Fingerle J, Meierkord S, Apfel H, et al.
Acta Physiol Scand. 2001 Mar;171(3):277-94. Skeletal muscle disorders in heart failure. Lunde PK, Sjaastad I, Schiotz Thorud HM, Sejersted OM. "Heart failure is associated with reduction of exercise capacity that cannot be solely ascribed to reduced maximal oxygen uptake...." "Is it possible that development of this contractile deficit in the myocardium is paralleled by a corresponding contractile deficit of the skeletal muscles?" "This question cannot be answered today. Both patient studies and experimental studies support that there is a switch to a faster muscle phenotype and energy metabolism balance is more anaerobic." 
Circ Res. 2001 Jun 22;88(12):1299-305. Contraction and intracellular Ca(2+) handling in isolated skeletal muscle of rats with congestive heart failure. Lunde PK, Dahlstedt AJ, Bruton JD, Lannergren J, Thoren P, Sejersted OM, Westerblad H. "In conclusion, functional impairments can be observed in limb muscle isolated from rats with CHF."
J Physiol. 2002 Apr 15;540(Pt 2):571-80. Contractile properties of in situ perfused skeletal muscles from rats with congestive heart failure. Lunde PK, Verburg E, Eriksen M, Sejersted OM. "We hypothesized that in congestive heart failure (CHF) slow-twitch but not fast-twitch muscles exhibit decreased fatigue resistance in the sense of accelerated reduction of muscle force during activity." "Initial force was almost the same in Sol from CHF and Sham rats, but relaxation was slower in CHF. Relaxation times (95-5 % of peak force) were 177 +/- 55 and 131 +/- 44 ms in CHF and Sham, respectively, following the first stimulation train. After 2 min of stimulation the muscles transiently became slower and maximum relaxation times were 264 +/- 71 and 220 +/- 45 ms in CHF and Sham, respectively (P < 0.05)." "Thus, slow-twitch muscle is severely affected in CHF by slower than normal relaxation and significantly reduced fatigue resistance, which may explain the sensation of both muscle stiffness and fatigue in CHF patients."
Pflugers Arch. 1995 Dec;431(2):253-8. Ca2+ entry and vasoconstriction during osmotic swelling of vascular smooth muscle cells. Lang F, Busch GL, Zempel G, Ditlevsen J, Hoch M, Emerich U, Axel D, Fingerle J, Meierkord S, Apfel H, et al. "Exposure of aortic strips from guinea-pigs to hypotonic extracellular fluid is followed by marked vasoconstriction...."
 Ukr Biokhim Zh. 1978 Sep-Oct;50(5):635-40. [Effect of carbonic acid of different concentrations of the glycolysis processes and tricarboxylic acid cycle in rat liver tissues] [Article in Russian] Lutsenko NI, Mel'nichuk DA, Zhuravskii NI. "A rise in the carbonic acid and pH level in rat blood determines an increase in oxidative properties of the liver cell cytoplasm." "The increase in the level of carbonic acid under the all studied values of pH produces a 1.5-fold decrease in the ammonia concentration."
Langmuir 1996, 12, 2045-2051. Charging of Oil-Water Interfaces Due to Spontaneous Adsorption of Hydroxyl Ions, Marinova KG, Alargova RG, Denkov ND, Velev OD, Petsev DN, Ivanov IB, and Borwankar RP.
Kosm Biol Aviakosm Med. 1983 Nov-Dec;17(6):46-9. [Metabolic disorders in men kept in an environment with a low ammonia content and their correction by physical exercise] [Article in Russian] Mukhamedieva LN, Zhuravlev VV, Nikitin EI, Grishina KV, Ivanova SM. "In two series of prolonged studies metabolic changes of men kept in an environment with an ammonia concentration of 2 and 5 mg/m3 were investigated. In this chronic study the following changes were seen: acetone in the exhaled air increased; glycolysis and lactate dehydrogenase enhanced; catalase decreased; changes of acid-base equilibrium manifested as metabolic acidosis of varying degree." 
Jpn J Physiol. 1984;34(5):803-13. Mechanism of inotropic action by hypotonic solution in the frog atrial muscle. Ohba M, Kishi M, Kawata H.
J Bacteriol. 1960 Jul;80:21-4. A relationship between multiple temperature optima for biological systems and the properties of water. Oppenheimer CH, Drost-Hansen W.
Shock. 2003 Apr;19(4):383-7. Hypertonic saline dextran alleviates hepatic injury in hypovolemic rats undergoing porta hepatis occlusion. Ozguc H, Tokyay R, Kahveci N, Serdar Z, Gur ES. 
 J Cardiovasc Pharmacol. 1991 Aug;18(2):261-6. Effects of components of myocardial ischaemia on cardiac action potentials in vitro. Pacini DJ, Kane KA.
Science. 2004 Aug 20;305(5687):1144-7. Intracellular acidosis enhances the excitability of working muscle. Pedersen TH, Nielsen OB, Lamb GD, Stephenson DG. 
Biophys J. 1998 Dec;75(6):2984-95. Volume changes of the myosin lattice resulting from repetitive stimulation of single muscle fibers. Rapp G, Ashley CC, Bagni MA, Griffiths PJ, Cecchi G.
Neuropsychologia. 2004;42(12):1709-14. Sex difference in brain nerve conduction velocity in normal humans. Reed TE, Vernon PA, Johnson AM.
Bull Eur Physiopathol Respir. 1976. Jan-Feb;12(1):19-32. [CO2 storage in various organs during chronic experimental hypercapnia] Reichart E, Claudon F, Sabliere S. "During a four week hypercapnia, this CO2 increase is very important in bone and brain compared with that of other organs and of the whole body. With regard to the whole body, the bone CO2 content is still increasing after four weeks." "A factorial analysis (BENZECRI) shows that the weight of H2Oe in the information diminishes for all organs, both with the duration of normal subjects observation (ageing) and with the hypercapnia duration."
Life Sci. 1993;52(18):1481-6. Hypertonic glucose inhibits the production of oxygen-derived free radicals by rat neutrophils. Sato N, Kashima K, Shimizu H, Uehara Y, Shimomura Y, Mori M.
Exp Physiol. 1997 Jan;82(1):213-26. Dissociation between metabolic and contractile responses during intermittent isometric exercise in man. Saugen E, Vollestad NK, Gibson H, Martin PA, Edwards RH.
J Biol Chem. 1990 Jul 5;265(19):1118-24. Respiratory failure and stimulation of glycolysis in Chinese hamster ovary cells exposed to normobaric hyperoxia. Schoonen WG, Wanamarta AH, van der Klei-van Moorsel JM, Jakobs C, Joenje H.
Monatsh. Chem. 132 (2001) 1295-1326.  Recent advances in the description of the structure of water, the hydrophobic effect, and the like-dissolves-like rule, Schmid, R.
Eur J Appl Physiol Occup Physiol. 1994;69(4):350-4. Hyperammonaemia in relation to high-intensity exercise duration in man. Sewell DA, Gleeson M, Blannin AK.
Toxicology. 1981;22(2):133-47. Relative effects of hyperbaric oxygen on cations and catecholamine metabolism in rats: protection by lithium against seizures. Singh AK, Banister EW. "Lithium itself affects neurological actions but the mechanisms remain obscure. It also modifies the toxic action of oxygen at high pressure (OHP), which causes convulsions, either suppressing or exacerbating it." "...OHP developed a sustained blood and brain hyperammonemia in rats which could be negatively modified by Li+ in the blood." 
Br J Pharmacol. 1996 Sep;119(1):43-8. Investigation of the negative inotropic effects of 17 beta-oestradiol in human isolated myocardial tissues. Sitzler G, Lenz O, Kilter H, La Rosee K, Bohm M.
 Philos Trans R Soc Lond B Biol Sci. 1984 Jan 7;304(1118):69-84. The interactions between pressure and anaesthetics. Smith RA, Dodson BA, Miller KW. Compression of animals causes excitation, which has recently posed a barrier to deeper diving.
Lab Anim Sci. 1977 Oct;27(5 Pt 1):655-9. Oxygen consumption and thyroid function in the squirrel monkey (Saimiri sciureus). Smoake JA, Mulvey PF Jr, Gerben M, Jones LG. [hypermetabolic]
Aging Cell. 2004 Jun;3(3):87-95. Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer. Speakman JR, Talbot DA, Selman C, Snart S, McLaren JS, Redman P, Krol E, Jackson DM, Johnson MS, Brand MD. "We found a positive association between metabolic intensity (kJ daily food assimilation expressed as g/body mass) and lifespan, but no relationships of lifespan to body mass, fat mass or lean body mass."
J Appl Physiol. 1990 Nov;69(5):1651-6. Enhanced leg exercise endurance with a high-carbohydrate diet and dihydroxyacetone and pyruvate. Stanko RT, Robertson RJ, Galbreath RW, Reilly JJ Jr, Greenawalt KD, Goss FL.
Rev Can Biol. 1959 Apr;18(1):23-52. Studies on the mechanism of the catabolic action of estrogens. Sternberg J, Pascoe-Dawson E.
Jpn J Physiol. 1993;43 Suppl 1:S67-75. The origin of rapid changes in birefringence, light scattering and dye absorbance associated with excitation of nerve fibers. Tasaki I, Byrne PM. "Based on the finding that the time-course of the birefringence change accurately coincides with that of swelling of the nerve, optical changes are interpreted as being brought about by invasion of water into the superficial layer of the nerve fibers. A close relationship has also been demonstrated between nerve swelling and changes in light scattering and in dye absorbance."
Postgrad Med J. 2000 Jul;76(897):424-6. Primary hypothyroidism masquerading as hepatic encephalopathy: case report and review of the literature. Thobe N, Pilger P, Jones MP. A 74 year old woman with hepatitis C of long duration was admitted to hospital in hyperammonaemic coma. Despite aggressive treatment of hepatic encephalopathy, there was no clinical improvement. As part of her evaluation for other causes of altered mental status, she was found to be profoundly hypothyroid. Treatment with thyroid replacement hormone was accompanied by prompt normalisation of her mental status and hyperammonaemia. Hypothyroidism may exacerbate hyperammonaemia and portosystemic encephalopathy in patients with otherwise well compensated liver disease. Hyopthyroidism should be considered in the differential diagnosis of encephalopathy in patients with liver disease.
J Trauma. 1992 Jun;32(6):704-12; discussion 712-3. Effects of hypertonic saline dextran resuscitation on oxygen delivery, oxygen consumption, and lipid peroxidation after burn injury. Tokyay R, Zeigler ST, Kramer GC, Rogers CS, Heggers JP, Traber DL, Herndon DN.
Eur J Pharmacol. 1999 Oct 15;382(3):177-85. Influence of increase in osmotic pressure with sucrose on relaxation and cyclonucleotides levels in isolated rat aorta. Tabrizchi R. 
J. Chem. Phys. 117 (2002) 5101-5104. Predicting water's phase diagram and liquid-state anomalies, Truskett TM and K. A. Dill KA.
J Appl Physiol. 1978 Mar;44(3):333-9. Selected brain amino acids and ammonium during chronic hypercapnia in conscious rats. Weyne J, Van Leuven F, Kazemi H, Leusen I. "Hypercapnia increased glutamine and GABA and decreased glutamic and aspartic acids. Changes occurred within 1 h and were maintained during the observation period of 3 wk." "The changes observed may have a role in metabolic pH homeostasis of brain tissue and may also be relevant to the modified brain excitability in hypercapnia."
J Appl Physiol. 2005 Apr 14; Caffeine increases exogenous carbohydrate oxidation during exercise. Yeo SE, Jentjens RL, Wallis GA, Jeukendrup AE.

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A R T I C L E

Meat physiology, stress, and degenerative physiology  

The US Department of Agriculture claims that the Pure Food and Drugs Act of 1906 and the Meat Inspection Act of the same year were passed because the food industry demanded them. Ordinary historians believe that Upton Sinclair's 1905 serial publication of his novel about the meat industry, The Jungle, caused the public and Theodore Roosevelt to pressure Congress to pass the laws. Sinclair's descriptions of the use of poisonous preservatives and deodorants to disguise the smell of rotten meat angered the public and the president enough to overcome the industry pressure that had kept the US Congress from regulating the commercial food supply long after European governments had begun regulating food production and sales.

Before the government's intervention, it was common practice to soak all kinds of meat in water or chemical solutions to increase their weight. At present, the US Department of Agriculture, through the mass media and funding the training of food technologists and "meat scientists," now takes the position that it is natural for meat to leak water after it is packaged, and says it is perfectly legal for meat producers to soak the meat in water with chemicals until it has increased its weight by 8%. The chemicals, such as trisodium phosphate (in a solution strength as high as 12%), are chosen because they powerfully stimulate swelling and water retention. Considerable amounts of some chemicals, such as sodium citrate, are allowed to add to the weight of the meat. The use of ozone and hydrogen peroxide to deodorize meat causes instantaneous oxidative changes, including lipid peroxidation and protein carbonyl formation, as well as increasing water retention.

Most supermarket meat is now packaged with thick diapers so the buyer won't notice that he is paying for a sizeable amount of pink water. The USDA has an internet site, and consumer hotlines, to inform angry consumers that they are mistaken if they believe that meat shouldn't leak. They explain that meat is now "bred" to contain less fat, and so it contains more water, and that it is simply the leanness of the meat that accounts for its poor flavor.

Before the slaughtered animal is put into the soaking solution to gain a specific amount of weight, the animal has almost always been treated in ways that cause it to go to slaughter in a state of massive edema. Even before the meat is soaked, the animal has been treated to maximize its water retention.

Muscle physiologists and endocrine physiologists know that fatigue, stress and excess estrogen can cause the tissues to swell hugely, increasing their weight and water content without increasing their protein content.

As soon as cheap synthetic estrogens, such as DES, became available in the 1940s, their use in animals was promoted because it was clear that they caused massive water retention. Women who suffer from hyperestrogenism always have a problem with water retention, but they have never been known to suffer from over-developed skeletal muscles. In fact, in humans of both sexes, an excess of estrogen has been commonly associated with sarcopenia, muscular dystrophy, and atrophy of the skeletal muscles. Similar observations have been made in a variety of animals. Meat scientists are the only people I know of who have ever referred to estrogen as an anabolic steroid, in the sense of "building muscle."

When it was publicized around 1970 that DES is powerfully carcinogenic, after it had been used for several decades in the meat industry, its use was outlawed, but its illegal use continued and was overlooked by the US government. The Swiss government has rejected meat from a large producer in Kansas because it contained DES. Other estrogens are openly used, and the US government continues to apply pressure to other countries to accept meat exports containing estrogens.

There are many ways to increase the water content of meat, besides feeding estrogen to the animal and soaking the meat after slaughter. Everything that causes water retention and tissue swelling in the living animal, that is, every kind of stress, fatigue, poisoning, malnutrition and injury, will make the animal gain weight, without consuming expensive nutritious food. Crowding, fright, and other suffering increase water retention and accelerate the breakdown of fats and proteins.

The water content of meat shouldn't be increased by any of those methods, not only because it is a form of stealing from the consumer, but because it makes the product toxic and unappetizing, and makes the production process a degrading experience. 
Any chemicals, such as estrogen or arsenic, that remain in the meat are of course harmful to the consumer, but the changes they produce in the animals' tissues are the main problem. When grains and soybeans are used for fattening animals, their characteristic fatty acids are present in the meat, and are harmful to the consumer, but their complex degradation products, such as isoprene, acrolein, and isoprostanes, remain, along with the complex changes they induce in every aspect of the tissue. The reactive products of oxidative fat degradation stimulate, among other things, the adaptive/defensive production of polyamines, small molecules derived from amino acids. The polyamines, in turn, can be oxidized, producing highly toxic aldehydes, including acrolein (Sakata, et al., 2003). These molecules stimulate cell multiplication, and alter, at least temporarily, the way the cell's genes function.
An excess of water stimulates cell division, and an important mechanism in producing that effect is the increased production of polyamines by the enzyme ornithine decarboxylase. This enzyme is activated by an excess of water (hypotonicity), by estrogen, and by stress.

Besides stimulating cell division and modifying the cell's state of differentiation (including developmental imprinting), the polyamines also contribute to nerve cell excitation and excitotoxicity. Estrogen and excess water can contribute to nerve cell excitation, for example producing convulsive seizures. The polyamines are increased during seizures, and they can affect the stability of the nerve cells, for example contributing to cocaine's seizure-sensitizing action. Although they tend to block free radicals, they accelerate nerve injury (Yatin, et al., 2001), and can contribute to breakdown of the blood-brain barrier (Wengenack, et al., 2000, Koenig, et al., 1989).

The polyamines are increased in cancers, and therapies to block their formation are able to stop the growth of various cancers, including prostate, bowel, and breast cancer. Metabolites of the polyamines in the urine appear to be useful as indicators of cancer and other diseases. (In pancreatic cancer, Yamaguchi, et al., 2004; in cervical cancer, Lee, et al., 2003; in adult respiratory stress syndrome, Heffner, et al., 1995.)  The quantity of polyamines in the urine of cancer patients has been reported to be 20 times higher than normal (Jiang, 1990). Polyamines in the red blood cells appear to indicate prognosis in prostate cancer (Cipolla, et al., 1990).

The prostaglandins in semen have been suspected to have a role in producing cervical cancer (Fernandez, et al., 1995).
In protein catabolism, one fate of the protein's nitrogen is to be converted to the polyamines, rather than to urea. In plants, at least, these small molecules help cells to balance osmotic stresses.

Adding water to meat, or stressing the animals before slaughter, will increase the meat's content of the polyamines, but the longer the meat is stored, the greater will be the production of reactive oxygen products and polyamines. 

The deliberate "aging" of meat is something that the meat scientists often write about, but it has a peculiar history, and is practiced mainly in the English speaking cultures. When a supermarket in Mexico City began selling U.S.-style meat for the American colony, I got some T-bone steaks and cooked them for some of my Mexican friends. The meat wasn't water-logged (it was 1962, and the beef had been grown in Mexico), but it had been aged for the American customers, and though my friends ate the steaks for the sake of politeness, I could see that they found it difficult. 

In Mexico, even in the present century, butcher shops often don't have refrigeration, and they don't need it because they sell the meat immediately. The fresh meat tastes fresh. Traditionally, liver is sold only on the day of slaughter, because its high enzyme content causes it to degrade much faster than the muscle meats. When it is fresh, it lacks the characteristic bad taste of liver in the US. 

Both the liver and the muscles contain a significant amount of glycogen when they are fresh, if the animal was healthy. At first, the lack of oxygen causes the glycogen to be metabolized into lactic acid, and some fatty acids are liberated from their bound form, producing slight changes in the taste of the meat. But when the glycogen has been depleted, the anaerobic metabolism accelerates the breakdown of proteins and amino acids.

In the absence of oxygen, no carbon dioxide is produced, and the result is that the normal disposition of ammonia from amino acids as urea is blocked, and the polyamines are formed instead. The chemical names of two of the main poly-amines are suggestive of the flavors that they impart to the aging meat: Cadaverine and putrescine. After two or three weeks of aging, there has been extensive breakdown of proteins and fats, with the production of very complex new mixtures of chemicals.

Mexicans, despite their low average income, have a very high per capita consumption of meat, as do several other Latin American countries. Argentina has a per capita meat consumption of nearly a pound a day. There is a lot of theorizing about the role of meat in causing cancer, for example comparing Japan's low mortality from prostate cancer, and their low meat consumption, with the high prostate cancer mortality in the US, which has a higher meat consumption. But Argentina and Mexico's prostate cancer mortality ranks very favorably with Japan's. 

If meat consumption in the US contributes to the very high cancer rate, it clearly isn't the quantity of meat consumed, but rather the quality of the meat.

The polar explorer Vilhjalmur Stefansson was interested in the health effects of a diet based on meat, because of his observation that fresh meat prevented scurvy much more effectively than the fruits and vegetables carried by other polar explorers. He commented on the importance of culture and learning in shaping food preferences:

"In midwinter it occurred to me to philosophize that in our own and foreign lands taste for a mild cheese is somewhat plebeian; it is at least a semi-truth that connoisseurs like their cheeses progressively stronger. The grading applies to meats, as in England where it is common among nobility and gentry to like game and pheasant so high that the average Midwestern American or even Englishman of a lower class, would call them rotten.

 "I knew of course that, while it is good form to eat decayed milk products and decayed game, it is very bad form to eat decayed fish. I knew also that the view of our populace that there are likely to be "ptomaines" in decaying fish and in the plebeian meats; but it struck me as an improbable extension of the class-consciousness that ptomaines would avoid the gentleman's food and attack that of a commoner.

 "These thoughts led to a summarizing query; If it is almost a mark of social distinction to be able to eat strong cheeses with a straight face and smelly birds with relish, why is it necessarily a low taste to be fond of decaying fish? On that basis of philosophy, though with several qualms, I tried the rotten fish one day, and if memory serves, liked it better than my first taste of Camembert. During the next weeks I became fond of rotten fish."

Since Stefansson's observations nearly a century ago, most Americans have become accustomed to the taste of half-spoiled meat, as part of the process of adapting to an industrial-commercial food system. Tests done by food technologists have found that most Americans prefer the taste of synthetic strawberry flavor in ice cream to the taste of ice cream made with real strawberries. If it took Stefansson only a few weeks to become fond of rotten fish, it isn't surprising that the public would, over a period of many decades, learn to enjoy a diet of stale foods and imitation foods. 

Polyamines are increased in stressed and stored vegetables, as in aged meats. This defensive reaction retards tissue aging, and researchers are testing the application of polyamines to fruits to retard their ripening. A plastic surgeon, Vladimir Filatov, discovered that tissue stored in the cold stimulated the healing process when used for tissue reconstruction, such as corneal transplants. He found that stressed plant tissues developed the same tissue stimulants. Another pioneer of tissue transplantation, L.V. Polezhaev, saw that degenerating tissue produced factors that seem to activate stem cells.

Although the diffusion of these stimulating factors from stressed tissues normally functions to accelerate healing and tissue regeneration, under less optimal conditions they are undoubtedly important factors in tissue degeneration and tumor formation. For example, the bystander effect (contributing to delayed radiation damage, and producing a field of precancerous changes around a cancer), in which substances diffusing from injured tissues damage surrounding cells, involves disturbances in polyamine metabolism.

The direct, optimal effects of the polyamines are protective, but when excessive, prolonged, or without maintained cellular energy, they become harmful.

The expression of genes involves their physical arrangement and accessibility to enzymes and substrates. The negatively charged nucleic acids are associated with positively charge proteins, the histones. The very small positively charged polyamines can powerfully modify the interactions between histones and DNA. In recent years people have begun to speak of the "histone code," as a kind of expansion of the idea of the "genetic code." But the polyamines, produced in response to stress, might be thought of as a complex expansion of the "histone code."

The addition of small molecules, methyl and acetyl groups, to the large molecules can regulate the expression of genes, and these patterns can be passed on transgenerationally, or modified by stress. Barbara McClintock's "controlling factors" were mobile genes that caused the genome to be restructured under the influence of stress. Her discoveries were the same as those made by Trofim Lysenko decades earlier, and like his observations, McClintock's were angrily rejected until the 1980s, when the genetic engineering industry needed some scientific background and natural precedent for their unnatural intervention in the genome.

The brain is extremely different from a malignant tumor, and the derangements produced by stress, by high cortisol and estrogen and an excess of water, are different in the two types of organ (considering the tumor as an ad hoc organ), but the polyamines have central roles in the degenerating brain and in the divergent disorganization of tumors. Their importance in stress physiology is coming to be recognized, along with the meaning of "epigenetic development," in which the influence of the environment becomes central, rather than just a place in which the "genotype" is allowed to passively express its "genetic potential." Every developmental decision involves an evaluation of resources and their optimal marshaling for adaptation. The polyamines are part of the cytoplasm's equipment for controlling the genome. The ratio between the different types of polyamine governs the nature of their regulation of cellular functions.

The old idea, "one is what one eats," has evolved far beyond ideas of simple nutritional adequacy or deprivation, and it's now commonly accepted that many things in foods have fairly direct effects on our brain transmitters and hormones, such as serotonin, dopamine, adrenalin, endorphins, prostaglandins, and other chemicals that affect our behavior and physiology.

In 1957 James McConnell discovered that when flatworms were fed other flatworms that had been trained, their performance was improved by 50%, compared with normal flatworms. Later, similar experiments were done with rats and fish, showing that tissue extracts from trained animals modified the behavior of the untrained animals so that it approximated that of the trained animals. Georges Ungar, who did many experiments with higher animals, demonstrated changes in brain RNA associated with learning, and he and McConnell believed that proteins and peptides were likely to be the type of substance that transmitted the learning.

A dogmatic belief that "memory molecules" would be unable to penetrate the "blood-brain barrier" allowed most biologists to dismiss their work. Ungar's death, and the hostility of most biologists to their work, have caused their ideas to be nearly forgotten for the last 30 years. Negatively charged molecules such as ordinary proteins tend to be repelled by negative charges on the wall of capillaries, but positively charged molecules spontaneously associate with cellular proteins, and easily penetrate the barrier. Highly positively charged molecules tend to concentrate in the brain (Jonkman, et al., 1983), and people are currently attempting to use the principle to deliver antibodies (which are normally excluded from the brain) therapeutically to the brain by combining them with small positively charged molecules (Herve, et al., 2001). This affinity of the brain for positively charged molecules is gradually being recognized as an important factor in the toxicity of ammonia and guanidine derivatives. As mentioned earlier, even endogenous polyamines can be involved in disruption of the blood-brain barrier.

So, apart from the question of exactly what molecules were responsible for the learning transfer produced by McConnell and Ungar, there should be no doubt that polyamines derived from food can enter tissues, especially the brain. People who eat meat from stressed animals are substantially replicating the experiments of McConnell and Ungar, except that people normally eat a variety of foods, and each type of food will have had slightly different experiences in its last days of life. But the deliberate aging of meat is subjecting it to a standardized stress--two or three weeks of cold storage. Because of the great generality of genetic processes, it wouldn't be surprising if cold storage of vegetables turned out to produce polyamine patterns similar to those of cold storage meats. Air pollution and other stressful growing conditions cause vegetables to have very high levels of polyamines.

Prolonged exposure to certain patterns of polyamines might produce particular syndromes, but the mere fact of increasing the total quantity of polyamines in our diet is likely to increase the incidence of stress-related diseases. Experiments with cells in culture show that added polyamines can produce a variety of extremely harmful changes, but so far, there has been almost no investigation of their specific regulatory functions, of their "code."

Besides rejecting stale foods produced under stressful conditions, there are probably some specific ways that we can protect ourselves from polyamine poisoning.

When the organism is functioning efficiently, its respiration is producing an abundance of carbon dioxide, which protectively modifies many systems and structures. Adequate carbon dioxide protects against fatigue, cellular and vascular leakiness, edema and swelling.

Increasing carbon dioxide will tend to direct ammonia into urea synthesis, and away from the formation of polyamines. Bicarbonate protects against many of the toxic effects of ammonia, and since carbon dioxide spontaneously reacts with amino groups, it probably helps to inactivate exogenous polyamines. This could account for some of the protective effects of carbon dioxide (or high altitude), for example its anti-seizure, anticancer, and antistress effects.

Other things that protect against excessive polyamines are procaine and other local anesthetics (Yuspa, et al., 1980), magnesium, niacin, vitamin A, aspirin, and, in some circumstances, caffeine. Since endotoxin stimulates the formation of polyamines, a diet that doesn't irritate the intestine is important. Tryptophan and methionine contribute to the formation of polyamines, so gelatin, which lacks those amino acids and is soothing to the intestine, should be a regular part of the diet.

Because the polyamines intensity the neurotoxic and carcinogenic effects of estrogen and of polyunsaturated fats, those three types of substance should be considered as a functional unit in making food choices. (Grass-fed organic beef fresh from a local farm would be a reasonable choice.) Unfortunately, the meat industry has maximized all of those dangers, just for the increased weight of their product. 

REFERENCES
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 J Clin Gastroenterol. 1989 Aug;11(4):434-41. Intestinal autointoxication: a medical leitmotif. Chen TS, Chen PS. The idea that putrefaction of the stools causes disease, i.e., intestinal autointoxication, originated with physicians in ancient Egypt. They believed that a putrefactive principle associated with feces was absorbed in to the general circulation, where it acted to produce fever and pus. This description of the materia peccans represented the earliest forerunner of our present notion of endotoxin and its effect. The ancient Greeks extended the concept of putrefaction to involve not only the residues of food, but also those of bile, phlegm, and blood, incorporating it into their humoral theory of disease. During the 19th century, the early biochemical and bacteriologic studies lent credence to the idea of ptomaine poisoning--that degradation of protein in the colon by anerobic bacteria generated toxic amines. Among the leading proponents of autointoxication was Metchnikoff, who hypothesized that intestinal toxins shortened lifespan. The toxic process, however, was reversed by the consumption of lactic acid-producing bacteria that changed the colonic microflora and prevented proteolysis. The next logical step in treatment followed in the early 20th century when surgeons, chief among them Sir W. Arbuthnot Lane, performed colectomy to cure intestinal autointoxication. By the 1920s, the medical doctrine fell into disrepute as scientific advances failed to give support. However, the idea persists in the public mind, probably as an extension of the childhood habit of toilet training.    
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Endokrinologie. 1982 Nov;80(3):294-8. The effect of androgen and estrogen on food intake and body weight in rats--age dependency. Kuchar S, Mozes S, Boda K, Koppel J. 
Cancer Lett. 2003 Nov 25;201(2):121-31.  Altered urinary profiles of polyamines and endogenous steroids in patients with benign cervical disease and cervical cancer. Lee SH, Yang YJ, Kim KM, Chung BC.
Oncol Res. 2005;15(3):113-28. Activation of cyclin D1 by estradiol and spermine in MCF-7 breast cancer cells: a mechanism involving the p38 MAP kinase and phosphorylation of ATF-2. Lewis JS, Vijayanathan V, Thomas TJ, Pestell RG, Albanese C, Gallo MA, Thomas T.
Nucleic Acids Res. 2005 Mar 23;33(6):1790-803. Print 2005. Polyamines preferentially interact with bent adenine tracts in double-stranded DNA. Lindemose S, Nielsen PE, Mollegaard NE. "Polyamines, such as putrescine, spermidine and spermine, have indirectly been linked with the regulation of gene expression, and their concentrations are typically increased in cancer cells." "These results provide the first clear evidence for the sequence-specific binding of polyamines to DNA, and thereby suggest a mechanism by which the cellular effects of polyamines in terms of differential gene transcriptional activity could, at least partly, be a direct consequence of sequence-specific interactions of polyamines with promoters at the DNA sequence level."
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Gastroenterol Clin North Am 1988 Dec;17(4):931-40. Biochemical markers in colorectal cancer: diagnostic and therapeutic implications.  Luk GD, Desai TK, Conteas CN, Moshier JA, Silverman AL .
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J Anim Sci  1995 Jul;73(7):1982-6.Effects of ground flaxseed in swine diets on pig performance and on physical and sensory characteristics and omega-3 fatty acid content of pork: I. Dietary level of flaxseed. Romans JR, Johnson RC, Wulf DM, Libal GW, Costello WJ.
J Anim Sci  1995 Jul;73(7):1987-99. Effects of ground flaxseed in swine diets on pig performance and on physical and sensory characteristics and omega-3 fatty acid content of pork: II. Duration of 15% dietary flaxseed. Romans JR, Wulf DM, Johnson RC, Libal GW, Costello WJ.
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Biochem Biophys Res Commun. 2003 May 23;305(1):143-9. Increase in putrescine, amine oxidase, and acrolein in plasma of renal failure patients. Sakata K, Kashiwagi K, Sharmin S, Ueda S, Irie Y, Murotani N, Igarashi K.
Biochem Soc Trans. 2003 Apr;31(2):375-80. Polyamines and prostatic cancer. Schipper RG, Romijn JC, Cuijpers VM, Verhofstad AA.
Nitric Oxide. 2000 Dec;4(6):583-9. Nitric oxide synthase inhibition promotes carcinogen-induced preneoplastic changes in the colon of rats. Schleiffer R, Duranton B, Gosse F, Bergmann C, Raul F. "l-Arginine is metabolized either to polyamines through arginase and ornithine decarboxylase (ODC) activities or to citrulline and nitric oxide (NO, nitrogen monoxide) through the NO synthase (NOS) pathway. Polyamine levels and ODC activity are high in tumor cells. The aim of this study was to test whether N(G)-nitro-l-arginine methyl ester (l-NAME), an inhibitor of NOS, modulates colon carcinogenesis." "In l-NAME-treated rats, the number of ACF was higher than in controls by 47%. ODC activity was enhanced by 11-fold. S-Adenosyl-methionine-decarboxylase activity and putrescine concentration were significantly increased in the colonic mucosa of l-NAME-treated rats. The data suggest that l-NAME promotes carcinogen-induced preneoplastic changes in the colon by inhibiting NOS activity and by stimulating polyamine biosynthesis."
Brain Res. 1997 Nov 14;775(1-2):198-202. Role of cerebral spermidine in the development of sensitization to convulsant activity of cocaine and lidocaine. Shimosato K, Watanabe S, Katsura M, Ohkuma S.
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http://www.fsis.usda.gov/wps/portal/fsis/topics/food-safety-education/get-answers/food-safety-fact-sheets/meat-preparation/water-in-meat-and-poultry/CT_Index
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J Neurosci Res. 2001 Mar 1;63(5):395-401. Role of spermine in amyloid beta-peptide-associated free radical-induced neurotoxicity. Yatin SM, Yatin M, Varadarajan S, Ain KB, Butterfield DA.
Mol Endocrinol. 2003 May;17(5):831-44. Epub 2003 Jan 23. Estrogen enhances depolarization-induced glutamate release through activation of phosphatidylinositol 3-kinase and mitogen-activated protein kinase in cultured hippocampal neurons. Yokomaku D, Numakawa T, Numakawa Y, Suzuki S, Matsumoto T, Adachi N, Nishio C, Taguchi T, Hatanaka H.
Poult Sci. 2004 Mar;83(3):400-5. Water-holding capacity in chicken breast muscle is enhanced by pyruvate and reduced by creatine supplements. Young JF, Karlsson AH, Henckel P.
 Proc Natl Acad Sci U S A. 1980 Sep;77(9):5312-6. Local anesthetics inhibit induction of ornithine decarboxylase by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate. Yuspa SH, Lichti U, Ben T. 
Exp Oncol. 2004 Sep;26(3):221-5. Role of polyamines in the function of nuclear transcription factor NF-kappaB in breast cancer cells. Zaletok S, Alexandrova N, Berdynskykh N, Ignatenko N, Gogol S, Orlovsky O, Tregubova N, Gerner E, Chekhun V.
Arkh Patol 1995 Jul-Aug;57(4):89-92. Biological markers of precancer of the large intestine. Zagrebin VM.

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A R T I C L E

MULTIPLE SCLEROSIS AND OTHER HORMONE-RELATED BRAIN SYNDROMES (1993)

Since I am trying to discuss a complex matter in a single article, I have separately outlined the essential technical points of the argument in a section at the beginning, then I explain how my ideas on the subject developed, and finally there is a glossary.  If you start with "Short-day brain stress," "Estrogen's effects," and "Symptoms and therapies," you will have the general picture, and can use the other sections to fill in the technical details.

THE ARGUMENT:   

1) The hormones pregnenolone, thyroid, and estrogen are involved in several ways with the changes that occur in multiple sclerosis, but no one talks about them.

2) The process of myelination is known to depend on the thyroid hormone.  The myelinating cells are the oligodendroglia (oligodendrocytes) which appear to stop functioning in MS (and  sometimes to a milder degree in Alzheimer's disease, and other  conditions).  The cells' absorption of thyroid hormone is influenced by dietary factors.

3) The oligodendrocytes are steroid-producing cells (1),  and steroidogenesis is dependent on thyroid hormone, and on  thyroid-dependent respiratory enzymes and on the heme-enzyme P-450scc, which are all sensitive (2) to poisoning by carbon monoxide and cyanide.  The steroid produced by the oligodendrocytes is pregnenolone, which is known to have a profound  anti-stress action (3), and which appears to be the main  brain-protective steroid.

4) Lesions resembling those of MS can be produced experimentally by carbon monoxide or cyanide poisoning.(4)  The lesions  tend to be associated with individual small blood vessels, which   are likely to contain clots.  (Since all animals have enzymes to  detoxify cyanide, this poison is apparently a universal problem,  and can originate in the bowel. "Detoxified" cyanide is still toxic to the thyroid.) 

5) Pregnenolone and progesterone protect against nerve damage (5) by the excitotoxic amino acids (glutamic acid, aspartic acid, monosodium glutamate, aspartame, etc.), while estrogen (6) and cortisol (7) are nerve-destroying, acting through the excitotoxic amino acids.  Excitotoxins destroy certain types of nerve, especially the dopaminergic and cholinergic types, leaving the noradrenergic types (8), paralleling the changes that occur in aging.  The clustering of oligodendrocytes around deteriorating nerve cells could represent an adaptive attempt to provide pregnenolone to injured nerve cells.

6) The involvement of hormones and environmental factors probably accounts for the intermittent progress of multiple sclerosis. To the extent that the environmental factors can be  corrected, the disease can probably be controlled.

 SHORT-DAY BRAIN STRESS

Shortly after I moved from Mexico to Montana, one of my students, a 32 year old woman, began having the same sensory symptoms her older sister had experienced at the same age, at the onset of multiple sclerosis.  Vertigo and visual distortions of some sort made her consider withdrawing from the university. I'm not sure why she tried eating a whole can of tuna for lunch a couple of days after the onset of symptoms, but it seemed to alleviate the symptoms, and she stayed on a high protein diet and never had a recurrence.  She told me some of the lore of MS: That it mostly affects young adults between the ages of 20 and 40, that it is common in high latitudes and essentially unknown in the tropics, and that it is sometimes exacerbated by pregnancy and stress.  (Later, I learned that systemic lupus erythematosis and other "auto-immune" diseases also tend to occur mainly during the reproductive years.  I discussed some of the implications of this in "Bean Syndrome.")

Having enjoyed the mild climate of Mexico, I became very conscious of the harm done to us by northern winters, and began developing the idea of "winter sickness."  In 1966-67, allergies, PMS, weight gain, colitis, and arthritis came to my attention as winter-related problems, and I assumed that the high-latitude incidence of MS related to what I was seeing and experiencing.  Studies in Leningrad began revealing that mitochondria are injured during darkness, and repaired during daylight.  I observed that hamsters' thymus glands shrank in the winter and regenerated in the summer; shrinkage of the thymus gland is a classical feature of stress, and usually reflects the dominance of cortisone, though estrogen and testosterone also cause it to shrink.  Winter's darkness is stressful in a very fundamental way, and like any stress it tends to suppress thyroid function.  In the hypothyroid state, any estrogen which is produced tends to accumulate in the body, because of liver sluggishness.

I began to see that PMS could be controlled by certain things--extra light, supplements of sodium and magnesium, high quality protein, and correction of deficiencies of thyroid and progesterone.  In working on my dissertation, I saw that tissue hypoxia (lower than optimal concentrations of oxygen in the blood) may result from estrogen excess, vitamin E deficiency, or aging.  There is a close biological parallel between estrogen-dominance and the other hypoxic states, such as stress/shock, and aging.

ESTROGEN'S EFFECTS

As a portrait painter, I had been very conscious of the blue aspect that can often be seen in the skin of young women. In pale areas, the color may actually be blue, and in areas with a rich supply of blood, such as the lips, the color is lavender during times of high estrogen influence--around ovulation and puberty, for example.  During these times of estrogen dominance, the blood is not only poorly oxygenated, but it has other special properties, such as an increased tendency to clot.  The Shutes' work in the 1930s began with the use of vitamin E to antagonize estrogen's clot-promoting tendency, and led them to the discovery that vitamin E can be very therapeutic in heart disease.  More recently, it has been found that men with heart disease have abnormally high estrogen (9), that women using oral contraceptives have higher mortality from heart attacks (10), and that estrogen tends to  promote spasm of blood vessels (11).  (These reactions are probably  related to the physiology of menstruation, in which progesterone withdrawal causes spasms in the spiral arteries of the uterus,  producing endometrial anoxia and cell death.)

In toxemia of late pregnancy, or eclampsia, the exaggerated clotting tendency caused by excess estrogen (or by inadequately opposed estrogen, i.e., progesterone deficiency), can cause convulsions and strokes.  Vascular spasms could be involved here, too.  The stasis caused by the vasospasm would facilitate clotting. (Vascular spasm has been observed in epilepsy, too.  Epilepsy can be brought on by the premenstrual excess of estrogen, and in that situation there is no evidence that clotting is involved.  Leakage of hemoglobin out of red cells can cause vasospasm, so bleeding, clotting, strokes, and seizures can interact complexly.)  The brains of women who have died following eclampsia show massive clotting in the blood vessels, and their livers are characteristically injured, with clots (12).

Tom Brewer and others have shown very clearly that malnutrition, especially protein deficiency, is the cause of toxemia of late pregnancy.  (In Nutrition for Women, I discussed the importance of protein in allowing the liver to eliminate estrogen.)

Various researchers have demonstrated that the plaques of MS usually occur in the area served by a single blood vessel (13, 14), and some have suggested that clotting is the cause.  MS patients have been found to have an abnormal clotting time, and it has been suggested that an altered diet might be able to correct the clotting tendency.

Studies in animals have shown clearly that a protein deficiency increases the fibrinogen content of blood. (Field and Dam, 1946.)  Other factors that increase blood clotting are elevated adrenalin and cortisone.  Protein deficiency causes an adaptive decrease in thyroid function, which leads to a compensatory increase in adrenaline and cortisone.  The combination of high estrogen with high adrenaline increases the tendency for both clots and spasms of the blood vessels (11).

In experimental poisoning of animals with carbon monoxide or cyanide, the brain lesions resembling MS include blood clots.  The patchy distribution of these spots in the brain suggests that the clotting is secondary to metabolic damage in the brain.  Presumably, the same would be true in ordinary MS, with clots and spasms being induced in certain areas by metabolic abnormalities in brain cells.  The injured cells that are responsible for myelination of nerve fibers are steroid-forming cells.  A failure to secrete their protective pregnenolone could cause a local spasm of a blood vessel.  The circulatory problem would exacerbate the respiratory problem. Steroid production is dependent on NADH and NADPH, and so requires adequate energy supplies and energy metabolism.  The phenomenon of blood-sludging, studied by M. Knisely at the University of Chicago in the l930s and l940s, is apparently a general result of decreased energy metabolism, and is likely to be a factor in energy-and-circulatory vicious circles.

SYMPTOMS AND THERAPIES         

Around 1976 I met a woman in her mid-thirties who heard about my work with progesterone in animals.  She had been disabled by a brain disease that resembled MS or Devic's disease, inflammation of the optic nerves.  It would sometimes cause blindness and paralysis that persisted for weeks at a time.  During remissions, sometimes using a wheelchair, she would go to the medical school library to try to understand her condition.  She came across Katherina Dalton's work with progesterone, and convinced a physician to give her a trial injection.  Although she had trouble finding people who were willing to give her progesterone, her recovery was so complete that she was able to climb stairs and drive her car, and she came  to my endocrinology class and gave a very good (and long) lecture on progesterone therapy.  Although her sensory and motor functions became normal, she remained very fat, and chronically suffered from sore areas on her arms and legs that seemed to be abnormal blood vessels, possibly with phlebitis.  She appeared to need thyroid hormone as well as larger amounts of progesterone, but never found a physician who would cooperate, as far as I know.

In the late 1970s I was seeing a lot of people who had puzzling health problems.  In a period of two or three years, there were five people who had been diagnosed by neurologists as having multiple sclerosis.  In talking to them, it seemed clear that they had multiple symptoms of hypothyroidism.   They weren't severely disabled.  Since they weren't fat or lethargic, their physicians hadn't thought they could be hypothyroid.  When they tried taking a thyroid supplement, all of their symptoms disappeared, including those that had led to their MS diagnosis.  One of the women went to her doctor to tell him that she felt perfectly healthy since taking thyroid, and he told her to stop taking it, because people who have MS need a lot of rest, and she wouldn't get enough rest if she was living in a normally active way. The assumption seemed to be that the diagnosis was more important than the person. (When I refer to a "thyroid supplement" I mean one that contains some T3.  Many people experience "neurological symptoms" when they take thyroxine by itself.  Experimentally, it has been found to suppress brain respiration, probably by diluting the T3 that was already present in the brain tissue.)  

METABOLISM OF THE OLIGODENDROCYTES

The rate-regulating step in steroid synthesis involves the entry of cholesterol into the mitochondria, where the heme-enzyme P-450scc then removes the side-chain of cholesterol  (by introducing oxygen atoms), to produce pregnenolone.  This enzyme can be poisoned by carbon monoxide or cyanide, and light can eliminate the poison (15); this could be one aspect of the winter-sickness problem.  

Peripheral nerves are myelinated by essentially the same sort of cell that is called an oligodendrocyte in the brain, but outside the brain it is called a Schwann cell.  It is easier to study the myelin sheath in peripheral nerves, and the electrical activity of a nerve is the most easily studied aspect of its physiology.  Certain experiments seemed to indicate a "jumping" (saltatory) kind of conduction along the nerve between Schwann cells, and it was argued that the insulating function of the myelin sheath made this kind of conduction possible.  This idea has become a standard item in physiology textbooks, and its familiarity leads many people to assume that the presence of myelin sheaths in the brain serves the same "insulating" function.

For a long time it has been known that heat production during nerve conduction reveals a more continuous mode of  conduction, that doesn't conform to the idea of an electrical  current jumping around an insulator.  Even if the myelin functioned primarily to produce "saltatory conduction" in peripheral nerves, it isn't clear how this process could function in the brain.  I think of the issue of "saltatory conduction at the nodes of Ranvier" as another of the fetish ideas that have served to obstruct progress in biology in the United States.  A more realistic approach to nerve function can be found in Gilbert Ling's work.  Ling has demonstrated in many ways that the ruling dogma of "cell membrane" function isn't coherently based on fact.  He found that hormones such as progesterone regulate the energetic and structural stability of cells.  Many people, unaware of his work, have felt that it was necessary to argue against the idea that there are anesthetic steroids with generalized protective functions, because of their commitment to a textbook dogma of "cell membrane" physiology.

I think the myelinating cells do have relevance to nerve conduction, but I don't think they serve primarily as electrical insulators.  If the adrenal cortex were inside the heart, it would be obvious to ask whether its hormones aren't important for the heart's function.  Since the oligodendrocytes are steroid-synthesizers, it seems obvious to ask whether their production of pregnenolone in response to stress or fatigue isn't relevant to the conduction processes of the nerves they surround.                             

OLD AGE

A biologist friend of mine who was about 85 became very senile.  His wife started giving him thyroid, progesterone, DHEA and pregnenolone, and within a few days his mental clarity had returned.  He continued to be mentally active until he was 89, when his wife interfered with his access to the hormones.

In old age the brain steroids fall to about 5% of their level in youth.  Pregnenolone and DHEA improve memory in old rats, and improve mood stability and mental clarity of old people.  Pregnenolone's action in improving the sense of being able to cope with challenges probably reflects a quieting and coordinating of the "sequencing" apparatus of the forebrain, which is the area most sensitive to energy deprivation.  This is the area that malfunctions in hyperactive and "dyslexic" children.  Weakening of the sequencing and sorting processes probably explains the common old-age inability to extract important sounds from environmental noise, creating a kind of "confusion deafness."  Insomnia, worry and "restless legs" at bedtime are problems for many old people, and I think they are variations of the basic energy-depletion problem.

The oligodendrocytes were reported (Hiroisi and Lee, 1936) to be the source of the senile plaques or amyloid deposits of Alzheimer's disease.(16)  Hiroisi and Lee showed the cells in different stages of degeneration, ending with translucent "mucoid" spots that stained the same as amyloid, the material in the senile plaques.  This type of cell also appears to form a halo or crown around degenerating nerve cells--possibly in a protective reaction to provide the nerve cell  with any pregnenolone the oligodendrocytes are able to make.  The  oligodendrocytes, the source of the brain steroids (that people previously believed came from the adrenals and gonads, and were just stored in the brain), myelinate nerve fibers under the  influence of thyroid hormone (17).  Thyroid is responsible for both myelination and hormone formation.  In old age, glial cells become more numerous, and nerve cells become structurally  and functionally abnormal, but usually there is no problem  with the formation of myelin.  In MS, the problem is just with  myelination, and there are no senile plaques or defects in the  nerve cells themselves.  

     These differences suggest the possibility that Alzheimer's  disease involves a specific premature loss of brain pregnen-  olone production, but not of thyroid.  Recent work suggests a central role for pregnenolone and progesterone in the regulation of consciousness (18), and possibly in the brain's detoxifying system.  Elsewhere, I have suggested that vitamin A deficiency might cause the excessive production of the "amyloid" protein.  A vitamin A deficiency severely inhibits steroid synthesis.  (It is used so massively in steroid synthesis that a progesterone supplement can prevent the symptoms of vitamin A deficiency.)  I suspect that vitamin A is necessary for the side-chain cleavage that converts cholesterol to pregnenolone.  Iron-stimulated lipid peroxidation is known to block steroid formation, and vitamin A is very susceptible to destruction  by iron and oxidation.  Iron tends to accumulated in tissues  with aging.  Gajdusek has demonstrated that brain deterioration  is associated with the retention of whatever metal happens to be abundant in the person's environment, not just with aluminum.  (One type of glial cell is known for its metal-binding function, causing them to be called "metallophils.").  According to Gajdusek, "calcium and other di- and trivalent elements" are "deposited as hydroxyapatites in brain cells" in brain degeneration of the Alzheimer's type.(19)

Even early forms of Alzheimer's disease begin at an age  when the youth-associated steroids have begun to decline. If  MS involves a deficiency of thyroid (or of T3 within the oligodendrocytes, where T3 normally can be made from thyroxine; many things, including protein deficiency, can block the conversion of T4 to T3), those cells would necessarily be deficient in their ability to produce pregenolone, but in  young people the brain would still be receiving a little pregnenolone, progesterone, and DHEA from the adrenals and gonads.  This relatively abundant youthful supply of hormones would keep most of the body's organs in good condition,  and could keep the bodies of the major brain cells from deteriorating. But if proper functioning of the nerve fibers requires that they be fed a relatively high concentration of pregnenolone from their immediately adjacent neighbors (with the amount increasing during stress and fatigue), then their function would be impaired when they had to depend on the hormones that arrived from the blood stream.

For many years it has been recognized that the brain atrophy of "Alzheimer's disease" resembles the changes seen in the brain in many other situations:  The traumatic dementia of boxers; toxic dementia; the slow-virus diseases; exposure of the brain to x-rays (20); ordinary old age; and in people with Down's syndrome who die around the age of thirty.           

In menopause, certain nerve cells have lost their ability to regulate the ovaries, because of prolonged exposure to estrogen (6).  The cells that fail as a result of prolonged estrogen exposure aren't the same cells that fail from prolonged exposure to the glucocorticoids (7), but they have in common the factor of excitatory injury.

Since people who experience premature menopause are known to be more likely than average to die prematurely, it is reasonable to view menopause as a model of the aging process. It is now well established that progesterone fails to be produced at the onset of menopause (the first missed period, increased loss of calcium, symptoms such as hot flashes, etc.), and that estrogen continues to be produced at monthly intervals for about four years.  The essential question for aging, in the present context, is why the anesthetic steroids are no longer produced at a rate that allows them to protect tissues, including brain cells, from the excitotoxins.  Using menopause as a model for aging, we can make the question more answerable by asking why progesterone stops being produced.

During stress, we are designed not to get pregnant, and the simplest aspect of this is that ACTH, besides stimulating the adrenals to produce stress-related hormones, inhibits the production of progesterone by the ovary.  Other stress-induced factors, such as increased prolactin and decreased thyroid, also inhibit progesterone production.  Stress eventually makes us more susceptible to stress.  Menopause and other landmarks of aging simply represent upward inflections in the rate-of-aging curve.  Individual variations in type of stress, hormonal response and diet, etc., probably govern the nature of the aging process in an individual.

The amphetamine-like action of estrogen, which undoubtedly  contributes to the general level of stress and excitotoxic  abuse of nerve cells, is probably the only "useful" facet of  estrogen treatment, but a little cocaine might achieve the  same effect with no more harm, possibly less.  The toxicity of catecholamines has been known for over thirty years, and estrogen's stimulating effects are partly the result of its conversion to catechol-estrogens which increase the activity of brain catecholamines.  Estrogen's powerful ability to nullify learning seems never to be mentioned by the people who promote its use.  The importance of a good balance of brain steroids for mood, attention, memory, and reasoning is starting to be recognized, but powerful economic forces militate against its general acceptance.

Since the brain is the organ that can allow us to adapt without undergoing stress in the hormonal sense, it is very important to protect its flexibility and to keep its energy level high, so it can work in a relaxed way.  It is the low energy cellular state that leads to the retention of calcium and iron, and to the production of age pigment, and other changes that constitute the vicious circle of aging.  And mental activity that challenges obsession and rigidity might be the most important brain energizer.  Pseudo-optimism, humor-as-therapy, has a certain value, but a deeper optimism involves a willingness to assimilate new information and to change plans accordingly.

SUPPLEMENTS

Nutritional supplements that might help to prevent or correct these brain syndromes include: Vitamin E and  coconut oil; vitamin A; magnesium, sodium; thyroid which  includes T3; large amounts of animal protein, especially  eggs; sulfur, such as magnesium sulfate or flowers of  sulfur, but not to take continuously, because of sulfur's interference with copper absorption; pregnenolone; progesterone if needed.  Bright light, weak in the blue end of the spectrum and with protection against ultraviolet, activates respiratory metabolism and quenches free radicals.  Raw carrot fiber and/or laxatives if needed; charcoal occasionally for gas or bowel  irritation.  Coconut oil serves several purposes.  Its butyric acid is known to increase T3 uptake by glial cells.  It has a general pro-thyroid action, for example by diluting and displacing antithyroid unsaturated oils, its short- and medium-chain fatty acids sustain blood sugar and have antiallergic actions, and it protects mitochondria against stressinjury. 

P.S.:  In 1979, a woman whose husband was suffering from advanced Amyotrophic Lateral Sclerosis (ALS) asked me if I had any ideas for slowing his decline.  I described my suspicion that ALS involved defective metabolism or regulation of testosterone.  In some tissues, testosterone is selectively concentrated to prevent atrophy, and ALS is a disease of middle-age, when hormone regulation often becomes a special problem.  In the late 1970s, there was discussion of a higher incidence of ALS in males, and especially in athletes.  I told her about progesterone's general protective effects, its antagonism to testosterone, and its prevention of atrophy in various tissues.  She decided to ask her doctor to try progesterone for her husband.  Later, I learned that her husband had gone into a very rapid decline immediately after the injection, and died within a week; the physician had given him testosterone, since, he said, "testosterone and progesterone are both male hormones."  Besides making me more aware of the problems patients have in communicating with physicians, this tended to reinforce my feeling that a hormone imbalance is involved in ALS.  Although I haven't written much about testosterone's toxicity, Marian Diamond's work showed that prenatal testosterone is similar to prenatal estrogen, in causing decreased thickness of the cortex of the brain; both of those hormones oppose progesterone's brain-protecting and brain-promoting actions.

REFERENCES

1)  Z. Y. Hu, et al., P.N.A.S. (USA) 84, 8215-9, 1987.

2)  P. F. Hall, Vitamins and Hormones 42, 315-370, 1985.

3)  J. J. Lambert, et al., Trends in Pharmac. Sci. 8, 224-7, 1987.

4)  W. A. D. A. Anderson, Pathology (second edition), C. V. Mosby, St. Louis, 1953.

5)  S. S. Smith, et al., Brain Res. 422, 52-62, 1987.

6)  P. M. Wise, Menopause, 1984; S. S. Smith, et al., Brain Res. 422, 40-51, 1987.

7)  R. M. Sapolsky, et al., J. Neuroscience 5, 1222-1227, 1985; R. M. Sapolsky and W. Pulsinelli, Science 229, 1397-9, 1985.

8)  C. B. Nemeroff, (Excitotoxins)  290-305, 1984.

9)  G. B. Phillips, Lancet 2, 14-18, 1976; G. B. Phillips, et al., Am. J. Med. 74, 863-9, 1983; M. H. Luria, et al., Arch Intern Med 142, 42-44, 1982; E. L. Klaiber, et al., Am J Med 73, 872-881, 1982.

10)  J. I. Mann, et al., Br Med J 2, 241-5, 1975.

11)  V. Gisclard and P. M. Vanhoutte, Physiologist 28, 324(48.1).

12)  W. A. D. A. Anderson, Pathology, 1953; H. H. Reese, et al.,  editors, 1936 Yearbook of Neurology, Psychiatry, and Endocrinology,  Yearbook Publishers, Chicago, 1937.   

13)  T. J. Putnam, Ann Int Med 9, 854-63, 1936; JAMA 108, 1477, 1937.

14)  R. S. Dow and G. Berglund, Arch Neurol and Psychiatry 47, 1, 1992.

15)  R. W. Estabrook, et al., Biochem Z. 338, 741-55, 1963.

16)  S. Hiroisi and C. C. Lee, Arch Neurol and Psychiat 35, 827-38, 1936.

17)  J. M. Matthieu, et al., Ann Endoc. 1974.

18)  K. Iwaharhi, et al., J Ster Biochem and Mol Biol 44(2), 163-4, 1993.

19)  D. C. Gajdusek, Chapter 63, page 1519 in Virology (B. N. Fields, et al., editors), Raven Press, N.Y., 1985.

20)  K. Lowenberg-Scharenberg and R. C. Bassett, J Neuropath and Exper Neurol 9, 93, 1950.

GLOSSARY  

1.  Amyloid is the old term for the "starchy" appearing (including the way it stains) proteins seen in various diseases, and in the brain in Alzheimer's disease.

2.  Cytochrome P450scc.  The cytochromes are "pigments," in the same sense that they contain the colored "heme" group that gives hemoglobin its color.  P450 means "protein that absorbs light at a wavelength of 450.  The scc means "side-chain cleaving," which refers to the removal of the 6 carbon atoms that distinguish cholesterol from pregnenolone. Other Cyt P450 enzymes are important for their detoxifying oxidizing action, and some of these are involved in brain metabolism.

3.  Glial means "glue-like," and glial cells are mostly spidery-shaped cells that used to be thought of as just connective, supportive cells in the brain.

4.  Mitochondria (the "thread-like bodies") are the structures in cells which produce most of our metabolic energy by respiration, in response to the thyroid hormones.

5.  Mucoid--refers to a mucoprotein, a protein which contains some carbohydrate.  A glycoprotein; usually not intended as a precise term.

6.  Myelination.  Myelin is a multilayered enclosure of the axons (the long processes) of nerve cells, composed of proteins and complex lipids, including cholesterol.  The layered material is a flat, thin extension of the cytoplasm of the oligodendroglial cells.

7.  Oligodendrocytes are one of the kinds of glial (or neuroglial) cells, and structurally they are unusual in having sheet-like, rather than just thread-like processes; they have a sensitivity ("receptors") to stress and valium, and produce pregnenolone when activated.  Under the influence of thyroid hormone, they wrap themselves in thin layers around the conductive parts of nerve cells, leaving a multilayered "myelin" coating.  Their absorption of thyroid hormone is promoted by butyrate, an anti-stress substance found in butter and coconut oil.

8.  Steroidogenesis is the creation of steroids, usually referring to the conversion of cholesterol to hormones.

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"...simultaneous treatment of intact...rats with testosterone and estradiol-17beta for 16 weeks consistenly induced a putative precancerous lesion, termed dysplasia, in the dorsolateral prostate of all animals.  Since treatment of rats with androgen alone did not elicit the same response, we concluded that estrogen played a critical role in the genesis of this proliferative lesion."       Shuk-mei Ho and M. Yu, in "Selective increase in type II estrogen-binding sites in the dysplastic dorsolateral prostates of Noble rats," Cancer Research 53, 528-532, 1993.

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Prostate Cancer

It was noticed several decades ago that estrogen causes the prostate gland to enlarge in experimental animals, but by then an oversimplified view of the sex hormones was already well established, that led people to say that "estrogen causes the female organs to grow, and testosterone causes the male organs to grow."  Logically extending this mistaken idea led many of the same people to suppose that the "hormones of one sex would inhibit the growth of the reproductive organs of the other sex."

When a friend of mine was told he had prostate cancer, though he had had no symptoms, and should receive large doses of estrogen, I reviewed the literature, to see whether his doctor might have seen something I had neglected.  Since that time, I have found it necessary to use quotation marks around the phrases "medical research" and "medical science," because there is a certain kind of "research" performed within the medical profession which is peculiar to that profession.

When I read through the studies cited by the current articles as the basis for using estrogen to treat prostate cancer, I saw that the decisive "research" had consisted of mailing a questionnaire to physicians asking them if they thought it was reasonable to administer estrogen to these patients on the basis of its opposition to testosterone, which was considered to be responsible for the growth of the prostate gland.  Many physicians answered the questionnaire affirmatively.

If the questioner's purpose was to determine his legal status in using a treatment, his research method was appropriate, to see whether the treatment seemed reasonable to others in the profession.  Legally, a physician is safe if he can count on others to testify that his practice is standard.  Unfortunately, for generations his study of the opinions of his peers became the "evidence" of the value of the estrogen treatment.  Phrases such as "it is indicated," "treatment of choice," and "standard practice" are used in medicine, as part of the pseudo-scientific mystique of the profession.  Physicans who attempt to base their practice on methods that have a sound scientific basis are likely to find that they are violating the norms of their profession.

More than 25 years ago, when I started pointing out that deliberate misrepresentation had been involved in the continued designation of estrogen as "the female hormone," used as a basis for "hormone replacement therapies," I saw that it was hard for people to sustain a critical attitude toward language.  Language is prior to judgment, law, science, reason.  Those who define the terms set the rules.

By the mid-1980s, some studies had shown that estrogen treatment didn't prolong the survival of prostate cancer patients at all, but it was argued that the patients who received estrogen were happier than those who didn't.

Apparently, many physicians who were experts in conventional cancer treatment hadn't been impressed by the happiness of their patients who were receiving estrogen, because a survey at a conference of physicians found that many of them would choose to have no treatment if they learned they had prostate cancer.  And more recently, there have been recommendations that older patients shouldn't be treated aggressively, because their cancers are usually so slow growing that they are likely to die of something else related to old age.

In spite of the articles I showed my friend, and my warning that estrogen can cause strokes and heart attacks, he decided to take the estrogen treatment.  Within a few days he began suffering from asthma and disturbed sleep.  Then he had a series of strokes and died. 

Since it was known that estrogen treatment was dangerous for men, and that it increases blood clotting and vascular spasms, there had to be some overriding belief that led to its general use in treating prostate cancer.  That belief seems to be that "estrogen, the female hormone, opposes testosterone, the male hormone, which is responsible for the growth--and therefore for the cancerization--of the prostate gland."  Everything is wrong with that sentence, but you can find every part of the belief present and functioning in the medical literature.  Just to give some context to the association of growth and cancerization, I should mention that Otto Warburg observed that all of the carcinogenic factors he studied caused tissue atrophy before cancer appeared.  Another important contextual point is that every hormone does many things, and every endocrine gland produces multiple hormones.

Since the time of Brown-Sequard and Eugen Steinach, it has been accepted that declining testicular function is a common feature of aging, and testosterone was probably the first hormone that was clearly found to decrease consistently with aging.  (Vermeulen, et al., 1972, 1979.) 

It has seemed odd to many people that enlargement of the prostate should occur mainly in older men, if testosterone is the hormone that causes its growth, and estrogen is antagonistic to its growth.  The nature of the growth of the old man's prostate is very different from its natural growth in youth.

It was also recognized decades ago that estrogen rises in men during old age (Pirke and Doerr, 1975), as it rises in stress, disease, malnutrition, and hypothyroidism (which are also associated with old age).  Estrogen is produced in fat (Siiteri, and MacDonald, 1973, Vermeulen, 1976) which tends to increase with age, when thyroid and progesterone are deficient.  The conversion of testosterone to estrogen occurs in the testicle itself, but this conversion is also inhibited by the favorable hormonal environment of youth.  The active thyroid hormone, T₃, declines with aging, and this necessarily lowers production of pregnenolone and progesterone.  Increasingly, in both sexes, it appears that DHEA may rise during stress as a result of a deficiency of thyroid, progesterone, and pregnenolone.

In 1786, John Hunter reported that castration causes a decrease in the size of the prostate gland, and by the end of the 19th century castration was being advocated for treating enlargement of the prostate.  In aging men, the prostate gland (both central and peripheral zones) atrophies, and it is within the atrophic gland that cancer cells can be found.  Nodular, noncancerous enlargement may occur, with or without cancer.  In 1935, an autopsy study showed carcinoma in the prostates of 30% of men by the age of 50.  Proliferation of ductal and epithelial tissue is closely associated with prostate cancer, a situation similar to that of the cancerous or precancerous breast.  (Simpson, et al., 1982; Wellings, et al., 1975; Jensen, et al., 1976.)  The high probability of "epitheliosis" in association with cancer was seen in women in their early 40s, and in women over 60. (Simpson, et al.)  (Epitheliosis just refers to an exaggerated proliferation of epithelial cells, the cells covering all surfaces, including the lining of glands, and things as simple as irritation and vitamin A deficiency can cause these cells to proliferate.)  In the breast, the proliferative epitheliosis is clearly caused by estrogenic stimulation.  The antagonism between estrogen and vitamin A in controlling epithelial proliferation (and possibly other cell types: Boettger-Tong and Stancel, 1995) is clear wherever it has been tested; vitamin A restrains epithelial proliferation.  (Wherever estrogen is a factor in the development of abnormal tissue, vitamin A supplementation would seem beneficial.)

 In aging women and men, as the breasts and prostate atrophy, their estrogen/antiestrogen ratio increases.

In men with prostate cancer, the fluid secreted by the prostate contains significantly more estradiol than the fluid from men without cancer (Rose, et al., 1984).  This is analogous to observations made in women with breast cancer.

The pituitary hormones have diverse functons, including effects on epithelial tissues, other than their "classical" functions.  Growth hormone, ACTH (Lostroh and Li, 1957), and ACTH with prolactin (Tullner, 1963) stimulate prostate growth.  Prolactin--which is increased by estrogen--stimulates growth of the rat's lateral prostate (Holland and Lee, 1980), and stimulates the growth of human prostate epithelial cells in vitro (Syms, et al., 1985).  LH (luteinizing hormone) increases when progesterone or testosterone is deficient, and growth hormone and prolactin (which are closely associated in evolution) both increase under a variety of stressful situations, and with estrogenic stimulation.  Prostate cancer patients who had higher levels of LH and lower testosterone died most quickly.  (Harper, et al., 1984.)  Also, a high ratio of testosterone to estradiol or of testosterone to prolactin corresponded to better survival (Rannikko, et al., 1981.)  Considered separately, patients with higher testosterone levels had a better prognosis than those with lower levels, and patients with lower growth hormone levels did better than those with higher growth hormone levels. (Wilson, et al., 1985.)  Has anyone ever tried testosterone therapy for prostate cancer?  Or, more practically, a generalized antiestrogenic therapy, using thyroid, progesterone, and pregnenolone?  Other drugs (naloxone, bromocriptine, gonadotropin-releasing hormone agonists, and anti-growth hormone druges, e.g.) are available to regulate the pituitary hormones, and might be useful therapeutically or preventively.  (See Blaakaer, et al., 1995.)  Biskind and Biskind's work (1944) with ovarian tumors might be relevant to both testicular and prostate cancer.

Abnormal patterns of pituitary hormones reflect stress and hormonal imbalance, but they are also directly involved in widespread changes in tissue content of glycoproteins.  The prostate is specialized to secrete large amounts of mucin.  The endocrine physiology of prostate mucin secretion is poorly understood, but it is likely that there are interactions between growth-regulatory and secretion-regulatory systems.

In recent years, prostate cancer has been one of the fastest increasing kinds of cancer, and it isn't apparent that increased treatment has had an effect in lowering the death rate.  The postwar baby-boom (following the baby-bust of the great depression) created an abnormal age-structure of the population, that has been used to argue that the war against cancer is being won.  Increasing environmental estrogens are known to cause many reproductive abnormalities, and their contribution to prostate cancer would get more attention if estrogen's role in prostate disease were better known.  Environmental estrogens are clearly responsible for genital deformities and sterility in many species of wild animals, but when the causal link is made between estrogens and human abnormalities, the estrogen industry sends its shills in to create controversy and confusion.  Even the effects of estrogens in sewage, known for decades, are treated as State Secrets:  "There had been reports of hermaphroditic fishes in one or two rivers, and government investigators had been studying them since the late 1970s.  But no one had been aware of the work because it was classified." (Lutz, 1996.)

Testicular cancer is easy to diagnose, and its incidence has clearly increased (100% in white men, 200% in black men) since 1950.  Undescended testicles, urethral abnormalities, etc., similar to those seen in DES sons and in wild animals, have also increased.  So the tremendous increase in the death rate from prostate cancer during the same time has a meaningful context.

Although the animal studies showed that estrogen treatment promotes enlargement of the prostate, it was possible to suppose that the human prostate's growth might be stimulated only by testosterone, until tests were done in vitro to determine the effects of hormones on cell division.

In human prostate slices, several hormones (including insulin, and probably prolactin) stimulated cell division; testosterone did not, under these experimental conditions. (McKeehan, et al., 1984.) Contrary to the stereotyped ideas, there are suggestions that supplementary androgens could control prostate cancer (Umekita, et al., 1996), and that antagonists to prolactin and estrogen might be appropriately used in hormonal therapy (for example, Wennbo, et al., 1997; Lane, et al., 1997).

By the age of 50, men often show an excess of both prolactin and estrogen, and a deficiency of thyroid and testosterone.  This is the age at which enlargement of the prostate often becomes noticeable.

Estrogen's role in prostate growth and cancerization is clear:  "...simultaneous treatment of intact...rats with testosterone and estradiol-17beta for 16 weeks consistenly induced a putative precancerous lesion, termed dysplasia, in the dorsolateral prostate of all animals.  Since treatment of rats with androgen alone did not elicit the same response, we concluded that estrogen played a critical role in the genesis of this proliferative lesion."  (Ho and Yu.)

Progesterone and pregnenolone also decline in aging men.  Several studies using synthetic progestins have shown that they effectively shrink the hypertrophic prostate, and the saw palmetto remedy for prostate enlargement has been reported to contain pregnenolone, or something similar to it.  These materials might be expected to reduce conversion of testosterone or other androgens to estrogen.

The prostaglandins were discovered in prostatic fluid, where they occur in significant concentrations.  They are so deeply involved with the development of cancers of all sorts that aspirin and other prostaglandin inhibitors should be considered as a basic part of cancer therapy.  The prostaglandins have local and systemic effects that promote cancer growth.  ("The prostaglandins and related eicosanoids synthesized from polyunsaturated fatty acid precursors have been implicated as modulators of tumor metastasis, host immunoregulation, tumor promotion, and cell proliferation."  Hubbard, et al., 1988.)

Estrogens cause elevation of free fatty acids, and  there are many interactions between the unsaturated fatty acids and estrogen, including their metabolism to prostaglandins, and their peroxidation.  Estrogen's roles as free-radical promoter, DNA toxin, carcinogen, tumor promotor, modifier of tissue growth factors, anti-thymic hormone, etc., as well as its local effects on the prostate gland, have to be kept in mind.  Most of the interest in studying estrogen's contributions to prostate cancer relates to the existence of estrogen receptors in various parts of the prostate.  While that is interesting, it tends to distract attention from the fact that many of estrogen's most important actions don't involve the "receptors."  A direct excitatory action on prostate cells, and indirect actions by way of the pituitary, pancreas, thyroid, adrenal, fatty acids, prostaglandins, histamine and circulation are probably essential parts of the cancerization process.

The unsaturated fatty acids, but not the saturated fatty acids, free estrogen from the serum proteins that bind it, and increase its availability and activity in tissue cells.

Thyroid supplementation, adequate animal protein, trace minerals, and vitamin A are the first things to consider in the prevention of prostate hypertrophy and cancer.  Nutritional and endocrine support can be combined with rational anticancer treatments, since there is really no sharp line between different approaches that are aimed at achieving endocrine and immunological balance, without harming anything.

Avoiding tissue atrophy is very closely related to promoting healthy regeneration.  These processes require efficient energy production, and an appropriate balance between stimulation and resources.  Growth hormone is sometimes recommend to correct tissue atrophy, but the evidence seems reasonably clear that it is a factor in the promotion of tumefaction of the prostate.  The only study I have seen suggesting that it might be beneficial in prostatic cancer was a 14 day experiment done in female rats.  Numerous publications suggest that blocking growth hormone is beneficial in treating prostate cancer; in future newsletters I will be discussing the evidence that growth hormone, like estrogen, cortisol, and unsaturated fats, tends to promote degenerative changes of aging - Growth hormone: Hormone of Stress, Aging, and Death?

    REFERENCES

M.C. Audy, et al., "17beta-Estradiol stimulates a rapid Ca2+ influx in LNCaP human prostate cancer cells," Eur. J. Endocrionol.135, 367-373, 1996.

M. S. Biskind and G. S. Biskind, "Development of tumors in the rat ovary after transplantation into the spleen," Proc. Soc. Exp. Biol. Med. 55, 176-179, 1944.

J. Blaakaer, et al., "Gonadotropin-releasing hormone agonist suppression of ovarian tumorigenesis in mice of the Wx/Wv genotype," Biol. of Reprod. 53, 775-779, 1995.

Clinton, SK Mulloy AL, Li SP, Mangian HJ, Visek WJ, J Nutr 1997 Feb;127(2):225-237 "Dietary fat and protein intake differ in modulation of prostate tumor growth, prolactin secretion and metabolism, and prostate gland prolactin binding capacity in rats." 

J. R. Drago, "The induction of Nb rat prostatic carcinomas," Anticancer Res. 4, 255-256, 1984.

J. Geller, et al., "The effect of cyproterone acetate on adenocarcinoma of the prostate," Surg. Gynec. Obst. 127, 748-758, 1968.

J. Geller, J. Fishman, and T. L. Cantor, "Effect of cyproterone acetate on clinical, endocrine and pathological features of benign prostatic hypertrophy," J. Steroid Biochemistry 6, 837-843, 1975.

Ho, Shuk-mei, and M. Yu, "Selective increase in type II estrogen-binding sites in the dysplastic dorsolateral prostates of Noble rats," Cancer Research 53, 528-532, 1993.  "...simultaneous treatment of intact...rats with testosterone and estradiol-17beta for 16 weeks consistenly induced a putative precancerous lesion, termed dysplasia, in the dorsolateral prostate of all animals.  Since treatment of rats with androgen alone did not elicit the same response, we concluded that estrogen played a critical role in the genesis of this proliferative lesion."

M. E. Harper, et al., "Carcinoma of the prostate: relationship of pretreatment hormone levels to survival," Eur. J. Cancer Clin. Oncol. 20, 477-482, 1984.

J. M. Holland and C. Lee, "Effects of pituitary grafts on testosterone stimulated growth of rat prostate," Biol. Reprod. 22, 351-355, 1980.

W. C. Hubbard, et al., "Profiles of prostaglandin biosynthesis in sixteen established cell lines derived from human lung, colon, prostate, and ovarian tumors," Cancer Research 48, 4770-4775, 1988.  "The prostaglandins and related eicosanoids synthesized from polyunsaturated fatty acid precursors have been implicated as modulators of tumor metastasis, host immunoregulation, tumor promotion, and cell proliferation."

Izes JK, Zinman LN, Larsen CR, Urology 1996 May;47(5):756-759 "Regression of large pelvic desmoid tumor by tamoxifen and sulindac,"  "A 54-year-old man was evaluated for symptoms of bladder outlet obstruction. Evaluation revealed a 10 by 9.8-cm tumor composed of bland, fibroblastic, poorly cellular material adjacent to the prostate. Administration of a course of antiestrogen (tamoxifen) and a nonsteroidal anti-inflammatory agent (sulindac) resulted in prompt relief of symptoms and a slow decrease in the size of the tumor as measured by computed tomography. After 54 months of therapy, the tumor was undetectable clinically and dramatically reduced in size as seen on computed tomography. Data on the natural history of desmoid tumors and the efficacy of various therapeutic strategies are reviewed.

Jungwirth A, Schally AV, Pinski J, Halmos G, Groot K, Armatis P, Vadillo-Buenfil M., Br J Cancer 1997;75(11):1585-1592, "Inhibition of in vivo proliferation of androgen-independent prostate cancers by an antagonist of growth hormone-releasing hormone."

Kroes R; Teppema JS Development and restitution of squamous metaplasia in the calf prostate after a single estrogen treatment. An electron microscopic study.  Mol Pathol, 1972 Jun, 16:3, 286-301.

Lane KE, Leav I, Ziar J, Bridges RS, Rand WM, Ho SM, Carcinogenesis 1997 Aug;18(8):1505-1510  "Suppression of testosterone and estradiol-17beta-induced dysplasia in the dorsolateral prostate of Noble rats by bromocriptine." "We, and others, have previously described the histological changes that occur in the prostate gland of intact Noble (NBL) rats following prolonged hormonal treatment. Dysplasia, a pre-neoplastic lesion, develops specifically in the dorsolateral prostates (DLPs) of NBL rats treated for 16 weeks with a combined regimen of testosterone (T) and estradiol-17beta (E2) (T + E2-treated rats). Concurrent with DLP dysplasia induction, the dual hormone regimen also elicits hyperprolactinemia, in addition to an elevation of nuclear type II estrogen binding sites (type II EBS), no alteration in estrogen receptors (ER), and marked epithelial cell proliferation in the dysplastic foci. The aim of this study was to investigate whether the dual hormone action is mediated via E2-induced hyperprolactinemia. Bromocriptine (Br), at a dose of 4 mg/kg body wt per day, was used to suppress pituitary prolactin (PRL) release. Serum PRL levels were lowered from values of 341 +/- 50 ng/ml in T + E2-treated rats to 32 +/- 10 ng/ml in Br co-treated animals. The latter values were comparable to those in untreated control rats. In addition, Br co-treatment effectively inhibited the evolution of dysplasia (six out of eight rats) and the often associated inflammation (five out of eight rats) in most animals. In contrast, Br co-treatment did not suppress the T + E2-induced type II EBS elevation nor alter ER levels in the DLPs of these rats, when compared with T + E2-treated rats. These data extend the many previous studies that have detailed marked influences of PRL on rat prostatic functions. However, the current study is the first to implicate PRL in prostatic dysplasia induction in vivo."

I. Leav, et al., "Biopotentiality of response to sex hormones by the prostate of castrated or hypophysectomized dogs:  Direct effects of estrogen," Am. J. Pathol., 93, 69-92, 1978.

H. C. Levine, et al., "Effects of the addition of estrogen to medical castration on prostatic size, symptoms, histology and serum prostate specific antigen in 4 men with benign prostatic hypertrophy," J. Urol. 146, 790-93, 1991.

Diana Lutz, The Sciences, January/February 1996.

W. L. McKeehan, et al., "Direct mitogenic effects of insulin, epidermal growth factor, glucocorticoid, cholera toxin, unknown pituitary factors and possibly prolactin,but not androgen, on normal rat prostate epithelial cells in serum-free, primary cell culture," Cancer Res. 44(5), 1998-2010, 1984.

Nevalainen MT, Valve EM, Ingleton PM, Nurmi M, Martikainen PM, Harkonen PL, J Clin Invest 1997 Feb 15;99(4):618-627 "Prolactin and prolactin receptors are expressed and functioning in human prostate." "The highest density of prolactin receptors was detected in the secretory epithelial cells by immunohistochemistry. Finally, we report that prolactin is locally produced in human prostate epithelium, as evidenced by marked prolactin immunoreactivity in a significant portion of prostate epithelial cells, with parallel expression of prolactin mRNA in human prostate. Collectively, these data provide significant support for the existence of an autocrine/paracrine loop of prolactin in the human prostate and may shed new light on the involvement of prolactin in the etiology and progression of neoplastic growth of the prostate."

A. J. Lostroh and C. H. Li, "Stimulation of the sex accessories of hypophysectomised male rat by non-gonadotrophin hormones of the pituitary gland," Acta endocr. Copenh. 25, 1-16, 1957.

F. B. Merk, et al., "Multiple phenotypes of prostatic glandular cells in castrated dogs after individual or combined treatment with androgen and estrogen," Lab. Invest. 54, 42-46, 1986.

Pirke, K.M. and P. Doerr, "Age related changes in free plasma testosterone, dihydrotesterone, and oestradiol," Acta endocr. Copenh. 89, 171-178, 1975

S. Rannikko, et al., "Hormonal patterns in prostatic cancer 1. Correlation with local extent of tumour, presence of metastases and grade of differentiation," Acta endocr. Copenh. 98, 625-633, 1981.

P. H. Rolland, et al., "Prostaglandins in human breast cancer:  Evidence suggesting that an elevated prostaglandin production is a marker of metastatic potential for neoplastic cells," J. Natl. Cancer Inst. 64, 1061-1070, 1980.

D. P. Rose, et al., "Hormone levels in prostatic fluid from healthy Finns and prostate cancer patients," Eur. J. Cancer clin. Oncol. 20, 1317-1319, 1984.

L. M. Schuman, et al., "Epidemiologic study of prostatic cancer:  Preliminary report," Cancer Treat. Rep. 61, 181-186, 1977.

Siiteri, P.K. and P. C. MacDonald, "Role of extraglandular estrogen in human endocrinology," In Handbook of Physiology, section 7, Endocrinology Vol II (Eds. S. R. Geiger, et al.,) pp. 615-629, Williams & Wilkins, Baltimore.

H. W. Simpson, et al., "Bimodal age-frequency distribution of epitheliosis in cancer mastectomies, Cancer 50, 2417-2422, 1982; S. R. Wellings, et al., "Atlas of subgross pathology of the human breast with special reference to possible precancerous lesions," J. Nat. Cancer Inst. 55, 231-273, 1975; H. M. Jensen, et al., "Preneoplastic lesions in the human breast," Science, N.Y. 191, 295-297,1976.

Sugimura Y, Sakurai M, Hayashi N, Yamashita A, Kawamura J., Prostate 1994;24(1):24-32  "Age-related changes of the prostate gland in the senescence-accelerated mouse." "Wet weight and numbers of ductal tips in ventral and dorsolateral prostate glands in senescence accelerated-prone (SA-P) mice were significantly smaller than those of senescence accelerated-resistant (SA-R) mice, although the changes of patterns of gross ductal morphology were virtually identical in these groups. High incidence of stromal hyperplasia with fibrosis and inflammation was observed...." "These data suggest that the aging process occurs heterogeneously within the prostate gland, and that SA-P mice may be an important model for the study of age-related changes in the prostate gland."

W. W. Tullner, "Hormonal factors in the adrenal-dependent growth of the rat ventral prostate," Nat. Cancer Inst. Monograph 12, 211-223, 1963.

Umekita Y, Hiipakka RA, Kokontis JM, Liao S, Proc Natl Acad Sci U S A 1996 Oct 15;93(21):11802-11807  "Human prostate tumor growth in athymic mice: inhibition by androgens and stimulation by finasteride," "When the human prostate cancer cell line, LNCaP 104-S, the growth of which is stimulated by physiological levels of androgen, is cultured in androgen-depleted medium for > 100 passages, the cells, now called LNCaP 104-R2, are proliferatively repressed by low concentrations of androgens. LNCaP 104-R2 cells formed tumors in castrated male athymic nude mice. Testosterone propionate (TP) treatment prevented LNCaP 104-R2 tumor growth and caused regression of established tumors in these mice. Such a tumor-suppressive effect was not observed with tumors derived from LNCaP 104-S cells or androgen receptor-negative human prostate cancer PC-3 cells. 5 alpha-Dihydrotestosterone, but not 5 beta-dihydrotesto- sterone, 17 beta-estradiol, or medroxyprogesterone acetate, also inhibited LNCaP 104-R2 tumor growth. Removal of TP or implantation of finasteride, a 5 alpha-reductase inhibitor, in nude mice bearing TP implants resulted in the regrowth of LNCaP 104-R2 tumors. Within 1 week after TP implantation, LNCaP 104-R2 tumors exhibited massive necrosis with severe hemorrhage. Three weeks later, these tumors showed fibrosis with infiltration of chronic inflammatory cells and scattered carcinoma cells exhibiting degeneration. TP treatment of mice with LNCaP 104-R2 tumors reduced tumor androgen receptor and c-myc mRNA levels but increased prostate-specific antigen in serum- and prostate-specific antigen mRNA in tumors. Although androgen ablation has been the standard treatment for metastatic prostate cancer for > 50 years, our study shows that androgen supplementation therapy may be beneficial for treatment of certain types of human prostate cancer and that the use of 5 alpha-reductase inhibitors, such as finasteride or anti-androgens, in the general treatment of metastatic prostate cancer may require careful assessment."

A. Vermeulen, "Testicular hormonal secretion and aging in males," in Benign prostatic hyperplasia (J. T. Grayhack, et al., eds), pp. 177-182, DHEW Publ. No. (NIH) 76-1113, 1976.

A. Vermeulen, et al., "Testosterone secretion and metabolism in male senescence," J. Clin. Endocr. Metab. 34, 730-735, 1972.

A. Vermeulen, et al., "Hormonal factors related to abnormal growth of the prostate," in Prostate Cancer (D. S. Coffey and J. T. Issacs, eds). UICC Technical Workshop Series, Vol 48, 81-92, UICC, Geneva.

S. Zuckerman and J. R. Groome, "The aetiology of benign enlargement of the prostate in the dog," J. Pathol. Bact. 44, 113-124, 1937.

B. Zumoff, et al., "Abnormal levels of plasma hormones in men with prostate cancer:  Evidence toward a 'time-defense' theory," The Prostate 3, 579-588, 1982.

M. Wehling, "Non-genomic steroid action--take a closer look, it's not rare!" Eur. J. of Endorinol. 135, 287-288, 1996.

Wennbo H, Kindblom J, Isaksson OG, Tornell J., Endocrinology 1997 Oct;138(10):4410-4415. "Transgenic mice overexpressing the prolactin gene develop dramatic enlargement of the prostate gland,"  "An altered endocrine status of elderly men has been hypothesized to be important for development of prostate hyperplasia. The present study addresses the question whether increased PRL expression is of importance for development of prostate hyperplasia in mice. Three lines of PRL transgenic mice were generated having serum levels of PRL of approximately 15 ng/ml, 100 ng/ml, and 250 ng/ml, respectively. These mice developed dramatic enlargement of the prostate gland, approximately 20 times the normal prostate weight and they had a 4- to 5-fold increased DNA content. Histologically, the prostate glands in the transgenic mice were distended from secretion, and the amount of interstitial tissue was increased. The levels oftestosterone and IGF-I were increased in the PRL transgenic animals. In mice overexpressing the bovine GH gene, displaying elevated IGF-I levels, the prostate gland was slightly larger compared with normal mice, indicating that the effect of PRL was not primarily mediated through elevated plasma IGF-I levels. "The present study suggests that PRL is an important factor in the development of prostate hyperplasia acting directly on the prostate gland or via increased plasma levels of testosterone."

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A R T I C L E

Growth hormone: Hormone of Stress, Aging, & Death?

The name "growth hormone" is misleading; stress produces somatic growth, in a process called "hormesis." Exercise produces muscle edema, to a degree similar to that produced by GH; edema stimulates growth, but GH effect isn't limited to bone and muscle.

Identity of GH: Molecular ambiguity, complex modifications change one substance into many; its evolution suggests a role in water regulation. Doctrine of a "specific molecule" and "specific receptor" and specific effects is a myth.

The osmoregulatory problem--keeping water under control--is centrally involved in stress.

In mammals, the kidneys and bowel are the main regulators of water balance.

GH is a stress hormone. Its effects can be produced osmotically, for example inducing milk production and cartilage growth, by osmotic (dilution) shock.

Estrogen produces increased GH, and increases its production in stress.

Nitric oxide is a pro-aging free radical induced by estrogen, releasing GH; all three produce edema.

Behind edema, hypoxia, hypocarbia; free fatty acids, diabetes, vascular leakiness, degenerative kidney changes, connective tissue changes, thickened.basement membrane, retinal degeneration. The same changes occur in aging: increased permeability; kidney disease, connective tissue changes.

The absence of GH protects kidneys against degeneration. Osteoarthritis, a characteristic aging condition, is caused by estrogen and GH.

Some studies found that heart failure and bone repair aren't improved by GH; GH is very high during heart failure, in which edema contributes to the problem; carpal tunnel syndrome, myalgia, tumor growth, gynecomastia, and many other problems have been produced by GH treatments.

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Bovine Growth Hormone is used to make cows give more milk.
Human Growth Hormone is supposed to make men lean and muscular, not to increase their milk production.

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Recently I heard Robert Sapolsky interviewed, and he was describing the changes that prepare the body for short-term stress. He said the energy-mobilizing hormones, adrenalin and cortisol, increase, while the hormones that don't contribute to meeting the immediate problem, including the sex hormones and growth hormone, are suppressed, to save energy; growth and reproductive processes can be suspended for the few minutes of acute stress, to make the body more able to meet its acute needs. He reiterated: Growth hormone is suppressed by stress.

Sapolsky has done very interesting work on the suppression of testosterone by stress, and on the way in which brain cells are killed by prolonged exposure to glucocorticoids. He showed that if extra glucose is supplied, the brain cells can survive their exposure to cortisol. In the body, adrenalin and the glucocorticoids increase the availability of glucose.

In the radio interview, he didn't have time for much detail, but it seemed to me that he wasn't talking about the same growth hormone that I have been reading about, and trying to understand, for years. Since people have asked me to write about the current anti-aging uses of GH, and its use in the dairy industry, Sapolsky's statements made me decide to think about some of the issues around the hormone.*

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*If Sapolsky had been talking about just mice and rats, his statement would have been generally accurate. Adrenaline stimulates rat pituitary cells to secrete GH, and since both increase the amount of free circulating fatty acids, it could be that rats' GH is suppressed by a fatty acid excess.

The "growth hormone" was named long before it was actually found, and the substance with that name turns out to be involved in many processes other than growth. It is being given to cows to make them produce more milk, and it is being given to people with the purpose of making them lean and muscular, and with the hope of building stronger bones.
It isn't surprising that the Growth Hormone helps breasts develop and promotes milk production, since it is very similar to prolactin. GH and prolactin are members of a family of proteins that have diverged from each other in evolution, but they still have many overlapping effects.

When GH is treated as a drug, it is supposed to have a discrete identity, based on the sequence of its amino acids. But the natural hormone (disregarding the existence of a variety of closely related peptides with slightly different amino acid composition) varies with time, being chemically modified even before it is secreted. For example, its acidic amino acids may be methylated, and its lysine groups may combine with sugars or carbon dioxide. The history of the protein in the body determines its exact structure, and therefore its biological effects.

Male animals secrete GH in pulses, but females secrete it more steadily. This pattern of secretion "masculinizes" or "feminizes" the liver (and other organs), determining the pattern of enzyme activity. It would be possible (though very difficult) to arrange a system for delivering doses in a pulsed, intermittent manner. In cows, this apparently isn't necessary, since the purpose of the growth hormone is presumably to "feminize" the milk-producing system. But the normal pattern of secretion is much more complex than simply being "pulsed" or "continuous," since it, like prolactin secretion, is responsive to changes in thyroid, estrogen, diet, stress, and many other factors.

For example, hormones in this family are, as far back in evolution as they have been studied, involved in the regulation of water and minerals. It is well established that increased water (hypotonicity) stimulates prolactin, and increased sodium inhibits its secretion. Growth hormone is also closely involved with the regulation of water and salts.

One of the best known metabolic effects of GH is that, like adrenalin, it mobilizes fatty acids from storage. GH is known to antagonize insulin, and one of the ways it does this is simply by the ability of increased free fatty acids to block the oxidation of glucose. At puberty, the increased GH creates a mild degree of diabetes-like insulin resistance, which tends to increase progressively with age.

In his book, Why Zebras Don't Get Ulcers, Sapolsky acknowledges some situations in which GH is increased by stress in humans, but I think he misses the real ways in which it operates in stress. One of the interesting features of cortisol, which Sapolsky showed killed brain cells by making them unable to use glucose efficiently, is that it makes cells take up unsaturated fatty acids more easily, interfering with their energy production. Since growth hormone also has this kind of "diatebetogenic" action, it might be desirable to suppress its secretion during stress, but in fact, there are several kinds of stress that clearly increase its secretion, and in animals as different as fish, frogs, cows, and people it can be seen to play roles in water and salt regulation, growth and development, stress, and starvation.

Heat, hypoglycemia, running, and some types of shock are known to stimulate growth hormone secretion, sometimes to levels ten or twenty times higher than normal. (Two kinds of stress that usually don't increase GH are cold and stimulus-deprivation.) I consider the growth hormone to be, almost as much as prolactin, a stress-inducible hormone. That's why I reasoned that, if an endocrinologist as good as Sapolsky can misunderstand GH to that degree, the public is even more likely to misunderstand the nature of the material, and to believe that it somehow acts just on muscle, fat, and bones.

And the normally functioning pituitary appears to be unnecessary to grow to normal height. (Kageyama, et al., 1998.)

W. D. Denckla discovered that the pituitary hormones are in some way able to accelerate the process of aging. They block the actions of thyroid hormone, decreasing the ability to consume oxygen and produce energy. The diabetes-like state that sets in at puberty involves the relative inability to metabolize glucose, which is an oxygen-efficient energy source, and a shift to fat oxidation, in which more free radicals are produced, and in which mitochondrial function is depressed. Diabetics, even though it is supposedly an inability of their cells to absorb glucose that defines their disease, habitually waste glucose, producing lactic acid even when they aren't "stressed" or exerting themselves enough to account for this seemingly anaerobic metabolism. It was noticing phenomena of this sort, occurring in a great variety of animal species, in different phyla, that led Denckla to search for what he called DECO (decreasing consumption of oxygen) or "the death hormone." (Vladimir Dilman noticed a similar cluster of events, but he consistently interpreted everything in terms of a great genetic program, and he offered no solution beyond a mechanistic treatment of the symptoms.)

Simply increasing the amount of free fatty acids in the blood will act like DECO or "the death hormone," but growth hormone has more specific metabolic effects than simply increasing our cells' exposure to fatty acids. The hormone creates a bias toward oxidizing of the most unsaturated fatty acids (Clejan and Schulz), in a process that appears to specifically waste energy.
Growth hormone plays an important role in puberty, influencing ovarian function, for example. 

Removing animals' pituitaries, Denckla found that their aging was drastically slowed. He tried to isolate the death hormone from pituitary extracts. He concluded that it wasn't prolactin, although prolactin had some of its properties. In the last publication of his that I know of on that subject, he reported that he was unable to isolate the death hormone, but that it was "in the prolactin fraction." Since rats have at least 14 different peptides in their prolactin family, not counting the multitude of modifications that can occur depending on the exact conditions of secretion, it isn't surprising that isolating a single factor with exactly the properties of the chronically functioning aging pituitary hasn't been successful.

Denckla's experiments are reminiscent of many others that have identified changes in pituitary function as driving forces in aging and degenerative diseases.

Menopause, for example, is the result of overactivity of the pituitary gonatropins, resulting from the cumulatively toxic effects of estrogen in the hypothalamus.

A. V. Everitt, in his book on the hypothalamus and pituitary in aging, reported on studies in which estrogen caused connective tissues to lose their elasticity, and in which progesterone seemed to be an antiestrogenic longevity factor. Later, he did a series of experiments that were very similar to Denckla's, in which removal of the pituitary slowed the aging process. Several of his experiments strongly pointed to the prolactin-growth hormone family as the aging factors. Removal of the pituitary caused retardation of aging similar to food restriction. These pituitary hormones, especially prolactin, are very responsive to food intake, and the growth hormone is involved in the connective tissue and kidney changes that occur in diabetes and aging. 

A mutant dwarf mouse, called "little," has only 5% to 10% as much growth hormone as normal mice, and it has an abnormally long lifespan.

Many experiments show that prolactin and estrogen have synergistic effects in causing tissue degeneration, including cancerization, and that their effects tend to operate with fewer protective restraining influences in old age. Estrogen stimulates both prolactin and growth hormone secretion. Thirty years ago, people were warning that estrogen contraceptives might produce diabetes, because they caused chronic elevation of growth hormone and free fatty acids.
Since estrogen causes a slight tendency to retain water while losing sodium, producing hypotonic body fluids, and since hypotonicity is a sufficient stimulus to cause prolactin secretion, I have proposed that it is estrogen's effect on the body fluids which causes it to stimulate prolactin. In pregnancy, the fetus is exposed to fluids more hypotonic than can be accounted for by estrogen and prolactin alone; since GH lowers the salt concentration of fish when they enter the ocean from freshwater, it seems to be a candidate for this effect in pregnancy.

Growth itself is an intrinsic property of all cells, but the growth hormone does have its greatest influence on certain tissues, especially cartilage. Gigantism and acromegaly were what originally made people interested in looking for a growth hormone, and these are characterized by continued, exaggerated enlargement of bones and cartilage. In old age, cartilaginous structures such as the bones and ears keep enlarging. The fact that simply diluting the culture medium is sufficient to stimulate the growth of cartilage suggests that the growth hormone might be acting by its effects on water metabolism. In fish which enter fresh water from the ocean, pituitary hormones of this family help them to balance salts in this new environment, but in the process, they develop osteoporosis and skeletal deformity, of the sort that occur more gradually in other animals with aging.

Growth hormone clearly causes edema, and this is probably involved in the pathological processes that it can produce. The expansion of extracellular water has been reported, but others have concluded that the increased weight of muscles following GH treatment must be the result of "growth," "because microscopic examination didn't show edema." Statements of that sort give incompetence a bad name, because any student of biology or biochemistry has to know, before he does almost any experiment, that the way to determine the water content of a tissue is to compare the wet weight to the weight after thorough drying. Looking for water under a microscope is the sort of thing they do at drug companies to pretend that they have done something.

Estrogen, growth hormone, and nitric oxide, which tend to work as a system, along with free fatty acids, all increase the permeability of blood vessels. The leaking of albumin into the urine, which is characteristic of diabetes, is promoted by GH. In diabetes and GH treatment, the basement membrane, the jelly-like material that forms a foundation for capillary cells, is thickened. The reason for this isn't known, but it could be a compensatory"anti-leak" response tending to reduce the leakage of proteins and fats.

Besides being involved in kidney degeneration, vascular leakiness contributes to brain edema, and probably contributes to the "autoimmune" diseases.

Whatever the exact mechanism may be, it is clearly established that GH contributes to kidney degereration, and the lack of GH, even the removal of the pituitary, is protective against kidney degeneration.

Denckla's and Everitt's experiments can be interpreted much more clearly now that GH's essential contribution to kidney degeneration is known. Growth Hormone may not be precisely the Death Hormone that Denckla was looking for, but it is very close to it. Anti-thyroid effects have been seen, and possibly even anti-growth effects during gestation, and in kidney disease. In newborns, high GH is associated with smaller size and slower growth; in one study, this was associated wtith rapid breathing, presumably hyperventilation which is associated with stress. The shift to the diabetes-like fatty acid oxidation would be expected to inhibit respiration, and the chronic elevation of serum free fatty acids will have a generalized antithyroid effect. Under the influence of GH, the proportion of unsaturated fatty acids is increased, as occurs under the influence of estrogen.

Growth hormone blocks gonadotropin-stimulated progesterone production, and this could also affect thyroid and respiratory metabolism.

The increase of GH during sleep might seem to be utterly incompatible with the idea that it is a stress hormone, but in fact the other stress hormones, adrenalin, cortisol, and prolactin also tend to increase during night-time sleep. Thyroid function and progesterone function decrease at night. As I have argued previously darkness is one of our major stressors. Considering GH's tendency to cause edema, tissue swelling, it could play a role in the nocturnal increase of the viscosity of blood, as the volume of blood is decreased by the leakage of fluid into the tissues. Another process with potentially deadly results that increase withaging and stress, is the passage of bacteria from the intestine into the blood stream; this process is increased under the influence of GH.

Acute, short term studies definitely show growth hormone to be a stress hormone with some destabilizing effects. Over a lifetime, it is possible that such things as chronically increased levels of unsaturated fatty acids in the blood, and increased leakiness of the blood vessels, could cumulatively produce the effects that Denckla ascribed to the Death Hormone.

REFERENCES

Intern Med 1998 May;37(5):472-5. A hypopituitary patient who attained tall stature without growth hormone. Kageyama K, Watanobe H, Nasushita R, Nishie M, Horiba N, Suda T. "We describe an unusual patient with hypopituitarism who attained tall stature even without growth hormone (GH)." 
Pediatr. Pulmonol. 1998 26(4):241-9. Sleep, respiratory rate, and growth hormone in chronic neonatal lung disease, D. Fitzgerald, et al.
"Insulin resistance in puberty [editorial]," Anonymousm Lancet, 1991 May 25, 337:8752, 1259-60. 
"The gonadotropic function of insulin," Poretsky L; Kalin MF, Endocr Rev, 1987 May, 8:2, 132-4.1.
J Clin Endocrinol Metab 1991 Apr;72(4):768-72 Expansion of extracellular volume and suppression of atrial natriuretic peptide after growth hormone administration in normal man. Moller J, Jorgensen JO, Moller N, Hansen KW, Pedersen EB, Christiansen JS University Department of Endocrinology and Internal Medicine, Aarhus Kommunehospital, Denmark. Sodium retention and symptoms and signs of fluid retention are commonly recorded during GH administration in both GH-deficient patients and normal subjects. Most reports have however, been casuistic or uncontrolled. In a randomized double blind placebo-controlled cross-over study we therefore examined the effect of 14-day GH administration (12 IU sc at 2000 h) on plasma volume, extracellular volume (ECV), atrial natriuretic peptide (ANP), arginine vasopressin, and the renin angiotensin system in eight healthy adult men. A significant GH induced increase in serum insulin growth factor I was observed. GH caused a significant increase in ECV (L): 20.45 +/- 0.45 (GH), 19.53 +/- 0.48 (placebo) (P less than 0.01), whereas plasma volume (L) remained unchanged 3.92 +/- 0.16 (GH), 4.02 +/- 0.13 (placebo). A significant decrease in plasma ANP (pmol/L) after GH administration was observed: 2.28 +/- 0.54 (GH), 3.16 +/- 0.53 (placebo) P less than 0.01. Plasma aldosterone (pmol/L): 129 +/- 14 (GH), 89 +/- 17 (placebo), P = 0.08, and plasma angiotensin II (pmol/L) levels: 18 +/- 12 (GH), 14 +/- 7 (placebo), P = 0.21, were not significantly elevated. No changes in plasma arginine vasopressin occurred (1.86 +/- 0.05 pmol/L vs. 1.90 +/- 0.05, P = 0.33). Serum sodium and blood pressure remained unaffected. Moderate complaints, which could be ascribed to water retention, were recorded in four subjects [periorbital edema (n = 3), acral paraesthesia (n = 2) and light articular pain (n = 1)]. The symptoms were most pronounced after 2-3 days of treatment and diminished at the end of the period. In summary, 14 days of high dose GH administration caused a significant increase in ECV and a significant suppression of ANP. 
Circulation 1991 Jun;83(6):1880-7. Pathogenesis of edema in constrictive pericarditis. Studies of body water and sodium, renal function, hemodynamics, and plasma hormones before and after pericardiectomy. Anand IS, Ferrari R, Kalra GS, Wahi PL, Poole-Wilson PA, Harris PC. "BACKGROUND. The pathogenesis of sodium and water accumulation in chronic constrictive pericarditis is not well understood and may differ from that in patients with chronic congestive heart failure due to myocardial disease. This study was undertaken to investigate some of the mechanisms. METHODS AND RESULTS. Using standard techniques, the hemodynamics, water and electrolyte spaces, renal function, and plasma concentrations of hormones were measured in 16 patients with untreated constrictive pericarditis and were measured again in eight patients after pericardiectomy. The average hemodynamic measurements were as follows: cardiac output, 1.98 l/min/m2; right atrial pressure, 22.9 mm Hg; pulmonary wedge pressure, 24.2 mm Hg; and mean pulmonary artery pressure 30.2 mm Hg. The systemic and pulmonary vascular resistances (36.3 +/- 2.5 and 3.2 +/- 0.3 mm Hg.min.m2/l, respectively) were increased. Significant increases occurred in total body water (36%), extracellular volume (81%), plasma volume (53%), and exchangeable sodium (63%). The renal plasma flow was only moderately decreased (49%), and the glomerular filtration rate was normal. Significant increases also occurred in plasma concentrations of norepinephrine (3.6 times normal), renin activity (7.2 time normal), aldosterone (3.4 times normal), cortisol (1.4 times normal), growth hormone (21.8 times normal), and atrial natriuretic peptide (5 times normal)." "The arterial pressure is maintained more by the expansion of the blood volume than by an increase in the peripheral vascular resistance." 
J Clin Endocrinol Metab 1991 Apr;72(4):768-72 Expansion of extracellular volume and suppression of atrial natriuretic peptide after growth hormone administration in normal man. Moller J, Jorgensen JO, Moller N, Hansen KW, Pedersen EB, Christiansen JS. University Department of Endocrinology and Internal Medicine, Aarhus Kommunehospital, Denmark. "Sodium retention and symptoms and signs of fluid retention are commonly recorded during GH administration in both GH-deficient patients and normal subjects." "GH caused a significant increase in ECV (L): 20.45 +/- 0.45 (GH), 19.53 +/- 0.48 (placebo) (P less than 0.01), whereas plasma volume (L) remained unchanged 3.92 +/- 0.16 (GH), 4.02 +/- 0.13 (placebo)."
Edema of cardiac origin. Studies of body water and sodium, renal function, hemodynamic indexes, and plasma hormones in untreated congestive cardiac failure. Anand IS, Ferrari R, Kalra GS, Wahi PL, Poole-Wilson PA, Harris PC. "This study provides data on plasma hormone levels in patients with severe clinical congestive cardiac failure who had never received therapy and in whom the presence of an accumulation of excess water and sodium had been established." "Total body water content was 16% above control, extracellular liquid was 33% above control, plasma volume was 34% above control, total exchangeable sodium was 37% above control, renal plasma flow was 29% of control, and glomerular filtration rate was 65% of control. Plasma norepinephrine was consistently increased (on average 6.3 times control), whereas adrenaline was unaffected. Although plasma renin activity and aldosterone varied widely, they were on average above normal (renin 9.5 times control, aldosterone 6.4 times control). Plasma atrial natriuretic peptide (14.3 times control) and growth hormone (11.5 times control) were consistently increased. Cortisol was also increased on average (1.7 times control). Vasopressin was increased only in one patient." 
J Pediatr Endocrinol 1994 Apr-Jun;7(2):93-105. Studies on the renal kinetics of growth hormone (GH) and on the GH receptor and related effects in animals. Krogsgaard Thomsen M, Friis C, Sehested Hansen B, Johansen P, Eschen C, Nowak J, Poulsen K. "Growth hormone (GH) is filtered through the kidney, and may exert effects on renal function when presented via the circulation. Investigations on kidney-related aspects of GH are increasing in number." "Short term administration of GH to rats and humans elicited electrolyte and water retention that may cause edema in adults."
Mech Ageing Dev 1983 Jul-Aug;22(3-4):233-51 The anti-aging action of hypophysectomy in hypothalamic obese rats: effects on collagen aging, age-associated proteinuria development and renal histopathology. Everitt AV, Wyndham JR, Barnard DL Hypophysectomy in young male Wistar rats aged 70 days, like food restriction begun at the same age, retarded the life-long rate of collagen aging in tail tendon fibres and inhibited the development of age-associated proteinuria and renal histopathology. Hypothalamic lesions which increased the food intake of hypophysectomized rats from 7 g to 15 g/day and produced obesity did not alter the rate of either collagen aging or proteinuria development, nor reduce life expectancy, but increased the incidence of abnormal glomeruli. In the intact rats elevation of food intake from 7 g to 15 g/day increased the rate of proteinuria development, but did not affect the rate of collagen aging. Hypophysectomy was found to have a greater anti-collagen aging effect than food restriction, when food intakes were the same in both groups. These studies suggest a pituitary-hormonal effect on collagen aging and a food-pituitary-hormone-mediated effect on the development of age-associated proteinuria. 
Growth Dev Aging 1992 Summer;56(2):85-93. Morphometrical analysis of the short-term effects of hypophysectomy and food restriction on skeletal muscle fibers in relation to growth and aging changes in the rat. Shorey CD, Manning LA, Grant AL, Everitt AV.
Metabolism of glomerular basement membrane in normal, hypophysectomized, and growth-hormone-treated diabetic rats," Reddi AS, Exp Mol Pathol, 1985 Oct, 43:2, 196-208. "The in vivo synthesis of the renal glomerular basement membrane (GBM) collagen was studied in normal, hypophysectomized (hypox), diabetic, and growth-hormone (GH)-treated diabetic rats...." "A significant decrease in both proline and hydroxyproline specific activities were observed in GBM of hypox rats at all periods of study. Administration of GH to hypox rats returned the GBM collagen synthesis to normal. Diabetic GBM had higher proline and hydroxyproline specific activities when compared to normal rats. Treatment of diabetic rats with GH for 10 days further increased both proline and hydroxyproline specific activities when compared either to diabetic or normal rats treated with GH. The activity of glucosyltransferase, an enzyme involved in the biosynthesis of the disaccharide unit of GBM collagen was found to be decreased in glomeruli of hypox rats. In contrast, the activity of N-acetyl-beta-glucosaminidase, a glycoprotein-degrading enzyme, was found to be significantly increased in hypox rats. GH treatment restored both enzyme activities to normal. The results of the present study show that GBM collagen synthesis is decreased in hypox rats and increased in diabetic rats. ....not only normalized GBM collagen synthesis in hypox rats but also caused significant increase in diabetic rats. This suggests that the renal GBM metabolism is influenced by GH, and this may be of particular significance in view of GH involvement in diabetic microvascular complications."
Ciba Found Symp 1982;(90):263-78 Prolactin and growth hormone receptors. Friesen HG, Shiu RP, Elsholtz H, Simpson S, Hughes J The two hormones prolactin and growth hormone exhibit considerable structural homology as well as exerting similar biological effects, especially the primate hormones. One effect of prolactin that deserves greater attention is its action on the immune system including the stimulation of growth of experimental lymphomas, both in vivo and in vitro." 
N Engl J Med 1999 Sep 9;341(11):785-92. Increased mortality associated with growth hormone treatment in critically ill adults.

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A R T I C L E

Phosphate, activation, and aging

Recent publications are showing that excess phosphate can increase inflammation, tissue atrophy, calcification of blood vessels, cancer, dementia, and, in general, the processes of aging. This is especially important, because of the increasing use of phosphates as food additives.

Previously, the complications of chronic kidney disease, with increased serum phosphate, were considered to be specific for that condition, but the discovery of a phosphate-regulating gene named klotho (after one of the Fates in Greek mythology) has caused a lot of rethinking of the biological role of phosphate. In the 19th century, phosphorus was commonly called brain food, and since about 1970, its involvement in cell regulation has become a focus of reductionist thinking. ATP, adenosine triphosphate, is seen as the energy source that drives cell movement as well as the "pumps" that maintain the living state, and as the source of the cyclic AMP that is a general activator of cells, and as the donor of the phosphate group that activates a great number of proteins in the "phosphorylation cascade." When tissues calcified in the process of aging, calcium was blamed (ignoring the existence of calcium phosphate crystals in the tissues), and low calcium diets were recommended. Recently, when calcium supplements haven't produced the intended effects, calcium was blamed, disregarding the other materials present in the supplements, such as citrate, phosphate, orotate, aspartate, and lactate.

I have a different perspective on the "phosphorylation cascade," and on the other functions of phosphate in cells, based largely on my view of the role of water in cell physiology. In the popular view, a stimulus causes a change of shape in a receptor protein, causing it to become an active enzyme, catalyzing the transfer of a phosphate group from ATP to another protein, causing it to change shape and become activated, and to transfer phosphate groups to other molecules, or to remove phosphates from active enzymes, in chain reactions. This is standard biochemistry, that can be done in a test tube.

Starting around 1970, when the involvement of phosphorylation in the activation of enzymes in glycogen breakdown was already well known, people began noticing that the glycogen phosphorylase enzyme became active immediately when the muscle cell contracted, and that phosphorylation followed the activation. Phosphorylation was involved in activation of the enzyme, but if something else first activated the enzyme (by changing its shape), the addition of the phosphate group couldn't be considered as causal, in the usual reductionist sense. It was one participant in a complex causal process. I saw this as a possible example of the effect of changing water structure on protein structure and function. This view of water questions the relevance of test tube biochemistry.

Enzymes are known which suddenly become inactive when the temperature is lowered beyond a certain point. This is because soluble proteins arrange their shape so that their hydrophobic regions, the parts with fat-like side-chains on the amino acids, are inside, with the parts of the chain with water-soluble amino acids arranged to be on the outside, in contact with the water. The "wetness" of water, its activity that tends to exclude the oily parts of the protein molecule, decreases as the temperature decreases, and some proteins are destabilized when the relatively hydrophobic group is no longer repelled by the surrounding cooler water. 

In the living cell, the water is all within a very short distance of a surface of fats or fat-like proteins. In a series of experiments, starting in the 1960s, Walter Drost-Hansen showed that, regardless of the nature of the material, the water near a surface is structurally modified, becoming less dense, more voluminous. This water is more "lipophilic," adapting itself to the presence of fatty material, as if it were colder. This change in the water's properties also affects the solubility of ions, increasing the solubility of potassium, decreasing that of sodium, magnesium, and calcium (Wiggins, 1973).

 When a muscle contracts, its volume momentarily decreases (Abbott and Baskin, 1962). Under extremely high pressure, muscles contract. In both situations, the work-producing process of contraction is associated with a slight reduction in volume. During contraction of a muscle or nerve, heat is given off, causing the temperature to rise. During relaxation, recovering from excitation, heat is absorbed (Curtin and Woledge, 1974; Westphal, et al., 1999; Constable, et al. 1997). In the case of a nerve, following the heating produced by excitation, the temperature of the nerve decreases below the starting temperature (Abbot, et al., 1965). Stretching a muscle causes energy to be absorbed (Constable, et al., 1997). Energy changes such as these, without associated chemical changes, have led some investigators to conclude that muscle tension generation is "entropy driven" (Davis and Rodgers, 1995). 

 Kelvin's description (1858) of the physics of water in a soap bubble, "…if a film such as a soap-bubble be enlarged . . . it experiences a cooling effect . . . ," describes the behavior of nerves and muscles, absorbing energy or heat when they are relaxing (or elongating), releasing it when they are excited/contracting. 

Several groups of experimenters over the last 60 years have tried to discover what happens to the missing heat; some have suggested electrical or osmotic storage, and some have demonstrated that stretching generates ATP, arguing for chemical storage. Physical storage in the form of structural changes in the water-protein-lipid system, interacting with chemical changes such as ATP synthesis, have hardly been investigated.

Early studies of muscle chemistry and contraction found that adding ATP to a viscous solution of proteins extracted from muscle reduced its viscosity, and also that the loss of ATP from muscle caused its hardening, as in rigor mortis; if the pH wasn't too acidic, the dead muscle would contract as the ATP content decreased. Szent-Gyorgyi found that a muscle hardened by rigor mortis became soft again when ATP was added. 

 Rigor mortis is an extreme state of fatigue, or energy depletion. Early muscle studies described the phenomenon of "fatigue contracture," in which the muscle, when it reaches the point at which it stops responding to stimulation, is maximally contracted (this has also been called delayed relaxation). Ischemic contracture, in the absence of blood circulation, occurs when the muscle's glycogen is depleted, so that ATP can no longer be produced anaerobically (Kingsley, et al., 1991). The delayed relaxation of hypothyroid muscle is another situation in which it is clear that ATP is required for relaxation. (In the Achilles tendon reflex test, the relaxation rate is visibly slowed in hypothyroidism.) A delayed T wave in the electrocardiogram, and the diastolic contracture of the failing heart show the same process of delayed relaxation. Supplementing the active thyroid hormone, T3, can quickly restore the normal rate of relaxation, and its beneficial effects have been demonstrated in heart failure (Pingitore, et al., 2008; Wang, et al., 2006; Pantos, et al., 2007; Galli, et al., 2008).

 A large part of the magnesium in cells is bound to ATP, and the magnesium-ATP complex is a factor in muscle relaxation. A deficiency of either ATP or magnesium contributes to muscle cramping. When a cell is stimulated, causing ATP to release inorganic phosphate, it also releases magnesium. Above the pH of 6.7, phosphate is doubly ionized, in which state it has the same kind of structural effect on water that magnesium, calcium, and sodium have, causing water molecules to be powerfully attracted to the concentrated electrical charge of the ion. Increasing the free phosphate and magnesium opposes the effect of the surfaces of fats and proteins on the water structure, and tends to decrease the solubility of potassium in the water, and to increase the water's "lipophobic" tendency to minimize its contacts with fats and the fat-like surface of proteins, causing the proteins to rearrange themselves. 

 These observations relating to the interactions of water, solutes and proteins in muscles and nerves provide a coherent context for understanding contraction and conduction, which is lacking in the familiar descriptions based on membranes, pumps, and cross-bridges, but I think they also provide a uniquely useful context for understanding the possible dangers of an excess of free phosphate in the body.

 A few people (M. Thomson, J. Gunawardena, A.K. Manrai) are showing that principles of mass-action help to simplify understanding the networks of phosphorylation and dephosphorylation that are involved in cell control. But independently from the phosphorylation of proteins, the presence of phosphate ion in cell water modifies the cell's ion selectivity, shifting the balance toward increased uptake of sodium and calcium, decreasing potassium, tending to depolarize and "activate" the cell.

 About 99% of the publications discussing the mechanism of muscle contraction fail to mention the presence of water, and there's a similar neglect of water in discussions of the energy producing processes in the mitochondrion. The failure of mitochondrial energy production leads to lipid peroxidation, activation of inflammatory processes, and can cause disintegration of the energy producing structure. Increased phosphate decreases mitochondrial energy production (Duan and Karmazyn, 1989), causes lipid peroxidation (Kowaltowski, et al., 1996), and activates inflammation, increasing the processes of tissue atrophy, fibrosis, and cancer.

 For about twenty years it has been clear that the metabolic problems that cause calcium to be lost from bones cause calcium to increase in the soft tissues, such as blood vessels. The role of phosphate in forming calcium phosphate crystals had until recently been assumed to be passive, but some specific "mechanistic" effects have been identified. For example, increased phosphate increases the inflammatory cytokine, osteopontin (Fatherazi, et al., 2009), which in bone is known to activate the process of decalcification, and in arteries is involved in calcification processes (Tousoulis, et al., 2012). In the kidneys, phosphate promotes calcification (Bois and Selye, 1956), and osteopontin, by its activation of inflammatory T-cells, is involved in the development of glomerulonephritis, as well as in inflammatory skin reactions (Yu, et al., 1998). High dietary phosphate increases serum osteopontin, as well as serum phosphate and parathyroid hormone, and increases the formation of tumors in skin (Camalier, et al., 2010).  Besides the activation of cells and cell systems, phosphate (like other ions with a high ratio of charge to size, including citrate) can activate viruses (Yamanaka, et al., 1995; Gouvea, et al., 2006). Aromatase, the enzyme that synthesizes estrogen, is an enzyme that's sensitive to the concentration of phosphate (Bellino and Holben, 1989).

 More generally, increased dietary phosphate increases the activity of an important regulatory enzyme, protein kinase B, which promotes organ growth. A high phosphate diet increases the growth of liver (Xu, et al., 2008) and lung (Jin, et al., 2007), and promotes the growth of lung cancer (Jin, et al., 2009). An extreme reduction of phosphate in the diet wouldn't be appropriate, however, because a phosphate deficiency stimulates cells to increase the phosphate transporter, increasing the cellular uptake of phosphate, with an effect similar to the dietary excess of phosphate, i.e., promotion of lung cancer (Xu, et al., 2010). The optimum dietary amount of phosphate, and its balance with other minerals, hasn't been determined.

 While increased phosphate slows mitochondrial energy production, decreasing its intracellular concentration increases the respiratory rate and the efficiency of ATP formation. A "deficiency" of polyunsaturated fatty acids has this effect (Nogueira, et al., 2001), but so does the consumption of fructose (Green, et al., 1993; Lu, et al., 1994).

In a 1938 experiment (Brown, et al.) that intended to show the essentiality of unsaturated fats, a man, William Brown, lived for six months on a 2500 calorie diet consisting of sucrose syrup, a gallon of milk (some of it in the form of cottage cheese), and the juice of half an orange, besides some vitamins and minerals. The experimenters remarked about the surprising disappearance of the normal fatigue after a day's work, as well as the normalization of his high blood pressure and high cholesterol, and the permanent disappearance of his frequent life-long migraine headaches. His respiratory quotient increased (producing more carbon dioxide), as well as his rate of resting metabolism. I think the most interesting part of the experiment was that his blood phosphate decreased. In two measurements during the experimental diet, his fasting plasma inorganic phosphorus was 3.43 and 2.64 mg. per 100 ml. of plasma, and six month after he had returned to a normal diet the number was 4.2 mg/100 ml. Both the deficiency of the "essential" unsaturated fatty acids, and the high sucrose intake probably contributed to lowering the phosphate.

 In 2000, researchers who were convinced that fructose is harmful to the health, reasoned that its harmful effects would be exacerbated by consuming it in combination with a diet deficient in magnesium. Eleven men consumed, for six months, test diets with high fructose corn syrup or starch, along with some fairly normal U.S. foods, and with either extremely low magnesium content, or with slightly deficient magnesium content. The authors' conclusion was clearly stated in the title of their article, that the combination adversely affects the mineral balance of the body. 

 However, looking at their results in the context of these other studies of the effects of fructose on phosphate, I don't think their conclusion is correct. Even on the extremely low magnesium intake, both their magnesium and calcium balances were positive, meaning that on average their bodies accumulated a little magnesium and calcium, even though men aged 22 to 40 presumably weren't growing very much. To steadily accumulate both calcium and magnesium, with the calcium retention much larger than the magnesium, the minerals were probably mostly being incorporated into their bones. Their phosphate balance, however, was slightly negative on the "high fructose" diet. If the sugar was having the same effect that it had on William Brown in 1938 (and in animal experiments), some of the phosphate loss was accounted for by the reduced amount in blood and other body fluids, but to continue through the months of the experiment, some of it must have represented a change in the composition of the bones. When there is more carbon dioxide in the body fluids, calcium carbonate can be deposited in the bones (Messier, et al., 1979). Increased carbon dioxide could account for a prolonged negative phosphate balance, by taking its place in the bones in combination with calcium and magnesium. 

 Another important effect of carbon dioxide is in the regulation of both calcium and phosphate, by increasing the absorption and retention of calcium (Canzanello, et al., 1995), and by increasing the excretion of phosphate. Increased carbon dioxide (as dissolved gas) and bicarbonate (as sodium bicarbonate) both increase the excretion of phosphate in the urine, even in the absence of the parathyroid hormone. Below the normal level of serum bicarbonate, reabsorption of phosphate by the kidneys is greatly increased (Jehle, et al., 1999). Acetazolamide increases the body's retention of carbon dioxide, and increases the amount of phosphate excreted in the urine. 

Much of the calcium dissolved in the blood is in the form of a complex of calcium and bicarbonate, with a single positive charge (Hughes, et al., 1984). Failure to consider this complexed form of calcium leads to errors in measuring the amount of calcium in the blood, and in interpreting its physiological effects, including its intracellular behavior. Hyperventilation can cause cramping of skeletal muscles, constriction of blood vessels, and excitation of platelets and other cells; the removal of carbon dioxide from the blood lowers the carbonic acid, changing the state and function of calcium. Hyperventilation increases phosphate and parathyroid hormone, and decreases calcium (Krapf, et al., 1992).

Since estrogen tends to cause hyperventilation, lowering carbon dioxide, its role in phosphate metabolism should be investigated more thoroughly. Work by Han, et al. (2002) and Xu, et al. (2003) showed that estrogen increases phosphate reabsorption by the kidney, but estrogen also increases cortisol, which decreases reabsorption, so the role of estrogen in the whole system has to be be considered. 

 This calcium solubilizing effect of bicarbonate, combined with its phosphaturic effect, probably accounts for the relaxing effect of carbon dioxide on the blood vessels and bronchial smooth muscles, and for the prevention of vascular calcification by the thyroid hormones (Sato, et al., 2005, Tatar, 2009, Kim, et al., 2012). Distensibility of the blood vessels and heart, increased by carbon dioxide, is decreased in hypothyroidism, heart failure, and by phosphate. 

 While fructose lowers intracellular phosphate, it also lowers the amount that the intestine absorbs from food (Kirchner, et al.,2008), and the Milne-Nielsen study suggests that it increases phosphate loss through the kidneys. The "anti-aging" protein, klotho, increases the ability of the kidneys to excrete phosphate (Dërmaku-Sopjani, et al., 2011), and like fructose, it supports energy production and maintains thermogenesis (Mori, et al., 2000). 

 Lowering the amount of phosphate in the blood allows the parathyroid hormone to decrease. While the parathyroid hormone also prevents phosphate reabsorption by the kidneys, it causes mast cells to release serotonin (and serotonin increases the kidneys' reabsorption of phosphate), and possibly has other pro-inflammatory effects.  For example, deleting the PTH gene compensates for the harmful (accelerated calcification and osteoporosis) effects of deleting the klotho gene, apparently by preventing the increase of osteopontin (Yuan, et al., 2012).

 Niacinamide is another nutrient that lowers serum phosphate (Cheng, et al., 2008), by inhibiting intestinal absorption (Katai, et al., 1989), and also by reducing its reabsorption by the kidneys (Campbell, et al., 1989). Niacinamide's reduction of free fatty acids by inhibiting lipolysis, protecting the use of glucose for energy, might be involved in its effect on phosphate (by analogy with the phosphate lowering action of a deficiency of polyunsaturated fatty acids). Aspirin is another antilipolytic substance (de Zentella, et al., 2002) which stimulates energy production from sugar and lowers phosphate, possibly combined with improved magnesium retention (Yamada and Morohashi, 1986).

 A diet that provides enough calcium to limit activity of the parathyroid glands, and that is low in phosphate and polyunsaturated fats, with sugar rather than starch as the main carbohydrate, possibly supplemented by niacinamide and aspirin, should help to avoid some of the degenerative processes associated with high phosphate: fatigue, heart failure, movement discoordination, hypogonadism, infertility, vascular calcification, emphysema, cancer, osteoporosis, and atrophy of skin, skeletal muscle, intestine, thymus, and spleen (Ohnishi and Razzaque, 2010; Shiraki-Iida, et al., 2000; Kuro-o, et al., 1997; Osuka and Razzaque, 2012). The foods naturally highest in phosphate, relative to calcium, are cereals, legumes, meats, and fish. Many prepared foods contain added phosphate. Foods with a higher, safer ratio of calcium to phosphate are leaves, such as kale, turnip greens, and beet greens, and many fruits, milk, and cheese. Coffee, besides being a good source of magnesium, is probably helpful for lowering phosphate, by its antagonism to adenosine (Coulson, et al., 1991).

Although increased phosphate generally causes vascular calcification (increasing rigidity, with increased systolic blood pressure), when a high level of dietary phosphate comes from milk and cheese, it is epidemiologically associated with reduced blood pressure (Takeda, et al., 2012).

 Phosphate toxicity offers some interesting insights into stress and aging, helping to explain the protective effects of carbon dioxide, thyroid hormone, sugar, niacinamide, and calcium. It also suggests that other natural substances used as food additives should be investigated more thoroughly. Excessive citric acid, for example, might activate dormant cancer cells (Havard, et al., 2011), and has been associated with malignancy (Blüml, et al., 2011). Nutritional research has hardly begun to investigate the optimal ratios of minerals, fats, amino acids, and other things in foods, and how they interact with the natural toxicants, antinutrients, and hormone disrupters in many organisms used for food.

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key factors in both vascular remodeling and development of atherosclerosis." "These preliminary results suggest that OPG and OPN levels are significantly correlated with vascular function contributing to the pathogenesis of atherosclerosis in CAD." 

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Am J Physiol Gastrointest Liver Physiol. 2008 Oct;295(4):G654-63. High dietary inorganic phosphate enhances cap-dependent protein translation, cell-cycle progression, and angiogenesis in the livers of young mice. Xu CX, Jin H, Lim HT, Kim JE, Shin JY, Lee ES, Chung YS, Lee YS, Beck G Jr, Lee KH, Cho MH.

Nutr Cancer. 2010;62(4):525-32. Low dietary inorganic phosphate stimulates lung tumorigenesis through altering protein translation and cell cycle in K-ras(LA1) mice. Xu CX, Jin H, Lim HT, Ha YC, Chae CH, An GH, Lee KH, Cho MH.

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"These studies demonstrate for the first time that estrogen stimulates intestinal sodium-dependent phosphate absorption in female rats. This stimulation is associated with increased NaPi-IIb mRNA and protein expression."

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reabsorption of Pi and Mg, respectively."

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A R T I C L E

Rosacea, inflammation, and aging: The inefficiency of stress

Rosacea, or acne rosacea, has been defined as "vascular and follicular dilation involving the nose and contiguous portions of the cheeks . . ." that may involve persistent erythema with hyperplasia of sebaceous glands. Stedman's Medical Dictionary 23rd edition.

Light-skinned people, especially women between the ages of 30 and 50, sometimes develop a persistent redness of their cheeks and nose. It may begin as a tendency to flush excessively, but the blood vessels can become chronically dilated. Similar processes occur in dark-skinned people less frequently.

The eyes are sometimes involved, with redness of the exposed areas (conjuctival hyperemia). New blood vessels develop in the area, and the flow of blood through the affected tissue is greatly increased. The tissues become thickened and fibrotic, with the multiplication of fibroblasts and the increased deposition of collagen.

The cornea normally receives its oxygen from the air, and its nutrients from the aqueous humor. As rosacea of the eye develops, the blood vessels surrounding the cornea become increasingly visible, and, especially on the inner (nasal) side of the eye, the vessels tend to enlarge and become tortuous. Rhinophyma, or potato nose, has been described as a late development of rosacea.

Too often, the medical reaction is to give the condition a name, and to distinguish its variants as if they were different problems, and then to use the most direct means to eliminate the problem they have defined.

A typical attitude is that "Rosacea is an enigmatic disease with multiple exacerbations and remissions, and, unfortunately, treatment is directed toward symptomatic control rather than cure" (Randleman).

Lasers or other radiation, caustic chemical abrasion, surgical planing and dermal shaves, and other forms of surgery may be used to destroy the superficial blood vessels, and to reduce the enlarged nose or other irregularities. A few decades ago, when rosacea was believed to be the result of a local infection, antibiotics were used to treat it, and some of them, including tetracycline, helped. It was discovered that some antibiotics have anti-inflammatory actions, apart from their germicidal effects, and now it is very common to prescribe the chronic use of tetracycline to suppress symptoms.

Rosacea, and the fibrotic changes associated with it (pingueculae and pterygia in the eyes, rhinophyma of the nose, etc.), are much more than "cosmetic" issues, involving the skin and eye surface. If the invasive proliferation of blood vessels can be prevented, it's important to do that, because, for example, pannus/neovascularization of the cornea can seriously impair vision. 

But possibly the strangest thing about the relationship of the medical profession to rosacea is that its essential features, invasive neovascularization and fibrotic growth, are of great interest when they occur elsewhere, and many physiological processes are known to regulate the growth of blood vessels and fibroblasts, but nearly all the attention given to rosacea and rhinophyma concerns control of symptoms for cosmetic effect. Rosacea is a physiological problem that deserves consideration in the light of all that's known about physiology and developmental biology.

The increased incidence of rosacea after the age of 30, and the fact that it occurs most commonly in the areas that are most exposed to sunlight (bald men sometimes develop it on the top of the head), indicate that aging and irritation are essential causes. Stress, irritation (such as produced by ultraviolet or ionizing radiation or free radicals), and aging are known to cause disorganized growth of fibrous and vascular tissues in various parts of the body. The occurrence of these processes at the surface, where the changes can be observed immediately, and without invasive procedures, should have aroused wide interest among those who study kidney disease, diabetes, and other degenerative diseases in which fibrosis and neovascularization play important roles.

A localized stress or irritation at first produces vasodilation that increases the delivery of blood to the tissues, allowing them to compensate for the stress by producing more energy. Some of the agents that produce vasodilation also reduce oxygen consumption (nitric oxide, for example), helping to restore a normal oxygen tension to the tissue. Hypoxia itself (produced by factors other than irritation) can induce vasodilation, and if prolonged sufficiently, tends to produce neovascularization and fibrosis. 

Sensitivity to the harmful effects of light can be increased by some drugs and by excess porphyrins produced in the body (and by the porphyrin precursor, delta-amino levulinic acid), leading to rosacea, so those factors should be considered, but too often alcohol (which can cause porphyrin to increase) is blamed for rosacea and rhinophyma, without justification. There are many ways in which poor health can increase light sensitivity. Some types of excitation produced by metabolites (or by the failure of inhibitory metabolites) can produce vasodilation, involving the release of nitric oxide (Cardenas, et al., 2000), setting off a series of potentially pathological reactions, including fibrosis. The nitric oxide increases glycolysis while lowering energy production. The excitatory metabolite glutamate, and nitric oxide, are both inhibited by aspirin (Moro, et al., 2000).

When blood flow in skin affected by rosacea was measured, circulation was 3 or 4 times higher than normal (Sibenge & Gawkrodger, 1992), and oxygen tension may be increased. An inability to extract oxygen from the blood, or to use it to produce energy, will produce the same hyperemia that would be produced by a lack of oxygen. These measurements suggest that mitochondrial defects would be the best place to look for a general cause of rosacea.

When mitochondria are damaged, active cells produce increased amounts of lactic acid, even in the presence of adequate oxygen. Otto Warburg identified this kind of metabolism, aerobic glycolysis, as an essential feature of cancer, and showed that it could be produced by stress, ionizing radiation, carcinogenic toxins, and even by a simple oxygen deficiency. Other investigators around the same time showed that lactic acid produces vasodilation (for example, in the cornea), and more recently it has been shown to promote the development of fibrosis, and it has been called a "phlogogen," a promoter of inflammation. 

Riboflavin, vitamin B2, is an essential component of the mitochondrial respiratory enzymes, and it is very easily destroyed by light (blue light and especially ultraviolet). When it is excited by high energy light, it can spread the damage to other components of the mitochondria, including the cytochromes and the polyunsaturated fatty acids. The other B vitamins are affected when riboflavin's actions are disturbed.

Vitamin K is also extremely light sensitive, and it interacts closely with coenzyme Q in regulating mitochondrial metabolism. For example, mitochondrial Complex-I, NADH-ubiquinone reductase, is probably the most easily damaged part of the mitochondrion, and it is protected by vitamin K. Vitamin E, coenzyme Q, and the polyunsaturated fatty acids are also light sensitive, and they are more susceptible to free radical damage when vitamin K is deficient.

Niacinamide, one of the B vitamins, provides energy to this mitochondrial system. Under stress and strong excitation, cells waste niacinamide-NADH, but niacinamide itself has a sedative antiexcitatory effect, and some of its actions resemble a hormone. Estrogen tends to interfere with the formation of niacin from tryptophan. Tryptophan, rather than forming the sedative niacin (pyridine carboxylic acid), can be directed toward formation of the excitatory quinolinic acid (pyridine dicarboxylic acid) by polyunsaturated fatty acids. Excitation must be in balance with a cell's energetic resources, and niacinamide can play multiple protective roles, decreasing excitation, increasing energy production, and stabilizing repair systems. The state of excitation and type of energy metabolism are crucial factors in governing cell functions and survival.

The polyunsaturated fatty acids, besides their interactions with estrogen and tryptophan metabolism, promote excitation and decrease energy production in several other ways. For example, they increase the excitatory effects of the glutamate pathways (Yu, et al., 1986; Nishikawa, 1994), and their breakdown products inhibit mitochondrial respiration (Humphries, et al., 1998; Picklo, et al., 1999; Lovell, et al., 2000).

The excess excitation that produces nitric oxide and lactic acid lowers the energy production of vascular cells, possibly enough to lower their contractile ability (Geng, et al., 1992), causing vasodilation. When flushing is caused by a mismatch between energy supply and energy demand, caffeine can decrease the vasodilation (Eikvar & Kirkebøen, 1998), but when vasodilation is caused more physiologically by carbon dioxide, caffeine doesn't have that effect (Meno, et al., 2005). In a study in which drinking hot water or coffee was compared with drinking room-temperature coffee or caffeine, it was found that the hot liquids caused flushing, but cool coffee and caffeine didn't.

Caffeine increases cells' energy efficiency, and by opposing the effects of adenosine (secreted by cells that are stressed and energy-depleted), it can inhibit vasodilation, angioneogenesis (Merighi, et al., 2007; Ryzhov, et al., 2007), and fibrosis (Chan, et al., 2006). 

One nearly ubiquitous source of inappropriate excitation and energy depletion is the endotoxin, bacterial lipopolysaccharides absorbed from the intestine (Wang and White, 1999). That this ubiquitous toxin has a role in rosacea is suggested by the observation that intestinal stimulation, to speed transit through the bowel, immediately relieved symptoms (Kendall, 2002). Increased cortisol (Simon, et al., 1998) and sepsis (Levy, 2007) interfere with mitochondrial energy production.

Simple nervous blushing or flushing is usually considered harmless, and when a person is overheated, the reddening of the skin has the function of facilitating heat loss, to restore a normal temperature. But even nerve-regulated flushing can involve a distinct interference with mitochondrial respiration, and can stimulate the overgrowth of blood vessels. 

Cancer's respiratory defect that Warburg identified, fermentation with lactic acid production even in the presence of adequate oxygen, was the result of some kind of injury to the mitochondria. He showed that one of the injuries that could produce aerobic glycolysis was a deficiency of riboflavin. He observed that tumors generally were anoxic, and that cancers typically appeared in the midst of tissue that was atrophying, and suggested that the cancer cells' survival was favored by their ability to live without oxygen. This may be relevant to the observations of many surgeons of a small cancer embedded in the fibrous tissue of large rhinophymas that have been removed.

The relatively high incidence of rosacea among women (some studies indicate that it may be 3 times as common in women as in men) isn't likely to be the result of greater sun exposure, so it's reasonable to look for hormonal causes.

In old age, it's well recognized that men's estrogen level rises. But the estrogen industry has convinced women that their estrogen declines as they get older. It's common knowledge that aging rodents often go into "persistent estrus," and that their estrogen levels generally increase with age (Parkening, et al., 1978; Anisimov and Okulov, 1981). Several studies in women have shown that serum estrogen levels rise from the teens into the 40s (Musey, et al., 1987; Wilshire, et al., 1995; Santoro, et al., 1996).

Other studies show that serum and tissue estrogen concentrations are not concordant, and that some tissues may contain several times as much estrogen as the serum (Jefcoate, et al., 2001). Local irritation increases tissue estrogen content.

The antiestrogens, especially progesterone, begin declining in the 30s, so that the rising estrogen has more effect on the tissues during those years. These are the years in which the incidence of rosacea rises suddenly. Rosacea develops later on average in men, whose estrogen levels rise significantly at later ages.

Estrogen's most immediate effect on cells is to alter their oxidative metabolism. It promotes the formation of lactic acid. In the long run, it increases the nutritional requirements for the B vitamins, as well as for other vitamins. It also increases the formation of aminolevulinic acid, a precursor of porphyrin, and increases the risk of excess porphyrin increasing light sensitivity. Both aminolevulinic acid and excess porphyrins are toxic to mitochondria, apart from their photosensitizing actions. Nitric oxide, glutamate, and cortisol all tend to be increased by estrogen.

Veins and capillaries are highly sensitive to estrogen, and women are more likely than men to have varicose veins, spider veins, leaky capillaries, and other vascular problems besides rosacea.  Estrogen can promote angioneogenesis by a variety of mechanisms, including nitric oxide (Johnson, et al., 2006). "Estrogens potentiate corticosteroid effects on the skin such as striae, telangiectasiae, and rosacea dermatitis" (Zaun, 1981). Early forms of oral contraceptives, high in estrogen, were found to increase acne rosacea more than three-fold (Prenen & Ledoux-Corbusier, 1971).

Lactic acid, produced under the influence of estrogen, nitric oxide, or other problems of energy formation, besides causing vasodilation, also stimulates the growth of fibroblasts. Oxygen deprivation, or damage to mitochondria, will increase lactic acid formation, and so it will immediately cause vasodilation, and if the problem is prolonged, new blood vessels will grow, and fibrous connective tissue will increase. Estrogen stimulates collagen synthesis, and it has been associated with a variety of inflammatory and fibrotic conditions (for example, Cutolo, et al., 2003. Payne, et al., 2006, suggest the use of the anti-estrogen, tamoxifen, to treat rhinophyma.)

The cornea normally contains more riboflavin even than the retina, which has a much higher rate of metabolism. When the cornea isn't able to get enough oxygen from the air for its needs (and if riboflavin is deficient, its need for oxygen is increased), surrounding blood vessels at first dilate in response to the diffusing lactic acid, to increase the blood supply to the edges of the cornea. If the problem is prolonged, the conjuctiva becomes chronically blood-shot, hyperemic, and larger more visible blood vessels grow, surrounding the cornea, or even invading the cornea. Many people, especially women, experienced problems of this sort from wearing contact lenses, especially when the lenses were made of materials very impermeable to oxygen (Dumbleton, et al., 2006).

Sunlight, and mechanical obstruction of the cornea, produce very localized effects, but those local effects are more likely to be harmful when there is a systemic nutritional deficiency or excess of estrogen. When the systemic problem is very severe, the cheeks, nose, and eyes might not be the first tissues to experience a functional disturbance. 

The mitochondrial inhibition produced by the action of the parasympathetic nervous system (occurring in simple blushing) can occur wherever those nerves act, and blood vessels in all parts of the body are responsive to the acetylcholine secreted by those nerves. Sleep typically involves a shift of dominance in the autonomic nervous system toward the parasympathetic nerves, with vasodilation. Nosebleeds, especially in children, commonly occur during sleep (Jarjour & Jarjour, 2005: high incidence in sleep, and association with migraine). 

A 3 year-old child who had been having an average of 3 nosebleeds every day, during a nap and at night, for several months, also had an extreme behavior problem. He became angry and sometimes violent when he went a little longer than normal between meals. After an oral dose of about ten milligrams of riboflavin, he was able to sleep without having another recurrence of the nosebleeds, and his tantrums became rare. Apparently, the nerve-regulated vasodilation produced by sleep, combined with a riboflavin deficiency, had been enough to produce nosebleeds. The energy deficit resulting from a systemic riboflavin deficiency had probably been causing him to be abnormally sensitive to glycogen depletion, producing sudden anger. In another individual, the energy problem might have taken the form of a memory problem, or of a hemorrhage in the brain or other essential organ.

A 37 year old slightly alcoholic man with a bright red nose and cheeks was an amateur fiction writer, but he was having trouble with his memory for words, and for everyday events. Even conversationally, he had to struggle for relatively familiar words. On the suggestion that riboflavin might help his memory, by allowing his brain cells to use oxygen more efficiently, he had his doctor give him an intravenous injection of B vitamins. When I saw him the next day, his conversation was perfectly fluent, and he obviously had easy access to a good vocabulary. Just as noticeable was the normal color of his nose and cheeks. For a week, he had a daily injection of the B vitamins, and his nose color and vocabulary stayed normal. But on the weekend, after not having the shots for two days, his nose and cheeks were again maraschino cherry red, and his speech was halting, as he struggled for words. He forgot the whole episode, and neglected to return to the doctor for more of the vitamin injections. Ten years later, he had developed a medium-sized potato nose, and had his heart valves replaced. 

His vitamin requirements were apparently abnormally high. At first, the problems resulting from damaged mitochondria seem mostly functional (flushing, mood, memory problems, etc.) and variable, but chronically disturbed functions lead to structural, anatomical changes, as prolonged stimulation alters tissue maintenance and growth.

Abram Hoffer, who had been treating schizophrenia and senile dementia with niacin, accidentally discovered that it cured his bleeding gums. That led to its use to treat heart disease.

The "orthomolecular" ideas of Hoffer and Linus Pauling were developed in a context of biochemistry governed by genetics, molecular biology, in which the goal was to provide a chemical that was lacking because of a genetic defect in metabolism. Their idea of using nutrients as drugs has led to many unphysiological practices, in which an isolated nutrient is supposed to have a drug-like action, and if in isolation it doesn't act like a drug, then it should be used only according to the normal genetically determined nutritional requirement.

But in reality, nutritional requirements are strongly influenced by history and present circumstances. For example, when corneal mitochondria have been damaged by riboflavin deficiency, they have been found to subsequently require more than the normal amount of the vitamin to function properly. And the presence of a certain amount of one nutrient often increases or decreases the amount of other nutrients needed.

When the interactions among energy expenditure and energy production, and cellular activation and cellular inhibition, are taken into account, then it's clear that any particular problem is likely to have many causes and many factors that could contribute to a cure.

Lactate, glutamate, ammonium, nitric oxide, quinolinate, estrogen, histamine, aminolevulinate, porphyrin, ultraviolet light, polyunsaturated fatty acids and endotoxin contribute to excitatory and excitotoxic processes, vasodilation, angioneogenesis, and fibrosis. 

Carbon dioxide, glycine, GABA, saturated fatty acids (for example, Nanji, et al., 1997), vitamin K, coenzyme Q10, niacinamide, magnesium, red light, thyroid hormone, progesterone, testosterone, and pregnenolone are factors that can be increased to protect against inappropriate cellular excitation.

All of the nutritional factors that participate in mitochondrial respiration contribute to maintaining a balance between excessive excitation and protective inhibition. Riboflavin, coenzyme Q10, vitamin K, niacinamide, thiamine, and selenium are the nutrients that most directly relate to mitochondrial energy production. 

Coffee is often avoided by people with rosacea, but it is a very good source of niacin and magnesium, and caffeine has some of the same cell-protective functions as niacinamide.

People suffering from rosacea have been found to be more likely than average to have suffered from styes in childhood, to have varicose veins and spider veins, and to suffer from migraines and depression. 

Hypothyroidism has been identified as a factor in all of those. Good thyroid function is necessary for resistance to bacterial infection, for regulation of blood sugar, neurotransmitters, and hormones related to mood, and for the formation of progesterone. Progesterone regulates smooth muscle tone, including the walls of veins, so that a deficiency allows veins to enlarge. It also prevents overgrowth of fibrotic tissue, and in some contexts may inhibit angioneogenesis.

GABA itself tends to raise body temperature (Ishiwata, et al., 2005), by controlling vasodilation, and the factors such as progesterone which protect mitochondrial energy production are also thermogenic, supporting the GABA system. Flushing, both by directly causing heat loss and by reducing mitochondrial energy production, tends to lower body temperature.

The sun-damaged areas in rosacea can be directly provided with some of the protective factors by applying them topically. In the same way that topical lactate can cause vasodilation and disturbed energy metabolism (Rendl, et al., 2001), topical niacinamide, progesterone, vitamin K, and coenzyme Q10 can improve the metabolism and function of the local tissues. Riboflavin can probably be useful when applied topically, but because of its extreme sensitivity to light, it should usually be used only internally, unless the treated skin is covered to prevent exposure to light. Topically applied caffeine, even after sun exposure, can reduce local tissue damage (Koo, et al., 2007). Aspirin and saturated fats can also be protective when applied topically.

Some of the benefit from antibiotics probably results from the reduced endotoxin stress when intestinal bacteria are suppressed. However, antibiotics can kill the intestinal bacteria that produce vitamin K, so it's important to include that in the diet when antibiotics are used.

Some fibers, such as raw carrots, that are effective for lowering endotoxin absorption also contain natural antibiotics, so regular use of carrots should be balanced by occasional supplementation with vitamin K, or by occasionally eating liver or broccoli.

Abram Hoffer's research was instrumental in getting niacin recognized as a heart protective drug, but nearly everyone who prescribes it does so to lower blood lipids. That wasn't Hoffer's understanding of its function. He thought it acted directly on blood vessels to protect their integrity. During his studies of its effects on heart disease, he saw that it also lowered cancer mortality, and so began treating cancer patients with it, with considerable success, but there was no medical cliché that could allow the profession to follow in that direction. 

The arguments I have outlined for considering rosacea to be essentially a problem of metabolic energy, and the mechanisms that I mention for restoring mitochondrial functions, might seem more complex than Hoffer's orthomolecular views. However, this approach is actually much simpler conceptually than any of the ideologies of drug treatment. It simply points out that certain excitatory factors can interfere with energy production, and that there are opposing "inhibitory" factors that can restore energy efficiency. Sometimes, using just one or two of the factors can be curative.

Because mitochondrial respiration is very similar in every kind of tissue, a physiological view of rosacea could incline us toward considering the effects of these metabolic factors in other organs during stress and aging--what would the analogous condition of rosacea and rhinophyma be in the brain, heart, liver, or kidney?

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Invest Ophthalmol Vis Sci. 1991 Jun;32(7):1981-5. Analysis of flavins in ocular tissues of the rabbit. Batey DW, Eckhert CD. Riboflavin is the precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), coenzymes required for the activity of flavoenzymes involved in the transfer of electrons in oxidation-reduction reactions. Flavins are light sensitive and rapidly degrade when exposed to light in the near ultraviolet and visible wavelengths. Some of the byproducts of flavin photodegradation are toxic. A quantitative survey of flavins in rabbit ocular tissues is reported. Adult male Dutch-Belt Rabbits were fed purified diets containing 3, 30, or 300 mg riboflavin/kg for 1 month. A method of aqueous extraction and high-performance liquid chromatography with fluorescence detection was used to measure riboflavin, FMN, and FAD in cornea, lens cortex, lens nucleus, retina, and blood. The retina contained the highest flavin concentration. In all tissues, the primary flavin was FAD followed by FMN and riboflavin. The highest concentration of riboflavin occurred in the cornea followed by the retina, lens cortex, and lens nucleus. A trend toward increasing concentrations of riboflavin occurred in the retina and blood in response to excess dietary riboflavin, but the concentration changes were not statistically significant. The highest concentration of FAD and FMN occurred in the retina followed by the cornea and the lens cortex and nucleus. The relative contribution of riboflavin, FMN, and FAD to the total flavin pool was markedly different in the various tissues of the eye. The proportion of tissue flavins present as riboflavin decreased from anterior to posterior. It was highest in the cornea followed by lens and retina. The pattern of distribution for FMN was: cornea greater than retina greater than lens cortex and nucleus.

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J Neurochem. 2000 May;74(5):2041-8. Implication of glutamate in the expression of inducible nitric oxide synthase after oxygen and glucose deprivation in rat forebrain slices. Cardenas A, Moro MA, Hurtado O, Leza JC, Lorenzo P, Castrillo A, Bodelon OG, Bosca L, Lizasoain I.

Br J Pharmacol. 2006 Aug;148(8):1144-55. Adenosine A(2A) receptors play a role in the pathogenesis of hepatic cirrhosis. Chan ES, Montesinos MC, Fernandez P, Desai A, Delano DL, Yee H, Reiss AB, Pillinger MH, Chen JF, Schwarzschild MA, Friedman SL, Cronstein BN.

Clin Exp Rheumatol.  2003 Nov-Dec;21(6):687-90. New roles for estrogens in rheumatoid arthritis.Cutolo M, Capellino S, Montagna P, Villaggio B, Sulli A, Seriolo B, Straub RH. Sex hormones appear to play an important role as modulators of autoimmune disease onset/perpetuation. Steroid hormones are implicated in the immune response, with estrogens as enhancers at least of humoral immunity, and androgens and progesterone (and glucocorticoids) as natural immune suppressors. Serum levels of estrogens have been found to be normal in rheumatoid arthritis (RA) patients. Synovial fluid levels (SF) of proinflammatory estrogens relative to androgens are significantly elevated in both male and female RA patients as compared to controls, which is most probably due to an increase in local aromatase activity. Thus, available steroid pre-hormones are rapidly converted to proinflammatory estrogens in the synovial tissue in the presence of inflammatory cytokines (i.e. TNF alpha, IL-1, IL-6). The increased estrogen concentrations observed in RA SF of both sexes are characterized mainly by the hydroxylated forms, in particular 16 alpha-hydroxyestrone, showing a mitogenic stimulating role. Indeed, recent studies by us indicate that 17-beta estradiol (E2) clearly enhanced the expression of markers of cell growth and proliferation, whereas testosterone (T) induced an increase in markers indicating DNA damage and apoptosis. In particular, our data further shows that the enhancing role of estrogens on the immune/inflammatory response is exerted by activating the NFkB complex. In conclusion, locally increased estrogens may exert activating effects on synovial cell proliferation, including macrophages and fibroblasts, suggesting new roles for estrogens in RA.

Tidsskr Nor Laegeforen. 1998 Mar 30;118(9):1390-5. [Receptor mediated effects of adenosine and caffeine] [Article in Norwegian] Eikvar L, Kirkebøen KA. "Adenosine consists of one ribose and one purine moiety and binds to specific receptors on cell membranes. The receptors are coupled to G-proteins and additionally to various effector-systems. When a mismatch occurs between energy supply and energy demand, adenosine is produced by the catabolism of adenosine triphosphate. The metabolism of an organ is thereby coupled to the local blood supply (metabolic vasodilation)."

Arch Dermatol. 1988 Jan;124(1):72-9. Health effects of sunlight exposure in the United States. Results from the first National Health and Nutrition Examination Survey, 1971-1974. Engel A, Johnson ML, Haynes SG. The dermatologic component of the first National Health and Nutrition Examination Survey (N = 20,637), conducted from 1971 through 1974, documented the deleterious effect of ultraviolet radiation on selected skin and eye conditions. Actinic skin damage was more frequent in white men with high as compared with low sunlight exposure, 36.7% vs 23.3%, respectively. Among white women, the corresponding figures were 34.1% vs 18.6%, respectively. Actinic damage was found more often in individuals with light eye color. Basal cell epitheliomas were found in 11.3% of white men aged 65 to 74 years who had severely actinic-damaged skin as compared with 1.0% of those with undamaged skin. Sunlight exposure was positively associated with localized hypomelanism, localized hypermelanism, seborrheic keratoses, senile lentigines, freckles, acne rosacea, spider nevi, varicose veins, venus star, dry skin, wrinkled skin, pterygia, arcus senilis, and a variety of minor oral lesions of the tongue, palate, and buccal mucosa. These findings suggest that a large number of dermatologic conditions, which may in part result from overexposure to sunlight, may be preventable.

Nippon Ganka Gakkai Zasshi. 1961 Dec 10;65:2439-44. [The effects of vitamin B2 group on the corneal metabolism. I.] [Article in Japanese] Funatsu H, Motegi T.

J Cosmet Dermatol. 2004 Apr;3(2):88-93. Nicotinic acid/niacinamide and the skin. Gehring W.

Circ Res. 1992 Nov;71(5):1268-76. Interferon-gamma and tumor necrosis factor synergize to induce nitric oxide production and inhibit mitochondrial respiration in vascular smooth muscle cells. Geng Y, Hansson GK, Holme E. "Nitric oxide (NO) is an important signal substance in cell-cell communication and can induce relaxation of blood vessels by activating guanylate cyclase in smooth muscle cells (SMCs)." "It was recently shown that SMCs may themselves produce NO or an NO-related compound. We have studied NO production and its effects on energy metabolism in cultured rat aortic smooth muscle cells. It was observed that the cytokines, interferon-gamma and tumor necrosis factor-alpha, synergistically induced an arginine-dependent production of NO in these cells. This was associated with an inhibition of complex I (NADH: ubiquinone oxidoreductase) and complex II (succinate: ubiquinone oxidoreductase) activities of the mitochondrial respiratory chain, suggesting that NO blocks mitochondrial respiration in these cells. Lactate accumulated in the media of the cells, implying an increased anaerobic glycolysis, but there was no reduction of viability. An NO-dependent inhibition of mitochondrial respiration and a switch to anaerobic glycolysis would reduce energy production of the SMCs. This would in turn reduce the contractile capacity of the cell and might represent another NO-dependent vasodilatory mechanism."

Q Bull Northwest Univ Med Sch. 1952;26(2):120-3. Riboflavin and the cornea. Gordon OE.

Bull Soc Fr Dermatol Syphiligr. 1950 May-Jun;57(3):277-80. Cutaneous-mucosal ariboflavinosis; rosacea of cornea and medio-facial seborrheic dermatitis. Gougerot H, Grupper C, Plas G.

Br J Dermatol. 2005 Dec;153(6):1176-81. Comorbidity of rosacea and depression: an analysis of the National Ambulatory Medical Care Survey and National Hospital Ambulatory Care Survey--Outpatient Department data collected by the U.S. National Center for Health Statistics from 1995 to 2002. Gupta MA, Gupta AK, Chen SJ, Johnson AM.

Biochemistry. 1998 Nov 10;37(45):15835-41. Selective inactivation of alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase: reaction of lipoic acid with 4-hydroxy-2-nonenal.Humphries KM, Szweda LI. "Previous research has established that 4-hydroxy-2-nonenal (HNE), a highly toxic product of lipid peroxidation, is a potent inhibitor of mitochondrial respiration. HNE exerts its effects on respiration by inhibiting alpha-ketoglutarate dehydrogenase (KGDH). Because of the central role of KGDH in metabolism and emerging evidence that free radicals contribute to mitochondrial dysfunction associated with numerous diseases, it is of great interest to further characterize the mechanism of inhibition." "These results therefore identify a potential mechanism whereby free radical production and subsequent lipid peroxidation lead to specific modification of KGDH and PDH and inhibition of NADH-linked mitochondrial respiration."

Biochemistry. 1998 Jan 13;37(2):552-7. Inhibition of NADH-linked mitochondrial respiration by 4-hydroxy-2-nonenal. Humphries KM, Yoo Y, Szweda LI. During the progression of certain degenerative conditions, including myocardial ischemia-reperfusion injury, mitochondria are a source of increased free-radical generation and exhibit declines in respiratory function(s). It has therefore been suggested that oxidative damage to mitochondrial components plays a critical role in the pathology of these processes. Polyunsaturated fatty acids of membrane lipids are prime molecular targets of free-radical damage. A major product of lipid peroxidation, 4-hydroxy-2-nonenal (HNE), is highly cytotoxic and can readily react with and damage protein. In this study, the effects of HNE on intact cardiac mitochondria were investigated to gain insight into potential mechanisms by which free radicals mediate mitochondrial dysfunction. Exposure of mitochondria to micromolar concentrations of HNE caused rapid declines in NADH-linked but not succinate-linked state 3 and uncoupled respiration. The activity of complex I was unaffected by HNE under the conditions of our experiments. Loss of respiratory activity reflected the inability of HNE-treated  mitochondria to meet NADH demand during maximum rates of O2 consumption. HNE exerted its effects on intact mitochondria by inactivating alpha-ketoglutarate dehydrogenase. These results therefore identify a potentially important mechanism by which free radicals bring about declines in mitochondrial respiration.

Tohoku J Exp Med. 1954 Dec 25;61(1):93-104. Contribution to the ocular manifestation of riboflavin deficiency. Irinoda K, Sato S.

Brain Res. 2005 Jun 28;1048(1-2):32-40.  Changes of body temperature and thermoregulatory responses of freely moving rats during GABAergic pharmacological stimulation to the preoptic area and anterior hypothalamus in several ambient temperatures. Ishiwata T, Saito T, Hasegawa H, Yazawa T, Kotani Y, Otokawa M, Aihara Y.

Pediatr Neurol. 2005 Aug;33(2):94-7. Migraine and recurrent epistaxis in children. Jarjour IT, Jarjour LK.

J Natl Cancer Inst Monogr 2000;(27):95-112. Tissue-specific synthesis and oxidative metabolism of estrogens. Jefcoate CR, Liehr JG, Santen RJ, Sutter TR, Yager JD, Yue W, Santner SJ, Tekmal R, Demers L, Pauley R, Naftolin F, Mor G, Berstein L "However, breast cancer tissue E2 levels are 10-fold to 50-fold higher in postmenopausal women than predicted from plasma levels."

Endocrine. 2006 Dec;30(3):333-42. Effects of estradiol-17beta on expression of mRNA for seven angiogenic factors and their receptors in the endometrium of ovariectomized (OVX) ewes. Johnson ML, Grazul-Bilska AT, Redmer DA, Reynolds LP.

Clin Exp Dermatol. 2004 May;29(3):297-9. Remission of rosacea induced by reduction of gut transit time. Kendall SN. Rosacea is a chronic disorder characterized by hypersensitivity of the facial vasculature, presenting with intense flushing eventually leading to chronic erythema and telangiectasia. Although the precise aetiology of rosacea is not known, numerous associations with inflammatory gastrointestinal tract disorders have been reported. Furthermore, substance P-immunoreactive neurones occur in considerably greater numbers in tissue surrounding affected blood vessels suggesting involvement of neurogenic inflammation and moreover plasma kallikrein-kinin activation is consistently found in patients. In this report, a patient without digestive tract disease is described, who experienced complete remission of rosacea symptoms following ingestion of a material intended to sweep through the digestive tract and reduce transit time below 30 h. It is possible that intestinal bacteria are capable of plasma kallikrein-kinin activation and that flushing symptoms and the development of other characteristic features of rosacea result from frequent episodes of neurogenic inflammation caused by bradykinin-induced hypersensitization of facial afferent neurones. The possible relevance of this hypothesis to other conditions featuring afferent hypersensitivity, such as fibromyalgia, is considered.

Br J Dermatol. 2007 May;156(5):957-64. Protection from photodamage by topical application of caffeine after ultraviolet  irradiation. Koo SW, Hirakawa S, Fujii S, Kawasumi M, Nghiem P.

Medicina (B Aires) 1985;45(2):110-6. [Fibrosis and cirrhosis in the rabbit induced by diethylstilbestrol and its inhibition with progesterone]. [Article in Spanish] Lanari A, de Kremer GH.

Free Radic Biol Med. 2000 Oct 15;29(8):714-20. Acrolein, a product of lipid peroxidation, inhibits glucose and glutamate uptake in primary neuronal cultures. Lovell MA, Xie C, Markesbery WR.

J Cereb Blood Flow Metab. 2005 Jun;25(6):775-84. Effect of caffeine on cerebral blood flow response to somatosensory stimulation. Meno JR, Nguyen TS, Jensen EM, Alexander West G, Groysman L, Kung DK, Ngai AC, Britz GW, Winn HR. "Hypercarbic vasodilatation was unaffected by either caffeine or theophylline."

Mol Pharmacol. 2007 Aug;72(2):395-406. Caffeine inhibits adenosine-induced accumulation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and interleukin-8 expression in hypoxic human colon cancer cells. Merighi S, Benini A, Mirandola P, Gessi S, Varani K, Simioni C, Leung E, Maclennan S, Baraldi PG, Borea PA.

Neuropharmacology. 2000 Apr 27;39(7):1309-18. Mechanisms of the neuroprotective effect of aspirin after oxygen and glucose deprivation in rat forebrain slices. Moro MA, De Alba J, Cardenas A, De Cristobal J, Leza JC, Lizasoain I, Diaz-Guerra MJ, Bosca L, Lorenzo P.

Am J Obstet Gynecol 1987 Aug;157(2):312-317. Age-related changes in the female hormonal environment during reproductive life. Musey VC, Collins DC, Musey PI, Martino-Saltzman D, Preedy JR "We found that increased age during reproductive life is accompanied by a significant rise in both basal and stimulated serum follicle-stimulating hormone levels. This was accompanied by an increase in the serum level of estradiol-17 beta and the urine levels of estradiol-17 beta and 17 beta-estradiol-17-glucosiduronate." "Serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate decreased with age, but serum testosterone was unchanged."

Hepatology. 1997 Dec;26(6):1538-45. Dietary saturated fatty acids down-regulate cyclooxygenase-2 and tumor necrosis factor alfa and reverse fibrosis in alcohol-induced liver disease in the rat. Nanji AA, Zakim D, Rahemtulla A, Daly T, Miao L, Zhao S, Khwaja S, Tahan SR, Dannenberg AJ.

J Physiol. 1994 Feb 15;475(1):83-93. Facilitatory effect of docosahexaenoic acid on N-methyl-D-aspartate response in pyramidal neurones of rat cerebral cortex. Nishikawa M, Kimura S, Akaike N. 

J Gerontol, 1978 Mar, 33:2, 191-6. Circulating plasma levels of pregnenolone, progesterone, estrogen, luteinizing hormone, and follicle stimulating hormone in young and aged C57BL/6 mice during various stages of pregnancy. Parkening TA; Lau IF; Saksena SK; Chang MC.

Antioxid Redox Signal. 1999 Fall;1(3):255-84. 4-Hydroxynonenal as a biological signal: molecular basis and pathophysiological implications. Parola M, Bellomo G, Robino G, Barrera G, Dianzani MU.

Ann Plast Surg. 2002 Jun;48(6):641-5. Further evidence for the role of fibrosis in the pathobiology of rhinophyma. Payne WG, Wang X, Walusimbi M, Ko F, Wright TE, Robson MC.

Ann Plast Surg. 2006 Mar;56(3):301-5. Down-regulating causes of fibrosis with tamoxifen: a possible cellular/molecular approach to treat rhinophyma. Payne WG, Ko F, Anspaugh S, Wheeler CK, Wright TE, Robson MC.

Neurochem Res. 1991 Sep;16(9):983-9. Release of arachidonic acid by NMDA-receptor activation in the rat hippocampus. Pellerin L, Wolfe LS.

J Neurochem. 1999 Apr;72(4):1617-24. 4-Hydroxy-2(E)-nonenal inhibits CNS mitochondrial respiration at multiple sites. Picklo MJ, Amarnath V, McIntyre JO, Graham DG, Montine TJ.

Biochim Biophys Acta. 2001 Feb 14;1535(2):145-52. Acrolein inhibits respiration in isolated brain mitochondria. Picklo MJ, Montine TJ.

Arch Belg Dermatol Syphiligr. 1971 Jul-Sep;27(3):253-8. [Hormonal contraception and dermatology]Prenen M, Ledoux-Corbusier M. PIP: A group of 150 Belgian women aged 17-47 taking various oral contraceptives was compared with a control group of 400 with respect to incidence of cholasma and piloseborrheic disorders. While taking pills, 10% of alopecia and 5.3% of juvenile acne cases were improved, but the following symptoms appeared: hypertrichosis in 4%, alopecia in 14.6, juvenile acne in 16.6%, and rosaceous acne in 3.3%. The incidence of these symptoms in the controls was cholasma .75%, hypertrichosis 5.25%, alopecia 11.5%, juvenile acne 21%, and acne rosacea 1%. The pill seemed to aggravate cholasma and rosaceous acne or to improve piloseborrheic symptoms, depending on whether the formulation was dominant in estrogen or progestagen.

Ann Plast Surg. 2000 Nov;45(5):515-9. Overexpression of transforming growth factor beta-2 and its receptor in rhinophyma: an alternative mechanism of pathobiology. Pu LL, Smith PD, Payne WG, Kuhn MA, Wang X, Ko F, Robson MC. "These findings support the authors' hypothesis that fibrosis may also play an important role in the pathobiology of rhinophyma."

www.emedicine.com/oph/topic115.htm Last Updated: May 14, 2007. Author: J Bradley Randleman, MD, Assistant Professor, Department of Ophthalmology, Cornea, External Disease, and Refractive Surgery Section, Emory University School of Medicine

Br J Dermatol. 2001 Jul;145(1):3-9. Topically applied lactic acid increases spontaneous secretion of vascular endothelial growth factor by human reconstructed epidermis. Rendl M, Mayer C, Weninger W, Tschachler E.

Nature. 1969 Aug 2;223(5205):516-7. Diminished responsiveness to thyroid hormone in riboflavin-deficient rats. Rivlin RS, Wolf G.

J Pharmacol Exp Ther. 2007 Feb;320(2):565-72. Role of adenosine receptors in the regulation of angiogenic factors and neovascularization in hypoxia. Ryzhov S, McCaleb JL, Goldstein AE, Biaggioni I, Feoktistov I.

J Clin Endocrinol Metab 1996 Apr;81(4):1495-501, Characterization of reproductive hormonal dynamics in the perimenopause. Santoro N, Brown JR, Adel T, Skurnick JH "Overall mean estrone conjugate excretion was greater in the perimenopausal women compared to that in the younger women [76.9 ng/mg Cr (range, 13.1-135) vs. 40.7 ng/mg Cr (range, 22.8-60.3); P = 0.023] and was similarly elevated in both follicular and luteal phases." "We conclude that altered ovarian function in the perimenopause can be observed as early as age 43 yr and include hyperestrogenism, hypergonado-tropism, and decreased luteal phase progesterone excretion. These hormonal alterations may well be responsible for the increased gynecological morbidity that characterizes this period of life." 

J Am Acad Dermatol. 1992 Apr;26(4):590-3. Rosacea: a study of clinical patterns, blood flow, and the role of Demodex folliculorum. Sibenge S, Gawkrodger DJ.

Cesk Oftalmol. 1951;7(1):37-42. [Effect of vitamin B1 and B2 on diseases of the cornea.] Simkova M.

FEBS Lett. 1998 Sep 11;435(1):25-8. Glucocorticoids decrease cytochrome c oxidase activity of isolated rat kidney mitochondria. Simon N, Jolliet P, Morin C, Zini R, Urien S, Tillement JP. "The importance of mitochondria is rising as a target in pathologic processes such as ischemia." "A regulation of cytochrome c oxidase activity by glucocorticoids will be of particular interest in pathology involving metabolic insult."

Am J Ophthalmol. 1950 Jul;33(7):1127-36. The ocular manifestations of riboflavin deficiency. Stern JJ.

Arch Ophthal. 1949 Oct;42(4):438-42. Conditioned corneal vascularity in riboflavin deficiency; report of a case. Stern HJ.

Nippon Ganka Kiyo. 1962 Nov;13:489-94. [Variations of total vitamin B2 content in the cornea, iris and ciliary body and the blood of rabbits in stress. (A preliminary report)] [Article in Japanese] Taketani T.

Free Radic Res. 1996 Jun;24(6):421-7. The effect of the lipid peroxidation product 4-hydroxynonenal and of its metabolite 4-hydroxynonenoic acid on respiration of rat kidney cortex mitochondria. Ullrich O, Henke W, Grune T, Siems WG. 

J Neurochem. 1999 Feb;72(2):652-60. The bacterial endotoxin lipopolysaccharide causes rapid inappropriate excitation in rat cortex. Wang YS, White TD.

Ophthalmologica. 1955 Jun;129(6):389-95. [Corneal changes in riboflavin-deficient rats.] [Article in German] Wiesinger H, Kaunitz H, Slanetz CA.

Arzneimittelforschung 1968 Dec;18(12): 1525-9. On the phlogogenic properties of lactic acid in animal experiments. Wilhelmi G, Gdynia R.

Ann Intern Med 1981 Oct;95(4):468-76. Flushing reactions: consequences and mechanisms. Wilkin JK

J Clin Endocrinol Metab 1995 Feb;80(2):608-613. Diminished function of the somatotropic axis in older reproductive-aged women. Wilshire GB, Loughlin JS, Brown JR, Adel TE, Santoro N "Studies in aging women have rarely controlled for menstrual cycle stage or status or body mass index. We hypothesized that GH and IGF-I levels in reproductive-aged women fall with age despite the stimulatory effects of endogenous estradiol (E2). Eight older reproductive-aged women (aged 42-46 yr) with regular menses, of normal weight, and in good health were compared to a group of eight young control subjects (aged 19-34 yr)." "Older reproductive-aged women had lower 12-h integrated daytime GH concentrations (mean +/- SE, 171 +/- 35 vs. 427 +/- 130 micrograms min/L; P = 0.036) than younger controls and a strong trend for lower IGF-I levels (22.7 +/- 2.1 vs. 31.3 +/- 3.5 nmol/L; P = 0.055) than younger controls despite having higher circulating E2 on the day of sampling (368 +/- 51 vs. 167 +/- 20 pmol/L; P = 0.002). We conclude that older reproductive-aged women have lower daytime GH concentrations than younger controls despite having higher E2 levels on the day of sampling and overall normal gonadal hormone parameters."

J Neurochem 1986 Oct;47(4):1181-9. Effects of arachidonic acid on glutamate and gamma-aminobutyric acid uptake in primary cultures of rat cerebral cortical astrocytes and neurons. Yu AC, Chan PH, Fishman RA.

Med Monatsschr Pharm. 1981 Jun;4(6):161-5. [Skin changes from taking hormonal contraceptives][Article in German] Zaun H. PIP: Hormonal contraceptives can induce changes in the skin and its appendages. "Estrogens potentiate corticosteroid effects on the skin such as striae, telangiectasiae, and rosacea dermatitis."

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A R T I C L E

Hot flashes, energy, and aging

Around the time that menstruation and fertility are ending, certain biological problems are more likely to occur. Between the ages of 50 and 55, about 60% of women experience repeated episodes of flushing and sweating. Asthma, migraine, epilepsy, arthritis, varicose veins, aneurysms, urticaria, reduced lung function, hypertension, strokes, and interstitial colitis are some of the other problems that often begin or get worse at the menopause, but that normally aren't considered to be causally related to it.

Recently, hot flashes are being taken more seriously, because of their association with increased inflammation, heart disease, and risk of dementia. Around the same age, late 40s to mid-50s, men begin to have a sudden increase of some of the same health problems, including night sweats, anxiety, and insomnia. In both sexes, the high incidence of depression in this age group has usually been explained "psychologically," rather than biologically.

When the estrogen industry began concentrating on women of menopausal age (after the disastrous years of selling it as a fertility drug), "estrogen replacement" therapy was promoted as a cure for the problems associated with menopause, including hot flashes, which were explained as the result of a deficiency of estrogen. However, in recent years, the phrase "estrogen deficiency" has begun to be replaced by the phrase "estrogen withdrawal," because it has been found that women with hot flashes don't necessarily have less estrogen in their blood stream than women who don't have hot flashes.

Associated with this change of terminology, there has been a recognition that changes in the temperature regulating system in the brain, rather than changes in the amount of estrogen, are responsible for the hot flashes, but mainstream medicine has carefully avoided the investigation of this subject. The effects of estrogen on the thermoregulatory system are very clear, but the standard medical view is that the physiology of hot flashes simply isn't understood.

Since the medical literature boldly describes the mechanisms of the circulatory system and the causes of major problems such as heart attacks, high blood pressure, and strokes, it's odd that it doesn't have an explanation for "hot flashes."

But looking at this historically, I think this selective ignorance is necessary, for the protection of some doctrines that have become very important for conventional medicine.

When doctors are talking about diseases of the heart and circulatory system, it's common for them to say that estrogen is protective, because it causes blood vessels to relax and dilate, improving circulation and preventing hypertension. The fact that estrogen increases the formation of nitric oxide, a vasodilator, is often mentioned as one of its beneficial effects. But in the case of hot flashes, dilation of the blood vessels is exactly the problem, and estrogen is commonly prescribed to prevent the episodic dilation of blood vessels that constitutes the hot flash. Nitric oxide increases in women in association with the menopause (Watanabe, et al., 2000), and it is increased by inflammation, and hot flushes are associated with various mediators of inflammation, but, as far as I can tell, no one has measured the production of nitric oxide during a hot flash. Inhibitors of nitric oxide formation reduce vasodilation during hot flushes (Hubing, et al., 2010).

Starting in the 1940s, the doctrine that menopause is the result of changes in the ovaries, involving a depletion of eggs and an associated loss of estrogen production, was widely taught to medical students. By the 1970s, the taboo against discussing menopause publicly was fading, and the mass media began teaching the public that hot flashes are the result of an estrogen deficiency, and that "estrogen replacement" is the most appropriate and effective treatment, and in the next 20 years almost half the women in the US began taking it around the time of menopause. This practice became routine at a time when "evidence based medicine" was being promoted as a new standard, but there was no evidence that women experiencing hot flashes were deficient in estrogen (in fact, there was evidence that they weren't), and there was evidence that hot flashes began when the first menstrual period was missed, which coincided with, and resulted from, a failure to produce a functional corpus luteum, preventing the production of a normal amount of progesterone. But the silly old doctrine of deficiency is often restated by professors, as if there was no doubt about it (for example, Rance, 2009; Bhattacharya and Keating, 2012).

This extremely persistent disregard for important evidence about the nature of menopause and its symptoms was guided by the estrogen industry, which began in the 1930s to call estrogen "the female hormone," disregarding the facts about the biological roles of estrogen and progesterone, because chemicals with estrogenic effects were numerous and cheap, while progesterone was expensive, and had no synthetic equivalents. At the time the pharmaceutical industry began promoting estrogen as the female hormone to prevent miscarriage, it was already well known that it could produce abortion, as well as causing inflammation and cancer, and some of the most famous estrogen researchers were warning of its multiple dangers in the 1930s.

Menopause is a major landmark of aging, and if its meaning is radically misunderstood, a coherent understanding of aging is unlikely, and without an understanding of the loss of functions with age, we won't really understand life. More specifically, the real causes of the many serious problems occurring in association with the menopause will be ignored. Finding the causes of the seemingly trivial hot flash will affect the way we understand aging and its diseases.

If a common occurrence is thought to have some importance in itself, or to relate closely to something of importance, it will be described carefully, and its general features will become part of the common understanding. It's clear that our medical culture hasn't considered the hot flash to be important, because there are still physicians who believe that the hot flash represents a rise of body temperature caused by a sudden increase of heat production, which they sometimes explain as an upward fluctuation of thyroid gland activity. Measurement of body temperature before and during hot flashes has shown clearly that the internal temperature is lowered slightly by the hot flash, as heat is lost from the skin, as a result of vasodilation. Physiologists have been studying the differences in temperature regulation between men and women, and the effects of hormones on temperature regulation, for more than 70 years, but the medical profession in the United States showed almost no interest in the subject for about 50 years.

August Weismann's doctrine of "mortal soma, immortal germ line," led people to postulate that "primordial germ" cells migrated into the ovary (consisting of "somatic" cells) during embryonic development, and that the baby was born with a supply of germ cells that was used up during the reproductive lifetime, accounting for the decline of fertility with aging. The fact that menstrual cycles ended around the time that fertility ended was explained by the idea that ovulation caused the release of estrogen, and that the absence of eggs caused a failure to produce estrogen, and that the absence of estrogen led to the failure of the cyclical uterine changes. It was all deduced from a mistaken ideology about the nature of life. 

Cancer of the endometrium (lining) of the uterus and breast cancer were known to be the first and second cancers, respectively, produced by uninterrupted exposure to estrogen (for example, Lipshutz, 1950). Investigation of the causes of endometrial cancer showed that women with anovulatory cycles, that failed to produce progesterone, or who had a reduced production of progesterone, developed overgrowth of the endometrium, and that these were the women who were later most likely to develop cancer of the endometrium. The peak incidence of endometrial cancer is in the postmenopausal years, resulting from prolonged exposure to estrogen, unopposed by progesterone. The medical belief* that "ovulation produces estrogen," and that the absence of menstruation means an absence of estrogen, has been very harmful to women's health.

Several laboratories, from the 1950s through the 1980s, investigated the causes of age-related infertility. A.L. Soderwall, among others, demonstrated that an excess of estrogen makes it impossible for the uterus to maintain a pregnancy. 

Subsequently, his lab showed that neither changes in the eggs nor changes in the uterus could explain age related infertility. Altered pituitary hormone cycles, resulting from changes in the brain, could account for the major changes in the ovaries and uterus.

Other experimenters, including P.M. Wise, V.M. Sopelak and R.L. Butcher (1982), P. Ascheim (1983), and D.C. Desjardins (1995) have clarified the interactions between the ovaries and the brain. For example, when the ovaries of an old animal are transplanted into a young animal, they are able to function in response to the new environment, but when the ovaries of a young animal are transplanted into an old animal, they fail to cycle. However, if the ovaries are removed from an animal when it's young, so that it lives to the normal age of infertility without being regularly exposed to surges of estrogen, it will then be able to support normal cycles when young ovaries are transplanted into it. But if it received estrogen supplements throughout its life, transplanted young ovaries will fail to cycle.

The work of Desjardins and others has demonstrated that free radicals generated by interactions of estrogen and iron with unsaturated fatty acids are responsible for damage to brain cells (Desjardins, et al., 1992). The damaged inhibitory nerve cells allow the pituitary to remain in a chronically active state; in old rats, this can produce a state of constant estrus. Several groups (Powers, et al., 2006; Everitt, et al., 1980; Telford, et al., 1986) have shown that removal of the pituitary gland can greatly extend lifespan, if thyroid hormone is supplemented.

One of the animal "models" used to study hot flashes is morphine withdrawal.  The model seems relevant to human hot flashes, because estrogen can stop the morphine withdrawal flushing, and estrogen's acute and chronic effects on the brain-pituitary-ovary system involve the endorphins and the opioidergic nerves (Merchenthaler, et al., 1998; Holinka, et al., 2008).

In young rats, sudden morphine withdrawal caused by injecting the anti-opiate naloxone, causes the tail skin to flush, with a temperature increase of a few degrees, and causes the core body temperature to fall slightly. However, old animals respond to the withdrawal in two different ways. One group responded to the naloxone with an exaggerated flushing and decrease of core temperature. The other group of old rats, which already had a lower body temperature, didn't flush at all (Simpkins, 1994). I think this provides an insight into the reason that menopausal treatment with estrogen can relieve some hot flashes--estrogen treatment might create a flush resistant state similar to that of the cooler old animals in Simpkins' experiment.

It has been known for a long time, from studies in animals and people, that estrogen lowers body temperature, and that this involves a tendency to increase blood flow to the skin in response to a given environmental temperature, that is, the temperature "set-point" is lowered by estrogen. Besides increasing heat loss, estrogen decreases heat production. These physiological effects of estrogen can be seen in the normal menstrual cycle, with progesterone having the opposite effect of estrogen on metabolic rate, skin circulation, body temperature, and heat loss. This causes the familiar rise in temperature when ovulation occurs. Occasionally, young women will experience hot flashes during the luteal phase of their menstrual cycle because of insufficient progesterone production, or at menstruation, when the corpus luteus stops producing progesterone.

Estrogen increases the free fatty acids circulating in the blood, and this shifts metabolism away from oxidation of glucose to oxidation of fat, and it also reduces oxidative metabolism, for example by lowering thyroid function (Vandorpe and Kühn, 1989). These changes are analogous to those of fasting, in which metabolism shifts to the oxidation of fatty acids for energy, causes decreased body temperature, and in some animals leads to a state of torpor or hibernation.

Despite decreasing oxidative metabolism, estrogen stimulates the adrenal cortex, both directly and indirectly through the brain and pituitary, increasing the production of cortisol. Cortisol, by increasing protein turnover, can increase heat production, but this effect isn't necessarily sufficient to maintain a normal body temperature. It increases blood glucose, mainly by blocking its use for energy production, but the glucose is derived from the breakdown of muscle protein. It allows some glucose to be stored as fat. Sudden increases in the amount of glucose can lower adrenaline, and chronically excessive cortisol tends to suppress adrenaline. Cushing's syndrome (produced by excessive cortisol) commonly involves flushing and depression, both of which are likely to be related to the decreased action of adrenaline.

While the biological changes occurring at menopause and during hot flashes are very similar to some of the direct actions of estrogen, and although the menopause itself is the result of prolonged exposure to estrogen, very large doses of estrogen can, in many women (as well as in morphine addicted rats), stop the flushing. In some of the published animal experiments, effective doses of estrogen were about 2000 times normal, and in some human studies, the dose was 30 times normal. By blocking the production of heat, the estrogen treatments might be creating conditions similar to those in Simpkin's cooler old rats, which failed to flush during morphine withdrawal. Menopausal estrogen treatment is known to lower temperature (Brooks, et al., 1994).

Since the Women's Health Initiative publicized the dangers of estrogen, there has been some interest in alternative treatments for hot flashes. Since a reduced production of progesterone has been associated with hot flushes for several decades, it isn't surprising that it is now being tested as an alternative to estrogen. Recently, 300 mg of oral progesterone was found to be effective for decreasing hot flashes, and a month after discontinuing it, the hot flushes were still less frequent than before using it (Prior and Hitchcock, 2012). Previously, transdermal progesterone was found to be effective (Leonetti, et al., 1999).

One of the things progesterone does is to stabilize blood sugar. In one experiment, hot flashes were found to be increased by lowering blood sugar, and decreased by moderately increasing blood sugar (Dormire and Reame, 2003).

Hypoglycemia increases the brain hormone, corticotropin release hormone, CRH (Widmaier, et al., 1988), which increases ACTH and cortisol. CRH causes vasodilation (Clifton, et al., 2005), and is more active in the presence of estrogen. Menopausal women are more responsive to its effects, and those with the most severe hot flushes are the most responsive (Yakubo, et al., 1990).

The first reaction to a decrease of blood glucose, at least in healthy individuals, is to increase the activity of the sympathetic nervous system, with an increase of adrenaline, which causes the liver to release glucose from its glycogen stores. The effect of adrenaline on the liver is very quick, but adrenaline also acts on the brain, stimulating CRH, which causes the pituitary to secrete ACTH, which stimulates the adrenal cortex to release cortisol, which by various means causes blood sugar to increase, consequently causing the sympathetic nervous activity to decrease. Even when the liver's glycogen stores are adequate, the system cycles rhythmically, usually repeating about every 90 minutes throughout the day.

Sympathetic nervous activity typically causes vasoconstriction in the skin and extremities, reducing heat loss, but the small cycles in the system normally aren't noticed, except as small changes in alertness or appetite. With advancing age, most tissues become less sensitive to adrenaline and the sympathetic nervous stimulation, and the body relies increasingly on the production of cortisol to maintain blood glucose. Many of the changes occurring around the menopause, such as the rise of free fatty acids and decrease of glucose availability, increase the sensitivity of the CRH nerves, causing the fluctuations of the adrenergic system to cause larger increases of ACTH and cortisol. Estrogen is another factor that increases the sensitivity of the CRH nerves, and unsaturated fatty acids (Widmaier, et al. 1995) and serotonin (Buckingham, et al., 1982) are other factors stimulating it. Serotonin, like noradrenalin, rises with hypoglycemia (Vahabzadeh, et al., 1995), and estrogen contributes to hypoglycemia, by impairing the counterregulatory system (Cheng and Mobbs, 2009).

With the reduced vasoconstrictive effects of the sympathetic nerves, and the increased activity of CRH, cyclic vasodilation under the influence of cortisol will become more noticeable. With the onset of menopause, and in proportion to the number and intensity of symptoms (on the Greene Climacteric Scale), the daily secretion of cortisol was increased (Cagnacci, et al., 2011).

Once the ideologically based doctrine of menopause as estrogen deficiency is discarded, it's possible to see its features as clues to the ways in which "stress" contributes to the age-related degeneration of the various systems of the body--not just the reproductive system, but also the immune system, the nutritive, growth, and repair processes, and the motivational, emotional, and cognitive processes of the nervous systems. The changes around menopause aren't the same for all women, but the ways in which they vary can be understood in terms of the basic biological principles of energy and adaptation that are universal.

 Each type of cell and organ is subject to injury, and in some cases these injuries are cumulative. In the healthy liver, which stores glycogen, toxins can be inactivated, for example by combining with glucuronic acid, derived from the stored glucose. With injury, such as alcoholism combined with a diet containing polyunsaturated fats, the liver's detoxifying ability is reduced. Even at an early stage, before there is a significant amount of fibrosis, the reduced activity of the liver causes estrogen to accumulate in the body. Estrogen's valuable actions are, in health, exerted briefly, and then the synthesis of estrogen is stopped, and its excretion reduces its activity, but when the liver's function is impaired, estrogen's activity continues, causing further deterioration of liver function, as well as injury of nerves such as Desjardins described, and the systemic energy shifts and stress activations mentioned above.

Besides lowering the liver's detoxifying ability, stress, hypoglycemia, malnutrition, hypothyroidism, and aging can cause estrogen to be synthesized inappropriately and continuously. With aging, estrogen begins to be produced throughout the body--in fat, muscles, skin, bones, brain, liver, breast, uterus, etc. Polyunsaturated fats are a major factor in the induction and activation of the aromatase enzyme, which synthesizes estrogen.

Increased synthesis of estrogen, with aromatase, and decreased excretion of it, by the liver and kidneys, are only two of the processes that affect the influence of estrogen during aging. Cellular stress (chemical, mechanical, hypoxemic, hypoglycemic [Clere, et al., 2012; Aguirre, et al., 2007, Zaman, et al., 2006, Saxon, et al., 2007; Tamir, et al., 2002; Briski, et al., 2010]) increases estrogen receptors (which activate CRH and the stress response). The presence of estrogen receptors means that estrogen will be bound inside cells, where it acts to modify those cells. Before estrogen can reach the liver to be inactivated, it must be released from cells. Ordinarily, the cyclic production of progesterone has that function, by destroying the estrogen-binding proteins. Progesterone also inhibits the aromatase which synthesizes estrogen, and shifts the activities of other enzymes, including sulfatases and dehydrogenates, in a comprehensive process of eliminating the presence and activity of estrogen. At menopause, when the ovary fails to produce the cyclic progesterone, all of these processes of estrogen inactivation fail. In the absence of progesterone, cortisol becomes more active, increasing aromatase activity, which now becomes chronic and progressive. The decrease of progesterone causes many other changes, including the increased conversion of polyunsaturated fatty acids to prostaglandins, and the formation of nitric oxide, all of which contribute to the tendency to flush.

  =========================

*The limits of the belief system or consciousness of US medicine are nicely defined by the topics included in the Index Medicus, which was published from 1879 to 2004, by the Surgeon General's Office of the U.S. Army, the American Medical Association, and the National Library of Medicine, at different times. If you look up any important topic in physiology or biochemistry in an index of scientific publications such as Biological Abstracts or Chemical Abstracts, and then look for the same subject in the Index Medicus, you will find some startling differences--long delays and antagonistic attitudes. At first the discrepancies seem ludicrous and hard to account for, but I think they can be explained by recognizing that the editors of medical journals consider science to be their enemy.

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A R T I C L E

MULTIPLE SCLEROSIS AND OTHER HORMONE-RELATED BRAIN SYNDROMES (1993)

Since I am trying to discuss a complex matter in a single article, I have separately outlined the essential technical points of the argument in a section at the beginning, then I explain how my ideas on the subject developed, and finally there is a glossary.  If you start with "Short-day brain stress," "Estrogen's effects," and "Symptoms and therapies," you will have the general picture, and can use the other sections to fill in the technical details.

THE ARGUMENT:

1) The hormones pregnenolone, thyroid, and estrogen are involved in several ways with the changes that occur in multiple sclerosis, but no one talks about them.

2) The process of myelination is known to depend on the thyroid hormone.  The myelinating cells are the oligodendroglia (oligodendrocytes) which appear to stop functioning in MS (and  sometimes to a milder degree in Alzheimer's disease, and other  conditions).  The cells' absorption of thyroid hormone is influenced by dietary factors.

3) The oligodendrocytes are steroid-producing cells (1),  and steroidogenesis is dependent on thyroid hormone, and on  thyroid-dependent respiratory enzymes and on the heme-enzyme P-450scc, which are all sensitive (2) to poisoning by carbon monoxide and cyanide.  The steroid produced by the oligodendrocytes is pregnenolone, which is known to have a profound  anti-stress action (3), and which appears to be the main  brain-protective steroid.

4) Lesions resembling those of MS can be produced experimentally by carbon monoxide or cyanide poisoning.(4)  The lesions  tend to be associated with individual small blood vessels, which   are likely to contain clots.  (Since all animals have enzymes to  detoxify cyanide, this poison is apparently a universal problem,  and can originate in the bowel. "Detoxified" cyanide is still toxic to the thyroid.) 

5) Pregnenolone and progesterone protect against nerve damage (5) by the excitotoxic amino acids (glutamic acid, aspartic acid, monosodium glutamate, aspartame, etc.), while estrogen (6) and cortisol (7) are nerve-destroying, acting through the excitotoxic amino acids.  Excitotoxins destroy certain types of nerve, especially the dopaminergic and cholinergic types, leaving the noradrenergic types (8), paralleling the changes that occur in aging.  The clustering of oligodendrocytes around deteriorating nerve cells could represent an adaptive attempt to provide pregnenolone to injured nerve cells.

6) The involvement of hormones and environmental factors probably accounts for the intermittent progress of multiple sclerosis. To the extent that the environmental factors can be  corrected, the disease can probably be controlled.

SHORT-DAY BRAIN STRESS

Shortly after I moved from Mexico to Montana, one of my students, a 32 year old woman, began having the same sensory symptoms her older sister had experienced at the same age, at the onset of multiple sclerosis.  Vertigo and visual distortions of some sort made her consider withdrawing from the university. I'm not sure why she tried eating a whole can of tuna for lunch a couple of days after the onset of symptoms, but it seemed to alleviate the symptoms, and she stayed on a high protein diet and never had a recurrence.  She told me some of the lore of MS: That it mostly affects young adults between the ages of 20 and 40, that it is common in high latitudes and essentially unknown in the tropics, and that it is sometimes exacerbated by pregnancy and stress.  (Later, I learned that systemic lupus erythematosis and other "auto-immune" diseases also tend to occur mainly during the reproductive years.  I discussed some of the implications of this in "Bean Syndrome.")

Having enjoyed the mild climate of Mexico, I became very conscious of the harm done to us by northern winters, and began developing the idea of "winter sickness."  In 1966-67, allergies, PMS, weight gain, colitis, and arthritis came to my attention as winter-related problems, and I assumed that the high-latitude incidence of MS related to what I was seeing and experiencing.  Studies in Leningrad began revealing that mitochondria are injured during darkness, and repaired during daylight.  I observed that hamsters' thymus glands shrank in the winter and regenerated in the summer; shrinkage of the thymus gland is a classical feature of stress, and usually reflects the dominance of cortisone, though estrogen and testosterone also cause it to shrink.  Winter's darkness is stressful in a very fundamental way, and like any stress it tends to suppress thyroid function.  In the hypothyroid state, any estrogen which is produced tends to accumulate in the body, because of liver sluggishness.

I began to see that PMS could be controlled by certain things--extra light, supplements of sodium and magnesium, high quality protein, and correction of deficiencies of thyroid and progesterone.  In working on my dissertation, I saw that tissue hypoxia (lower than optimal concentrations of oxygen in the blood) may result from estrogen excess, vitamin E deficiency, or aging.  There is a close biological parallel between estrogen-dominance and the other hypoxic states, such as stress/shock, and aging.

ESTROGEN'S EFFECTS

As a portrait painter, I had been very conscious of the blue aspect that can often be seen in the skin of young women. In pale areas, the color may actually be blue, and in areas with a rich supply of blood, such as the lips, the color is lavender during times of high estrogen influence--around ovulation and puberty, for example.  During these times of estrogen dominance, the blood is not only poorly oxygenated, but it has other special properties, such as an increased tendency to clot.  The Shutes' work in the 1930s began with the use of vitamin E to antagonize estrogen's clot-promoting tendency, and led them to the discovery that vitamin E can be very therapeutic in heart disease.  More recently, it has been found that men with heart disease have abnormally high estrogen (9), that women using oral contraceptives have higher mortality from heart attacks (10), and that estrogen tends to  promote spasm of blood vessels (11).  (These reactions are probably  related to the physiology of menstruation, in which progesterone withdrawal causes spasms in the spiral arteries of the uterus,  producing endometrial anoxia and cell death.)

In toxemia of late pregnancy, or eclampsia, the exaggerated clotting tendency caused by excess estrogen (or by inadequately opposed estrogen, i.e., progesterone deficiency), can cause convulsions and strokes.  Vascular spasms could be involved here, too.  The stasis caused by the vasospasm would facilitate clotting. (Vascular spasm has been observed in epilepsy, too.  Epilepsy can be brought on by the premenstrual excess of estrogen, and in that situation there is no evidence that clotting is involved.  Leakage of hemoglobin out of red cells can cause vasospasm, so bleeding, clotting, strokes, and seizures can interact complexly.)  The brains of women who have died following eclampsia show massive clotting in the blood vessels, and their livers are characteristically injured, with clots (12).

Tom Brewer and others have shown very clearly that malnutrition, especially protein deficiency, is the cause of toxemia of late pregnancy.  (In Nutrition for Women, I discussed the importance of protein in allowing the liver to eliminate estrogen.)

Various researchers have demonstrated that the plaques of MS usually occur in the area served by a single blood vessel (13, 14), and some have suggested that clotting is the cause.  MS patients have been found to have an abnormal clotting time, and it has been suggested that an altered diet might be able to correct the clotting tendency.

Studies in animals have shown clearly that a protein deficiency increases the fibrinogen content of blood. (Field and Dam, 1946.)  Other factors that increase blood clotting are elevated adrenalin and cortisone.  Protein deficiency causes an adaptive decrease in thyroid function, which leads to a compensatory increase in adrenaline and cortisone.  The combination of high estrogen with high adrenaline increases the tendency for both clots and spasms of the blood vessels (11).

In experimental poisoning of animals with carbon monoxide or cyanide, the brain lesions resembling MS include blood clots.  The patchy distribution of these spots in the brain suggests that the clotting is secondary to metabolic damage in the brain.  Presumably, the same would be true in ordinary MS, with clots and spasms being induced in certain areas by metabolic abnormalities in brain cells.  The injured cells that are responsible for myelination of nerve fibers are steroid-forming cells.  A failure to secrete their protective pregnenolone could cause a local spasm of a blood vessel.  The circulatory problem would exacerbate the respiratory problem. Steroid production is dependent on NADH and NADPH, and so requires adequate energy supplies and energy metabolism.  The phenomenon of blood-sludging, studied by M. Knisely at the University of Chicago in the l930s and l940s, is apparently a general result of decreased energy metabolism, and is likely to be a factor in energy-and-circulatory vicious circles.

SYMPTOMS AND THERAPIES

Around 1976 I met a woman in her mid-thirties who heard about my work with progesterone in animals.  She had been disabled by a brain disease that resembled MS or Devic's disease, inflammation of the optic nerves.  It would sometimes cause blindness and paralysis that persisted for weeks at a time.  During remissions, sometimes using a wheelchair, she would go to the medical school library to try to understand her condition.  She came across Katherina Dalton's work with progesterone, and convinced a physician to give her a trial injection.  Although she had trouble finding people who were willing to give her progesterone, her recovery was so complete that she was able to climb stairs and drive her car, and she came  to my endocrinology class and gave a very good (and long) lecture on progesterone therapy.  Although her sensory and motor functions became normal, she remained very fat, and chronically suffered from sore areas on her arms and legs that seemed to be abnormal blood vessels, possibly with phlebitis.  She appeared to need thyroid hormone as well as larger amounts of progesterone, but never found a physician who would cooperate, as far as I know.

In the late 1970s I was seeing a lot of people who had puzzling health problems.  In a period of two or three years, there were five people who had been diagnosed by neurologists as having multiple sclerosis.  In talking to them, it seemed clear that they had multiple symptoms of hypothyroidism.   They weren't severely disabled.  Since they weren't fat or lethargic, their physicians hadn't thought they could be hypothyroid.  When they tried taking a thyroid supplement, all of their symptoms disappeared, including those that had led to their MS diagnosis.  One of the women went to her doctor to tell him that she felt perfectly healthy since taking thyroid, and he told her to stop taking it, because people who have MS need a lot of rest, and she wouldn't get enough rest if she was living in a normally active way. The assumption seemed to be that the diagnosis was more important than the person. (When I refer to a "thyroid supplement" I mean one that contains some T3.  Many people experience "neurological symptoms" when they take thyroxine by itself.  Experimentally, it has been found to suppress brain respiration, probably by diluting the T3 that was already present in the brain tissue.)  

METABOLISM OF THE OLIGODENDROCYTES

The rate-regulating step in steroid synthesis involves the entry of cholesterol into the mitochondria, where the heme-enzyme P-450scc then removes the side-chain of cholesterol  (by introducing oxygen atoms), to produce pregnenolone.  This enzyme can be poisoned by carbon monoxide or cyanide, and light can eliminate the poison (15); this could be one aspect of the winter-sickness problem.  

Peripheral nerves are myelinated by essentially the same sort of cell that is called an oligodendrocyte in the brain, but outside the brain it is called a Schwann cell.  It is easier to study the myelin sheath in peripheral nerves, and the electrical activity of a nerve is the most easily studied aspect of its physiology.  Certain experiments seemed to indicate a "jumping" (saltatory) kind of conduction along the nerve between Schwann cells, and it was argued that the insulating function of the myelin sheath made this kind of conduction possible.  This idea has become a standard item in physiology textbooks, and its familiarity leads many people to assume that the presence of myelin sheaths in the brain serves the same "insulating" function.

For a long time it has been known that heat production during nerve conduction reveals a more continuous mode of  conduction, that doesn't conform to the idea of an electrical  current jumping around an insulator.  Even if the myelin functioned primarily to produce "saltatory conduction" in peripheral nerves, it isn't clear how this process could function in the brain.  I think of the issue of "saltatory conduction at the nodes of Ranvier" as another of the fetish ideas that have served to obstruct progress in biology in the United States.  A more realistic approach to nerve function can be found in Gilbert Ling's work.  Ling has demonstrated in many ways that the ruling dogma of "cell membrane" function isn't coherently based on fact.  He found that hormones such as progesterone regulate the energetic and structural stability of cells.  Many people, unaware of his work, have felt that it was necessary to argue against the idea that there are anesthetic steroids with generalized protective functions, because of their commitment to a textbook dogma of "cell membrane" physiology.

I think the myelinating cells do have relevance to nerve conduction, but I don't think they serve primarily as electrical insulators.  If the adrenal cortex were inside the heart, it would be obvious to ask whether its hormones aren't important for the heart's function.  Since the oligodendrocytes are steroid-synthesizers, it seems obvious to ask whether their production of pregnenolone in response to stress or fatigue isn't relevant to the conduction processes of the nerves they surround.

OLD AGE

A biologist friend of mine who was about 85 became very senile.  His wife started giving him thyroid, progesterone, DHEA and pregnenolone, and within a few days his mental clarity had returned.  He continued to be mentally active until he was 89, when his wife interfered with his access to the hormones.

In old age the brain steroids fall to about 5% of their level in youth.  Pregnenolone and DHEA improve memory in old rats, and improve mood stability and mental clarity of old people.  Pregnenolone's action in improving the sense of being able to cope with challenges probably reflects a quieting and coordinating of the "sequencing" apparatus of the forebrain, which is the area most sensitive to energy deprivation.  This is the area that malfunctions in hyperactive and "dyslexic" children.  Weakening of the sequencing and sorting processes probably explains the common old-age inability to extract important sounds from environmental noise, creating a kind of "confusion deafness."  Insomnia, worry and "restless legs" at bedtime are problems for many old people, and I think they are variations of the basic energy-depletion problem.

The oligodendrocytes were reported (Hiroisi and Lee, 1936) to be the source of the senile plaques or amyloid deposits of Alzheimer's disease.(16)  Hiroisi and Lee showed the cells in different stages of degeneration, ending with translucent "mucoid" spots that stained the same as amyloid, the material in the senile plaques.  This type of cell also appears to form a halo or crown around degenerating nerve cells--possibly in a protective reaction to provide the nerve cell  with any pregnenolone the oligodendrocytes are able to make.  The  oligodendrocytes, the source of the brain steroids (that people previously believed came from the adrenals and gonads, and were just stored in the brain), myelinate nerve fibers under the  influence of thyroid hormone (17).  Thyroid is responsible for both myelination and hormone formation.  In old age, glial cells become more numerous, and nerve cells become structurally  and functionally abnormal, but usually there is no problem  with the formation of myelin.  In MS, the problem is just with  myelination, and there are no senile plaques or defects in the  nerve cells themselves.  

     These differences suggest the possibility that Alzheimer's  disease involves a specific premature loss of brain pregnen-  olone production, but not of thyroid.  Recent work suggests a central role for pregnenolone and progesterone in the regulation of consciousness (18), and possibly in the brain's detoxifying system.  Elsewhere, I have suggested that vitamin A deficiency might cause the excessive production of the "amyloid" protein.  A vitamin A deficiency severely inhibits steroid synthesis.  (It is used so massively in steroid synthesis that a progesterone supplement can prevent the symptoms of vitamin A deficiency.)  I suspect that vitamin A is necessary for the side-chain cleavage that converts cholesterol to pregnenolone.  Iron-stimulated lipid peroxidation is known to block steroid formation, and vitamin A is very susceptible to destruction  by iron and oxidation.  Iron tends to accumulated in tissues  with aging.  Gajdusek has demonstrated that brain deterioration  is associated with the retention of whatever metal happens to be abundant in the person's environment, not just with aluminum.  (One type of glial cell is known for its metal-binding function, causing them to be called "metallophils.").  According to Gajdusek, "calcium and other di- and trivalent elements" are "deposited as hydroxyapatites in brain cells" in brain degeneration of the Alzheimer's type.(19)

Even early forms of Alzheimer's disease begin at an age  when the youth-associated steroids have begun to decline. If  MS involves a deficiency of thyroid (or of T3 within the oligodendrocytes, where T3 normally can be made from thyroxine; many things, including protein deficiency, can block the conversion of T4 to T3), those cells would necessarily be deficient in their ability to produce pregenolone, but in  young people the brain would still be receiving a little pregnenolone, progesterone, and DHEA from the adrenals and gonads.  This relatively abundant youthful supply of hormones would keep most of the body's organs in good condition,  and could keep the bodies of the major brain cells from deteriorating. But if proper functioning of the nerve fibers requires that they be fed a relatively high concentration of pregnenolone from their immediately adjacent neighbors (with the amount increasing during stress and fatigue), then their function would be impaired when they had to depend on the hormones that arrived from the blood stream.

For many years it has been recognized that the brain atrophy of "Alzheimer's disease" resembles the changes seen in the brain in many other situations:  The traumatic dementia of boxers; toxic dementia; the slow-virus diseases; exposure of the brain to x-rays (20); ordinary old age; and in people with Down's syndrome who die around the age of thirty.           

In menopause, certain nerve cells have lost their ability to regulate the ovaries, because of prolonged exposure to estrogen (6).  The cells that fail as a result of prolonged estrogen exposure aren't the same cells that fail from prolonged exposure to the glucocorticoids (7), but they have in common the factor of excitatory injury.

Since people who experience premature menopause are known to be more likely than average to die prematurely, it is reasonable to view menopause as a model of the aging process. It is now well established that progesterone fails to be produced at the onset of menopause (the first missed period, increased loss of calcium, symptoms such as hot flashes, etc.), and that estrogen continues to be produced at monthly intervals for about four years.  The essential question for aging, in the present context, is why the anesthetic steroids are no longer produced at a rate that allows them to protect tissues, including brain cells, from the excitotoxins.  Using menopause as a model for aging, we can make the question more answerable by asking why progesterone stops being produced.

During stress, we are designed not to get pregnant, and the simplest aspect of this is that ACTH, besides stimulating the adrenals to produce stress-related hormones, inhibits the production of progesterone by the ovary.  Other stress-induced factors, such as increased prolactin and decreased thyroid, also inhibit progesterone production.  Stress eventually makes us more susceptible to stress.  Menopause and other landmarks of aging simply represent upward inflections in the rate-of-aging curve.  Individual variations in type of stress, hormonal response and diet, etc., probably govern the nature of the aging process in an individual.

The amphetamine-like action of estrogen, which undoubtedly  contributes to the general level of stress and excitotoxic  abuse of nerve cells, is probably the only "useful" facet of  estrogen treatment, but a little cocaine might achieve the  same effect with no more harm, possibly less.  The toxicity of catecholamines has been known for over thirty years, and estrogen's stimulating effects are partly the result of its conversion to catechol-estrogens which increase the activity of brain catecholamines.  Estrogen's powerful ability to nullify learning seems never to be mentioned by the people who promote its use.  The importance of a good balance of brain steroids for mood, attention, memory, and reasoning is starting to be recognized, but powerful economic forces militate against its general acceptance.

Since the brain is the organ that can allow us to adapt without undergoing stress in the hormonal sense, it is very important to protect its flexibility and to keep its energy level high, so it can work in a relaxed way.  It is the low energy cellular state that leads to the retention of calcium and iron, and to the production of age pigment, and other changes that constitute the vicious circle of aging.  And mental activity that challenges obsession and rigidity might be the most important brain energizer.  Pseudo-optimism, humor-as-therapy, has a certain value, but a deeper optimism involves a willingness to assimilate new information and to change plans accordingly.

SUPPLEMENTS

Nutritional supplements that might help to prevent or correct these brain syndromes include: Vitamin E and  coconut oil; vitamin A; magnesium, sodium; thyroid which  includes T3; large amounts of animal protein, especially  eggs; sulfur, such as magnesium sulfate or flowers of  sulfur, but not to take continuously, because of sulfur's interference with copper absorption; pregnenolone; progesterone if needed.  Bright light, weak in the blue end of the spectrum and with protection against ultraviolet, activates respiratory metabolism and quenches free radicals.  Raw carrot fiber and/or laxatives if needed; charcoal occasionally for gas or bowel  irritation.  Coconut oil serves several purposes.  Its butyric acid is known to increase T3 uptake by glial cells.  It has a general pro-thyroid action, for example by diluting and displacing antithyroid unsaturated oils, its short- and medium-chain fatty acids sustain blood sugar and have antiallergic actions, and it protects mitochondria against stressinjury. 

P.S.:  In 1979, a woman whose husband was suffering from advanced Amyotrophic Lateral Sclerosis (ALS) asked me if I had any ideas for slowing his decline.  I described my suspicion that ALS involved defective metabolism or regulation of testosterone.  In some tissues, testosterone is selectively concentrated to prevent atrophy, and ALS is a disease of middle-age, when hormone regulation often becomes a special problem.  In the late 1970s, there was discussion of a higher incidence of ALS in males, and especially in athletes.  I told her about progesterone's general protective effects, its antagonism to testosterone, and its prevention of atrophy in various tissues.  She decided to ask her doctor to try progesterone for her husband.  Later, I learned that her husband had gone into a very rapid decline immediately after the injection, and died within a week; the physician had given him testosterone, since, he said, "testosterone and progesterone are both male hormones."  Besides making me more aware of the problems patients have in communicating with physicians, this tended to reinforce my feeling that a hormone imbalance is involved in ALS.  Although I haven't written much about testosterone's toxicity, Marian Diamond's work showed that prenatal testosterone is similar to prenatal estrogen, in causing decreased thickness of the cortex of the brain; both of those hormones oppose progesterone's brain-protecting and brain-promoting actions.

REFERENCES

1)  Z. Y. Hu, et al., P.N.A.S. (USA) 84, 8215-9, 1987.

2)  P. F. Hall, Vitamins and Hormones 42, 315-370, 1985.

3)  J. J. Lambert, et al., Trends in Pharmac. Sci. 8, 224-7, 1987.

4)  W. A. D. A. Anderson, Pathology (second edition), C. V. Mosby, St. Louis, 1953.

5)  S. S. Smith, et al., Brain Res. 422, 52-62, 1987.

6)  P. M. Wise, Menopause, 1984; S. S. Smith, et al., Brain Res. 422, 40-51, 1987.

7)  R. M. Sapolsky, et al., J. Neuroscience 5, 1222-1227, 1985; R. M. Sapolsky and W. Pulsinelli, Science 229, 1397-9, 1985.

8)  C. B. Nemeroff, (Excitotoxins)  290-305, 1984.

9)  G. B. Phillips, Lancet 2, 14-18, 1976; G. B. Phillips, et al., Am. J. Med. 74, 863-9, 1983; M. H. Luria, et al., Arch Intern Med 142, 42-44, 1982; E. L. Klaiber, et al., Am J Med 73, 872-881, 1982.

10)  J. I. Mann, et al., Br Med J 2, 241-5, 1975.

11)  V. Gisclard and P. M. Vanhoutte, Physiologist 28, 324(48.1).

12)  W. A. D. A. Anderson, Pathology, 1953; H. H. Reese, et al.,  editors, 1936 Yearbook of Neurology, Psychiatry, and Endocrinology,  Yearbook Publishers, Chicago, 1937.   

13)  T. J. Putnam, Ann Int Med 9, 854-63, 1936; JAMA 108, 1477, 1937.

14)  R. S. Dow and G. Berglund, Arch Neurol and Psychiatry 47, 1, 1992.

15)  R. W. Estabrook, et al., Biochem Z. 338, 741-55, 1963.

16)  S. Hiroisi and C. C. Lee, Arch Neurol and Psychiat 35, 827-38, 1936.

17)  J. M. Matthieu, et al., Ann Endoc. 1974.

18)  K. Iwaharhi, et al., J Ster Biochem and Mol Biol 44(2), 163-4, 1993.

19)  D. C. Gajdusek, Chapter 63, page 1519 in Virology (B. N. Fields, et al., editors), Raven Press, N.Y., 1985.

20)  K. Lowenberg-Scharenberg and R. C. Bassett, J Neuropath and Exper Neurol 9, 93, 1950.

GLOSSARY  

1.  Amyloid is the old term for the "starchy" appearing (including the way it stains) proteins seen in various diseases, and in the brain in Alzheimer's disease.

2.  Cytochrome P450scc.  The cytochromes are "pigments," in the same sense that they contain the colored "heme" group that gives hemoglobin its color.  P450 means "protein that absorbs light at a wavelength of 450.  The scc means "side-chain cleaving," which refers to the removal of the 6 carbon atoms that distinguish cholesterol from pregnenolone. Other Cyt P450 enzymes are important for their detoxifying oxidizing action, and some of these are involved in brain metabolism.

3.  Glial means "glue-like," and glial cells are mostly spidery-shaped cells that used to be thought of as just connective, supportive cells in the brain.

4.  Mitochondria (the "thread-like bodies") are the structures in cells which produce most of our metabolic energy by respiration, in response to the thyroid hormones.

5.  Mucoid--refers to a mucoprotein, a protein which contains some carbohydrate.  A glycoprotein; usually not intended as a precise term.

6.  Myelination.  Myelin is a multilayered enclosure of the axons (the long processes) of nerve cells, composed of proteins and complex lipids, including cholesterol.  The layered material is a flat, thin extension of the cytoplasm of the oligodendroglial cells.

7.  Oligodendrocytes are one of the kinds of glial (or neuroglial) cells, and structurally they are unusual in having sheet-like, rather than just thread-like processes; they have a sensitivity ("receptors") to stress and valium, and produce pregnenolone when activated.  Under the influence of thyroid hormone, they wrap themselves in thin layers around the conductive parts of nerve cells, leaving a multilayered "myelin" coating.  Their absorption of thyroid hormone is promoted by butyrate, an anti-stress substance found in butter and coconut oil.

8.  Steroidogenesis is the creation of steroids, usually referring to the conversion of cholesterol to hormones.

© Ray Peat Ph.D. 2013. All Rights Reserved. www.RayPeat.com

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A R T I C L E

When energy fails: Edema, heart failure, hypertension, sarcopenia, etc. 

More than 100 years ago the idea of a morphogenetic field was proposed by A.G. Gurwitsch, as a way to explain the orderly movements of cells in embryos and growing tissues, and to understand the principles that cause cells to change appropriately when their location in the organism changes. For 30 years, the concept guided research in embryology, but also led to important discoveries in the biology of cancer, aging, wound repair, and other important areas. But by the late 1940s, a more abstract approach to biology, based on the gene doctrine of Mendel and Weismann, took charge of academic and governmental biological research. This ideology at first said that organisms are determined by unchanging units of inheritance, "genes," and later when genes were found to be susceptible to mutation, the changes were said to be always random. The Central Dogma of the ideology was that any meaningful, adaptive changes that occur in an organism can't influence the genes. For many years, adaptive changes were said to be nothing but changes in the size or function of existing cells, because the cells of the major organs of the body were supposed to be created before birth, or in infancy. 

Besides the purely ideological commitment to the theory of genes, there were other influences that contributed to the culture of Molecular Biology. People learned histology from slides or pictures made by killing, hardening, dehydrating, and slicing parts of organisms. Biochemists studied the chemistry of life mainly by grinding cells or tissues, and extracting water soluble materials to study the actions of enzymes on various materials. These unrealistic artifacts filled the textbooks and the minds of generations of biologists and physicians. The culture of molecular biology used these artifacts to create theories of embryology and physiology, and holistic ideas such as the developmental field were disregarded.

The mental image of a living organism that has been created by that culture is simply wrong. The concept of a developmental field is essential for understanding embryology, because things that exist on a scale bigger than molecules and cells govern the functions of the molecules and cells, and the principles of embryology don't arbitrarily stop operating at birth, but can be seen to continue operating during maturity and aging. The interactions of cells with their environment are different at different stages of life, but there are commonalities that are extremely important.

The processes that govern the pregnant woman's blood circulation, in sustaining the development of a fetus, are very similar to the processes that govern anyone's blood circulation, providing for the maintenance and renewal of all the body's organs. The common problems of pregnancy involving the circulatory system can provide insights into the problems of the various organs that have been the focus of the medical specialties, and to some basic medical issues, including aging, obesity, and inflammation.

The development of a fertilized egg into an embryo consumes energy at a very high rate, and the way the embryo develops depends on a continuously adequate supply of oxygen and sugar, and other nutrients. The intense flow of energy through each stage of a developing structure shapes the following stage. The necessary energy and materials are provided abundantly by the mother's blood. When the development has advanced far enough to make life possible outside the uterus, energy will be used more slowly, for growth, maintenance, and renewal of tissues. 

Failure to renew cells and tissues leads to the loss of function and substance. Bones and muscles get weaker and smaller with aging. Diminished bone substance, osteopenia, is paralleled, at roughly the same rate, by the progressive loss of muscle mass, sarcopenia (or myopenia). The structure of aging tissue changes, with collagen tending to fill the spaces left by the disappearing cells. It's also common for fat cells to increase, as muscle cells disappear.

When conditions are ideal, as during healthy development in the uterus, tissue damage is corrected by the multiplication of cells to replace any that were lost. But when conditions are less perfect, injuries are imperfectly repaired, usually with highly collagenous scar tissue bridging the area that was destroyed. During this imperfect repair, there is inflammation, which apparently exists to the extent that the substances needed for regeneration are lacking. For example, when oxygen is lacking, lactic acid is likely to be produced, along with increases of pro-inflammatory regulators such as histamine and serotonin, leading to the loss of many important proteins and functions, and the over-production of collagen instead.

Since cellular renewal of tissues, in a healthy individual, is a constant process, we can think of the metabolic rate of a healthy adult as just what is needed to sustain this constant, limited sort of regeneration, but not quite intense enough to produce scarless healing of a wound (without special intervention).

If something reduces the systemic ability to produce energy, there will be a gap between the available energy and the energy needed for the constant turnover of cells in each tissue and organ, and a generalized inflammation will develop. The replacement of cells will be slowed, and the organism will mobilize the processes used for producing scar tissue, producing an excess of collagen, filling the spaces left by the lost cells.

We are susceptible to many things that interfere with energy production---the substitution of iron for copper in the respiratory enzyme, the absorption of endotoxin, the accumulation of PUFA, a deficiency of thyroid hormone, the formation of increased amounts of nitric oxide, serotonin, and histamine, etc. Different environments will condition the way the defensive mechanisms of inflammation are produced. 

Toxemia of pregnancy, or preeclampsia, is a state of generalized inflammation, and some of the causes and remedies are known. Despite the predominance of crazy genetic theories of preeclampsia in 20th century medical literature, there was clear evidence (reviewed by Tom Brewer, Douglas Shanklin, and Jay Hodin) that it was caused by malnutrition, and that it could be cured by adequate protein, salt, and calcium.   

The old medical practice of restricting salt intake during pregnancy was an important factor in causing it, so it's interesting to look at the effects of salt restriction as a treatment for hypertension.

The pregnant woman's blood volume expands, to permit the supply of energy to match the needs of the embryo. If the blood volume doesn't increase, or if it decreases, as in pregnancy toxemia, her blood pressure will increase. Typically, the decrease of blood volume is accompanied by an increase in the extracellular fluid, edema, resulting from leakage of fluid through the walls of the capillaries, and albumin appears in the urine as it leaks through the capillaries in the kidneys. The amount of blood pumped by the heart, however, is increased in toxemia (Hamilton, 1952), showing that the increased blood pressure is at least partially compensating for the smaller volume of blood. 

A similar situation, reduced blood volume and edema, can be seen (Tarazi, 1976) in "essential hypertension," the "unexplained" high blood pressure that occurs more often with increasing age and obesity. At the beginning of "essential hypertension," the amount of blood pumped is usually greater than normal.

In both situations, preeclampsia and essential hypertension, there is an increased amount of aldosterone, an adrenal steroid which allows the kidneys to retain sodium, and to lose potassium and ammonium instead. A restriction of salt in the diet causes more aldosterone to be produced, and increased salt in the diet causes aldosterone to decrease. One effect of aldosterone is to increase the production of a substance called vascular endothelial growth factor, VEGF, or vascular permeability factor, which causes capillaries to become leaky, and causes new blood vessels to grow.

While increased salt in the diet tends to lower both aldosterone and VEGF, reducing the leakiness of blood vessels, sodium also has a direct effect that tends to prevent the leakage of water and albumin out of the blood vessels, helping to maintain the blood volume which is needed to perfuse the kidneys, preventing them from producing signals to increase blood pressure and aldosterone. There is a large amount of albumin in the blood serum, and sodium ions associate with the negative electrical charges on the albumin molecule. This association causes the complex of albumin and sodium to attract a large amount of water, that is to exert osmotic or oncotic pressure. This oncotic pressure causes any excess extracellular water to be attracted into the blood vessels, preventing edema while maintaining the blood volume. When there is too little sodium, the albumin molecule itself easily leaves the blood stream along with the water.

Instead of considering the significance of sodium's effects on albumin, aldosterone, and VEGF, textbooks have often talked about the factors that "pump" sodium, and factors that specifically regulate the movement of water. Experiments in which an excess of aldosterone is combined with a high salt intake produce increased blood pressure, and--by invoking various genes--salt is said to cause hypertension in certain people. This reasoning is hardly different from the reasoning of the drug companies in the 1950s who said that since women with toxemia have hypertension and edema, they should be treated with a diuretic and a low salt diet, to eliminate water and to reduce blood pressure.

The physiological loss of sodium occurs when energy metabolism fails, as indiabetes, hypothyroidism, hyperestrogenism, and starvation. What these conditions have in common is an increased level of free fatty acids in the blood. Increased free fatty acids impair the use of glucose. The consumption of carbohydrate, like an increase of thyroid hormone, insulin, or progesterone, increases the retention of sodium; fructose is the most effective carbohydrate (Rebello, et al., 1983). 

The loss of sodium is often accompanied by the retention of water, reducing the osmotic pressure of the body fluids. The leakiness of blood vessels allows the extracellular fluid volume to increase, as understood in the standard definition of edema. However, when this fluid is hypo-osmotic, it will enter cells, causing them to swell. Cell swelling excites cells (Ayus, et al., 2008; Baxter, et al., 1991), and can kill them if they are unable to produce enough energy to restore their original volume, by measures including the excretion of amino acids and potassium.  Both low sodium (hyponatremia) and low osmotic pressure stimulate the adrenergic nervous system.

The increase of adrenalin,f caused by a deficiency of sodium, is one of the factors that can increase blood pressure; if the tissues's glycogen stores are depleted, the adrenalin will mobilize free fatty acids from the tissues, which tends to inhibit energy production from glucose, and to increase leakiness. After I had read Tom Brewer's work on preventing or curing preeclampsia with added salt, I realized that the premenstrual syndrome involved some of the features of preeclampsia (edema, insomnia, cramps, hypertension, salt craving), so I suggested to a friend that she might try salting her food to taste, instead of trying to restrict salt to "prevent edema." She immediately noticed that it prevented her monthly edema problem. For several years, all the women who tried it had similarly good results, and often mentioned that their sleep improved. I mentioned this to several people with sleep problems, and regardless of age, their sleep improved when they ate as much salt as they wanted. Around that time, several studies had shown that salt restriction increases adrenalin, and one study showed that most old people on a low sodium diet suffered from insomnia, and had unusually high adrenalin. When they ate a normal amount of salt, their adrenalin was normalized, and they slept better.

It's very common for physicians who are aware of progesterone's "anti-aldosterone" activity to think that both estrogen and progesterone are responsible for the increased risk of sodium loss in women, especially during pregnancy, but Hans Selye demonstrated that progesterone will normalize sodium retention even when there is no aldosterone at all, following removal of the adrenal glands. It is estrogen which is responsible for the dangerous loss of sodium.      

The ratio of estrogen to progesterone--regardless of age or gender--is an important factor in regulating minerals and water, cell energy metabolism, and blood pressure. The ratios of many other regulatory substances (including serotonin/dopamine, glucagon/insulin, and aldosterone/cortisol+progesterone) vary according to the quality of the individual's level of adaptation to the environment. Improving the environment can shift the ratio in the direction of restoration, rather than mere survival.

Gershom Zajicek and his colleagues have demonstrated an organized renewal of tissues, in which new cells are born with the division of stem cells, and "stream" away from their origin as they mature, and finally are shed or dissolved. A few studies have demonstrated a similar kind of migration of new cells in the brain (Eriksson, et al., 1998; Gould, et al., 1999), a process which differs by the absence of systematic dissolution of mature brain cells. While Zajicek has demonstrated the conversion of one kind of cell, such as a pancreatic ductal epithelial or acinar cell into insulin-secreting beta cells, other researchers have shown that after injury to the pancreas beta cells can be formed from glucagon-secreting alpha cells, as well as from other beta cells. 

Stress, increasing the need for energy, increases the formation of cortisol and free fatty acids when glucose isn't available, and those--while they provide alternative sources of energy--interfere with the ability to produce energy from glucose. Free fatty acids and cortisol can cause the insulin-secreting beta cells to die. Glucose, and insulin which allows glucose to be used for energy production, while it lowers the formation of free fatty acids, promotes the regeneration of the beta-cells. Although several research groups have demonstrated the important role of glucose in regeneration of the pancreas, and many other groups have demonstrated the destructive effect of free fatty acids on the beta cells, the mainstream medical culture still claims that "sugar causes diabetes."

In the adrenal glands, renewing cells stream from the capsule on the surface of the gland toward the center of the gland. The first cells to be produced in a regenerating gland are those that produce aldosterone, the next in the stream are the cortisol producing cells, and the last to be formed are the cells that produce the sex hormones, the androgens including DHEA, and progesterone. In aging, after the age of thirty, the renewal slows, but the dissolution of the sex hormone zone continues, so the proportion shifts, increasing the ratio of the aldosterone and cortisol producing cells to the layer that produces the protective androgens and progesterone (Parker, et al., 1997).

Even before aldosterone was identified, progesterone's role in regulating the salts, water, and energy metabolism was known, and after the functions of aldosterone were identified, progesterone was found to protect against its harmful effects, as it protects against an excess of cortisol, estrogen, or the androgens. New anti-aldosterone drugs are available that are effective for treating hypertension and heart failure, and their similarity to progesterone is recognized.

While stress typically causes the adrenal glands to produce cortisol, extreme stress, as described by Hans Selye, damages the adrenal cortex, and can cause the cells to die, leading to the death of the animal. There is evidence that it is the breakdown of unsaturated fatty acids that causes damage to the adrenal cortex in extreme stress. Although many factors influence the production of the adrenal steroids, arachidonic acid, even without being converted to prostaglandins, is an important activator of aldosterone synthesis. Adrenalin, produced in response to a lack of glucose, liberates free fatty acids from the tissues, so when the tissues contain large amounts of the polyunsaturated fatty acids, the production of aldosterone will be greater than it would be otherwise. 

The continuing accumulation of polyunsaturated fats in the tissues is undoubtedly important in the changing relationship between the pancreas and the adrenal glands in aging. Aspirin, which is antilipolytic, decreasing the release of free fatty acids, as well as inhibiting their conversion to prostaglandins, lowers the production of stress-induced aldosterone, and helps to lower blood pressure, if it's taken in the evening, to prevent the increase of free fatty acids during the night. Aspirin increases insulin sensitivity. A low salt diet increases the free fatty acids, leading to insulin resistance, increasing free fatty acids in the blood, and contributing to atherosclerosis (Prada, et al., 2000; Mrnka, et al., 2000; Catanozi, et al., 2003; Garg, et al., 2011).

The same factors that support or interfere with cellular renewal in the pancreas and adrenal glands have similar effects in the bones, skin, skeletal and heart muscle, nervous system, liver, and other organs. In every case, the local circulation of blood is influenced by both local and systemic factors. The loss of control over the water in the body is the result of energy failure, and hypertension is one of the adaptations that helps to preserve or restore energy production. 

Lowering inflammation and the associated excess of free fatty acids in the blood, and improving the ability to oxidize glucose, will lower blood pressure while improving tissue renewal, but lowering blood pressure without improving energy production and use will create new problems or intensify existing problems. After 40 years the medical profession quietly retreated from their catastrophic approach to pregnancy toxemia, but in the more general problem of essential hypertension, the mistaken ideology is being preserved, even as less harmful treatments are introduced. That ideology prevents a comprehensive and rational approach to the problems of stress and aging.

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A R T I C L E

Fats, functions & malfunctions

Saturated fatty acids terminate the stress reactions, polyunsaturated fatty acids amplify them.

The most highly unsaturated fats, including DHA, accumulate with aging, and their toxic fragments are increased in Alzheimer's disease. 

The most highly unsaturated fats found in fish oil break down into chemicals that block the use of glucose and oxygen.

The ratio of saturated fatty acids to polyunsaturated fatty acids is decreased in cancer. Omega-3 fats promote metastasis.

Around the beginning of the 20th century, it was commonly believed that aging resulted from the accumulation of insoluble metabolic by-products, sort of like the clinker ash in a coal furnace. Later, age pigment or lipofuscin, was proposed to be such a material. It is a brown pigment that generally increases with age, and its formation is increased by consumption of unsaturated fats, by vitamin E deficiency, by stress, and by exposure to excess estrogen. Although the pigment can contribute to the degenerative processes, aging involves much more than the accumulation of insoluble debris; aging increases the tendency to form the debris, as well as vice versa.

There is a growing recognition that a persistent increase of free fatty acids in the serum, which is seen in shock, heart failure, and aging, indicates a bad prognosis, but there is no generally recognized explanation for the fact that free fatty acids are harmful. I want to mention some evidence showing that it is the accumulation of polyunsaturated fats in the body that makes them harmful.

The physical and functional properties of saturated fatty acids and polyunsaturated fatty acids (PUFA) are as different from each other as day is from night. The different fatty acids are directly involved, very often with opposite effects, in cell division and growth, cell stability and dissolution, the organization of cells, tissues, and organs, the regulation of pituitary hormones, adrenalin and sympathetic nervous activation, histamine and serotonin synthesis, adrenal cortex hormones, thyroid hormones, testosterone, estrogen, activators of the immune system and inflammation (cytokines), autoimmune diseases, detoxification, obesity, diabetes, puberty, epilepsy, 

Parkinson's disease, other degenerative nerve diseases and Alzheimer's disease, cancer, heart failure, atherosclerosis, and strokes. In each of these situations, the PUFA have harmful effects.

Most people are surprised to hear about the systematically harmful effects of the common dietary polyunsaturated fats and the protective effects of saturated fats. That's because there is a pervasive mythology of fats in our culture. Officials are proposing to tax saturated fats. Laws are being passed prescribing the fats that can be served in restaurants, and people write letters to editors about them, and great amounts of money are spent publicizing the importance of eating the right fats. Their focus is on obesity, atherosclerosis, and heart disease. The details of the myth change a little, as new fat products and industries appear. 

As I understand the basic myth, the difference between the "essential" polyunsaturated fats and the saturated fats has to do with their shape---the unsaturated fatty acids bend or fold in a way that makes them more mobile than saturated fats of the same length, and this causes the all-important "membranes" of cells to be more fluid, and thus to have "better functions," though the myth isn't very clear on the issue of fluidity and functionality. At that point, it passes responsibility to the more fundamental biological myth, of the metabolically active cell membrane. 

Practically everyone learns, in grade school and from television, about the good and the bad oils, and cell membranes, but it might seem likely that people who spend their lives investigating the role of fats in organisms would have acquired a different, more complicated, view. But one of the most famous food fat researchers, J.M. Bourre, has succinctly (and thoughtlessly) expressed his understanding of the function of fatty substances in the body: "In fact the brain, after adipose tissue, is the organ richest in lipids, whose only role is to participate in membrane structure." (J.M. Bourre, 2004.) The fact that his editor let him publish the statement shows how the myth functions, causing people to accept things because they are "common knowledge." The influence of the medical and pharmaceutical industries is so pervasive that it becomes the context for most biological research.

Luckily, many people are working outside the myth, in specialized problems of physiology and cell biology, and their observations are showing a reality much more complex and interesting than the mythology. 

When we eat more protein or carbohydrate than we need, the excess can be converted to fats, to be stored (as triglycerides), but even on a maintenance diet we synthesize some fats that are essential parts of all of our cells, including a great variety of phospholipids. People seldom talk about the importance of fats in the nucleus of the cell, but every nucleus contains a variety of lipids--phospholipids, sphingolipids, cholesterol, even triglycerides--similar to those that are found elsewhere in the cell and in every part of the body, including the brain (Balint and Holczinger, 1978; Irvine, 2002). Phospholipids are often considered to be "membrane lipids," but they have been demonstrated in association with elements of the cell's skeleton, involved in cell division, rather than in membranes (Shogomori, et al., 1993).

The cytoskeleton, a fibrous framework of the cell that's responsible for maintaining the organized structure of the cell, internal movement of organelles, coordination, locomotion, and cell division, is made up of three main kinds of protein, and all of these are affected differently by different kinds of fat. 

Actions of lipids on the cell skeleton can change cells' movements, migrations, and invasiveness. Unsaturated fats cause clumping of some types of cell filament, condensation and polymerization of other types, in ways that are associated with brain degenerative diseases and cancer. For example, DHA alters the structure of the protein alpha-synuclein, causing it to take the form seen in Parkinson's disease and other brain conditions. The synucleins regulate various structural proteins, and are affected by stress, aging, and estrogen exposure, as well as by the polyunsaturated fats. One type of synuclein is involved in the promotion of breast cancer. Saturated fatty acids have exactly the opposite effects of PUFA on the synucleins, reversing the polymerization caused by the PUFA (Sharon, et al., 2003). 

When cancers are metastasizing, their phospholipids contain less stearic acid than the less malignant tumors (Bougnoux, et al., 1992), patients with advanced cancer had less stearic acid in their red blood cells (Persad, et al., 1990), and adding stearic acid to their food delayed the development of cancer in mice (Bennett, 1984). The degree of saturation of the body's fatty acids corresponds to resistance to several types of cancer that have been studied (Hawley and Gordon, 1976; Singh, et al., 1995).

The phospholipids are being discussed in relation to drugs that can modify "signaling" by acting on phospholipid receptors, using language that was developed in relation to hormones. A surface barrier membrane, with receptors that send signals to the nucleus, is invoked by many of the recent discussions of phospholipids. There's no question that the fats do affect regulatory processes, but the theory and the language should correspond to the physiological and ecological realities. Vernadski's metaphor, that an organism is a "whirlwind of atoms," is probably more appropriate than "targeted signals and receptors" for understanding the physiology of fatty acids and phospholipids. The rate of change and renewal of these structural fats is very high. In rats, one study found a 30% decrease in the total phospholipid pool in the brain in the first 30 minutes after death (Adineh, et al., 2004).  Another study in the brains of living rats found that a particular class of brain lipids, ethanolamine plasmalogens, had a turnover time of about 5 hours (Masuzawa, et al., 1984). (This type of lipid is an important component of the lipoproteins secreted by the liver into the serum [Vance, 1990], and is also a major lipid in the heart and brain.)  Stresses such as the loss of sleep cause great distortions in phospholipid metabolism throughout the body, especially in the brain and liver.

Actions of lipids on the cell skeleton can change cells' movements, migrations, and invasiveness, even in short term experiments. The effects of the "essential fatty acid" linoleic acid have been compared to the drug colchicine, which is known to interfere with the cell skeleton and cell division. According to Hoover, et al., (1981), it disturbed the structure of the cytoskeleton more than colchicine does; it caused the cell filaments to clump together, while saturated fatty acids didn't have such an effect.

The fatty molecules that participate in the normal cell functions are made by cells even when they are grown in a fat-free solution in a culture dish. They include saturated fatty acids such as palmitate and stearate, and omega-9 unsaturated fats, such as oleic acid and omega-9 polyunsaturated fatty acids. The saturated fatty acids found in the nucleus associated with the chromosomes are resistant to change when the composition of the animal's diet changes (Awad and Spector, 1976), while the unsaturated fats change according to the diet. These intracellular fats are essential for cell division and the regulation of the genes, and for cell survival (Irvine, 2002). Although cells make the saturated fats that participate in those basic functions, the high rate of metabolism means that some of the lipids will quickly reflect in their structure the free fatty acids that circulate in the blood. The fats in the blood reflect the individual's diet history, but recently eaten fats can appear in the serum as free fatty acids, if the liver isn't able to convert them into triglycerides.

The polyunsaturated fatty acids differ from the saturated fats in many ways, besides their shape and their melting temperature, and each type of fatty acid is unique in its combination of properties. The polyunsaturated fatty acids, made by plants (in the case of fish oils, they are made by algae), are less stable than the saturated fats, and the omega-3 and omega-6 fats derived from them, are very susceptible to breaking down into toxins, especially in warm-blooded animals. Other differences between saturated and polyunsaturated fats are in their effects on surfaces (as surfactant), charges (dielectric effects), acidity, and their solubility in water relative to their solubility in oil. The polyunsaturated fatty acids are many times more water soluble than saturated fatty acids of the same length. This property probably explains why only palmitic acid functions as a surfactant in the lungs, allowing the air sacs to stay open, while unsaturated fats cause lung edema and respiratory failure.

The great difference in water/oil solubility affects the strength of binding between a fatty acid and the lipophilic, oil-like, parts of proteins. When a protein has a region with a high affinity for lipids that contain double bonds, polyunsaturated fatty acids will displace saturated fats, and they can sometimes displace hormones containing multiple double bonds, such as thyroxine and estrogen, from the proteins that have a high specificity for those hormones. Transthyretin (also called prealbumin) is important as a carrier of the thyroid hormone and vitamin A. The unsaturation of vitamin A and of thyroxin allow them to bind firmly with transthyretin and certain other proteins, but the unsaturated fatty acids are able to displace them, with an efficiency that increases with the number of double bonds, from linoleic (with two double bonds) through DHA (with six double bonds). 

The large amount of albumin in the blood is important in normal fatty acid binding and transport, but it is also an important part of our detoxifying system, since it can carry absorbed toxins from the intestine, lungs, or skin to the liver, for detoxification. Albumin facilitates the uptake of saturated fatty acids by cells of various types (Paris, et al., 1978), and its ability to bind fatty acids can protect cells to some extent from the unsaturated fatty acids (e.g., Rhoads, et al., 1983). The liver's detoxification system processes some polyunsaturated fats for excretion, along with hormones and environmental toxins.

The movement of proteins from the plasma into cells has often been denied, but there is clear evidence that a variety of proteins, including IgG, transferrin haptoglobin, and albumin can be found in a variety of cells, even in the brain (Liu, et al., 1989). Cells are lipophilic, and absorb molecules in proportion to their fattiness; this long ago led people to theorize that cells are coated with a fat membrane. 

The idea of a semipermeable membrane, similar in function to the membrane inside an egg shell, was proposed about 150 years ago, to explain the ability of living cells to concentrate certain chemicals, such as potassium ions, while excluding others, such as sodium ions. This idea of a molecular sieve was shown to be invalid when radioactive isotopes made it possible to observe that sodium ions diffuse freely into cells, and it was replaced by the idea of a metabolically active membrane, containing "pumps" that made up for the inability to exclude various things, and that allowed cells to retain high concentrations of some dissolved substances that are free to diffuse out of the cell. The general idea of the membrane as a barrier persisted as a sort of "common sense" idea, that has made people ignore experiments that show that some large molecules, including some proteins, can quickly and massively enter cells. Albumin and transthyretin are two proteins that are sometimes found in large quantities inside cells, and their primary importance is that they bind and transport biologically active oily molecules. 

While the competition by PUFA for protein binding sites blocks the effects of thyroid hormone and vitamin A, the action of PUFA on the sex steroid binding protein (SBP, or SSBG, for sex steroid binding globulin) increases the activity of estrogen. That's because the SSBG neutralizes estrogen by binding it, keeping it out of cells; free PUFA keep it from binding estrogen (Reed, et al., 1986). People with low SSBG/estrogen ratio have an increased risk of cancer. When the SSBG protein is free of estrogen, it is able to enter cells, and in that estrogen-free state it probably serves a similar protective function, capturing estrogen molecules that enter cells before they can act on other proteins or chromosomes. Transthyretin, the main transporter of thyroid and vitamin A, and albumin (which can also transport thyroid hormone) are both able to enter cells, while loaded with thyroid hormone and vitamin A. Albumin becomes more lipophilic as it binds more lipid molecules, so its tendency to enter cells increases in proportion to its fat burden. Albumin in the urine is a problem associated with diabetes and kidney disease; albumin loaded with fatty acids passes from the blood into the urine more easily than unloaded albumin, and it is the fatty acids, not the albumin, which causes the kidney damage (Kamijo, et al., 2002). It's possible that SSBG's opposite behavior, entering cells only when it carries no hormones, is the result of becoming less lipophilic when it's loaded with estrogen.

Since most people believe that cells are enclosed within a barrier membrane, a new industry has appeared to sell special products to "target" or "deliver" proteins into cells across the barrier. Combining anything with fat makes it more likely to enter cells. Stress (which increases free fatty acids and lowers cell energy) makes cells more permeable, admitting a broader range of substances, including those that are less lipophilic. 

Linoleic acid and arachidonic acid, which are said to "make the lipid membrane more permeable," in fact make the whole cell more permeable, by binding to the structural proteins throughout the cell, increasing their affinity for water, causing generalized swelling, as well as mitochondrial swelling (leading to reduced oxidative function or disintegration), allowing more calcium to enter the cell, activating excitatory processes, stimulating a redox shift away from oxidation and toward inflammation, leading to either (inappropriate) growth or death of the cell.  

When we don't eat for many hours, our glycogen stores decrease, and adrenaline secretion is increased, liberating more glucose as long as glycogen is available, but also liberating fatty acids from the fatty tissues. When the diet has chronically contained more polyunsaturated fats than can be oxidized immediately or detoxified by the liver, the fat stores will contain a disproportionate amount of them, since fat cells preferentially oxidize saturated fats for their own energy, and the greater water solubility of the PUFA causes them to be preferentially released into the bloodstream during stress.

In good health, especially in children, the stress hormones are produced only in the amount needed, because of negative feedback from the free saturated fatty acids, which inhibit the production of adrenalin and adrenal steroids, and eating protein and carbohydrate will quickly end the stress. But when the fat stores contain mainly PUFA, the free fatty acids in the serum will be mostly linoleic acid and arachidonic acid, and smaller amounts of other unsaturated fatty acids. These PUFA stimulate the stress hormones, ACTH, cortisol, adrenaline, glucagon, and prolactin, which increase lipolysis, producing more fatty acids in a vicious circle. In the relative absence of PUFA, the stress reaction is self limiting, but under the influence of PUFA, the stress response becomes self-amplifying. 

When stress is very intense, as in trauma or sepsis, the reaction of liberating fatty acids can become dangerously counter-productive, producing the state of shock. In shock, the liberation of free fatty acids interferes with the use of glucose for energy and causes cells to take up water and calcium (depleting blood volume and reducing circulation) and to leak ATP, enzymes, and other cell contents (Boudreault and Grygorczyk, 2008; Wolfe, et al., 1983; Selzner, et al, 2004; van der Wijk, 2003), in something like a systemic inflammatory state (Fabiano, et al., 2008) often leading to death. 

The remarkable resistance of "essential fatty acid deficient" animals to shock (Cook, et al., 1981; Li et al., 1990; Autore, et al., 1994) shows that the polyunsaturated fats are centrally involved in the maladaptive reactions of shock. The cellular changes that occur in shock--calcium retention, leakiness, reduced energy production--are seen in aging and the degenerative diseases; the stress hormones and free fatty acids tend to be chronically higher in old age, and an outstanding feature of old age is the reduced ability to tolerate stress and to recover from injuries.

Despite the instability of polyunsaturated fatty acids, which tend to break down into toxic fragments, and despite their tendency to be preferentially liberated from fat cells during stress, the proportion of them in many tissues increases with age (Laganiere and Yu, 1993, 1987; Lee, et al., 1999; Smidova, et al., 1990;Tamburini, et al., 2004; Nourooz-Zadeh J and Pereira, 1999 ). This progressive increase with age can be seen already in early childhood (Guerra, et al., 2007). The reason for this increase seems to be that the saturated fatty acids are preferentially oxidized by many types of cell, (fat cells can slowly oxidize fat for their own energy maintenance). Albumin preferentially delivers saturated fatty acids into actively metabolizing cells such at the heart (Paris, 1978) for use as fuel. This preferential oxidation would explain Hans Selye's results, in which canola oil in the diet caused the death of heart cells, but when the animals received stearic acid in addition to the canola oil, their hearts showed no sign of damage.

Since healthy cells are very lipophilic, saturated fatty acids would have a greater tendency to enter them than the more water soluble polyunsaturated fats, especially those with 4, 5, or 6 double bonds, but as cells become chronically stressed they more easily admit the unsaturated fats, which slow oxidative metabolism and create free radical damage. The free radicals are an effect of stress and aging, as well as a factor in its progression.

When stress signals activate enzymes in fat cells to release free fatty acids from the stored triglycerides, the enzymes in the cytoplasm act on the surface of the droplet of fat. This means that the fatty acids with the greatest water solubility will be liberated from the fat to move into the blood stream, while the more oil soluble fatty acids will remain in the droplet. The long chain of saturated carbon atoms (8 in the case of oleic acid, 15 in palmitic acid, and 17 in stearic acid) in the "tail" of oleic, palmitic, and stearic acid will be buried in the fat droplet, while the tail of the n-3 fatty acids, with only 2 saturated carbons, will be the most exposed to the lipolytic enzymes. This means that the n-3 fatty acids are the first to be liberated during stress, the n-6 fatty acids next. Saturated and monounsaturated fatty acids are selectively retained by fat cells (Speake, et al., 1997).

Women are known to have a greater susceptibility than men to lipolysis, with higher levels of free fatty acids in the serum and liver, because of the effects of estrogen and related hormones. 

Women on average have more DHA circulating in the serum than men (Giltay, et al., 2004; McNamara, et al., 2008; Childs, et al., 2008). This highly unsaturated fatty acid is the first to be liberated from the fat stores under stress, and, biologically, the meaning of estrogen is to mimic stress. Estrogen and polyunsaturated fatty acids have similar actions on cells, increasing their water content and calcium uptake. Long before the Women's Health Initiative reported in 2002 that the use of estrogen increased the risk of dementia, it was known that the incidence of Alzhemer's disease was 2 or 3 times higher in women than in men. Men with Alzheimer's disease have higher levels of estrogen than normal men (Geerlings, et al., 2006). The amount of DHA in the brain (and other tissues) increases with aging, and its breakdown products, including neuroprostanes, are associated with dementia. Higher levels of DHA and total PUFA are found in the plasma of demented patients (Laurin, et al., 2003).

Another interesting association of the highly unsaturated fats and estrogen in relation to brain function is that DHA increases the entry of estrogen into the pregnant uterus, but inhibits the entry of progesterone (Benassayag, et al., 1999), which is crucial for brain cell growth. When Dirix, et al., (2009) supplemented pregnant women with PUFA, they found that fetal memory was impaired. 

The crucial mitochondrial respiratory enzyme, cytochrome c oxidase, declines with aging (Paradies, et al., 1997), as the lipid cardiolipin declines, and the enzyme's activity can be restored to the level of young animals by adding cardiolipin. The composition of cardiolipin changes with aging, "specifically an increase in highly unsaturated fatty acids" (Lee, et al., 2006). Other lipids, such as a phosphatidylcholine containing two myristic acid groups, can support the enzyme's activity (Hoch, 1992). Even supplementing old animals with hydrogenated peanut oil restores mitochondrial respiration to about 80% of normal (Bronnikov, et al., 2010). 

Supplementing thyroid hormone increases mitochondrial cardiolipin (Paradies and Ruggiero, 1988). Eliminating the polyunsaturated fats from the diet increases mitochondrial respiration (Rafael, et al., 1984).

Excitotoxicity is the process in which activation of a nerve cell beyond its capacity to produce energy injures or kills the cell, by increasing intracellular calcium. Glutamic acid and aspartic acid are the normal neurotransmitter excitatory amino acids. Estrogen increases the activity of the excitatory transmitter glutamate (Weiland, 1992), and glutamate increases the release of free fatty acids (Kolko, et al., 1996). DHA (more strongly even than arachidonic acid) inhibits the uptake of the excitotoxic amino acid aspartate, and in some situations glutamate, prolonging their actions. Thymocytes are much more easily killed by stress than nerve cells, and they are easy to study. The PUFA kill them by increasing their intracellular calcium. The toxicity of DHA is greater than that of EPA, whose toxicity is greater than alpha-linolenic acid, and linoleic acid was the most potent (Prasad, et al., 2010). Excitotoxicity is probably an important factor in Alzheimer's disease (Danysz and Parsons, 2003).

When the brain is injured, DHA and arachidonic acid contribute to brain edema, weakening the blood-brain-barrier, increasing protein breakdown, inflammation, and peroxidation, while a similar amount of stearic acid in the same situation caused no harm (Yang, et al., 2007). In other situations, such as the important intestinal barrier, EPA and DHA also greatly increased the permeability (Dombrowsky, et al., 2011).

The process by which excitotoxicity kills a cell is probably a foreshortened version of the aging process. 

Excitotoxins (including endotoxin) increase the formation of neuroprostanes and isoprostanes (from n-3 and n-6 PUFA) (Milatovic, et al., 2005), and acrolein and other fragments, which inhibit the use of glucose and oxygen.  DHA and EPA produce acrolein and HHE, which react with lysine groups in proteins, and modify nucleic acids, changing the bases in DNA. 

Increased intracellular calcium activates lipolysis (by phospholipases), producing more free fatty acids, as well as excitation and protein breakdown, and in the brain neurodegenerative diseases, calcium excess contributes to the clumping of synuclein (Wojda, et al., 2008), an important regulator of the cytoskeletal proteins. The reduced function of normal synuclein makes cells more susceptible to excitotoxicity (Leng and Chuang, 2006).

If the cells adapt to the increased calcium, rather than dying, their sensitivity is reduced. This is probably involved in the "defensive inhibition" seen in many types of cell. In the brain, DHA and arachidonic acid "brought the cells to a new steady state of a moderately elevated [intracellular calcium] level, where the cells became virtually insensitive to external stimuli. This new steady state can be considered as a mechanism of self-protection" (Sergeeva, et al., 2005). In the heart, the PUFAs decreased the sensitivity to stimulation (Coronel et al., 2007) and conduction velocity (Tselentakis, et al., 2006; Dhein, et al., 2005). Both DHA and EPA inhibit calcium-ATPase (which keeps intracellular calcium low to allow normal neurotransmission) in the cerebral cortex; this suggests "a mechanism that explains the dampening effect of omega-3 fatty acids on neuronal activity" (Kearns and Haag, 2002).

In normal aging, most processes are slowed, including nerve conduction velocity, and conduction velocity in the heart (Dhein and Hammerath, 2001). A similar "dampening" or desensitization is seen in sensory, endocrine, and immune systems, as well as in energy metabolism. Calorie restriction, by decreasing the age-related accumulation of PUFA (20:4, 22:4, and 22:5), can prevent the decrease of sensitivity, for example in lymphoid cells (Laganier and Fernandes, 1991). The known effects of the unsaturated fats on the organizational framework of the cell are consistent with the changes that occur in aging.

One of the essential protective functions that decline with aging is the liver's ability to detoxify chemicals, by combining them with glucuronic acid, making them water soluble so that they can be excreted in the urine. The liver (and also the intestine and stomach) efficiently process DHA by glucuronidation (Little, et al., 2002). Oleic acid, one of the fats that we synthesize ourselves, increases (about 8-fold) the activity of the glucuronidation process (Krcmery and Zakim, 1993; Okamura, et al., 2006). However, this system is inhibited by the PUFA, arachidonic acid (Yamashita, et al., 1997), and also by linoleic acid (Tsoutsikos, et al., 2004), in one of the processes that contribute to the accumulation of PUFA with aging.

Animals that naturally have a relatively low level of the highly unsaturated fats in their tissues have the greatest longevity. For example, the naked mole rate has a life expectancy of more than 28 years, about 9 times as long as other rodents of a similar size. Only about 2% to 6% of its phospholipids contain DHA, while about 27% to 57% of the phospholipids of mice contain DHA Mitchell, et al., 2007). 

The famously long-lived people of Azerbaijan eat a diet containing a low ratio of unsaturated to saturated fats, emphasizing fruits, vegetables, and dairy products (Grigorov, et al., 1991).

Some of the clearest evidence of the protective effects of saturated fats has been published by A.A. Nanji's group, showing that they can reverse the inflammation, necrosis, and fibrosis of alcoholic liver disease, even with continued alcohol consumption, while fish oil and other unsaturated fats exacerbate the problem (Nanji, et al., 2001). Glycine protects against fat accumulation in alcohol-induced liver injury (Senthilkumar, et al., 2003), suggesting that dietary gelatin would complement the protective effects of saturated fats.

The least stable n-3 fats which accumulate with age and gradually reduce energy production also have their short term effects on endurance. Endurance was much lower in rats fed a high n-3 fat diet, and the effect persisted even after 6 weeks on a standard diet (Ayre and Hulbert, 1997). Analogous, but less extreme effects are seen even in salmon, which showed increased oxidative stress on a high n-3 diet (DHA or EPA), and lower mitochondrial cytochrome oxidase activity (Kjaer, et al., 2008). 

Maintaining a high rate of oxidative metabolism, without calorie restriction, retards the accumulation of PUFA, and a high metabolic rate is associated with longevity. An adequate amount of sugar maintains both a high rate of metabolism, and a high respiratory quotient, i.e., high production of carbon dioxide. Mole rats, bats, and queen bees, with an unusually great longevity, are chronically exposed to high levels of carbon dioxide. Carbon dioxide forms carbamino bonds with the amino groups of proteins, inhibiting their reaction with the reactive "glycating" fragments of PUFA.

To minimize the accumulation of the highly unsaturated fatty acids with aging, it's probably reasonable to reduce the amount of them directly consumed in foods, such as fish, but since they are made in our own tissues from the "essential fatty acids," linoleic and linolenic acids, it's more important to minimize the consumption of those (from plants, pork, and poultry, for example).

In the resting state, muscles consume mainly fats, so maintaining relatively large muscles is important for preventing the accumulation of fats. 

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J Biol Chem. 2011 Jul 29;286(30):26931-42. Unsaturated fatty acids drive disintegrin and metalloproteinase (ADAM)-dependent cell adhesion, proliferation, and migration by modulating membrane fluidity. Reiss K, Cornelsen I, Husmann M, Gimpl G, Bhakdi S.

J Neurochem. 1982 May;38(5):1255-60. Effects of free fatty acids on synaptosomal amino acid uptake systems. Rhoads DE, Kaplan MA, Peterson NA, Raghupathy E.

Biochem J. 1967 Sep;104(3):1040-7. Characterization and metabolism of ovine foetal lipids. Scott TW, Setchell BP, Bassett JM.

Cell Death Differ. 2004 Dec;11 Suppl 2:S172-80. Water induces autocrine stimulation of tumor cell killing through ATP release and P2 receptor binding. Selzner N, Selzner M, Graf R, Ungethuem U, Fitz JG, Clavien PA.

Pol J Pharmacol. 2003 Jul-Aug;55(4):603-11. Glycine modulates hepatic lipid accumulation in alcohol-induced liver injury. Senthilkumar R, Viswanathan P, Nalini N.

Reprod Nutr Dev. 2005 Sep-Oct;45(5):633-46. Regulation of intracellular calcium levels by polyunsaturated fatty acids, arachidonic acid and docosahexaenoic acid, in astrocytes: possible involvement of phospholipase A2. Sergeeva M, Strokin M, Reiser G.

Neuron. 2003 Feb 20;37(4):583-95. The formation of highly soluble oligomers of alpha-synuclein is regulated by fatty acids and enhanced in Parkinson's disease. Sharon R, Bar-Joseph I, Frosch MP, Walsh DM, Hamilton JA, Selkoe DJ.

Zygote. 1993 Aug;1(3):215-23. Non-plasmalemmal localisation of the major ganglioside in sea urchin eggs. Shogomori H, Chiba K, Kubo H, Hoshi M.

Invasion Metastasis. 1995;15(3-4):144-55. Stearate inhibits human tumor cell invasion. Singh RK, Hardy RW, Wang MH, Williford J, Gladson CL, McDonald JM, Siegal GP.

Physiol Bohemoslov. 1990;39(2):125-34. Proportion of individual fatty acids in the non-esterified (free) fatty acid(FFA) fraction in the serum of laboratory rats of different ages. Smidova L, Base J, Mourek J, Cechova I.

Exp Gerontol. 2005 Apr;40(4):335-43. Unsaturated fatty acids intake and all-causes mortality: a 8.5-year follow-up of the Italian Longitudinal Study on Aging. Solfrizzi V, D'Introno A, Colacicco AM, Capurso C, Palasciano R, Capurso S,Torres F, Capurso A, Panza F.

J Pharm Biomed Anal. 2001 Mar;24(5-6):1157-62. Bioanalysis of age-related changes of lipid metabolism in nonagenarians. Solichova D, Juraskova B, Blaha V, Bratova M, Kusalova M, Zdansky P, Zadak Z.

Biochim Biophys Acta. 1997 Apr 21;1345(3):317-26. The preferential mobilisation of C20 and C22 polyunsaturated fatty acids from the adipose tissue of the chick embryo: potential implications regarding the provision of essential fatty acids for neural development. Speake BK, Cerolini S, Maldjian A, Noble RC.

J Nutr. 2003 Nov;133(11):3664-9. Fish intake is positively associated with breast cancer incidence rate. Stripp C, Overvad K, Christensen J, Thomsen BL, Olsen A, Moller S, Tjonneland A.

Br J Pharmacol. 2003 Jul;139(5):1014-22. Docosahexaenoic acid and arachidonic acid release in rat brain astrocytes is mediated by two separate isoforms of phospholipase A2 and is differently regulated by cyclic AMP and Ca2+. Strokin M, Sergeeva M, Reiser G.

Aging Clin Exp Res. 2004 Dec;16(6):425-31. Effects of dietary restriction on age-related changes in the phospholipid fatty acid composition of various rat tissues. Tamburini I, Quartacci MF, Izzo R, Bergamini E. "The most abundant PUFAs, 20:4(n-6) and 22:6(n-3), either remained the same or increased with age."

Am J Physiol. 1989 Jan;256(1 Pt 1):G178-87. Saturated fatty acid diet prevents radiation-associated decline in intestinal uptake. Thomson AB, Keelan M, Lam T, Cheeseman CI, Walker K, Clandinin MT.

J Surg Res. 2006 Sep;135(1):68-75. Inflammation effects on the electrical properties of atrial tissue and inducibility of postoperative atrial fibrillation. Tselentakis EV, Woodford E, Chandy J, Gaudette GR, Saltman AE.

Biochem Pharmacol. 2004 Jan 1;67(1):191-9. Evidence that unsaturated fatty acids are potent inhibitors of renal UDP-glucuronosyltransferases (UGT): kinetic studies using human kidney cortical microsomes and recombinant UGT1A9 and UGT2B7.Tsoutsikos P, Miners JO, Stapleton A, Thomas A, Sallustio BC, Knights KM.

Aging Cell. 2007 Feb;6(1):15-25. N-3 polyunsaturated fatty acids impair lifespan but have no role for metabolism. Valencak TG, Ruf T.

Biochim Biophys Acta. 1990 Jul 16;1045(2):128-34. Lipoproteins secreted by cultured rat hepatocytes contain the antioxidant 1-alk-1-enyl-2-acylglycerophosphoethanolamine. Vance JE.

Biol Chem. 2003 Oct 10;278(41):40020-5. Increased vesicle recycling in response to osmotic cell swelling. Cause and consequence of hypotonicity-provoked ATP release. van der Wijk T, Tomassen SF, Houtsmuller AB, de Jonge HR, Tilly BC.

Endocrinology. 1992 Dec;131(6):2697-702. Glutamic acid decarboxylase messenger ribonucleic acid is regulated by estradiol and progesterone in the hippocampus. Weiland NG.

IUBMB Life. 2008 Sep;60(9):575-90. Calcium ions in neuronal degeneration. Wojda U, Salinska E, Kuznicki J.

Prog Clin Biol Res 1983;111:89-109. Energy metabolism in trauma and sepsis: the role of fat. Wolfe RR, Shaw JH, Durkot MJ

Biochem Pharmacol. 1997 Feb 21;53(4):561-70. Inhibition of UDP-glucuronosyltransferase activity by fatty acyl-CoA. Kinetic studies and structure-activity relationship. Yamashita A, Nagatsuka T, Watanabe M, Kondo H, Sugiura T, Waku K.

Neurotoxicology. 2007 Nov;28(6):1220-9. Detrimental effects of post-treatment with fatty acids on brain injury in ischemic rats. Yang DY, Pan HC, Yen YJ, Wang CC, Chuang YH, Chen SY, Lin SY, Liao SL, Raung SL, Wu CW, Chou MC, Chiang AN, Chen CJ.

J Org Chem. 2007 Dec 7;72(25):9698-703. Asymmetric synthesis of 14-A4t-neuroprostane: hunting for a suitable biomarker for neurodegenerative diseases. Zanoni G, Brunoldi EM, Porta A, Vidari G. "Since isoprostanes are considered as golden standards for oxidative stress, and due to the specificity of neuroprostanes for this condition in neurons and their relation with Alzheimer's and Parkinson's diseases, they are envisioned to be suitable biomarkers for these pathologies."

© Ray Peat Ph.D. 2013. All Rights Reserved. www.RayPeat.com

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A R T I C L E

Sugar issues

Since the first doctor noticed, hundreds of years ago, that the urine of a diabetic patient tasted sweet, it has been common to call the condition the sugar disease, or sugar diabetes, and since nothing was known about physiological chemistry, it was commonly believed that eating too much sugar had to be the cause, since the ability of the body to convert the protein in tissues into sugar wasnt discovered until 1848, by Claude Bernard (who realized that diabetics lost more sugar than they took in). Even though patients continued to pass sugar in their urine until they died, despite the elimination of sugar from their diet, medical policy required that they be restrained to keep them from eating sugar. That prescientific medical belief, that eating sugar causes diabetes, is still held by a very large number, probably the majority, of physicians.

Originally, diabetes was understood to be a wasting disease, but as it became common for doctors to measure glucose, obese people were often found to have hyperglycemia, so the name diabetes has been extended to them, as type 2 diabetes. High blood sugar is often seen along with high blood pressure and obesity in Cushing's syndrome, with excess cortisol, and these features are also used to define the newer metabolic syndrome.

Following the old reasoning about the sugar disease, the newer kind of obese diabetes is commonly blamed on eating too much sugar. Obesity, especially a fat waist, and all its associated health problems, are said by some doctors to be the result of eating too much sugar, especially fructose. (Starch is the only common carbohydrate that contains no fructose.) Obesity is associated not only with diabetes or insulin resistance, but also with atheroslcerosis and heart disease, high blood pressure, generalized inflammation, arthritis, depression, risk of dementia, and cancer.

There is general agreement about the problems commonly associated with obesity, but not about the causes or the way to prevent or cure obesity and the associated conditions.

In an earlier newsletter, I wrote about P. A. Piorry in Paris, in 1864, and Dr. William Budd in England, in 1867, who treated diabetes by adding a large amount of ordinary sugar, sucrose, to the patient's diet. Glucose was known to be the sugar appearing in the diabetics' urine, but sucrose consists of half glucose, and half fructose. In 1874, E. Kulz in Germany reported that diabetics could assimilate fructose better than glucose. In the next decades there were several more reports on the benefits of feeding fructose, including the reduction of glucose in the urine. With the discovery of insulin in 1922, fructose therapy was practically forgotten, until the 1950s when new manufacturing techniques began to make it economical to use.

Its use in diabetic diets became so popular that it became available in health food stores, and was also used in hospitals for intravenous feeding.

However, while fructose was becoming popular, the cholesterol theory of heart disease was being promoted. This was the theory that eating foods containing saturated fat and cholesterol caused heart disease. (My newsletter, Cholesterol, longevity, intelligence, and health, discussed the development of that theory.)

A Swedish physician and researcher, Uffe Ravnskov, has reviewed the medical arguments for the theory that lipids in the blood are the cause of atherosclerosis and heart disease, and shows that there has never been evidence of causality, something which some people, such as Broda Barnes, understood from the beginning. In the 1950s, an English professor, John Yudkin, didn't accept the idea that eating saturated fat was the cause of high blood levels of triglycerides and cholesterol, but he didnt question the theory that lipids in the blood caused the circulatory disease. He argued that it was sugar, especially the fructose component of sucrose, rather than dietary fat, that caused the high blood lipids seen in the affluent countries, and consequently the diseases. He was sure it was a specific chemical effect of the fructose, because he argued that the nutrients that were removed in refining white flour and white sugar were insignificant, in the whole diet.

Following the publication of Yudkin's books, and coinciding with increasing promotion of the health benefits of unsaturated vegetable oils, many people were converted to Yudkin's version of the lipid theory of heart disease, i.e., that the "bad lipids" in the blood are the result of eating sugar. This has grown into essentially a cult, in which sugar is believed to act like an intoxicant, forcing people to eat until they become obese, and develop the "metabolic syndrome," and "diabetes," and the many problems that derive from that.

The publicity campaign against "saturated fat" as an ally of cholesterol derived its support from the commercial promotion of the polyunsaturated seed oils as food for humans. Although the early investigators of vitamin E knew that the polyunsaturated oils could cause sterility, and others later found that their use in commercial animal foods could cause brain degeneration, there were a few biologists (mostly associated with George Burr) who believed that this type of fatty acid is an essential nutrient.

George and Mildred Burr had created what they claimed to be a disease in rats caused by the absence of linoleic or linolenic acid in their food. Although well known researchers had previously published evidence that animals on a fat free diet were healthy--even healthier than on a normal diet--Burr and his wife published their contradictory claim without bothering to discuss the conflicting evidence. I haven't seen any instance in which Burr or his followers ever mentioned the conflicting evidence. Although other biologists didn't accept Burr's claims, and several researchers subsequently published contrary results, he later became famous when the seed oil industry wanted scientific-seeming reasons for selling their product as an "essential" food. The fact that eating the polyunsaturated fats could cause the blood cholesterol level to decrease slightly was advertised as a health benefit. Later, when human trials showed that more people on the "heart healthy" diet died of heart disease and cancer, more conventional means of advertising were used instead of human tests.

Burr's experimental diet consisted of purified casein (milk protein) and purified sucrose, supplemented with a vitamin concentrate and some minerals. Several of the B vitamins weren't known at the time, and the mineral mixture lacked zinc, copper, manganese, molybdenum, and selenium. More of the essential nutrients were unknown in his time than in Yudkin's, so his failure to consider the possibility of other nutritional deficiencies affecting health is more understandable.

In 1933, Burr observed that his fat-deficient rats consumed oxygen at an extremely high rate, and even then, the thought didn't occur to him that other nutritional deficiencies might have been involved in the condition he described. Ordinarily, the need for vitamins and minerals corresponds to the rate at which calories are being burned, the metabolic rate. Burr recalled that the rats on the fat free diet drank more water, and he reasoned that the absence of linoleic or linolenic acid in their skin was allowing water vapor to escape at a high rate. He didn't explain why the saturated fats the rats were synthesizing from sugar didn't serve at least as well as a "vapor barrier"; they are more effective at water-proofing than unsaturated fats, because of their greater hydrophobicity. The condensed and cross-linked keratin protein in skin cells is the main reason for the skin's relatively low permeability. When an animal is burning calories at a higher rate, its sweat glands are more actively maintaining a normal body temperature, cooling by evaporation; the amount of water evaporated is an approximate measure of metabolic rate, and of thyroid function.

In 1936, a man in Burr's lab, William Brown, agreed to eat a similar diet for six months, to see whether the "essential fatty acid deficiency" affected humans as it did rats.

The diet was very similar to the rats', with a large part of the daily 2500 calories being provided at hourly intervals during the day by sugar syrup (flavored with citric acid and anise oil), protein from 4 quarts of special fat-free skimmed milk, a quart of which was made into cottage cheese, the juice of half an orange, and a "biscuit" made with potato starch, baking powder, mineral oil, and salt, with iron, viosterol (vitamin D), and carotene supplemented.

Brown had suffered from weekly migraine headaches since childhood, and his blood pressure was a little high when he began the diet. After six weeks on the diet, his migraines stopped, and never returned. His plasma inorganic phosphorus declined slightly during the experiment (3.43 mg./100 cc. of plasma and 2.64 on the diet, and after six months on a normal diet 4.2 mg.%), and his total serum proteins increased from 6.98 gm.% to 8.06 gm.% on the experimental diet. His leucocyte count was lower on the high sugar diet, but he didn't experience colds or other sickness. On a normal diet, his systolic blood pressure varied from 140 to 150 mm. of mercury, the diastolic, 95 to 100. After a few months on the sugar and milk diet, his blood pressure had lowered to about 130 over 85 to 88. Several months after he returned to a normal diet, his blood pressure rose to the previous level.

On a normal diet, his weight was 152 pounds, and his metabolic rate was from 9% to 12% below normal, but after six months on the diet it had increased to 2% below normal. After three months on the sugar and milk diet, his weight leveled off at 138 pounds. After being on the diet, when he ate 2000 calories of sugar and milk within two hours, his respiratory quotient would exceed 1.0, but on his normal diet his maximum respiratory quotient following those foods was less than 1.0.

The effect of diabetes is to keep the respiratory quotient low, since a respiratory quotient of one corresponds to the oxidation of pure carbohydrate, and extreme diabetics oxidize fat in preference to carbohydrate, and may have a quotient just a little above 0.7. The results of Brown's and Burr's experiments could be interpreted to mean that the polyunsaturated fats not only lower the metabolic rate, but especially interfere with the metabolism of sugars. In other words, they suggest that the normal diet is diabetogenic.

During the six months of the experiment, the unsaturation of Brown's serum lipids decreased. The authors reported that "There was no essential change in the serum cholesterol as a result of the change in diet." However, in November and December, two months before the experiment began, it had been 252 mg.% in two measurements. At the beginning of the test, it was 298, two weeks later, 228, and four months later, 206 mg%. The total quantity of lipids in his blood didn't seem to change much, since the triglycerides increased as the cholesterol decreased.

By the time of Brown's experiment, other researchers had demonstrated that the cholesterol level was increased in hypothyroidism, and decreased as thyroid function, and oxygen consumption, increased. If Burr's team had been reading the medical literature, they would have understood the relation between Brown's increased metabolic rate and decreased cholesterol level. But they did record the facts, which is valuable.

The authors wrote that "The most interesting subjective effect of the 'fat-free' regimen was the definite disappearance of a feeling of fatigue at the end of the day's work."

A lowered metabolic rate and energy production is a common feature of aging and most degenerative diseases. From the beginning of an animal's life, sugars are the primary source of energy, and with maturation and aging there is a shift toward replacing sugar oxidation with fat oxidation. Old people are able to metabolize fat at the same rate as younger people, but their overall metabolic rate is lower, because they are unable to oxidize sugar at the same high rate as young people. Fat people have a similar selectively reduced ability to oxidize sugar.

Stress and starvation lead to a relative reliance on the fats stored in the tissues, and the mobilization of these as circulating free fatty acids contributes to a slowing of metabolism and a shift away from the use of glucose for energy. This is adaptive in the short term, since relatively little glucose is stored in the tissues (as glycogen), and the proteins making up the body would be rapidly consumed for energy, if it were not for the reduced energy demands resulting from the effects of the free fatty acids.

One of the points at which fatty acids suppress the use of glucose is at the point at which it is converted into fructose, in the process of glycolysis. When fructose is available, it can by-pass this barrier to the use of glucose, and continue to provide pyruvic acid for continuing oxidative metabolism, and if the mitochondria themselves aren't providing sufficient energy, it can leave the cell as lactate, allowing continuing glycolytic energy production. In the brain, this can sustain life in an emergency.

Many people lately have been told, as part of a campaign to explain the high incidence of fatty liver degeneration in the US, supposedly resulting from eating too much sugar, that fructose can be metabolized only by the liver. The liver does have the highest capacity for metabolizing fructose, but the other organs do metabolize it.

If fructose can by-pass the fatty acids' inhibition of glucose metabolism, to be oxidized when glucose can't, and if the metabolism of diabetes involves the oxidation of fatty acids instead of glucose, then we would expect there to be less than the normal amount of fructose in the serum of diabetics, although their defining trait is the presence of an increased amount of glucose. According to Osuagwu and Madumere (2008), that is the case. If a fructose deficiency exists in diabetes, then it is appropriate to supplement it in the diet.

Besides being one of the forms of sugar involved in ordinary energy production, interchangeable with glucose, fructose has some special functions, that aren't as well performed by glucose. It is the main sugar involved in reproduction, in the seminal fluid and intrauterine fluid, and in the developing fetus. After these crucial stages of life are past, glucose becomes the primary molecular source of energy, except when the system is under stress. It has been suggested (Jauniaux, et al., 2005) that the predominance of fructose rather than glucose in the embryo's environment helps to maintain ATP and the oxidative state (cellular redox potential) during development in the low-oxygen environment. The placenta turns glucose from the mother's blood into fructose, and the fructose in the mother's blood can pass through into the fetus, and although glucose can move back from the fetus into the mother's blood, fructose is unable to move in that direction, so a high concentration is maintained in the fluids around the fetus.

The control of the redox potential is sometimes called the "redox signalling system," since it coherently affects all processes and conditions in the cell, including pH and hydrophobicity. For example, when a cell prepares to divide, the balance shifts strongly away from the oxidative condition, with increases in the ratios of NADH to NAD+, of GSH to GSSG, and of lactate to pyruvate. These same shifts occur during most kinds of stress.

In natural stress, decreased availability of oxygen or nutrients is often the key problem, and many poisons can produce similar interference with energy production, for example cyanide or carbon monoxide, which block the use of oxygen, or ethanol, which inhibits the oxidation of sugars, fats, and amino acids (Shelmet, et al., 1988).

When oxygen isn't constantly removing electrons from cells (being chemically reduced by them) those electrons will react elsewhere, creating free radicals (including activated oxygen) and reduced iron, that will create inappropriate chemical reactions (Niknahad, et al., 1995; MacAllister, et al., 2011).

Stresses and poisons of many different types, interfering with the normal flow of electrons to oxygen, produce large amounts of free radicals, which can spread structural and chemical damage, involving all systems of the cell. Ethyl alcohol is a common potentially toxic substance that can have this effect, causing oxidative damage by allowing an excess of electrons to accumulate in the cell, shifting the cells' balance away from the stable oxidized state.

Fructose has been known for many years to accelerate the oxidation of ethanol (by about 80%). Oxygen consumption in the presence of ethanol is increased by fructose more than by glucose (Thieden and Lundquist, 1967). Besides removing the alcohol from the body more quickly, it prevents the oxidative damage, by maintaining or restoring the cell's redox balance, the relatively oxidized state of the NADH/NAD+, lactate/pyruvate, and GSH/GSSH systems. Although glucose has this stabilizing, pro-oxidative function in many situations, this is a general feature of fructose, sometimes allowing it to have the opposite effect of glucose on the cell's redox state. It seems to be largely this generalized shift of the cell's redox state towards oxidation that is behind the ability of a small amount of fructose to catalyze the more rapid oxidation of a large amount of glucose.

Besides protecting against the reductive stresses, fructose can also protect against the oxidative stress of increased hydrogen peroxide (Spasojevic, et al., 2009). Its metabolite, fructose 1,6-bisphosphate, is even more effective as an antioxidant.

Keeping the metabolic rate high has many benefits, including the rapid renewal of cells and their components, such as cholesterol and other lipids, and proteins, which are always susceptible to damage from oxidants, but the high metabolic rate also tends to keep the redox system in the proper balance, reducing the rate of oxidative damage.

Endotoxin absorbed from the intestine is one of the ubiquitous stresses that tends to cause free radical damage. Fructose, probably more than glucose, is protective against damage from endotoxin.

Many stressors cause capillary leakage, allowing albumin and other blood components to enter extracellular spaces or to be lost in the urine, and this is a feature of diabetes, obesity, and a variety of inflammatory and degenerative diseases including Alzheimer's disease (Szekanecz and Koch, 2008; Ujiie, et al., 2003). Although the mechanism isn't understood, fructose supports capillary integrity; fructose feeding for 4 and 8 weeks caused a 56% and 51% reduction in capillary leakage, respectively (Chakir, et al., 1998; Plante, et al., 2003).

The ability of the mitochondria to oxidize pyruvic acid and glucose is characteristically lost to some degree in cancer. When this oxidation fails, the disturbed redox balance of the cell will usually lead to the cell's death, but if it can survive, this balance favors growth and cell division, rather than differentiated function. This was Otto Warburg's discovery, that was rejected by official medicine for 75 years.

Cancer researchers have become interested in this enzyme system that controls the oxidation of pyruvic acid (and thus sugar) by the mitochondria, since these enzymes are crucially defective in cancer cells (and also in diabetes). The chemical DCA, dichloroacetate, is effective against a variety of cancers, and it acts by reactivating the enzymes that oxidize pyruvic acid. Thyroid hormone, insulin, and fructose also activate these enzymes. These are the enzymes that are inactivated by excessive exposure to fatty acids, and that are involved in the progressive replacement of sugar oxidation by fat oxidation, during stress and aging, and in degenerative diseases; for example, a process that inactivates the energy-producing pyruvate dehydrogenase in Alzheimer's disease has been identified (Ishiguro, 1998). Niacinamide, by lowering free fatty acids and regulating the redox system, supporting sugar oxidation, is useful in the whole spectrum of metabolic degenerative diseases.

A few times in the last 80 years, people (starting with Nasonov) have recognized that the hydrophobicity of a cell changes with its degree of excitation, and with its energy level. Recently, even in non-living physical-chemical systems, hydrophobicity and redox potential have been seen to vary together and to influence each other. Recent work shows how the oxidation of fatty acids contributes to the dissolution of mitochondria (Macchioni, et al., 2010). At first glance it might seem odd that the presence of fatty material could reduce the "fat loving" (lipophilic, equivalent to hydrophobic) property of a cell, but the fat used as fuel is in the form of fatty acids, which are soap-like, and spontaneously introduce "wetness" into the relatively water-resistant cell substance. The presence of fatty acids, impairing the last oxidative stage of respiration, increases the tendency of the mitochondrion to release its cytochrome c into the cell in a reduced form, leading to the apoptotic death of the cell. The oxidized form of the cytochrome is more hydrophobic, and stable.

Burr didn't understand that it was his rats' high sugar diet, freed of the anti-oxidative unsaturated fatty acids, that caused their extremely high metabolic rate, but since that time many experiments have made it clear that it is specifically the fructose component of sucrose that is protective against the antimetabolic fats.

Although Brown, et al., weren't focusing on the biological effects of sugar, their results are important in the history of sugar research because their work was done before the culture had been influenced by the development of the lipid theory of heart disease, and the later idea that fructose is responsible for increasing the blood lipids.

In 1963 and 1964, experiments (Carroll, 1964) showed that the effects of glucose and fructose were radically affected by the type of fat in the diet. Although 0.6% of calories as polyunsaturated fat prevents the appearance of the Mead acid (which is considered to indicate a deficiency of essential fats) the "high fructose" diets consistently add 10% or more corn oil or other highly unsaturated fat to the diet. These large quantities of PUFA aren't necessary to prevent a deficiency, but they are needed to obscure the beneficial effects of fructose.

Many studies have found that sucrose is less fattening than starch or glucose, that is, that more calories can be consumed without gaining weight. During exercise, the addition of fructose to glucose increases the oxidation of carbohydrate by about 50% (Jentjens and Jeukendrup, 2005). In another experiment, rats were fed either sucrose or Coca-Cola and Purina chow, and were allowed to eat as much as they wanted (Bukowiecki, et al, 1983). They consumed 50% more calories without gaining extra weight, relative to the standard diet. Ruzzin, et al. (2005) observed rats given a 10.5% or 35% sucrose solution, or water, and observed that the sucrose increased their energy consumption by about 15% without increasing weight gain. Macor, et al. (1990) found that glucose caused a smaller increase in metabolic rate in obese people than in normal weight people, but that fructose increased their metabolic rate as much as it did that of the normal weight people. Tappy, et al. (1993) saw a similar increase in heat production in obese people, relative to the effect of glucose. Brundin, et al. (1993) compared the effects of glucose and fructose in healthy people, and saw a greater oxygen consumption with fructose, and also an increase in the temperature of the blood, and a greater increase in carbon dioxide production.

These metabolic effects have led several groups to recommend the use of fructose for treating shock, the stress of surgery, or infection (e.g., Adolph, et al., 1995).

The commonly recommended alternative to sugar in the diet is starch, but many studies show that it produces all of the effects that are commonly ascribed to sucrose and fructose, for example hyperglycemia (Villaume, et al., 1984) and increased weight gain. The addition of fructose to glucose "can markedly reduce hyperglycemia during intraportal glucose infusion by increasing net hepatic glucose uptake even when insulin secretion is compromised" (Shiota, et al., 2005). "Fructose appears most effective in those normal individuals who have the poorest glucose tolerance" (Moore, et al., 2000).

Lipid peroxidation is involved in the degenerative diseases, and many publications argue that fructose increases it, despite the fact that it can increase the production of uric acid, which is a major component of our endogenous antioxidant system (e.g., Waring, et al., 2003). When rats were fed for 8 weeks on a diet with 18% fructose and 11% saturated fatty acids, the content of polyunsatured fats in the blood decreased, as they had in the Brown, et al., experiment, and their total antioxidant status was increased (Girard, et al., 2005). When stroke-prone spontaneously hypertensive rats were given 60% fructose, superoxide dismutase in their liver was increased, and the authors suggest that this "may constitute an early protective mechanism" (Brosnan and Carkner, 2008). When people were given a 300 calorie drink containing glucose, or fructose, or orange juice, those receiving the glucose had a large increase in oxidative and inflammatory stress (reactive oxygen species, and NF-kappaB binding), and those changes were absent in those receiving the fructose or orange juice (Ghanim, et al., 2007).

One of the observations in Brown, et al., was that the level of phosphate in the serum decreased during the experimental diet. Several later studies show that fructose increases the excretion of phosphate in the urine, while decreasing the level in the serum. However, a common opinion is that it's only the phosphorylation of fructose, increasing the amount in cells, that causes the decrease in the serum; that could account for the momentary drop in serum phosphate during a fructose load, but--since there is only so much phosphate that can be bound to intracellular fructose--it can't account for the chronic depression of the serum phosphate on a continuing diet of fructose or sucrose.

There are many reasons to think that a slight reduction of serum phosphate would be beneficial. It has been suggested that eating fruit is protective against prostate cancer, by lowering serum phosphate (Kapur, 2000). The aging suppressing gene discovered in 1997, named after the Greek life-promoting goddess Klotho, suppresses the reabsorption of phosphate by the kidney (which is also a function of the parathyroid hormone), and inhibits the formation of the activated form of vitamin D, opposing the effect of the parathyroid hormone. In the absence of the gene, serum phosphate is high, and the animal ages and dies prematurely. In humans, in recent years a very close association has been has been documented between increased phosphate levels, within the normal range, and increased risk of cardiovascular disease. Serum phosphate is increased in people with osteoporosis (Gallagher, et al., 1980), and various treatments that lower serum phosphate improve bone mineralization, with the retention of calcium phosphate (Ma and Fu, 2010; Batista, et al., 2010; Kelly, et al., 1967; Parfitt, 1965; Kim, et al., 2003).

At high altitude, or when taking a carbonic anhydrase inhibitor, there is more carbon dioxide in the blood, and the serum phosphate is lower; sucrose and fructose increase the respiratory quotient and carbon dioxide production, and this is probably a factor in lowering the serum phosphate.

Fructose affects the body's ability to retain other nutrients, including magnesium, copper, calcium, and other minerals. Comparing diets with 20% of the calories from fructose or from cornstarch, Holbrook, et al. (1989) concluded "The results indicate that dietary fructose enhances mineral balance." Ordinarily, things (such as thyroid and vitamin D) which improve the retention of magnesium and other nutrients are considered good, but the fructose mythology allows researchers to conclude, after finding an increased magnesium balance, with either 4% or 20% of energy from fructose (compared to cornstarch, bread, and rice), "that dietary fructose adversely affects macromineral homeostasis in humans." (Milne and Nielsen, 2000).

Another study compared the effects of a diet with plain water, or water containing 13% glucose, or sucrose, or fructose, or high fructose corn syrup on the properties of rats' bones: Bone mineral density and mineral content, and bone strength, and mineral balance. The largest differences were between animals drinking the glucose and the fructose solutions. The rats getting the glucose had reduced phosphorus in their bones, and more calcium in their urine, than the rats that got fructose. "The results suggested that glucose rather than fructose exerted more deleterious effects on mineral balance and bone" (Tsanzi, et al., 2008).

An older experiment compared two groups with an otherwise well balanced diet, lacking vitamin D, containing either 68% starch or 68% sucrose. A third group got the starch diet, but with added vitamin D. The rats on the vitamin D deficient starch diet had very low levels of calcium in their blood, and the calcium content of their bones was low, exactly what is expected with the vitamin D deficiency. However, the rats on the sucrose diet, also vitamin D deficient, had normal levels of calcium in their blood. The sucrose, unlike the starch, maintained claim homeostasis. A radioactive calcium tracer showed normal uptake by the bone, and also apparently normal bone development, although their bones were lighter than those receiving vitamin D.

People have told me that when they looked for articles on fructose in PubMed they couldn't find anything except articles about its bad effects. There are two reasons for that. PubMed, like the earlier Index Medicus, represents the material in the National Library of Medicine, and is a medical, rather than a scientific, database, and there is a large amount of important research that it ignores. And because of the authoritarian and conformist nature of the medical profession, when a researcher observes something that is contrary to majority opinion, the title of the publication is unlikely to focus on that. In too many articles in medical journals, the title and conclusions positively misrepresent the data reported in the article.

When the idea of "glycemic index" was being popularized by dietitians, it was already known that starch, consisting of chains of glucose molecules, had a much higher index than fructose and sucrose. The more rapid appearance of glucose in the blood stimulates more insulin, and insulin stimulates fat synthesis, when there is more glucose than can be oxidized immediately. If starch or glucose is eaten at the same time as polyunsaturated fats, which inhibit its oxidation, it will produce more fat. Many animal experiments show this, even when they are intending to show the dangers of fructose and sucrose.

For example (Thresher, et al., 2000), rats were fed diets with 68% carbohydrate, 12% fat (corn oil), and 20% protein. In one group the carbohydrate was starch (cornstarch and maltodextrin, with a glucose equivalence of 10%), and in other groups it was either 68% sucrose, or 34% fructose and 34% glucose, or 34% fructose and 34% starch. (An interesting oddity, fasting triglycerides were highest in the fructose+starch group.)

The weight of their fat pads (epididymal, retroperitoneal, and mesenteric) was greatest in the fructose+starch group, and least in the sucrose group. The starch group's fat was intermediate in weight between those of the sucrose and the fructose+glucose groups.

At the beginning of the experimental diet, the average weight of the animals was 213.1 grams. After five weeks, the animals in the fructose+glucose group gained 164 grams, those in the sucrose group gained 177 grams, and those in the starch group gained 199.2 grams. The animals ate as much of the diet as they wanted, and those in the sucrose group ate the least.

The purpose of their study was to see whether fructose causes "glucose intolerance" and "insulin resistance." Since insulin stimulates appetite (Chance, et al, 1986; Dulloo and Girardier, 1989; Czech, 1988; DiBattista, 1983; Sonoda, 1983; Godbole and York, 1978), and fat synthesis, the reduced food consumption and reduced weight gain show that fructose was protecting against these potentially harmful effects of insulin.

Much of the current concern about the dangers of fructose is focussed on the cornstarch-derived high fructose corn syrup, HFCS. Many studies assume that its composition is nearly all fructose and glucose. However, Wahjudi, et al. (2010) analyzed samples of it before and after hydrolyzing it in acid, to break down other carbohydrates present in it. They found that the carbohydrate content was several times higher than the listed values. "The underestimation of carbohydrate content in beverages may be a contributing factor in the development of obesity in children," and it's especially interesting that so much of it is present in the form of starch-like materials.

Many people are claiming that fructose consumption has increased greatly in the last 30 or 40 years, and that this is responsible for the epidemic of obesity and diabetes. According to the USDA Economic Research Service, the 2007 calorie consumption as flour and cereal products increased 3% from 1970, while added sugar calories decreased 1%. Calories from meats, eggs, and nuts decreased 4%, from dairy foods decreased 3%, and calories from added fats increased 7%. The percentage of calories from fruits and vegetables stayed the same. The average person consumed 603 calories per day more in 2007 than in 1970. If changes in the national diet are responsible for the increase of obesity, diabetes, and the diseases associated with them, then it would seem that the increased consumption of fat and starch is responsible, and that would be consistent with the known effects of starches and polyunsaturated fats.

In monkeys living in the wild, when their diet is mainly fruit, their cortisol is low, and it rises when they eat a diet with less sugar (Behie, et al., 2010). Sucrose consumption lowers ACTH, the main pituitary stress hormone (Klement, et al., 2009; Ulrich-Lai, et al., 2007), and stress promotes increased sugar and fat consumption (Pecoraro, et al., 2004). If animals' adrenal glands are removed, so that they lack the adrenal steroids, they choose to consume more sucrose (Laugero, et al., 2001). Stress seems to be perceived as a need for sugar. In the absence of sucrose, satisfying this need with starch and fat is more likely to lead to obesity.

The glucocorticoid hormones inhibit the metabolism of sugar. Sugar is essential for brain development and maintenance. The effects of environmental stimulation and deprivation-stress can be detected in the thickness of the brain cortex in as little as 4 days in growing rats (Diamond, et al., 1976). These effects can persist through a lifetime, and are even passed on transgenerationally. Experimental evidence shows that polyunsaturated (omega-3) fats retard fetal brain development, and that sugar promotes it. These facts argue against some of the currently popular ideas of the evolution of the human brain based on ancestral diets of fish or meat, which only matters as far as those anthropological theories are used to argue against fruits and other sugars in the present diet.

Honey has been used therapeutically for thousands of years, and recently there has been some research documenting a variety of uses, including treatment of ulcers and colitis, and other inflammatory conditions. Obesity increases mediators of inflammation, including the C-reactive protein (CRP) and homocysteine. Honey, which contains free fructose and free glucose, lowers CRP and homocysteine, as well as triglycerides, glucose, and cholesterol, while it increased insulin more than sucrose did (Al-Waili, 2004). Hypoglycemia intensifies inflammatory reactions, and insulin can reduce inflammation if sugar is available. Obesity, like diabetes, seems to involve a cellular energy deficiency, resulting from the inability to metabolize sugar.

Sucrose (and sometimes honey) is increasingly being used to reduce pain in newborns, for minor things such as injections (Guala, et al., 2001; Okan, et al., 2007; Anand, et al., 2005; Schoen and Fischell, 1991). It's also effective in adults. It acts by influencing a variety of nerve systems, and also reduces stress. Insulin is probably involved in sugar analgesia, as it is in inflammation, since it promotes entry of endorphins into the brain (Witt, et al., 2000).

An extracellular phosphorylated fructose metabolite, diphosphoglycerate, has an essential regulatory effect in the blood; another fructose metabolite, fructose diphosphate, can reduce mast cell histamine release and protect against oxidative and hypoxic injury and endotoxic shock, and it reduces the expression of the inflammation mediators TNF-alpha, IL-6, nitric oxide synthase, and the activation of NF-kappaB, among other protective effects, and its therapeutic value is known, but its relation to dietary sugars hasn't been investigated.

A daily diet that includes two quarts of milk and a quart of orange juice provides enough fructose and other sugars for general resistance to stress, but larger amounts of fruit juice, honey, or other sugars can protect against increased stress, and can reverse some of the established degenerative conditions.

Refined granulated sugar is extremely pure, but it lacks all of the essential nutrients, so it should be considered as a temporary therapeutic material, or as an occasional substitute when good fruit isn't available, or when available honey is allergenic.

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A R T I C L E

Glucose and sucrose for diabetes

Diabetes has been known since ancient times as a wasting disease in which sugar was lost in the urine, but more recently the name has been used to describe the presence of more than the normal amount of glucose in the blood, even in the absence of glucose in the urine. Some of the medical ideas regarding the original form of the condition have been applied to the newer form.
Cultural "paradigms" or ideologies are so convenient that people often don't bother to doubt them, and they are sometimes so rigorously enforced that people learn to keep their doubts to themselves. Public concern about diabetes has been growing for decades, but despite the introduction of insulin and other drugs to treat it, and massive campaigns to "improve" eating habits, mortality from diabetes has been increasing during the last 100 years. Diabetes ("type 1") has been increasing even among children (Barat, et al., 2008).

A basic meaning of homeopathic medicine is the support of the organism's ability to heal itself; the essence of allopathy is that the physician fights "a disease" to cure the patient, e.g., by cutting out tumors or killing germs.

Confidence in the organism's essential rationality led the doctors with a homeopathic orientation to see a fever as part of a recuperative process, while their allopathic opponents sometimes saw fever as the essence of the sickness to be cured. Homeopaths concentrated on the nature of the patient; allopaths concentrated on a disease entity in itself, and were likely to ignore the patient's idiosyncrasies and preferences.

Diabetes was named for the excessive urination it causes, and for the sugar in the urine. It was called the sugar disease, and physicians were taught that sugar was the problem. Patients were ordered to avoid sweet foods, and in hospitals they were sometimes locked up to keep them from finding sweets. The practice was derived from ideology, not from any evidence that the treatment helped.

In 1857, M. Piorry in Paris and William Budd in Bristol, England, reasoned that if a patient was losing a pound of sugar every day in 10 liters of urine, and was losing weight very rapidly, and had an intense craving for sugar, it would be reasonable to replace some of the lost sugar, simply because the quick weight loss of diabetes invariably led to death. Keeping patients from eating what they craved seemed both cruel and futile.

After Budd's detailed reports of a woman's progressive recovery over a period of several weeks when he prescribed 8 ounces of sugar every day, along with a normal diet including beef and beef broth, a London physician, Thomas Williams, wrote sarcastically about Budd's metaphysical ideas, and reported his own trial of a diet that he described as similar to Budd's. But after two or three days he decided his patients were getting worse, and stopped the experiment.

Williams' publication was presented as a scientific refutation of Budd's deluded homeopathic ideas, but Budd hadn't explained his experiment as anything more than an attempt to slow the patient's death from wasting which was sure to be the result of losing so much sugar in the urine. The following year Budd described another patient, a young man who had become too weak to work and who was losing weight at an extreme rate. Budd's prescription included 8 ounces of white sugar and 4 ounces of honey every day, and again, instead of increasing the amount of glucose in the urine, the amount decreased quickly as the patient began eating almost as much sugar as was being lost initially, and then as the loss of sugar in the urine decreased, the patient gained weight and recovered his strength.

Drs. Budd and Piorry described patients recovering from an incurable disease, and that has usually been enough to make the medical profession antagonistic. Even when a physician has himself diagnosed diabetes and told a patient that it would be necessary to inject insulin for the rest of his life, if that patient recovers by changing his diet, the physician will typically say that the diagnosis was wrong, because diabetes is incurable.

Twenty-five years ago, some rabbits were made diabetic with a poison that killed their insulin-secreting pancreatic beta-cells, and when some of them recovered from the diabetes after being given supplemental DHEA, it was found that their beta-cells had regenerated. The more recent interest in stem cells has led several research groups to acknowledge that in animals the insulin-producing cells are able to regenerate.

It is now conceivable that there will be an effort to understand the factors that damage the beta-cells, and the factors that allow them to regenerate. The observations of Budd and Piorry would be a good place to start such a reconsideration.

For many years, physicians have been taught that diabetes is either "genetic" or possibly caused by a viral infection, that might trigger an "autoimmune reaction," but the study of cellular respiration and energy metabolism and endocrinology has provided more convincing explanations. The antibodies that are found in the "autoimmune" conditions are evidence of tissue damage, but the damage may have been done by metabolic toxins, with the immune system's involvement being primarily the removal of defective cells.

In the 1940s, Bernardo Houssay found that coconut oil protected animals from poison-induced diabetes, while a lard-based diet failed to protect them. Later, glucose itself was found to protect the pancreatic beta-cells from poisons.

In 1963, P.J. Randle clearly described the inhibition of glucose oxidation by free fatty acids. Later, when lipid emulsions came into use for intravenous feeding in hospitals, it was found that they blocked glucose oxidation, lowered the metabolic rate, suppressed immunity, and increased lipid peroxidation and oxidative stress.
Estrogen and stress are both known to create some of the conditions of diabetes, while increasing fat oxidation and inhibiting glucose oxidation. Emotional stress, overwork, trauma, and infections have been known to initiate diabetes. Estrogen increases free fatty acids and decreases glycogen storage, and when birth control pills were becoming popular, some researchers warned that they might cause diabetes. But the food oil industry and the estrogen industry were satisfied with the medical doctrine that diabetes was caused by eating too much sugar.
If the essence of diabetes is the presence of too much sugar, then it seems reasonable to argue that it is the excess sugar that's responsible for the suffering and death associated with the disease, otherwise, how would the prohibition of sugar in the diet be justified? In fact, the argument is made (e.g., Muggeo, 1998) that it is the hyperglycemia that causes problems such as hypertension, kidney failure, heart failure, neuropathy, blindness, dementia, and gangrene.

As information about the many physiological and biochemical events associated with diabetes has accumulated, the basic doctrine that "sugar causes diabetes" has extended itself to whatever the topic of discussion is: "Glucose causes" the death of beta-cells, glucose causes blood vessels to become leaky, glucose causes cells to be unable to absorb glucose, glucose causes the formation of free radicals, glucose impairs immunity and wound healing, but causes inflammation while preventing the "respiratory burst" in which free radicals are produced by cells that cause inflammation, it disturbs enzyme functions, impairs nerve conduction and muscle strength, etc., and it is also addictive, causing people to irrationally seek the very material that is poisoning them.

Tens of thousands of publications describe the pathogenic effects of sugar. To prove their point, they grow cells in a culture dish, and find that when they are exposed to excess glucose, often 5 times the normal amount, they deteriorate. In the artificial conditions of cell culture, the oversupply of glucose causes lactic acid to accumulate, leading to toxic effects. But in the organism, the hyperglycemia is compensating for a sensed deficiency of glucose, a need for more energy.

If diabetes means that cells can't absorb or metabolize glucose, then any cellular function that requires glucose will be impaired, despite the presence of glucose in the blood. It is the intracellular absence of glucose which is problematic, rather than its extracellular excess.
Neuroglycopenia (or neuroglucopenia) or intracellular glycopenia refers to the deficit of glucose in cells. When the brain senses a lack of glucose, nerves are activated to increase the amount of glucose in the blood, to correct the problem. As long as the brain senses the need for more glucose, the regulatory systems will make the adjustments to the blood glucose level.

The antagonism between fat and sugar that Randle described can involve the suppression of sugar oxidation when the concentration of fats in the bloodstream is increased by eating fatty food, or by releasing fats from the tissues by lipolysis, but it can also involve the suppression of fat oxidation by inhibiting the release of fatty acids from the tissues, when a sufficient amount of sugar is eaten.

When a normal person, or even a "type 2 diabetic," is given a large dose of sugar, there is a suppression of lipolysis, and the concentration of free fatty acids in the bloodstream decreases, though the suppression is weaker in the diabetic (Soriguer, et al., 2008). Insulin, released by the sugar, inhibits lipolysis, reducing the supply of fats to the respiring cells.

Free fatty acids suppress mitochondrial respiration (Kamikawa and Yamazaki, 1981), leading to increased glycolysis (producing lactic acid) to maintain cellular energy. The suppression of mitochondrial respiration increases the production of toxic free radicals, and the decreased carbon dioxide makes the proteins more susceptible to attack by free radicals. The lactate produced under the influence of excessive fat metabolism stimulates the release of endorphins, which are lipolytic, releasing more free fatty acids from the tissues. Acting through cytokines such as interleukin-6, lactate shifts the balance toward the catabolic hormones, leading to tissue wasting.

Lactic acid itself, and the longer chain fatty acids, inhibit the regulatory enzyme pyruvate dehydrogenase (which is activated by insulin), reducing the oxidative production of energy. Drugs to activate this enzyme are being studied by the pharmaceutical industry as treatments for diabetes and cancer (for example, DCA, dichloroacetate).

Oxidative damage of proteins is often described as glycation or glycosylation, but it really consists of many addition and crosslinking reactions, most often onto, or between, lysine groups. Carbon dioxide normally associates with lysine groups, so the destructive reactions are favored when carbon dioxide is displaced by lactic acid. The reactive fragments of polyunsaturated fatty acids are much more often the source of the protein-damaging radicals than the carbohydrates are.

The importance of the fats in causing type-2 diabetes is coming to be accepted, for example Li, et al., recently (2008) said "The cellular link between fatty acids and ROS (reactive oxygen species) is essentially the mitochondrion, a key organelle for the control of insulin secretion. Mitochondria are the main source of ROS and are also the primary target of oxidative attacks."
But much earlier (Wright, et al., 1988) it had been demonstrated that a deficiency of the "essential fatty acids" prevents toxin-induced diabetes and greatly increases resistance to inflammation (Lefkowith, et al., 1990). The lack of those so-called "essential fatty acids" also prevents autoimmune diabetes in a strain of diabetic mice (Benhamou, et al., 1995),

Suppressing fatty acid oxidation improves the contraction of the heart muscle and increases the efficiency of oxygen use (Chandler, et al., 2003). Various drugs are being considered for that purpose, but niacinamide is already being used to improve heart function, since it lowers the concentration of free fatty acids.

The antimetabolic and toxic effects of the polyunsaturated fatty acids can account for the "insulin resistance" that characterizes type-2 diabetes, but similar actions in the pancreatic beta-cells can impair or kill those cells, creating a deficiency of insulin, resembling type-1 diabetes.
The suppression of mitochondrial respiration causes increased free radical damage, and the presence of polyunsaturated fatty acids in the suppressed cell increases the rate of fat decomposition and production of toxins.

Increasing the rate of respiration by replacing the fats with glucose reduces the availability of electrons that can trigger lipid peroxidation and produce toxic free radicals, and the shift of fuel also increases the amount of carbon dioxide produced, which can protect the protein amino groups such as lysine from glycation and lipoxidation.

While it's clear that it is the excessive oxidation of fat that damages cells in the "diabetic" state in which cells aren't able to use glucose, it's important to look at some of the situations in which so many researchers are blaming problems on hyperglycemia.

Important problems in diabetes are slow wound healing, excessive permeability or leakiness of blood vessels which allows molecules such as albumin to be extravasated, and the impaired function and survival of pancreatic beta-cells.

During the healing of a wound in a diabetic individual, the local concentration of glucose decreases and then entirely disappears, as healing stops. Applying glucose and insulin topically to the wound, it heals quickly. The very old practice of treating deep wounds with honey or granulated sugar has been studied in controlled situations, including the treatment of diabetic ulcers, infected deep wounds following heart surgery, and wounds of lepers. The treatment eradicates bacterial infections better than some antiseptics, and accelerates healing without scarring, or with minimal scarring. The sugar regulates the communication between cells, and optimizes the synthesis of collagen and extracellular matrix.

An excess of insulin, causing hypoglycemia, can cause blood vessels, for example in the brain and kidneys, to become leaky, and this has been claimed to be an effect of insulin itself. However, the same leakiness can be produced by an analog of glucose that can't be metabolized, so that intracellular glycopenia is produced. The harmful effect that has been ascribed to excessive insulin can be prevented by maintaining an adequate supply of glucose (Uezu and Murakami, 1993), showing that it is the lack of glucose, rather than the excess insulin, that causes the vascular malfunction. Fructose also reduces the leakiness of blood vessels (Plante, et al., 2003). Many of the complications of diabetes are caused by increased vascular leakiness (Simard, et al., 2002).

Sugar can protect the beta-cells from the free fatty acids, apparently in the same ways that it protects the cells of blood vessels, restoring metabolic energy and preventing damage to the mitochondria. Glucose suppresses superoxide formation in beta-cells (Martens, et al., 2005) and apparently in other cells including brain cells. (Isaev, et al., 2008).

The beta-cell protecting effect of glucose is supported by bicarbonate and sodium. Sodium activates cells to produce carbon dioxide, allowing them to regulate calcium, preventing overstimulation and death. For a given amount of energy released, the oxidation of glucose produces more carbon dioxide and uses less oxygen than the oxidation of fatty acids.

The toxic excess of intracellular calcium that damages the insulin-secreting cells in the relative absence of carbon dioxide is analogous to the increased excitation of nerves and muscles that can be produced by hyperventilation.

In every type of tissue, it is the failure to oxidize glucose that produces oxidative stress and cellular damage. Even feeding enough sucrose to cause fat deposition in the liver can protect the liver from oxidative stress (Spolarics and Meyenhofer, 2000), possibly by mechanisms such as those involved in the treatment of alcoholic liver disease with saturated fats.

The active thyroid hormone, T3, protects the heart by supporting the oxidation of glucose (Liu, et al., 1998). The amount of T3 produced by the liver depends mainly on the amount of glucose available.

Animals that have been made diabetic with relatively low doses of the poison streptozotocin can recover functional beta-cells spontaneously, and the rate of recovery is higher in pregnant animals (Hartman, et al., 1989). Pregnancy stabilizes blood sugar at a higher level, and progesterone favors the oxidation of glucose rather than fats.

A recent study suggests that recovery of the pancreas can be very fast. A little glucose was infused for 4 days into rats, keeping the blood glucose level normal, and the mass of beta-cells was found to have increased 2.5 times. Cell division wasn't increased, so apparently the additional glucose was preventing the death of beta-cells, or stimulating the conversion of another type of cell to become insulin-secreting beta-cells (Jetton, et al., 2008).

That study is very important in relation to stem cells in general, because it either means that glandular cells are turning over ("streaming") at a much higher rate than currently recognized in biology and medicine, or it means that (when blood sugar is adequate) stimulated cells are able to recruit neighboring cells to participate in their specialized function. Either way, it shows the great importance of environmental factors in regulating our anatomy and physiology.

"Diabetologists" don't regularly measure their patients' insulin, but they usually make the assumption that insulin is the main factor regulating blood sugar. In one study, it was found that the insulin molecule itself, immunoreactive insulin, accounted for only about 8% of the serum's insulin-like action. The authors of that study believed that potassium was the main other factor in the serum that promoted the disposition of glucose. Since potassium and glucose are both always present in the blood, their effects on each other have usually been ignored.

Cellular activation (by electrical, nervous, chemical, or mechanical stimulation) causes glucose to be absorbed and oxidized, even in the absence of insulin and in otherwise insulin-resistant individuals. I think this local interaction between the need for energy and the production of energy predominates in good health, with insulin and other hormones facilitating the process in times of stress. A variety of local tissue regulators, including GABA and glutamate, probably participate in these interactions, in the brain, endocrine glands, muscles, and other tissues, and are probably involved in the relaxing and analgesic actions of the sugars.

The GABA system (GABA is highly concentrated in the beta-cells) is involved in regulating blood sugar, inhibiting the release of glucagon when glucose isn't needed, and apparently allowing the beta cells to discriminate between amino acids and glucose (Gu, et al., 1993) and acting as a survival and growth factor for neighboring cells (Ligon, et al., 2007).

The damaged beta-cells lose the enzyme (glutamate dehydrogenase) that makes GABA, and their ratio of linoleic acid to saturated and monounsaturated fat increases, a change that corresponds to a decreased metabolism of glucose.

The free intracellular calcium that can become toxic is normally bound safely by well-energized mitochondria, and in the bloodstream it is kept safely complexed with carbon dioxide. The thyroid hormone, producing carbon dioxide, helps to sustain the level of ionized calcium (Lindblom, et al., 2001). In a vitamin D deficiency, or a calcium deficiency, the parathyroid hormone increases, and this hormone can contribute to many inflammatory and degenerative processes, including diabetes. Consuming enough calcium and vitamin D to keep the parathyroid hormone suppressed is important to protect against the degenerative conditions.

When animals were fed an otherwise balanced diet lacking vitamin D, with the addition of either 68% sucrose or 68% starch, the bones of those on the starch diet failed to develop normally, as would be expected with a vitamin D deficiency, and their serum calcium was low. However, the bones of those on the diet with sucrose developed properly, and didn't show evidence of being calcium deficient, though they weren't quite as heavy as those that also received an adequate amount of vitamin D (Artus, 1975). This study suggests that the famous dietetic emphasis on the "complex carbohydrates," i.e., starches, has made an important contribution to the prevalence of osteoporosis, as well as obesity and other degeneration conditions.

Both vitamin D and vitamin K, another important calcium-regulating nutrient, are now known to prevent diabetes. Both of these vitamins require carbon dioxide for disposing of calcium properly, preventing its toxicity. When carbon dioxide is inadequate, for example from simple hyperventilation or from hypothyroidism, calcium is allowed to enter cells, causing inappropriate excitation, sometimes followed by calcification.

Keeping an optimal level of carbon dioxide (for example, when adapted to high altitude) causes calcium to be controlled, resulting in lowered parathyroid hormone, an effect similar to supplementing with calcium, vitamin D, and vitamin K. (E.g., Nicolaidou, et al, 2006.) Glycine, like carbon dioxide, protects proteins against oxidative damage (Lezcano, et al., 2006), so including gelatin (very rich in glycine) in the diet is probably protective.

The contribution of PTH to inflammation and degeneration is just being acknowledged (e.g., Kuwabara, 2008), but the mechanism undoubtedly involves the fact that it is lipolytic, increasing the concentration of free fatty acids that suppress metabolism and interfere with the use of glucose.

When we talk about increasing the metabolic rate, and the benefits it produces, we are comparing the rate of metabolism in the presence of thyroid, sugar, salt, and adequate protein to the "normal" diet, containing smaller amounts of those "stimulating" substances. It would be more accurate if we would speak of the suppressive nature of the habitual diet, in relation to the more optimal diet, which provides more energy for work and adaptation, while minimizing the toxic effects of free radicals.

Feeding animals a normal diet with the addition of Coca-Cola, or with a similar amount of sucrose, has been found to let them increase their calorie intake by 50% without increasing their weight gain (Bukowiecki, et al., 1983). Although plain sucrose can alleviate the metabolic suppression of an average diet, the effect of sugars in the diet is much more likely to be healthful in the long run when they are associated with an abundance of minerals, as in milk and fruit, which provide potassium and calcium and other protective nutrients.

Avoiding the starches such as cereals and beans, and using fruits as a major part of the diet helps to minimize the effects of the polyunsaturated fats.

Celiac disease or gluten sensitivity is associated with diabetes and hypothyroidism. There is a cross reaction between the gluten protein molecule and an enzyme which is expressed under the influence of estrogen. This is another reason for simply avoiding cereal products.

Brewers' yeast has been used traditionally to correct diabetes, and its high content of niacin and other B vitamins and potassium might account for its beneficial effects. However, eating a large quantity of it is likely to cause gas, so some people prefer to extract the soluble nutrients with hot water. Yeast contains a considerable amount of estrogen, and the water extract probably leaves much of that in the insoluble starchy residue. Liver is another rich source of the B vitamins as well as the oily vitamins, but it can suppress thyroid function, so usually one meal a week is enough.

The supplements that most often help to correct diabetes-like conditions are niacinamide, thiamine, thyroid, and progesterone or pregnenolone. Vitamins D and K are clearly protective against developing diabetes, and their effects on many regulatory processes suggest that they would also help to correct existing hyperglycemia.

Drinking coffee seems to be very protective against developing diabetes. Its niacin and magnesium are clearly important, but it is also a rich source of antioxidants, and it helps to maintain normal thyroid and progesterone production. Chocolate is probably protective too, and it is a good source of magnesium and antioxidants.

A recent study (Xia, et al., 2008) showed that inhibition of cholesterol synthesis by beta-cells impairs insulin synthesis, and that replenishing cholesterol restores the insulin secretion. Green tea contains this type of inhibitor, but its use has nevertheless been associated with a reduced risk of diabetes. Caffeine is likely to be the main protective substance in these foods.

Although antioxidants can be protective against diabetes, not all things sold as "antioxidants" are safe; many botannical "antioxidants" are estrogenic. Hundreds of herbal products can lower blood sugar, but many of them are simply toxic, and the reduction of blood glucose can make some problems worse.

The supplements I mention above--including caffeine--have antiinflammatory, antioxidative and energy-promoting effects. Inflammation, interfering with cellular energy production, is probably the essential feature of the things called diabetes.

Aspirin has a very broad spectrum of antiinflammatory actions, and is increasingly being recommended for preventing complications of diabetes. One of the consequences of inflammation is hyperglycemia, and aspirin helps to correct that (Yuan, et al., 2001), while protecting proteins against oxidative damage (Jafarnejad, et al, 2001).

If Dr. Budd's thinking (and results) had been more widely accepted when his publications appeared, thinking about "diabetes" might have led to earlier investigation of the syndromes of stress and tissue wasting, with insulin being identified as just one of many regulatory substances, and a large amount of useless and harmful activity treating hyperglycemia as the enemy, rather than part of an adaptive reaction, might have been avoided.

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A R T I C L E

Cascara, energy, cancer and the FDA's laxative abuse

The medical culture and the general culture share some attitudes about the nature of the most common ailments--colds, cancer, arthritis, constipation, heart problems, etc., and they often agree about which things can be treated at home, and which require special medical care.

These background ideas are important because they influence the actions of insurance companies, legislators, and regulatory agencies. They also influence the judgments people make about their own health, and, too often, the way physicians treat their patients.

The prevalence of chronic constipation in North America has been estimated to be 27%, and in a ten year study, the occurrence of new cases was about 16%.--the prevalence increases with aging. In some studies, women are 3 times as likely as men to suffer from constipation. A recent Canadian article commented that While chronic constipation (CC) has a high prevalence in primary care, there are no existing treatment recommendations to guide health care professionals.

Almost everyone in the US is familiar with the idea of laxative abuse, of using laxatives when they arent absolutely necessary, and with the idea that chronic laxative use will create a dependency, the way an addictive drug does. Contemporary doctors are likely to prescribe stool softeners for constipated old people, rather than stimulant laxatives, probably because softener doesnt have the pejorative connotation that stimulant drug has--not because there is a scientific basis for the choice.

Many doctors advise constipated patients to drink more water and exercise. While there is some physiological basis for recommending exercise, the advice to drink more water is simply unphysiological. A study in Latin America found no evidence of benefit from either of those recommendations, and recommended the use of fiber in the diet. The right kind of fiber can benefit a variety of bowel problems. However, some types of fiber can exacerbate the problem, and some types (such as oat bran) have been found to increase bowel cancer in animal studies.
Despite the greater prevalence of constipation in women and older people, even specialists in gastroenterology are very unlikely to consider the role of hypothyroidism or other endocrine problems in chronic constipation.

Because of the cultural clichés about constipation--that its caused by not eating enough fiber or drinking enough water, for example--and the belief that its not very important, there is seldom an effort made to understand the actual condition of the intestine, and the causes of the problem.

Aging and stress increase some of the inflammatory mediators, tending to reduce the barrier function of the bowel, letting larger amounts of bacterial toxins enter the bloodstream, interfering with energy metabolism, creating inflammatory vicious circles of increasing leakiness and inflammation.

Often people visualize something like a sausage casing when they think of the intestine, but when the intestine is becoming inflamed its wall may swell to become an inch thick. As it thickens, the channel narrows to a few millimeters in diameter, and may even close in some regions. In the swollen, edematous, inflamed condition the contractile mechanism of the smooth muscle is impaired. The failure of contraction is caused by the same structural changes that increase permeability. (Garcia, et al., 1996; Skarsgard, et al., 2000; Plaku and von der Weid, 2006; Uray, et al., 2006; Miller and Sims, 1986; Schouten, et al., 2008; Gosling, et al., 2000.)

Obviously, in the very swollen, structurally deformed intestine, with almost no lumen, neither a stimulant nor a simple fibrous bulk could restore functioning, because even with stimulation the smooth muscle is unable to contract, and the closed channel wont admit bulk. Even gas is sometimes unable to pass through the inflamed intestine. Mechanical thinking about the intestine fails when inflammation is involved; now that inflammation is known to play an important role in Alzheimers disease and heart disease, it will be more acceptable to consider its role in constipation.

The contractile ability of smooth muscle, thats impaired by swelling and inflammation, can be restored by antiinflammatory agents, for example aspirin (or other inhibitor of prostaglandin synthesis) or antihistamines. This applies to the muscles of lymphatic vessels (Wu, et al., 2005, 2006; Gosling, 2000), that must function to reduce edema, as well as to the bowel muscles that cause peristalsis.

If someone thinks of constipation as the result of a lack of neuromuscular stimulation, then it might seem reasonable to design a drug that intensifies the contractions produced by one of the natural transmitter substances, such as serotonin, histamine, or acetylcholine. Thats apparently what Novartis did, with tegaserod, a drug that increases the bowels sensitivity to serotonin. That drug, called Zelnorm, was approved by the FDA in 2002, after a couple of years of publications praising it. At the time of its approval, there was already evidence that people using it were more likely to have abdominal surgery, especially for gallbladder disease, and there was doubt about its effectiveness.

Strangely, the drug was approved to be used for only 4 to 6 weeks, taking two tablets daily without interruption. When patients benefitted from the first treatment, they might be eligible for an additional 4 to 6 weeks, but then it would be necessary for them to find another way to deal with their constipation.

Zelnorm side effects: abdominal pain, chest pain, flushing, facial edema, hypertension, hypotension, angina pectoris, syncope, arrythmia, anxiety, vertigo, ovarian cyst, miscarriage, menorrhagia, cholecystitis, appendicitis, bilirubinemia, gastroenteritis, increased creatine phosphokinase. back pain, cramps, breast cancer, attempted suicide, impaired concentration, increased appetite, sleep disorder, depression, anxiety, asthma, increased sweating, renal pain, polyuria. (Later, it was found to cause heart attacks and intestinal ischemia/necrosis.) Why would the FDA approve a drug, without evidence that it was more effective than harmless things that were already widely available?

Zelnorm Prices ~ In the US, Novartis estimates that Zelnorm tablets will sell for somewhere in the range of $3 to $4 each. The drug is expected to generate $1 billion in annual sales for Novartis.

During the years just before the new drug was approved, there were several publications reporting that emodin, the main active factor in cascara, a traditional laxative, had some remarkable antiviral and anticancer activities. Other studies were reporting that it protected against some known mutagens and carcinogens. Less than 3 months before approving Zelnorm, the FDA announced its Final rule [Federal Register: May 9, 2002 (Volume 67, Number 90)] Certain Additional Over-the-Counter Drug Category II and III Active Ingredients. the stimulant laxative ingredients aloe (including aloe extract and aloe flower extract) and cascara sagrada (including casanthranol, cascara fluidextract aromatic, cascara sagrada bark, cascara sagrada extract, and cascara sagrada fluidextract), determining that they are not generally recognized as safe and effective or are misbranded. This final rule is part of FDA's ongoing OTC drug product review. This rule is effective November 5, 2002.

Historically, the FDA has ruled against traditional generic drug products when the drug industry is ready to market a synthetic substitute product.

In 2007, the FDA withdrew its approval for Zelnorm, but allowed it to be licensed as an Investigational New Drug. On April 2, 2008, after more than eight months of availability, the company has re-assessed the program and has made a decision to close it. Novartis is in the process of communicating this decision to physicians participating in the program. Patients who had access to Zelnorm via this program are instructed to discuss alternative treatment options with their physicians.

Cascara and aloe are not among the treatment options approved by the FDA, so cascara isnt widely available (though anyone can grow aloe plants easily). However, there is considerable interest in the drug industry in the possibility of developing products based on emodin, or aloe-emodin, as anticancer or antiviral drugs. Even if it were proved to be safe and effective for use as a laxative, its potential use as an alternative to extremely profitable cancer and virus treatments would make it a serious threat to the drug industry.

Although the standard medical journals have only recently begun writing about it as a cancer treatment, emodin and related chemicals have been of interest as a non-toxic way to treat cancer, allergies, and viral and bacterial diseases for a long time.

In 1900, Moses Gomberg demonstrated the synthesis of a stable free radical (triphenylmethyl), but for years many chemists believed free radicals couldnt exist. A student of Gombergs, William F. Koch, came to believe that cellular respiration involved free radicals, and experimented with the metabolic effects of many organic molecules, quinones of several kinds, that can form free radicals, looking for the most useful ones.

For more than 50 years the U.S. Government and the main medical instititutions actively fought the idea that a free radical or quinone could serve as a biological catalyst to correct a wide variety of health problems.

A free radical has an unpaired electron. In 1944 Yevgeniy Zavoisky devised a way to measure the behavior of unpaired electrons in crystals, but it was many years before it was recognized that they are essential to cellular respiration. Alex Comfort demonstrated them in living tissue in 1959.

By the time coenzyme Q₁₀, ubiquinone, was officially discovered, Koch had moved to Brazil to continue his work with the biological effects of the quinones, including the anthraquinone compound of brazilwood, which is used as a dye. He also used a naphthoquine, lapachon Although vitamin K was identified as a quinone (naphthoquinone) not long after coQ₁₀ was found to be a ubiquitous component of the mitochondrial respiratory system, it wasnt immediately recognized as another participant in that system, interacting with coQ₁₀.

Although Koch was unable to publish in any English language medical journal after 1914, his work was widely known. In the 1930s, Albert Szent-Gyorgyi, following Kochs ideas about electrons in cells, interacting with free radicals, began working on the links between electronic energy and cellular movement. Since free (or relatively free) electrons absorb light, Szent-Gyorgyi worked with many colorful substances. When he came to the US in 1947, and wanted to expand his research, a team of professors from Harvard investigated, and told the government funding agency that his work didnt deserve support. For the rest of his life, he worked on related ideas, expanding ideas that Koch had first developed.

Emodin and the anthraquinones (and naphthoquinones, such as lapachone) werent the reagents that Koch considered the most powerful, but emodin can produce to some degree all of the effects that he believed could be achieved by correcting the cellular respiratory apparatus: Antiinflammatory, antifibrotic (Wang, et al., 2007) antiviral, antidepressant, heart protective, antioxidant, memory enhancing, anticancer, anxiolytic and possibly antipsychotic.

Working backward from these effects, we get a better perspective on the laxative function of emodin and cascara. Koch and Szent-Gyorgyi believed that cellular movement and secretion were electronically regulated. In one of his demonstrations, Szent-Gyorgyi showed that muscles could be caused to contract when they were exposed to two substances which, when combined, partially exchange an electron, causing an intense color reaction, but without causing an ordinary chemical (oxidation-reduction) reaction. This kind of reaction is called a Donor-Acceptor reaction, and it is closely related to the phenomenon of semiconduction. The reacting molecules have to be exactly tuned to each other, allowing an electron to resonate between the molecules.

In a muscle, any D-A matched pair of molecules would cause a contraction, but the same molecules, combined in pairs that werent exactly tuned to each other, failed to cause contraction. Szent-Gyorgyi believed that biological signal substances operated in a similar way, by adjusting the electronic balance of cellular proteins.

An effective laxative (besides preventing inflammation) causes not only coordinated contraction of the smooth muscles of the intestine, but also adjusts secretions and absorption, so that an appropriate amount of fluid stays in the intestine, and the cells of the intestine dont become water-logged.

In the presence of bacterial endotoxin, respiratory energy production fails in the cells lining the intestine. Nitric oxide is probably the main mediator of this effect.
The shift from respiration to glycolysis, from producing carbon dioxide to producing lactic acid, involves a global change in cell functions, away from specialized differentiated functioning, toward defensive and inflammatory processes.

This global change involves a change in the physical properties of the cytoplasm, causing a tendency to swell, and to admit dissolved substances that normally wouldnt enter the cells.
The interface between the cells lining the intestine and the bacteria-rich environment involves processes similar to those in cells at other interfacial situations throughout the body--kidney, bladder, secretory membranes of glands, capillary cells, etc. The failure of the intestinal barrier is especially dangerous, because of the generalized toxic consequences, but the principles of maintaining and restoring it are general, and they have to do with the nature of life.

Some leakage from the lumen of the intestine or the lumen of a blood vessel can occur between cells, but it is often claimed that the paracellular route accounts for all leakage. (Anthraquinones may inhibit paracellular leakage [Karbach & Wanitschke, 1984].) When a cell is inflamed or overstimulated or fatigued, its cytoplasmic contents leak out. In that state, its barrier function is weakened, and external material can leak in. This was demonstrated long ago by Nasonov, but the membrane doctrine is incompatible with the facts, so the paracellular route is claimed to explain leakage. Since the cells that form the barrier begin to form regulatory substances such as nitric oxide when they are exposed to endotoxin, it is clear that major metabolic and energetic changes coincide in the cell with the observed leakiness. Permeability varies with the nature of the substance, its oil and water solubility, and the direction of its movement, arguing clearly that it isnt a matter of mere holes between cells.

Besides endotoxin, estrogen, vibrational injury, radiation, aging, cold, and hypoosmolarity, increase NO synthesis and release, and increase cellular permeabilities throughout the body.
Estrogen excess (relative to progesterone and androgens), as in pregnancy, stress, and aging, reduces intestinal motility, probably by increasing nitric oxide production. The anthraquinones inhibit the formation of nitric oxide, which is constantly being promoted by endotoxin.

Cells regulate their water content holistically, and, to a great extent, autonomously, by adjusting their structural proteins and their metabolism, but in the process they communicate with surrounding cells and with the organism as a whole, and consequently they will receive various materials needed to improve their stability, by adjusting their energy production, sensitivity, and structural composition.

When these intrinsic corrective processes are inadequate, as in hypothyroidism, with increased estrogen and serotonin, extrinsic factors, including special foods and drugs, can reinforce the adaptive mechanisms. These adaptogens can sometimes restore the system to perfect functioning, other times they can merely prevent further injury. Sometimes the adaptogens are exactly like those the body normally has, but that are needed in larger amounts during stress. Coenzyme Q₁₀, vitamin K, short-chain fatty acids, ketoacids, niacinamide, and glycine are examples of this sort--they are always present, but increased amounts can improve resistance to stress.

Another kind of adaptogen resembles the bodys intrinsic defensive substances, but isnt produced in significant quantities in our bodies. This type includes caffeine and the anthraquinones (such as emodin) and aspirin and other protective substances from plants. These overlap in functions with some of our intrinsic regulatory substances, and can also complement each others effects.

Emodin inhibits the formation of nitric oxide, increases mitochondrial respiration, inhibits angiogenesis and invasiveness, inhibits fatty acid synthase (Zhang, et al., 2002), inhibits HER-2 neu and tyrosine phosphorylases (Zhang, et al., 1995, 1999), and promotes cellular differentiation in cancer cells (Zhang, et al., 1995). The anthraquinones, like other antiinflammatory substances, reduce leakage from blood vessels, but they also reduce the absorption of water from the intestine. Reduced water absorption can be seen in a slight shrinkage of cells in certain circumsstances, and is probably related to their promotion of cellular differentiation.

All of these are basic antistress mechanisms, suggesting that emodin and the antiinflammatory anthraquinones are providing something central to the life process itself.

Zelnorm was said to act like serotonin. Serotonin slows metabolism, reduces oxygen consumption, and increases free radicals such as superoxide and nitric oxide; the production of reactive oxygen species is probably an essential part of its normal function. Emodin has an opposing effect, increasing the metabolic rate. It increases mitochondrial oxygen consumption and ATP synthesis, while decreasing oxidative damage (Du and Ko, 2005, 2006; Huang, et al., 1995).

The Zelnorm episode was just an isolated case of a drug companys exploiting cultural beliefs, with the FDA providing a defensive framework, but the contrast between tegaserod and emodin hints at a deeper and more deadly problem.

W.F. Kochs approach to immunity emphasized the role of energy in maintaining the coherence of the organism, in which toxins were oxidized and made nontoxic. There was no emphasis on destruction either of bacteria or of cancer cells, but only of the toxic factors that interfered with respiration. He demonstrated that the udders of healthy cows could contain more bacteria than those with mastitis, but the bacterial toxins were absent after the cows were treated with his catalyst. He identified the activated carbonyl group as the essential feature of antibiotics, the same group that makes coenzyme Q₁₀ function in the respiratory system.

Kochs understanding of the oxidative apparatus of life, as a matter of electron balances, involved the idea that molecules with a low ionization potential, making them good electron donors, amines specifically, interfered with respiration, while quinones, with a high affinity for electrons, making them electron acceptors, activated respiration. The toxic effects of tryptophan derivatives, indoles, and other amines related to the behavior of their electrons. (Serotonin wasnt known at the time Koch was doing his basic research.) Koch believed that similar electronic functions were responsible for the effects of viruses.

Both chemical and physical interactions of substances cause electrons to shift in each substance, according to its composition. The shift of electrons accounts for the ability of adsorbed molecules or ions to form multiple layers on a surface, and changes in the electrons of a complex biological molecule affect the shape and function not only of that molecule, but of the molecules associated with it. Interactions of the large molecules of cells, and their adsorbed substances, tend toward stable arrangements, or phases. The type of energy production, and the nature of the regulatory molecules that are present, influence the stability of the various states of an organisms cells. (For more information on cooperative adsorption, see www.gilbertling.org.)

Koch and Szent-Gyorgyi were applying to biology and medicine concepts that were simultaneously being developed in metallurgy, electrochemistry, colloid and surface science, and electronics. They were in the scientific mainstream, and it was the medical-pharmaceutical industry that moved away from this kind of exploration of the interactions of substances, electrons, and organisms.

For Koch, antibiotics and anticancer agents werent necessarily distinct from each other, and would be expected to have other beneficial effects as well.

But an entirely different view of the immune system was taking over the medical culture just as Koch began his research. Mechnikovs morphogenic view, in which the essential function of the immune system was to maintain the integrity of the organism, was submerged by Ehrlichs approach, which emphasized killing pathogens, and at the same time, the genetic theory of cancer was replacing the developmental-environmental theory.

Following the early work on the carcinogenicity of estrogens, and the estrogenicity of carcinogens such as polycyclic aromatic hydrocarbons from soot, a few German and French chemists (e.g., Schmidt and the Pullmans) began calculating the high electron densities of highly reactive regions of the anthracene molecule, showing formally why certain molecules are carcinogenic.

At that time, their work was compatible with a developmental view of cancer. But the fact that the polycyclic molecules could interact with the new model of the DNA gene caused the Pullmans work to be reduced to nothing but a minor theory of mutagenesis.

Anthraquinones, because of the presence of several oxygen molecules, had low electron densities and were stable. The tetracyclines, with related structure, have some similar properties, and are antiinflammatory, as well as antibiotic.

When a polycyclic bacterial antibiotic, adriamycyn (later called doxorubicin), was found to be too toxic to use as an antibiotic, the fact that it was toxic to cancer cells caused it to be developed as a cancer drug. It continued to be widely used even after it was found to cause heart failure in many of the cured patients, because of its success in killing cancer cells.

The fact that many kinds of cancer cells can be killed by emodin makes it slightly interesting as a cancer drug, but its simple generic nature has caused the drug industry to look for a more Ehrlichian magic bullet; for example, they are still looking for ways to keep doxorubicin from destroying the heart.

Emodin isnt a magic bullet (in fact it isnt a bullet/toxin of any sort), but when combined with all the other adaptogens, it does have a place in cancer therapy, as well as in treating many other ailments.

None of the basic metaphors of mainstream medicine--receptors, lock-and-key, membrane pores and pumps--can account for the laxative, anticancer, cell-protective effects of emodin. The new interest in it provides an opportunity to continue to investigate the effects of adjusting the electrical state of the cell substance, building on the foundations created by William F. Koch, Albert Szent-Gyorgyi, and Gilbert Ling.

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Osteoporosis, aging, tissue renewal, and product science

The incidence of osteoporosis, like obesity, has been increasing in recent decades. The number of hip fractures in many countries has doubled in the last 30 or 40 years (Bergstrom, et al., 2009). An exception to that trend was Australia in the period between 2001 and 2006, where the annual incidence of hip fractures in women over 60 years old decreased by 28.3%. During those years, the number of prescriptions for "hormone replacement therapy" decreased by 54.6%, and the number of prescriptions for bisphosphonate increased by 245%. The publication of the Women's Health Initiative results in 2002 (showing that the Prem-Pro treatment caused breast cancer, heart attacks, and dementia), led to a great decrease in the use of estrogen treatments everywhere.
After the FDA approved estrogen's use in 1972 for the prevention of osteoporosis the number of women using it increased greatly, and by 1994, 44% of women in the US had used it. After the WHI results were published, the number of prescriptions for "HRT" fell by more than half, and following that decrease in estrogen sales, the incidence of breast cancer decreased by 9% in women between the ages of 50 and 54.
With the incidence of hip fractures increasing while the percentage of women using estrogen was increasing, it seems likely that there is something wrong with the theory that osteoporosis is caused by an estrogen deficiency. That theory was derived from the theory that menopause was the consequence of ovarian failure, resulting from the failure to ovulate and produce estrogen when the supply of eggs was depleted. The theory was never more than an ideological preference, but the estrogen industry saw it as an opportunity to create a huge market.
There are many studies that seem to imply that the greater incidence of osteoporotic fractures among women is the result of their exposure to estrogen during their reproductive years. This would be analogous to the understanding that it is the cumulative exposure to estrogen that ages the nerves in the hypothalamus that control the cyclic release of the gonadotropic hormones, causing the menopause.
. . . the nature of science itself changed around the middle of the last century, becoming product and disease oriented, so that now relatively few people are continuing to study bones objectively.
Animal studies show that estrogen stunts growth, including bone growth. The high estrogen levels in girls' teen years and early twenties accounts for the fact that women's bones are lighter than men's. In rat studies, treatment with estrogen was found to enlarge the space between the jawbone and the teeth, which is a factor in periodontal disease (Elzay, 1964). Teeth are very similar to bones, so it's interesting that treating male or female rats with estrogen increases their incidence of tooth decay, and removing their gonads was found to decrease the incidence (Muhler and Shafer, 1952). Supplementing them with thyroid hormone decreased the incidence of cavities in both males and females (Bixler, et al., 1957).
One of the "estrogen receptors" appears to actively contribute to bone loss (Windahl, et al., 1999, 2001). Studies in dogs following the removal of their ovaries found that there was an increase of bone remodeling and bone formation rate in the first month, followed by a few months of slowed bone formation, but that by 10 months after the surgery the bones had returned to their normal remodeling rate, and that "at no time was a significant reduction in bone volume detected" (Boyce, et al., 1990). With the removal of the ovaries, the production of progesterone as well as estrogen is affected, but the adrenal glands and other tissues can produce those hormones.
Until the influence of the estrogen industry overwhelmed it, ordinary science was studying bone development in comprehensive ways, understanding its biological roles and the influences of the environment on it. But the nature of science itself changed around the middle of the last century, becoming product and disease oriented, so that now relatively few people are continuing to study bones objectively.
The outstanding physical-chemical property of bone is that it is a reservoir-buffer of carbon dioxide, able to bind huge amounts of the gas into its structure.
When carbon dioxide increases in the bloodstream it is at first absorbed rapidly by the bones, and if the blood level of CO2 is kept high day after day, the rate of absorption gradually slows down, but in experiments that have continued for several weeks the bones were still slowly absorbing more carbon dioxide; the absorption curve seems to be asymptotic. When people move to or from high altitudes, their bones appear to continue adapting to the different gas pressures for years. A reduction of atmospheric pressure (which allows the tissues to retain more carbon dioxide) helps to reduce the calcium loss caused by immobility (Litovka and Berezovs'ka, 2003; Berezovs'kyi, et al., 2000), and promotes the healing of damaged bone (Bouletreau, et al., 2002). Ultrasound treatment, which accelerates bone healing, stimulates processes similar to reduced oxygen supply (Tang, et al., 2007).
The mineral in newly formed bone is calcium carbonate, and this is gradually changed to include a large amount of calcium phosphate. Besides forming part of the mineral, carbon dioxide is also incorporated into a protein (in a process requiring vitamin K), in a process that causes this protein, osteocalcin, to bind calcium. The osteocalcin protein is firmly bonded to a collagen molecule. Collagen forms about 30% of the mass of bone; several percent of the bone consists of other organic molecules, including osteocalcin, and the rest of the mass of the bone consists of mineral.
Thyroid hormone is essential for forming carbon dioxide. In the early 1940s, experimental rabbits were fed their standard diet, with the addition of 1% desiccated thyroid gland, which would be equivalent to about 150 grains of Armour thyroid for a person. They became extremely hypermetabolic, and couldn't eat enough to meet their nutritional needs for growth and tissue maintenance. When they died, all of their tissues weighed much less than those of animals that hadn't received the toxic dose of thyroid, except for their bones, which were larger than normal. Experiments with the thin skull bones of mice have shown that the active thyroid hormone, T3, increases the formation of bone. To increase cellular respiration and carbon dioxide production, T3 increases the activity of the enzyme cytochrome oxidase, which uses copper as a co-factor. Increased thyroid activity increases the absorption of copper from foods.
There is an inherited condition in humans, called osteopetrosis or marble bone disease, caused by lack of a carbonic anhydrase enzyme, which causes them to retain a very high level of carbon dioxide in their tissues. Using a chemical that inhibits carbonic anhydrase, such as the diuretic acetazolamide, a similar condition can be produced in animals. Acetazolamide inhibits the bone resorbing actions of parathyroid hormone, including lactic acid formation and the release of the lysosomal enzyme, beta-glucuronidase (Hall and Kenny, 1987).
While lactic acidosis causes bone loss, acidosis caused by increased carbonic acid doesn't; low bicarbonate in the body fluids seems to remove carbonate from the bone (Bushinsky, et al., 1993), and also mineral phosphates (Bushinsky, et al., 2003). The parathyroid hormone, which removes calcium from bone, causes lactic acid to be formed by bone cells (Nijweide, et al., 1981; Lafeber, et al., 1986). Lactic acid produced by intense exercise causes calcium loss from bone (Ashizawa, et al., 1997), and sodium bicarbonate increases calcium retention by bone. Vitamin K2 (Yamaguchi, et al., 2003) blocks the removal of calcium from bone caused by parathyroid hormone and prostaglandin E2, by completely blocking their stimulation of lactic acid production by bone tissues. Aspirin, which, like vitamin K, supports cell respiration and inhibits lactic acid formation, also favors bone calcification. Vitamin K2 stimulates the formation of two important bone proteins, osteocalcin and osteonectin (Bunyaratavej, et al., 2009), and reduces the activity of estrogen by oxidizing estradiol (Otsuka, et al, 2005).
The formation of eggshell, which is mostly calcium carbonate, is analogous to the early stage of bone formation. In hot weather, when chickens pant and lower their carbon dioxide, they form thin shells. A sodium bicarbonate supplement improves the quality of the eggshell (Balnave and Muheereza, 1997; Makled and Charles, 1987). Chickens that habitually lay eggs with thinner shells have lower blood bicarbonate than those that lay thick shelled eggs (Wideman and Buss, 1985).
One of the arguments for stopping the sale of DDT in the US was that it was threatening to cause extinction of various species of bird because it caused them to lay eggs with very weak shells. Several other synthetic estrogenic substances, ethynylestradiol, lindane, PCBs, cause eggshell thinning, partly by altering carbonic anhydrase activity (Holm, et al, 2006). Estrogen and serotonin activate carbonic anhydrase in some tissues, progesterone tends to inhibit it. DDE, a metabolite of DDT, reduces medullary bone formation in birds (Oestricher, et al., 1971) and bone mineral density in men (Glynn, et al., 2000). Among its estrogenic effects, DDE increases prolactin (Watson, et al., 2007); one form of DDT inhibits progesterone synthesis and increases estrogen (Wojtowics, et al., 2007)
In youth, the mineralization of the collagen framework is slightly lower than in maturity, and the bones are more flexible. With aging, the mineralization increases progressively, and the proportion of collagen decreases slightly, and the bones become increasingly brittle. (Rogers, et al., 1952; Mbuyi-Muamba, et al., 1987).
Collagen is a major part of the extracellular substance everywhere in the body, and its concentration increases with aging in the non-calcified tissues. There is considerable renewal and modification of collagen, as new molecules are formed and old molecules broken down, but its average structure changes with aging, becomes less soluble and more rigid, as the result of chemical cross-links formed between molecules. These cross-links are involved in regulating the differentiation of bone cells (Turecek, et al., 2008). Recently (August 2, 2011), Deasey et al., have published evidence showing that cross-linking is required for bone mineralization (2011).
The outstanding physical-chemical property of bone is that it is a reservoir-buffer of carbon dioxide, able to bind huge amounts of the gas into its structure.
Around 1950, Fritz Verzar began studying the changes of collagen that occur with aging, and his work led to the "collagen theory of aging." He showed that older, stiffer, less elastic tendons have a higher "melting" or contracting temperature than young tendons. (This effect is responsible for the curling of a piece of meat when it is frying.)
Verzar and his colleagues investigated the effects of hormonal treatments on the aging of rat collagen, especially in their tail tendons. They found that estrogen treatment increased the stiffness and the melting temperature of collagenous tissues. While estrogen increased the cross-linking with aging, removing the pituitary gland was found to retard the aging.
Later, the cross-linking enzymes transglutaminase and lysyl oxidase, which are induced by estrogen, were found to be a major factor in the cross-linking of collagen and other molecules.
When estrogen was found to age the connective tissues, it was assumed that continual breeding during an animal's life-time, greatly increasing the total exposure of the tissues to estrogen, would increase the aged rigidity of the connective tissues, but these animals were found to have less rigid tissues. During pregnancy other hormones, especially progesterone, were also increased, and it was suggested that this reversed the effects of aging and estrogen. Since most people had believed that frequent pregnancies would cause a woman to age more rapidly, a large survey of records was done, to compare the longevity of women with the number of pregnancies. It was found, in the very extensive Hungarian records, that life-span was increased in proportion to the number of pregnancies.
Despite these very interesting results in the 1950s and 1960s, the growing influence of the estrogen industry changed the direction of aging research, favoring the belief that decreasing estrogen accelerated the deterioration of tissues in aging, and the popularity of Denham Harman's "free radical theory of aging" led many people to assume that random reactions produced by lipid peroxidation were responsible for most of the cross-linking, and that theory was gradually replaced by the "glycation" theory of aging, in which sugar molecules break down and form the cross-links, by random, non-enzymic processes. Estrogen's role in aging was completely by-passed.
The meat industry is interested in reducing the toughness of meat, by influencing the nature of the collagen in muscle. Castrated animals were found to produce meat that was tenderer than that of intact males. When castrated animals were treated with testosterone, the amount of collagen was increased, making the meat tougher. But when dihydrotestoserone, which can't be converted to estrogen was used, the meat didn't become tough. Treatment with estrogen produced the same increase of collagen as treatment with testosterone, showing that testosterone's effect was mainly the result of its conversion to estrogen (Miller, et al., 1990).
In the 1960s and '70s the estrogen industry was looking for ways to build on the knowledge that in puberty estrogen is responsible for accelerating the calcification of the growth plate at the ends of the long bones, and to find a rationale for selling estrogen to all women concerned with the problems of aging. As bone metabolism was investigated, two kinds of cell were found to be active in constantly remodeling the bone structure: Osteoclasts (breaking it down), and osteoblasts (building new bone). Estrogen was found to slow the actions of the osteoclasts, so the idea that it would delay osteoporosis became the basis for a huge new marketing campaign. Slowing bone metabolism became the focus. Although estrogen was known to increase prolactin, and prolactin was known to accelerate bone loss, nearly all publications began to focus on substances in the blood or urine that corresponded to the rate of bone turnover, with the implication that increasing bone turnover would correspond to a net loss of bone.
This was the context in which, during the 1980s, articles about thyroxine's role in causing osteoporosis began to appear. The thyroid hormone supports bone renewal, and increases indicators of bone breakdown in the blood and urine. If estrogen's use was to be justified by slowing bone turnover, then the effects of thyroid, accelerating bone turnover, should be interpreted as evidence of bone destruction.
A basic problem with many of the publications on thyroid and bone loss was that they were talking about an unphysiological medical practice (prescribing the pre-hormone, thyroxine), which frequently failed to improve thyroid function, and could even make it worse, by lowering the amount of T3 in the tissues.
Later, it was noticed that high TSH was associated with the signs of lower bone turnover. TSH rises when there is less thyroid hormone, but (after the recombinant TSH became available for medical use) a few publications argued that it was the TSH itself, rather than the absence of thyroid hormone, that was "protecting" the bones (lowering the evidence of bone turnover). The doctrine that had been developed to support estrogen therapy was now used to oppose thyroid therapy. Keeping the TSH high would slow bone turnover.
Working in this cultural context, genetic engineers at Amgen identified a protein that inhibited the formation of osteoclast cells, and slowed bone metabolism. It was suggested that it was responsible for estrogen's suppression of the osteoclasts, and many publications appeared showing that it was increased by estrogen. It was named "osteoprotegerin," meaning "the bone protecting protein." Prolactin increases osteoprotegerin (OPG), reducing bone resorption just as estrogen does. Serotonin also increases OPG, and it turns out that OPG is elevated in all of the pathological conditions associated with high serotonin, including cancer, pulmonary artery hypertension, vascular calcification, and even bone loss.
While Arthur Everitt, Verzar, and others were studying the effects of the rat's pituitary (and other glands) on collagen, W. D. Denckla investigated the effects of reproductive hormones and pituitary removal in a wide variety of animals, including fish and mollusks. He had noticed that reproduction in various species (e.g., salmon) was quickly followed by rapid aging and death. Removing the pituitary gland (or its equivalent) and providing thyroid hormone, he found that animals lacking the pituitary lived much longer than intact animals, and maintained a high metabolic rate. Making extracts of pituitary glands, he found a fraction (closely related to prolactin and growth hormone) that suppressed tissue oxygen consumption, and accelerated the degenerative changes of aging.
Aging, estrogen, cortisol, and a variety of stresses, including radiation and lipid peroxidation, chemically alter collagen, producing cross-links that increase its rigidity, and affect the way it binds minerals. The cross-linking enzymes induced by estrogen are involved in the normal maturation of bone collagen, and at puberty when estrogen increases, bone growth is slowed, as the cross-linking and mineralization are accelerated. With aging and the accumulation of heavy metals and polyunsaturated fats, random oxidative processes increase the cross-linking. In bones, the relatively large masses of cartilage absorb oxygen and nutrients slowly, so internally the amount of oxygen is very limited, about 1/5 as much as at the surface, and this low oxygen tension is an important factor in regulating growth, differentiation, cross-linking, and calcification, maintaining bone integrity. But in blood vessels the connective tissues are abundantly supplied with oxygen and nutrients; this is normally a factor regulating the production of collagen and its cross-linking, and preventing calcification.
When the factors promoting collagen synthesis and maturation are increased systemically, with aging and stress, the excess cross-linking slows the biological renewal process in bones, but in blood vessels the same processes creating excess cross-linking initiate a calcification process, involving the various factors that in youth are responsible for normal maturation of bone.
Prolactin, like estrogen, interferes with thyroid function and oxygen consumption (Wade, et al., 1986; Strizhkov, 1991; Spatling, et al., 1982). Many years ago, repeated lactation was considered to cause osteoporosis and loss of teeth, and prolactin, which mobilizes calcium from bones for the production of milk, was recognized as an important factor in bone loss. Drugs that increase prolactin were found to cause osteoporosis. In the 40 years since the drug industry began its intense promotion of estrogen to prevent and treat osteoporosis, there has been very little attention to the fact that estrogen increases prolactin, which contributes to osteoporosis, but some people (e.g., Horner, 2009) have noticed that oral contraceptives and menopausal hormone treatments have damaged the bones of the inner ear, causing otosclerosis and impaired hearing, and have suggested that prolactin mediates the effect.
A few years ago, the "serotonin reuptake inhibitor" antidepressants, already known to increase prolactin by increasing the effects of serotonin, were found to be causing osteoporosis after prolonged use. Estrogen increases serotonin, which besides promoting the secretion of prolactin, also stimulates the production of parathyroid hormone and cortisol, both of which remove calcium from bone, and contribute to the calcification of blood vessels. The association between weakened bones and hardened arteries is now widely recognized, but researchers are being careful to avoid investigating any mechanisms that could affect sales of important drug products, especially estrogen and antidepressants.
Following the recognition that the SSRI drugs were causing osteoporosis, it was discovered that the serotonin produced in the intestine causes bone loss, and that inhibiting intestinal serotonin synthesis would stop bone loss and produce a bone building anabolic effect (Inose, et al., 2011). One group that had been concentrating on the interactions of genes commented that, recognizing the effects of intestinal serotonin, they had suddenly become aware of "whole organism physiology" (Karsenty and Gershon, 2011).
In previous newsletters I have talked about the ability of intestinal irritation and the associated increase of serotonin to cause headaches, asthma, coughing, heart and blood vessel disease, muscular dystrophy, flu-like symptoms, arthritis, inflammation of muscles and nerves, depression, and inflammatory brain diseases. With the new recognition that serotonin is a basic cause of osteoporosis, intestinal health becomes a major issue in aging research.
The protein that inhibits intestinal formation of serotonin is the low density lipoprotein receptor-related protein. This seems likely to have something to do with the fact that "low" HDL is associated with better bones. A low level of LDL is associated with increased vertebral fractures (Kaji, et al., 2010).
Cartilage synthesis and turnover are highest at night. It is inhibited by metabolic acidosis (increased lactic acid), but not by respiratory acidosis (CO2) (Bushinsky, 1995). Since most calcium is lost from bone during the night (Eastell, et al., 1992; even in children: DeSanto, et al., 1988) in association with the nocturnal rise of the catabolic substances, such as free fatty acids, cortisol, prolactin, PTH, and adrenalin, things which minimize the nocturnal stress can decrease the bone turnover. These include calcium (Blumsohn, et al., 1994) and sugar. Catabolic substances and processes increase with aging, especially at night. Babies grow most during the night when bone turnover is high, and even a daytime nap accelerates collagen turnover (Lutchman, et al., 1998).
Discussions about whether a certain person's osteoporosis is "menopausal osteoporosis" or "senile osteoporosis" have neglected the possibility that osteoporosis doesn't begin in either menopause or old age, but that it is the result of life-long developmental processes that interact with all the factors that are involved in aging. The fact that the collagen content of old bone is lower than in young bone (as a percentage of bone weight) shows that the problem in osteoporosis isn't a lack of calcification, it's a deficiency of tissue renewal, parallel to sarcopenia, the decrease of muscle mass with aging. Systemically decreased tissue renewal would account for the association of bone loss with other processes such as male baldness (Morton, et al., 2007) and Alzheimer's disease (Zhou, et al., 2011, Duthie, et al., 2011).
A high level of respiratory energy production that characterizes young life is needed for tissue renewal. The accumulation of factors that impair mitochondrial respiration leads to increasing production of stress factors, that are needed for survival when the organism isn't able to simply produce energetic new tissue as needed. Continually resorting to these substances progressively reshapes the organism, but the investment in short-term survival, without eliminating the problematic factors, tends to exacerbate the basic energy problem. This seems to be the reason that Denckla's animals, deprived of their pituitary glands, but provided with thyroid hormone, lived so long: they weren't able to mobilize the multiple defenses that reduce the mitochondria's respiratory energy production.
Several things that the geneticists would never be able to fit into their schemes of "bone regulatory molecules" such as OPG, growth hormone, parathyroid hormone, and estrogen, fit neatly with the idea that bone health is maintained by respiratory energy and tissue renewal, under the influence of thyroid hormone. For example, adrenaline, which is increased by stress, aging, and hypothyroidism (and in many cases by estrogen), causes bone loss. Even the bone loss caused by immobility can be blocked by an adrenaline blocker such as propranolol. (The stress of immobility also famously increases serotonin.) Adrenaline tends to decrease carbon dioxide and increase lactic acid, and it strongly increases parathyroid hormone (Ljunhgall S, et al., 1984).
Calcium activates mitochondrial respiration, and lowers adrenaline (Luft, et al., 1988), parathyroid hormone (Ohgitani, et al., 1997), and prolactin (Kruse and Kracht, 1981). Copper, which is the co-factor for the cytochrome C oxidase enzyme, activated by thyroid, is essential for bone formation and maintenance, and is consistently deficient in osteoporosis. Thyroid hormone increases the body's ability to assimilate copper.
Aspirin, which stimulates bone formation, has other thyroid-like actions, including activation of mitochondrial respiration and energy production, with an increase of cytochrome C oxidase (Cai, et al., 1996), and it lowers serotonin (Shen, et al., 2011). It also apparently protects against calcification of the soft tissues, (Vasudev, et al., 2000), though there has been surprisingly little investigation of that. "Aspirin can promote trabecular bone remodeling, improve three-dimensional structure of trabecular bone and increase bone density of cancellous in osteoporotic rats by stimulating bone formation. It may become a new drug for the treatment of osteoporosis" (Chen, et al., 2011).
A wide range of inflammatory mediators that accelerate inflammation and bone loss also inhibit thyroid function. People who ate more polyunsaturated fat, which inhibits thyroid and oxidative metabolism, were several times more likely to have osteoporotic fractures (that is, essentially spontaneous fractures) than people who ate the least (Martinez-Ramirez, et al., 2007).
Arachidonic acid stimulates prolactin secretion, and prolactin acts on the thyroid gland to decrease its activity, and on other tissues to increase their glycolysis (with lactate production), while decreasing oxidative metabolism (Spatling, et al., 1982; Strizhkov, 1991).
Living at high altitude, which strengthens bones, increases thyroid activity and decreases prolactin (Richalet, et al., 2010) and parathyroid hormone (Khan, et al., 1996). It lowers free fatty acids, which lower bone mass by reducing bone formation and increasing bone resorption (Chen, et al., 2010). In menopausal women, polyunsaturated fatty acids and even monounsaturated fats are associated with bone loss, fruit and vegetable consumption protects against bone loss (Macdonald, et al., 2004).
While it's very interesting that the drug propranol which blocks adrenaline, and drugs that block serotonin formation, have bone protective and restorative effects, they also have undesirable side effects. Food choices that optimize oxidative metabolism are the safest, as well as the most economical, way to approach the problem of osteoporosis and other degenerative changes. A person can easily perceive changes in appetite, quality of sleep, changes in skin, hair, and mood, etc., but blood tests could be used to confirm that the right choices were being made. Tests for vitamin D, parathyroid hormone, free fatty acids, and CO2/bicarbonate, as well as the hormones, can be helpful, if a person isn't sure whether their diet, sunlight exposure, and thyroid supplementation is adequate.
The popular medical understanding of the organism is based on a mechanistic view of causality, in which genes have a central role, causing things to develop and function in certain ways, and that hormones and drugs can cause genes to increase or decrease their activity. Genes that build bones can be activated by one substance, and genes that tear down bones can be inhibited by another substance. The "osteoprotegerin" story illustrates the problem with that kind of thinking.
Vernadsky's description of an organism as a "whirlwind of atoms" is probably a better way to think of how "causality" works. The moving air in a whirlwind forms a self-intensifying system, with the motion reducing the pressure, causing more air to be drawn into the system. The atoms moving in coordination aren't acting as separate things, but as parts in a larger thing. The way in which increased metabolism in the bones acts favorably on the metabolism of kidneys, blood vessels, lungs, liver, digestive system, etc., which in turn favors the bones' renewal, is analogous to the tendency of a whirlwind to intensify as long as there is a source of energy. The intensity of oxidative metabolism is the basic factor that permits continuing coordination of activity, and the harmonious renewal of all the components of the organism.

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A R T I C L E

Regeneration and degeneration:
Types of inflammation change with aging

For about 100 years it has been popular to explain the degenerative diseases as the result of mutations in the genes, a slow accumulation of somatic mutations, as opposed to the germ cell mutations that are involved in Huntingtons chorea and sickle cell anemia. Some people explained all the changes of aging on the same basis, but 50 years ago, the somatic mutation theory of aging was clearly shown to be false. The gene-mutation theory of cancer is more persistent, but the work of people like Harry Rubin has made it clear that functional changes in cells that are becoming cancerous destabilize the chromosomes and cause defects to appear in the genes, rather than the reverse.

Older ways of understanding aging and degenerative disease are now returning to the foreground. The developmental interactions of the organism with its environment, and the interactions of its cells, tissues, and organs with each other, have again become the focus of biological aging research. In place of the old belief that we are defined and limited by our genes, the new perspective is showing us that we are limited by our environment, and that our environment can be modified. As we react to unsuitable environments, our internal environments become limiting for our cells, and instead of renewing themselves, repairing damage, and preparing for new challenges, our cells find themselves in blind alleys. Looking at aging in this way suggests that putting ourselves into the right environments could prevent aging.

A bird developing inside its eggshell illustrates the way organs and the environment interact. The chicken created a very good environment for the early development of its young. When the egg is formed, it contains everything needed to produce a chicken, except for oxygen and a steady warm temperature. But before the chicks body has finished developing, using yolk fat for energy, the glucose contained in the egg has been consumed, and at that point the chicks brain stops growing. A researcher who knew that brain growth in other kinds of animals requires glucose, injected glucose (or glycine) into the developing eggs when the original glucose had been depleted. The supplemental glucose allowed the chicks brain to continue growing until it hatched. These chicks had larger brains, containing more numerous cells. The same experimenters also found that progesterone increases brain size, while corticosterone decreases it. Although the egg is a very good environment for the development of chickens, these experiments showed that it isnt the best that can be achieved. If the hens environment had been different, it might have been able to provide as much glucose and progesterone as the experimenters did.

Mammals were able to develop bigger brains than birds, by gestating their offspring internally, allowing a continuous supply of nutrients, such as glucose, and hormones such as progesterone. But the environment of the mother still can profoundly affect the development of the offspring, by influencing her physiology.

Another factor involved in developing a large brain is the metabolic rate, which is closely associated with the temperature. Birds have larger brains relative to their bodies than reptiles do, and birds maintain a consistently high body temperature, sometimes as high as 110 degrees F, while reptiles temperature varies somewhat according to the temperature of their surroundings and their level of activity. Amphibians have much lower metabolic rates, and are generally unable to live at the higher temperatures required by reptiles.

The high metabolic rate of a bird, combined with its development inside an egg, means that compromises are made. The high rate of metabolism uses the stored energy rapidly, so the growth of the brain is limited. But their very high body temperature maximizes the effectiveness of that brain. Birds, such as owls, parrots, and crows, that hatch in a less developed, more dependent condition, are able to continue their brain growth, and have larger brains than other birds, such as chickens. In birds and mammals, longevity generally corresponds to brain size and metabolic rate. (For example, a pet crow, Tata, died at the age of 59 in 2006 in New York; parrots sometimes live more than 100 years.) These (altricious) birds are the opposite of precocious, they preserve embryonic or infantile traits into adulthood.

For whole organisms or for single cells, development depends on the adequacy of the environment. Temperature and the quality of nourishment are important, and by thinking about the other special features of the growth processes during gestation, we might be able to find that some of the compromises that are customarily made in our more mature lives arent necessary.
One way of looking at aging is that its a failure of regeneration or healing, related to changes in the nature of inflammation.

In childhood, wounds heal quickly, and inflammation is quickly resolved; in extreme old age, or during extreme stress or starvation, wound healing is much slower, and the nature of the inflammation and wound closure is different. In the fetus, healing can be regenerative and scarless, for example allowing a cleft palate to be surgically corrected without scars (Weinzweig, et al., 2002).

Fifty years ago, inflammation was seen as a necessary part of the healing process, but now it is recognized as a cause of heart disease, diabetes, cancer, and aging itself. During the development of the organism, the nature of healing changes, as the nature of inflammation changes. Early in life, healing is regenerative or restorative, and there is little inflammation. In adulthood as the amount of inflammation increases, healing fails to completely restore lost structures and functions, resulting in scarring, the replacement of functional tissue with fibrous tissue. Identifiable changes in the nature of inflammation under different conditions can explain some of these losses of healing capacity. Factors that limit inflammation and fibrosis, while permitting tissue remodeling, could facilitate regeneration and retard aging.

Several cytokines (proteins that regulate cell functions) appear at much higher concentrations in adult tissues than in fetal tissues (PDGF A, three forms of TGF, IGF 1, and bFGF; Wagner, et al., 2007), and when one of these (TGF-beta1) is added to the healing fetus, it produces inflammation and fibrosis (Lanning, et al., 1999). Two prostaglandins, PGE2 and PGF2a, potently produce inflammation in fetal rabbits, but not in adult rabbits. (Morykwas, et al., 1994).

Tissue injury that would produce inflammation in adults causes other signals in the fetus that activate repair processes. When a cell is injured or stressed, for example when deprived of oxygen, it becomes incontinent, and releases ATP into its surroundings. The extracellular ATP, and its breakdown products, ADP, AMP, adenosine, and inorganic phosphate or pyrophosphate, stimulate cells in various ways. ATP causes vasodilation, increasing circulation, and usually signals cells to divide, and can activate stem cells (Yu, et al., 2010) The lactic acid produced by distressed cells also has signalling effects, including vasodilation and stimulated division. Stressed cells digest their own proteins and other structural materials (autophagy), and the breakdown products act as signals to guide the differentiation of their replacement cells. Mobile phagocytes, ingesting the material of decomposing cells, are essential for guiding tissue restoration.

In adults, prostaglandins are known to be involved in many of the harmful effects of inflammation. They are formed from the polyunsaturated fats, linoleic acid and arachidonic acid, which we are unable to synthesize ourselves, so the adults exposure to the prostaglandins is influence by diet. Since the fetus is able to synthesize fat from glucose, the newborn animal usually contains a high proportion of saturated fats and their derivatives, such as stearic acid, oleic acid, and Mead acid, which can be synthesized from glucose or amino acids. Newborn calves have very little polyunsaturated fat in their tissues, but even the small percentage of PUFA in milk causes its tissues to gradually accumulate a higher percentage of PUFA as it matures. The fatty acids of newborn humans, and other non-ruminants, reflect their mothers diets more closely, but Mead acid is still present in human newborns (Al, et al., 1990). In a study of prenatal learning (habituation rate), the experimenters found that the relative absence of the supposedly essential fatty acids improved the short term and long term memory of the fetus (Dirix, et al., 2009). The size of the baby was found to be negatively associated with the highly unsaturated fatty acids DHA and AA (Dirix, et al., 2009), showing a general growth-retarding effect of these environmentally derived fats.

The embryo or fetus is enclosed in a germ-free environment, so it doesnt need an immune system in the ordinary sense, but it does contain phagocytes, which are an essential part of development, in the embryo, as well as in the adult (Bukovky, et al., 2000). They are involved in removing malignant cells, healing wounds, and remodeling tissues. In adults, the long-chain omega-3 fatty acids such as DHA are known to be immunosuppressive, but in tests on monocytes from the umbilical cord blood of newborns, the highly unsaturated fatty acids kill the monocytes that are so important for proper development and regeneration (Sweeney, et al., 2001), and interfere with signals that govern their migration (Ferrante, et al., 1994). DHA is now being sold with many health claims, including the idea that adding it to baby formula will improve their eyesight and intelligence. As the consumption of PUFA has increased in the US and many other countries, the incidence of birth defects has increased. The formation of excessive amounts of prostaglandin, or killing macrophages, among other toxic effects, might be responsible for those visible anatomical changes during growth, as well as for the subtler loss of regenerative capacity.

In the adult, the PUFA and prostaglandins are known to increase collagen synthesis. Serotonin and estrogen, which interact closely with PUFA, promote collagen synthesis and fibrosis. In the fetus, hyaluronic acid, rather than collagen, is the main extracellular material in wound repair (Krummel, et al., 1987). Both it and its decomposition products have important regulatory signal functions in wound healing (Gao, et al., 2008), inflammation, and cell differentiation (Krasinski and Tchórzewski, 2007).

Prostaglandins also inhibit local cell division (observed in the cornea, Staatz and Van Horn, 1980), shifting responsibility for tissue repair to mobile cells, for example stem cells from the blood. PUFA also interfere with the turnover of collagen by inhibiting proteolytic enzymes that are necessary for tissue remodeling. These are among the changes that characterize scar formation, rather than the scarless regeneration that can occur in the fetus. They also occur throughout the body with aging, as part of a progressive fibrosis.

Besides minimizing dietary PUFA, other things are known that will reduce the fibrosis associated with injury, inflammation, or aging. Thyroid hormone, progesterone, and carbon dioxide all reduce inflammation while facilitating normal tissue remodeling. Fibrosis of the heart and liver, which are often considered to be unavoidably progressive, can be regressed by thyroid hormone, and various fibroses, including breast, liver, and mesentery, have been regressed by progesterone treatment.

The thyroid hormone is necessary for liver regeneration, and the ability of the thyroid gland itself to regenerate might be related to the also great ability of the adrenal cortex to regenerate--the cells of these endocrine glands are frequently stimulated, even by intrinsic factors such as T3 in the thyroid, and seem to have an intrinsic stem-cell-like quality, turning-over frequently. Secretion of stimulating substances is probably one of the functions of macrophages in these glands (Ozbek & Ozbek, 2006) The failure to recognize the glands regenerative ability leads to many inappropriate medical treatments.

The amount of disorganized fibrous material formed in injured tissue is variable, and it depends on the state of the individual, and on the particular situation of the tissue. For example, the membranes lining the mouth, and the bones and bone marrow, and the thymus gland are able to regenerate without scarring. What they have in common with each other is a relatively high ratio of carbon dioxide to oxygen. Salamanders, which are able to regenerate legs, jaw, spinal cord, retina and parts of the brain (Winklemann & Winklemann, 1970), spend most of their time under cover in burrows, which besides preventing drying of their moist skin, keeps the ratio of carbon dioxide to oxygen fairly high.

The regeneration of finger tips, including a well-formed nail if some of the base remained, will occur if the wounded end of the finger is kept enclosed, for example by putting a metal or plastic tube over the finger. The humidity keeps the wound from forming a dry scab, and the cells near the surface will consume oxygen and produce carbon dioxide, keeping the ratio of carbon dioxide to oxygen much higher than in normal uninjured tissue.

Carbon dioxide is being used increasingly to prevent inflammation and edema. For example, it can be used to prevent adhesions during abdominal surgery, and to protect the lungs during mechanical ventilation. It inhibits the formation of inflammatory cytokines and prostaglandins (Peltekova, et al., 2010, Peng, et al., 2009, Persson & van den Linden, 2009), and reduces the leakiness of the intestine (Morisaki, et al., 2009). Some experiments show that as it decreases the production of some inflammatory materials by macrophages (TNF: Lang, et al., 2005), including lactate, it causes macrophages to activate phagocytic neutrophils, and to increase their number and activity (Billert, et al., 2003, Baev & Kuprava, 1997).

Factors that are associated with a decreased level of carbon dioxide, such as excess estrogen and lactate, promote fibrosis. Adaptation to living at high altitude, which is protective against degenerative disease, involves reduced lactate formation, and increased carbon dioxide. It has been suggested that keloid formation (over-growth of scar tissue) is less frequent at high altitudes (Ranganathan, 1961), though this hasnt been carefully studied. Putting an injured arm or leg into a bag of pure carbon dioxide reduces pain and accelerates healing.

In aging, the removal of inactive cells becomes incomplete (Aprahamian, et al., 2008). It is this removal of cellular debris that is essential for regenerative healing to take place. Degenerating tissue stimulates the formation of new tissue, but this requires adequate cellular energy for phagocytosis, which requires proper thyroid function. Hyperthyroidism has been shown to accelerate the process (Lewin-Kowalik, et al., 2002). The active thyroid hormone, T3, stimulates the removal of inactive cells (Kurata, et al., 1980).

Regenerative healing also requires freedom from substances that inhibit the digestion of the debris. The great decline in proteolytic autophagy that occurs with aging (Del Roso, et al., 2003) can be reduced by inhibiting the release of fatty acids. This effect is additive to the antiaging effects of calorie restriction, suggesting that it is largely the decrease of dietary fats that makes calorie restriction effective (Donati, et al., 2004, 2008).

Niacinamide is a nutrient that inhibits the release of fatty acids, and it also activates phagocytic activity and lowers phosphate. It protects against the development of scars in spinal cord injuries, facilitates recovery from traumatic brain injury, and accelerates healing generally. While it generally supports immunity, its protective against autoimmunity. It can cause tumor cells to either mature or disintegrate, but it prolongs the replicative life of cultured cells, and protects against excitotoxicity.

The amounts needed seem large if niacinamide is thought of as vitamin B3, but it should be considered as a factor that compensates for our unphysiological exposure to inappropriate fats. Aspirin and vitamin E are other natural substances that are therapeutic in unnaturally large amounts because of our continual exposure to the highly unsaturated plant-derived n-3 and n-6 fats.

When animals are made deficient in the polyunsaturated fatty acids, their wounds heal, with normal or accelerated collagen synthesis, and with more vigorous collagen breakdown (Parnham, et al., 1977). Their blood vessels are more resistant, preventing shock that would otherwise be caused by many factors. All phases of development, from gestation to aging, are altered by the presence of the unsaturated fats, and these effects correspond closely to the loss of the regenerative capacity, the ability to replenish and restore tissues.

If the very small amounts of polyunsaturated fats reaching the fetus can retard growth and brain development (Liu and Borgman, 1977; Borgman, et al., 1975) and function, it is apparently acting on some very important biological processes. The toxic effects of PUFA seen in the animal studies probably have their equivalent in humans, for example the association of childhood hyperactivity with a smaller brain. The incidence of the attention deficit-hyperactivity disorder is increasing in the US, somewhat faster among girls than boys (Robison, et al.,2002). In schizophrenic teenagers, the brain shrinks, suggesting an interaction of the hormones of puberty with environmental toxins or deficiencies. The progressive accumulation of much larger amounts of these fats later in life, especially after the rate of growth decreases, could be expected to cause even greater interference with those processes of development and function.
All tissues age, but the brain might be the least ambiguous organ to consider. The aging brain often shrinks, and becomes more susceptible to excitotoxicity, which kills brain cells. Degenerative brain diseases, such as Huntingtons chorea and Creutzfeld-Jacob disease, have been compared to the dementia of pellagra, in which chorea and other excitatory processes are obvious. (Anti-glutamatergic drugs are beginning to be used therapeutically, to restore some inhibitory balance in the degenerating brain.)

Pellagra occurs about twice as often in women as in men, and this is because estrogen activates an enzyme that alters metabolism of tryptophan, blocking the formation of niacin. The alternative products include the excitotoxin, quinolinic acid, and some carcinogens.

Progesterone inhibits the activity of that enzyme. Progesterone also lowers brain serotonin (Izquierdo, et al., 1978), decreases the excitatory carcinogens (Moursi, et al., 1970) and increases the formation of niacin (Shibata, et al., 2003) The polyunsaturated fats, DHA, EPA, and linoleic acid activate the conversion of tryptophan to quinolinic acid (Egashira, et al., 2003, 2004), and inhibit the formation of niacin (Egashira, et al., 1995).

The normal pathway from tryptophan to niacin leads to formation of the coenzyme NAD, which is involved in a great variety of cellular processes, notably energy production, the maintenance of the cellular differentiated state by regulating gene expression, and the activity of phagocytes.
Glucose and niacinamide work very closely with each other, and with the thyroid hormone, in the maintenance and repair of cells and tissues. When one of these energy-producing factors is lacking, the changes in cell functions -- a sort of pre-inflammatory state -- activate corrective processes. Energy depletion itself is an excitatory state, that calls for increased fuel and oxygen. But when cells are exposed to PUFA, their ability to use glucose is blocked, increasing their exposure to the fats. Saturated fats activate the pyruvate dehydrogenase enzyme that is essential for the efficient use of glucose, while PUFA block it. (The MRL mouse strain has a high regenerative ability, associated with a retained tendency to metabolize glucose rather than fatty acids.) The negative energetic effects of PUFA include interfering with thyroid and progesterone. The energy resources are suppressed, at the same time that the inflammatory signals are amplified, and many regulatory pathways (including the replenishment of NAD from tryptophan) are diverted.

In the fetus, especially before the fats from the mothers diet begin to accumulate, signals from injured tissue produce the changes that lead quickly to repair of the damage, but during subsequent life, similar signals produce incomplete repairs, and as they are ineffective they tend to be intensified and repeated, and eventually the faulty repair processes become the main problem. Although this is an ecological problem, it is possible to decrease the damage by avoiding the polyunsaturated fats and the many toxins that synergize with them, while increasing glucose, niacinamide, carbon dioxide, and other factors that support high energy metabolism, including adequate exposure to long wavelength light and avoidance of harmful radiation. As long as the toxic factors are present, increased amounts of protective factors such as progesterone, thyroid, sugar, niacinamide, and carbon dioxide can be used therapeutically and preventively.

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Biochem Biophys Res Commun. 2008 Feb 15;366(3):786-92. Epub 2007 Dec 17. In vivo effect of an antilipolytic drug (3,5'-dimethylpyrazole) on autophagic proteolysis and autophagy-related gene expression in rat liver. Donati A, Ventruti A, Cavallini G, Masini M, Vittorini S, Chantret I, Codogno P, Bergamini E.
Biochim Biophys Acta. 2004 Nov 8;1686(1-2):118-24. Differential effects of dietary fatty acids on rat liver alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase activity and gene expression. Egashira Y, Murotani G, Tanabe A, Saito K, Uehara K, Morise A, Sato M, Sanada H. Hepatic alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD; formerly termed picolinic carboxylase) [EC4.1.1.45] plays a key role in regulating NAD biosynthesis and the generation of quinolinate (quinolinic acid) from tryptophan. Quinolinate is a potent endogenous excitotoxin of neuronal cells. We previously reported that ingestion of fatty acids by rats leads to a decrease in their hepatic ACMSD activity. However, the mechanism of this phenomenon is not clarified. We previously purified ACMSD and cloned cDNA encoding rat ACMSD. Therefore, in this study, we examined the differential effect of fatty acids on ACMSD mRNA expression by Northern blot. Moreover, we measured quinolinic acid concentration in rats fed on fatty acid. When diets containing 2% level of fatty acid were given to male Sprague-Dawley rats (4 weeks old) for 8 days, long-chain saturated fatty acids and oleic acid did not affect ACMSD mRNA expression in the liver. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) strongly suppressed the liver ACMSD mRNA expression. In rats fed with high linoleic acid diet for 8 days, serum quinolinic acid was significantly increased as compared with the rats fed on a fatty acid-free diet under the condition of the approximately same calorie ingestion. These results suggest that the transcription level of ACMSD is modulated by polyunsaturated fatty acids, and suppressive potency of ACMSD mRNA is n-3 fatty acid family>linoleic acid (n-6 fatty acid)>saturated fatty acid. Moreover, this study provides the information that a high polyunsaturated fatty acid diet affects the production of quinolinic acid in serum by suppressing the ACMSD activity.
Int J Vitam Nutr Res. 2007 Mar;77(2):142-8. Dietary protein level and dietary interaction affect quinolinic acid concentration in rats. Egashira Y, Sato M, Saito K, Sanada H. In this study, we examined whether dietary protein level, fatty acid type, namely saturated fatty acid and polyunsaturated fatty acid, and their interaction affect serum quinolinic acid concentration in rats. Male Sprague-Dawley rats (4-weeks old) were fed with 20% casein + 10% stearic acid diet (20C10S), 20% casein + 10% linoleic acid diet (20C10L), 40% casein + 10% stearic acid diet (40C10S), or 40% casein + 10% linoleic acid diet (40C10L) for 8 days, and serum quinolinic acid concentration and ACMSD activity were determined. Serum quinolinic acid concentration was significantly increased in the 40C10L group compared with other three groups. There was also the negative correlation between the sum of liver and kidney ACMSD activities, and serum quinolinic acid concentration per tryptophan intake (r = 0.8209, p < 0.01). Increased serum QA concentrations are probably due to a decreased ACMSD activity.
Biochim Biophys Acta. 2004 Nov 8;1686(1-2):118-24. Differential effects of dietary fatty acids on rat liver alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase activity and gene expression. Egashira Y, Murotani G, Tanabe A, Saito K, Uehara K, Morise A, Sato M, Sanada H.
Int J Vitam Nutr Res. 2007 Mar;77(2):142-8. Dietary protein level and dietary interaction affect quinolinic acid concentration in rats. Egashira Y, Sato M, Saito K, Sanada H.
Comp Biochem Physiol A Physiol. 1995 Aug;111(4):539-45. Effect of dietary linoleic acid on the tryptophan-niacin metabolism in streptozotocin diabetic rats. Egashira Y, Nakazawa A, Ohta T, Shibata K, Sanada H.
Adv Exp Med Biol. 2003;527:671-4. Dietary linoleic acid suppresses gene expression of rat liver alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD) and increases quinolinic acid in serum. Egashira Y, Sato M, Tanabe A, Saito K, Fujigaki S, Sanada H.
J Clin Invest. 1994 Mar;93(3):1063-70. Neutrophil migration inhibitory properties of polyunsaturated fatty acids. The role of fatty acid structure, metabolism, and possible second messenger systems. Ferrante A, Goh D, Harvey DP, Robinson BS, Hii CS, Bates EJ, Hardy SJ, Johnson DW, Poulos A.
Clin Invest Med. 2008;31(3):E106-16. Hyaluronan oligosaccharides are potential stimulators to angiogenesis via RHAMM mediated signal pathway in wound healing. Gao F, Yang CX, Mo W, Liu YW, He YQ.
Pharmacol Res Commun. 1978 Jul;10(7):643-56. Role of ACTH on the effect of medroxyprogesterone in brain stem serotonin. Izquierdo JA, Savini C, Borghi E, Rabiller G, Costas S, Justel E.
Postepy Hig Med Dosw (Online). 2007 Nov 19;61:683-9. [Hyaluronan-mediated regulation of inflammation] [Article in Polish] Krasinski R, Tchórzewski H.
J Pediatr Surg. 1987 Jul;22(7):640-4. Fetal response to injury in the rabbit. Krummel TM, Nelson JM, Diegelmann RF, Lindblad WJ, Salzberg AM, Greenfield LJ, Cohen IK.
Acta Haematol. 1980;63(4):185-90. Thrombocytopenia in Graves' disease: effect of T3 on platelet kinetics. Kurata Y, Nishioeda Y, Tsubakio T, Kitani T.
Clin Chim Acta. 1977 Sep 1;79(2):479-87. Influence of glucose and inhibitors of glycolysis on release of total proteins and enzymes from human leukocytes. Lahrichi M, Tarallo P, Houpert Y, Siest G.
Am J Physiol Lung Cell Mol Physiol. 2005 Jul;289(1):L96-L103. Epub 2005 Mar 18. Effect of CO2 on LPS-induced cytokine responses in rat alveolar macrophages. Lang CJ, Dong P, Hosszu EK, Doyle IR.
J Pediatr Surg. 1999 May;34(5):695-700. TGF-beta1 alters the healing of cutaneous fetal excisional wounds. Lanning DA, Nwomeh BC, Montante SJ, Yager DR, Diegelmann RF, Haynes JH.
Restor Neurol Neurosci. 2002;20(5):181-7. Experimental hyperthyroidism increases the effectiveness of predegenerated peripheral nerve graft implantation into hippocampus of adult rats. Lewin-Kowalik J, Golka B, Larysz-Brysz M, Swiech-Sabuda E, Granek A.
Am J Vet Res. 1977 Oct;38(10):1657-9. Influence in rats of dietary fats during the perinatal period: effects upon development and behavior of dams and offspring. Liu YL, Borgman RF.
Intensive Care Med. 2009 Jan;35(1):129-35. Hypercapnic acidosis minimizes endotoxin-induced gut mucosal injury in rabbits. Morisaki H, Yajima S, Watanabe Y, Suzuki T, Yamamoto M, Katori N, Hashiguchi S, Takeda J.
Int J Tissue React. 1993;15(4):151-6. Effects of prostaglandins and indomethacin on the cellular inflammatory response following surgical trauma in fetal rabbits. Morykwas MJ, Perry SL, Argenta LC.
Bull World Health Organ. 1970;43(5):651-61. The influence of sex, age, synthetic oestrogens, progestogens and oral contraceptives on the excretion of urinary tryptophan metabolites. Moursi GE, Abdel-Daim MH, Kelada NL, Abdel-Tawab GA, Girgis LH.
Int J Dev Neurosci. 2007 Dec;25(8):499-508. Signal transduction pathways associated with ATP-induced proliferation of cell progenitors in the intact embryonic retina. Nunes PH, Calaza Kda C, Albuquerque LM, Fragel-Madeira L, Sholl-Franco A, Ventura AL.
Mikrobiyol Bul. 2006 Oct;40(4):325-32. [Histologic demonstration of adrenal macrophages as a member of mononuclear phagocytic system in guinea pig models] [Article in Turkish] Ozbek A, Ozbek E.
Prostaglandins. 1977 Oct;14(4):709-14. Increased collagen metabolism in granulomata induced in rats deficient in endogenous prostaglandin precursors. Parnham MJ, Shoshan S, Bonta IL, Neiman-Wollner S.
Intensive Care Med. 2010 May;36(5):869-78. Epub 2010 Mar 6. Hypercapnic acidosis in ventilator-induced lung injury. Peltekova V, Engelberts D, Otulakowski G, Uematsu S, Post M, Kavanagh BP.
J Surg Res. 2009 Jan;151(1):40-7. Epub 2008 Apr 23. Heated and humidified CO2 prevents hypothermia, peritoneal injury, and intra-abdominal adhesions during prolonged laparoscopic insufflations. Peng Y, Zheng M, Ye Q, Chen X, Yu B, Liu B.
Med Hypotheses. 2009 Oct;73(4):521-3. Epub 2009 Jul 8. Intraoperative field flooding with warm humidified CO2 may help to prevent adhesion formation after open surgery. Persson M, van der Linden J.
British Medical Journal 1961 Feb. 4, 1:364. Keloids after B.C.G. Ranganathan KS.
CNS Drugs. 2002;16(2):129-37. Is attention deficit hyperactivity disorder increasing among girls in the US? Trends in diagnosis and the prescribing of stimulants. Robison LM, Skaer TL, Sclar DA, Galin RS.
Adv Exp Med Biol. 2003;527:435-41. Increase in conversion of tryptophan to niacin in pregnant rats. Shibata K, Fukuwatari T, Murakami M, Sasaki R.
Invest Ophthalmol Vis Sci. 1980 Aug;19(8):983-6. The effects of aging and inflammation on corneal endothelial wound healing in rabbits.Staatz WD, Van Horn DL.
Pediatr Surg Int. 2001 May;17(4):254-8. Polyunsaturated fatty acids influence neonatal monocyte survival. Sweeney B, Puri P, Reen DJ. PUFAs modulate apoptosis of certain tumour cells and cell lines. Monocytes, which are major effector cells of the innate immune system, play a central role in the initiation, development, and outcome of the immune response. They are crucial in the defence against invading pathogens and are involved in the lysis of infected or malignant cells, wound healing, repair, and remodeling of tissues. In the present study we investigated whether PUFAs might evoke apoptosis in newborn monocytes. In the absence of fatty acids, 30 +/- 4% of control cord monocytes underwent apoptosis or necrosis after 24 h incubation. At a concentration of 50 microM, none of the PUFAs had a significant effect on monocyte cell death,but at a dose of 100 microM, DHA resulted in 60 +/- 4% cell death (P < 0.05) while the other PUFAs had no significant effect. In contrast, at higher concentrations (200 microM), all the PUFAs significantly increased monocyte cell death (AA: 70 +/- 5%, DHA: 86 +/- 2%, EPA: 70 +/- 4%). PUFAs thus exert a potent influence on cord monocyte cell survival in vitro. Their effect is dose-dependent and DHA appears to be the most potent of the fatty acids tested. The influence of PUFAs on neonatal monocyte-cell survival suggests a novel mechanism whereby PUFAs may modulate the immune response.
J Cell Mol Med. 2007 Nov-Dec;11(6):1342-51. Differential cytokine activity and morphology during wound healing in the neonatal and adult rat skin. Wagner W, Wehrmann M.
Pharmacol Res Commun. 1978 Jul;10(7):643-56. Role of ACTH on the effect of medroxyprogesterone in brain stem serotonin. Izquierdo JA, Savini C, Borghi E, Rabiller G, Costas S, Justel E.
J Cell Mol Med. 2007 Nov-Dec;11(6):1342-51. Differential cytokine activity and morphology during wound healing in the neonatal and adult rat skin. Wagner W, Wehrmann M.
Plast Reconstr Surg. 2002 Jun;109(7):2355-62. The fetal cleft palate: III. Ultrastructural and functional analysis of palatal development following in utero repair of the congenital model. Weinzweig J, Panter KE, Spangenberger A, Harper JS, McRae R, Edstrom LE.
Z Mikrosk Anat Forsch 1970 Jan. 82(2): 149-71. [Experimental studies on the regeneration of the telencephalon of Ambystoma mexicanum after the resection of both hemispheres] E Winkelmann, A Winkelmann.
Am J Physiol Cell Physiol. 2010 Mar;298(3):C457-64. Shockwaves increase T-cell proliferation and IL-2 expression through ATP release, P2X7 receptors, and FAK activation. Yu T, Junger WG, Yuan C, Jin A, Zhao Y, Zheng X, Zeng Y, Liu J.

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A R T I C L E

Pathological Science & General Electric:
Threatening the paradigm

Everything in biology depends on the internal order of cells, and on the interactions of each cell with its surroundings. All of these orderly interactions involve contacts between biological molecules and water. The forces regulating interactions on that scale must be understood before life can be understood, but the nature of the forces at these interfaces has been controversial for 100 years.
In 1953, physicist Irving Langmuir gave a talk at the General Electric laboratory about what he called "pathological science." That talk is still resonating in the scientific culture, and it is used to reinforce attitudes similar to those held by Langmuir, i.e., the dominant scientific paradigm of the 20th century, and to justify certain institutions that regulate innovation.
For Langmuir, there was a clearly defined "scientific method," and he said some people were led away from the proper method by wishful thinking to interpret ambiguous results as confirmations of their hypothesis. He listed 6 symptoms of pathological science: 1) An effect produced by a barely detectable cause, and 2) the effect is barely detectable, or many measurements are needed because of the very low statistical significance of the results, 3) claims of great accuracy, 4) they involve fantastic theories contrary to experience, 5) criticisms are met by ad hoc excuses, and 6) the ratio of supporters to critics approaches 50%, then fades toward zero. He failed to mention these features in any research that supported his view of things, and called an idea pathological when people continued to work on it despite disapproval by the recognized experts. He didn't mention the Nobel prizes that were given for the worm theory of cancer or for treating psychological problems with lobotomies, and he didn't mention that there were organized campaigns against the publication of disapproved ideas.
The dominant view in biology, which is analogous to Langmuir's view in physics, is that all decisive cellular processes involve the direct mechanical contact of one molecule with another, the activation of a lock (an enzyme or receptor) by a key that has the right shape, or the adhesion of a molecule to another substance according to its chemical composition. An alternative view, now clearly supported by the evidence, is that there are forces that aren't merely between molecular surfaces, but rather that the local conditions at the surfaces of proteins and other molecules, and the properties of the solvent water, are modified by the surrounding conditions. It is this alternative view that is now making progress in understanding disease and health, regeneration and degeneration. But to judge the new work, it's important to know the nature of the opposition.
Thomas Edison, who was adept at publicizing himself as the inventor of ideas he had bought or stolen, founded General Electric. Attempting to eliminate Nikola Tesla's system of alternating current, since Edison was invested in direct current systems, Edison's GE tried to convince the public that direct current was safer, by using alternating current to electrocute an elephant, and by promoting its use in the electric chair. GE eventually gave up the direct current technology for electrifying cities, and they refined the electric light bulb and were fairly successful in controlling, practically monopolizing, that market, and in shortening the life of incandescent bulbs. Carbon filament bulbs made around 1900 often lasted decades; I had one that kept working until it was broken during a move in 1960. Light bulbs made in England 65 years ago, and in the Soviet Union, and bulbs currently made in China, had a life expectancy five times as long as the bulbs made in the US since GE learned how to carefully control the rate at which the tungsten filament deteriorates.
Irving Langmuir was their leading light bulb scientist. In his 1932 Nobel lecture, he tediously argued that molecules of gas can form only one layer on a surface such as a filament. About 17 years earlier, Michael Polanyi had demonstrated that molecules can be adsorbed in multilayers, but his evidence was dismissed because, according to the understanding of industrial experts such as Langmuir, and the leading scientific authorities, Einstein, Nernst, and Haber, it was impossible. They were committed to an explanatory system that didn't allow events such as those Polanyi described.
Although Polanyi knew that his adsorption isotherm was more realistic than Langmuir's (he had demonstrated many cases that Langmuir's didn't describe correctly), and also easier to understand, he taught Langmuir's isotherm to his students, because he knew that they would be required to know it to pass their examinations. He knew he had risked his career by his earlier exposition of his ideas, and he was unwilling to endanger his students' careers by involving them in the controversy.
From 1920 to 1926, before the advent in 1927 of "quantum physics" (with its still-argued features of delocalized electrons, molecular orbitals, resonance, non-locality, incommensurability, indeterminism), Polanyi had turned his attention from the physics of adsorption to chemical structure, and his group was the first to show that cellulose was made up of long molecules, polymers, rather than of just associated clusters. That idea didn't catch on, so he turned to the behavior of crystals and metals. He found that crystals were much weaker than they should be, according to the strength of the bonds between their atoms, and showed that this was because of defects, and that during repeated stresses, they became weaker, as energy migrated through relatively long distances in the substance, to concentrate the defects. The idea of lattice defects was acceptable at that time, but long-range mobility of bond energy was no more acceptable then than it had been when J.C. Bose described metal fatigue, decades earlier.
Polanyi also showed that the strength and rigidity of a crystal were altered when the crystal was immersed in water. Again, such an influence of a surface on the over-all physical properties of a solid substance had no noticeable effect on the scientific culture, although his results were published in the major journals. To adjust one's interpretive system at that time to rationalize Polanyi's results would have required discarding the basic assumptions that were behind Einstein's explanation of the photoelectric effect, and maybe even his theory of Brownian motion. However, by 2011, fewer people have invested their personal development in those ideas of short-range electrical binding forces that prevailed early in the 20th century, and now, for example, the evidence of "delocalized holes in DNA" can be discussed more openly. Eventually, science textbooks may be rewritten to show a steady progression of understanding from Bose, though Polanyi, Perutz, Szent-Gyorgyi, Ling, and Damadian (inventor of the MRI, holder of the patents infringed by GE, non-winner of the Nobel prize).
In 1933 J.D. Bernal had proposed a structural model of water that contained a considerable amount of order (Bernal and Fowler, 1933) but by the 1950s the idea of spontaneous ordering in water was out of style, and he worked out a more random structure. Max Perutz, continuing the study of hemoglobin he had begun with Bernal, became concerned with long range forces acting through water: "The nature of the forces which keep particles parallel and equidistant across such great thicknesses of water is not yet clear." Normal wet crystals of methemoglobin contain regular layers of water 15 Angstroms thick. He suggested that a laminated structure of the water could plausibly explain his measurements. Comparing the protein crystal to montmorillonite particles, which incorporate several layers of water, each 3 Angstroms thick, each layer of water in the protein crystal would be 4 Angstroms thick, since swelling proceeds in discrete steps of that thickness. 52.4% of the volume of Perutz's normal, stable, wet protein crystals consisted of liquid. Part of the water is a fixed monolayer, but the rest is apparently in the form of mobile, interactive, multilayers. By 1952, Perutz had decided that long range forces weren't involved in hemoglobin crystallization, but he didn't comment on the long range ordering of clays, tobacco mosaic viruses, and other particles and gels. In 2005, an interlaminar distance of 17.9 Angstroms, or six layers of water, still seems to be stable in hydrated montmorillonite (Odriozola & Aguilar, 2005). Clay continues to be studied in relation to nuclear waste disposal, so the effects of surfaces on water's properties haven't been entirely excluded from science. The interfacial water in clay has special catalytic properties that make it interesting to many researchers (Anderson, 1970)
Bernal's and Perutz' conformity in the 1950s rejection of long range forces and an ordered structure of water represented the dominant ideas in physics and physical chemistry, but many people (with very little financial or institutional support) were continuing to study the structure of water, both in the bulk phase and near surfaces, as in cells. Philippa Wiggins, Albert Szent-Gyorgyi, Carlton Hazlewood, Freeman Cope, and Ray Damadian were among the most active proponents of the importance of structured water in living cells. Walter Drost-Hansen showed that water near surfaces (vicinal water) is several percent less dense, and has a greater heat capacity, than bulk water, and that bulk water undergoes transitions at certain temperatures that alter its effects on enzyme reactions.

The question regarding the nature of the forces at surfaces or interfaces affects how we think about everything, from life to nuclear energy. The political and economic implications of "non-local energy" (which is most obvious at surfaces) have at times led to organized campaigns to discourage research in those areas. When Alexandre Rothen found (beginning in 1946) that enzymes and antibodies had non-local effects, several prestigious publications claimed to show how he must have been mistaken: The films he used must have been porous, despite his demonstrations of their continuity.
The methods he developed at Rockefeller Institute quickly became standard for accurately measuring very thin films. In the early 1970s, a GE employee, Ivar Giaever, visited Rothen's lab to learn his methods. Shortly after his visit, he demonstrated his "new method" to the press. I saw an article about it in Science News, and wrote them a short letter, pointing out that the method had been developed and used by Rothen much earlier; they printed my note, which could be seen as a criticism of the author of the news article. About a week later, I got a letter from Rothen, thanking me for writing to the magazine; he said they had refused to publish his own letter explaining the situation, including his interactions with Giaever during the visit. I assume that the magazine felt some kind of pressure to protect Giaever and GE from an authoritative accusation of scientific dishonesty.
In 1968 when I began studying biology at the University of Oregon, the professor of microscopy, Andrew Bajer, posted a display of dozens of micrographs, with explanatory captions, along the halls near the entrance of one of the science buildings. The one that interested me most showed orderly rows of regularly formed objects on a smooth surface. The caption described it as clusters of sodium atoms, deposited from vapor, on a film of a polymer (formvar, I think), under which was a quartz crystal. The caption noted that the sodium atoms had condensed in a pattern representing the crystal structure of the underlying quartz. Although Rothen's work involved proteins deposited from solution, rather than sodium atoms deposited from vapor, Bajer's image illustrated visually the projection of the forces of crystal structure through an amorphous film. This seemed to be a graphic representation of Polanyi's adsorption potential, a force acting on atoms in the space near a surface, as opposed to Langmuir's local atomic force that didn't reach beyond the first layer of atoms. The long range order in this case arranged atoms geometrically, while Rothen's preparations showed a "projected" specificity, but of a more complex sort.
Just a few months later, someone who knew of Stephen Carter's demonstration that fibroblasts will migrate on a glass slide coated with a gold film, toward areas of greater thickness of the metal, did a similar experiment, but with a formvar film between the gold and the cells. The cells still migrated up the gradient, toward the area of thicker gold under the film. The reaction to that publication was the same as the reaction to Rothen's work 20 years before, the formvar films contained holes, and the cells were reaching through the film to touch the metal surface, sort of like kids peeking around a blindfold when they aren't supposed to be watching. I didn't understand how the holes would explain anything, even if there were holes and if the cells had put out many long filopodia to reach through the film, but in fact making a formvar film is a very standardized technique. They can be made "holey," or like a very open net, or they can be made solid, just by choosing the concentration of the polymer used. The difference is very clear, under an electron microscope, but the professors needed an excuse for dismissing something they didn't want to understand. Further work was discouraged by their ridicule.
In Russia, GE had very little influence on the acceptability of ideas in science, and Boris Deryagin continued (from the 1930s until 1990) to study the properties of water near surfaces. In 1987 his group demonstrated that cells can clear particles from a space around themselves, extending more than a cell's diameter away. This distance is similar to the cell free zone in flowing blood adjacent to the walls of arterioles, which is probably the result of multiple interacting forces. At present, processes such as cell adhesion of leukocytes and stem cells (and tumor cells) to the blood vessel wall and movement through the blood vessel into the tissues (diapedesis) is explained in terms of adhesion molecules, disregarding the plausible effects of long range attractive or repulsive forces. Clumping or sludging of red blood cells occurs when the organism is failing to adapt to stress, and could be reasonably explained by a failure of protective repulsive fields. These fields are developed and maintained by metabolism, primarily oxidative energy metabolism, and are modified by endogenous regulatory substances and external conditions, including electromagnetic and electrical fields.
100 years ago, Albert Einstein was a major influence in popularizing the "only local" dogma of atomic interactions. (His work led directly to "quantum physics," but he never accepted its irrational implications.⁽¹⁾ I don't think he ever considered that the assumptions in his [atomic-quantized] theory of the photoelectric effect were the problem.) One charged atom is completely neutralized by its association with an oppositely charged atom, and the force is described by the inverse square law, that the force decreases with the square of the distance between point charges, meaning that the force is very strong at very small distances. However, a physicalsurface, a plane where one substance ends and another begins, follows different rules.
Different substances have different electron affinities, creating a phase boundary potential, a charged layer at the interface. (Electrical double layers at interfaces are important in semiconductors and electrodes, but biologists have carefully avoided discussing them, except in the very narrow context of electrodes.) The electrically active surface of a substance, even though it's made of atoms and electrons, projects its electrical field in proportion to its area. This principle is as old as Coulomb's law, but the habit of thinking of electrical charge on the atomic scale seems to make people forget it. It's exactly the sort of space-filling field that Polanyi's adsorption isotherm describes. It's also involved in crystal strength and elasticity as studied by Polanyi, in piezoelectricity, and in generation of semiconduction in amorphous materials, as used in Stan Ovshinsky's processes.
Long range structural and electronic interactions produce "antenna" effects, which are sensitive to very weak fields, whether they originate inside or outside of the organism. Magnetobiology is often treated as a pseudo-science or pathological science, because "real science" considers heating and chemical bond reactions to be the only possible effects of low energy fields or radiation. Solco Tromp, beginning in the 1930s, showed that cells behave like liquid crystals, and that liquid crystals can respond to very low electrical and magnetic fields.
If the adsorption potential structures the water in its region of space, this interfacial water is now a new phase, with different physical properties, including new catalytic properties, such as those recognized by the clay investigators (which increased its ability to dissolve the clay minerals).
Several versions of Langmuir's Pathological Science talk have been published, some of them adding new examples, including "polywater." Langmuir died in 1957, and the first example of polywater was observed by N.N. Fedyakin was observed in 1961. When finely drawn quartz or Pyrex glass capillary tubes (with inside diameter of up to a tenth of a millimeter) are suspended in a container with the air pressure reduced, above a container of distilled water, so that they are exposed to pure water vapor at room temperature, after a period of an hour or more (sometimes days or weeks were required) a small drop of liquid condenses inside some (a small percentage) of the capillary tubes. Above some of the original drops, a second drop sometimes appeared, that would enlarge as the first drop shrank. This separation of water into two fractions was itself anomalous, and the upper drop was found to be denser than normal water. Many people began studying its properties. Fedyakin found that its thermal expansion was greater, and its vapor pressure lower, than ordinary water. Others found that it had a higher refractive index, viscosity, and surface tension, as well as greater density, than ordinary water. Birefringence (the splitting of a beam of light into two rays when it passes through an ordered material) was observed in the anomalous water, and this usually indicates the presence of a polymer (Fedyakin, et al., 1965; Willis et al., 1969; Lippincott, et al., 1969) or crystallinity. The water associated with clay is also birefringent (Derjaguin and Greene-Kelly, 1964), and its properties are different when the clay absorbs it from the vapor phase or from liquid water.

Hysteresis is a lag in the behavior of a system, resulting when the internal state of the system is altered by an action, so that it responds differently to a repetition of that action; it's the memory of a system that exists only when the system has internal structure. For example, a gas has relatively little hysteresis. Perfect elasticity is one extreme of an ordered solid, but most solids have some hysteresis, in which the deformed material fails to spring back immediately. Hysteresis of adsorption can be seen at the edges of a drop of water on a tilted surface, with a steeper contact angle on the newer contact at the lower edge, showing a reluctance of the water to wet a new surface, a lower contact angle where the drop is pulling away from the upper surface, a reluctance to break the contact. The same is seen at the edges of an evaporating-shrinking drop, or a growing drop. Everyone perceives this memory function of water.
Boris Deryagin studied both the elasticity and the hysteresis of water near surfaces, and both approaches showed that it contained internal structure. Many dogmatic professors denied that water could show elasticity or "memory," because of their interpretive system/mental rigidity.
When Fedyakin got the help of Deryagin's lab in analyzing the anomalous material, many different methods of purifying the glass and the water and the vessel were tried, and its properties were analyzed in many different ways. When Deryagin first described the material at a conference in Europe, there was great interest, and eventually hundreds of people began investigating it.
A British laboratory was the first to get a sample of Deryagin's material in 1966, and their tests confirmed Deryagin's.
The US Bureau of Standards, having the best analytical instruments in the world (including a microscope spectrometer), studied it carefully. They (Lippincott, Stromberg, Grant, & Cessac, 1969) found that its bonds were stronger than those in ordinary water, and they compared its absorption spectrum (by computer) with those of 100,000 known substances, and found that it corresponded with nothing previously known. It didn't have the absorption band of normal water. When it evaporated, it left no visible residue, and it turned into ordinary water when heated. They concluded that the physical structure that would best fit its absorption spectrum was a polymerized form of water, so they called it "polywater." Later, Lippincott and others (Page, et al., 1970; Petsko, 1970) did proton magnetic resonance analyses that showed a difference of polywater from normal water in the hydrogen bonding, a "deshielding" of the protons, meaning that the electrons were arranged differently in the molecules.
In 1969 there were many threats to the dominant paradigm, and many people were demanding a change in the government's funding priorities. The public excitement about polywater following the many confirmations of its existence was disturbing to the defenders of the paradigm. Philip Abelson, the chief editor of Science magazine, used the magazine to further his political beliefs.
Denis Rousseau, a young researcher at Bell Labs (who now writes about pathological science), published a series of articles in Science describing his tests of polywater. He played tennis until his tee-shirt was soaked with sweat, then extracted and concentrated the sweat into a small gummy pellet. He reported that the infrared spectrum of the sweat concentrate (largely sodium lactate) was very similar to that of polywater. One of the techniques he used to identify impurities (electron spectroscopy) requires a high vacuum, so there couldn't be any normal water present. The water associated with ionic impurities is driven off at low temperatures compared to the temperature needed to decompose the anomalous water.
Although Rousseau's "explanation" was ludicrous, it was just the thing the professors needed to prevent further challenges to their paradigm. Although Deryagin published more evidence of the purity of the anomalous water in 1972, by 1973 the mass media, including Science magazine, were saying that polywater didn't exist, and that Deryagin had admitted that he was mistaken. But polywater was Lippincott's term, and what Deryagin said was that silica was the only impurity that could be identified in the anomalous material.
There are many antecedents to anomalous water in the literature. In the 1920s, W.A. Patrick of Johns Hopkins and J. L. Shereshefsky at Howard university investigated the properties of water in fine capillary tubes and found that the vapor pressure wasn't the same as that of normal water. (This is what would have been expected, if Polanyi's adsorption isotherm had been accepted.) The density of water in clay has been found to be slightly less than normal. This water bound to clay requires a high temperature to eliminate, similar to the decomposition temperature of polywater. The catalytic properties of interfacial water in clay are recognized, causing it to solublize components of the clay. So it's hard to imagine that there wouldn't be some silica in the material formed in quartz or glass capillary tubes.
The only thing pathological about the polywater episode was the extreme effort that was made to stigmatize a whole category of research, to restore faith in the old doctrine that insisted there are no long range ordering processes anywhere in the universe. The successful campaign against polywater strengthened the mainstream denial of the evidence of ordering in interfacial and intracellular water, kept the doctrine of the lipid bilayer cell membrane alive, and up until the present has prevented the proper use of MRI scans in medical diagnosis.

In 1946, while the government was studying the way nuclear fallout was influenced by the weather, a group at GE, led by Langmuir, began experimenting with weather control by means of "cloud seeding." Langmuir observed that the energy in a cloud system was greater than that in an atomic bomb, and that by seeding clouds in Europe, disastrous weather effects could be created in the Soviet Union. The GE group convinced the Pentagon to become involved in weather control. (The physicist Ross Gunn was transferred directly from work on the atomic bomb to direct the cloud seeding project.) In one of Langmuir's seeding experiments, he claimed that he had changed the direction of a hurricane moving toward the U.S. When a young researcher pointed out that the weather service had predicted exactly that change of direction, based on the temperatures of ocean currents, Langmuir became angry, and told the man that he wasn't going to explain it to him, because he was too stupid to understand.
Langmuir's attitude toward science was exactly what GE wanted; his career and reputation were part of the corporation's public relations and business plan. Science was whatever GE thought was good for their business. That science was pathological, sometimes by Langmuir's own defining features, most of the time by the effects it has had on society. The Manhattan Project was central to GE's business plan, and when the bomb project was completed GE and the Atomic Energy Commission found that the same subsidies could be used to develop nuclear generators of electricity. Following Edison's pioneering work with x-rays, x-ray imaging machines had become very profitable for GE. It was important to assure the public that medical, industrial, and military radiation was well understood, well controlled, safe, and essential for the general welfare. In their view, if every woman could have access to GE's x-ray mammograms, for example, almost all breast cancers could be cured. The radiation exposure from living near a GE nuclear power generator is infinitesimal compared to living in Denver or flying in an airplane. (There is some discussion of these issues in my January, 2011 newsletter, "Radiation and growth.") Public relations involves everything from "basic research" to television advertising.
If nuclear energy is as safe as the industry and governments say it is, the reactors should be located in the centers of large cities, because transmitting electric power long distances is presently wasting 50% of the power (Hirose Takashi, The Nuclear Disaster that could destroy Japan...and the world, 2011). Admiral Rickover, influential advocate of nuclear power, said "...every time you produce radiation, [a] horrible force [is unleashed,] and I think there the human race is going to wreck itself. [We must] outlaw nuclear reactors" (January, 1982 congressional testimony) Helen Caldicott says Fukushima is many times worse than Chernobyl. The radioactive cesium in German mushrooms and truffles hasn't decreased 25 years after Chernobyl, and the German government is spending increasing amounts to compensate hunters for the wild boars (who eat truffles) that must be disposed of as radioactive waste.(2)
General Electric sent its condolences to the people of Japan, and said the reactors of that design had functioned well for 40 years; they didn't mention that Unit I at Fukushima had been scheduled to be shut down on March 26, 2011, the end of its 40 year life expectancy. In late March, as the accident continued, Tepco applied for a permit to build two new reactors at the Fukushima site. In the US, the government continues its loan guarantee policy to subsidize new reactor construction.
After many years of working with his metalized slides, Alexandre Rothen found that their activity, the strength of their long-range influence, varied with a 24 hour cycle, and that their activity could also be destroyed or restored by putting them in a magnetic field, parallel or perpendicular to the surface. Around the same time, a Russian biochemist, Simon Shnoll, noticed that there were cyclic changes in well defined enzymic reactions. Like Rothen, Shnoll did experiments that showed that the earth's motion (relative to the stars) affected measurements in the laboratory, even measurements of alpha particles produced by nuclear fission. Organized matter, whether it's cellular or in the crystalline solid state, is susceptible to surrounding conditions.
In 1971 or '72 I learned of H.C. Dudley's idea of a "neutrino sea," that he suggested might be equivalent to the "luminiferous ether" that had previously been used to explain light and electromagnetism. I wrote to him, asking if he thought neutrinos could be involved in biological ordering processes by resonating with matter under some circumstances. He had been developing a theory, in which atomic nuclei might interact with a neutrino "ether," in ways that could affect the decay rate of the unstable isotopes, and so it didn't seem unreasonable to him that biological structures might also interact with neutrinos. In October, 1972, he published a purely theoretical article in which he explained that nuclear reactors might under some conditions become dangerously unstable. I had earlier seen a newspaper article about an experiment by a physicist, J.L. Anderson, in which radioactive carbon-14 didn't follow the normal rules of random decay, when the isotope was incorporated into an oil, which was spread in a monolayer on a metal surface. By chance, Anderson's experimental article was published simultaneously with Dudley's theoretical article, though neither one knew of the other's work.
Nearly all physicists said his results weren't possible, because the small forces involved in adsorbing an oil to a metal surface were infinitesimal compared to the force needed to cause nuclear reactions. Over the next few years, Dudley and others did some experiments that appeared to confirm Anderson's results, showing that the rate of nuclear reactions can be modified by mild changes in the physical state of the unstable elements.
Anderson's and Dudley's work didn't get much attention from the public, so there was no need for the defenders of the dominant paradigm to attack it. There was no financial support for continuing their research.
Behind the industries' assurances that "low level" radiation is safe, whether it's ionizing radiation, microwave or broadcast frequency electromagnetic radiation, is their reductionist approach to physics, chemistry, and biology. Those doctrines no longer have the prestige that they once did, but their pathological, authoritarian "science" culture is being sustained by the influence of corporations on mass culture.
With the institutions of research and education controlled by pharmaceutical, military and industrial interests for their own benefit, fundamental progress in knowledge is a threat to the system.

NOTES
1. From Einstein's 1926 letter to Max Born: "Quantum mechanics is very worthy of regard. But an inner voice tells me that this is not yet the right track. The theory yields much, but it hardly brings us closer to the Old One's secrets. I, in any case, am convinced the He does not play dice." Quoted in P. Busch and G. Jaeger, "Unsharp quantum reality," 4 May 2010.
2. None of the major institutions in the US are providing basic information about protection from Fukushima's radioactive fallout. Eating foods produced before the arrival of the radioactive rain, feeding old foods to chickens and milk animals, and keeping your metabolic rate high, are the main defenses. Eventually, fertilizing crops with mined minerals, and enriching the atmosphere with carbon from coal will dilute the radioactive isotopes from the nuclear accidents.

REFERENCES
DM Anderson, Role of interfacial water and water in thin films in the origin of life,http://history.nasa.gov/CP-2156/ch1.4.htm
DM Anderson and AR Tice, 1970, Low-temperature phases of interfacial water in clay-water systems, Crrel Research Reports, Army Dept, US, Res Rpt 290. "The low temperature exotherms do not depend critically upon water content, but clearly they are related to clay mineral and exchangeable cation type. The evolution of heat in this temperature range probably corresponds to a phase change in the interfacial water.")
J. Physical Cehmistry 76(4), 1976, "Non-Poisson distributions observed during counting of certain carbon-14 labeled (sub) monolayers," Anderson JL.
Biophys. Chem. 113 (2005): 245-253, Structural and kinetic effects of mobile phone microwaves on acetylcholinesterase activity, Barteri M, Pala A, Rotella S.
J. Chem. Phys. 1, 515), 1933, Bernal JD & Fowler RH.
J Cell Biol 1964, 127(1):117-128. Electric field-directed fibroblast locomotion involves cell surface molecular reorganization and is calcium independent, Brown MJ and Loew LM.
Nature 1965 208(5016):1183-7, Principles of cell motility: the direction of cell movement and cancer invasion, Carter SB.
Nature 1967 213: 256-60, Haptotaxis and mechanism of cell motility, Carter SB.
Popular Science, June 1973, How you can grow your own polywater, PA Christian and LH Berka: "Some experts claim this rare substance doesn't exist. Yet here's how you can harvest enough of it for own experiments." Pyrex thermometer tubing from a mail-order scientific supply store ....
Biophysical Journal 9 (1969),303-319, Nuclear magnetic resonance evidence using D2O for structured water in muscle and brain, Cope FW.
Langmuir 3(5): 607-612 (1987), Structure of water in thin layers, Deryagin BV, Churaev NV.
Langmuir 3(5): 601-606 (1987), Modern state of the investigation of long-range surface forces, Deryagin BV.
Trans. Faraday Soc. 60 (1964: 449-455, Birefringence of thin liquid films, Derjaguin BV and Greene-Kelly R.
Pure & Appl. Chem. 61(11) (1989): 1955-1958, Influence of surface forces on the formation of structural peculiarities of the boundary layers of liquids and boundary phases, Derjaguin BV. "The surface forces acting beyond the range of boundary monolayers, are able to change the concentration of dissolved ions and molecules.
Trans. Faraday Soc. 60, 449 (1964), Reversible and irreversible modification of the properties of liquids under the influence of a lyophilic surface, Derjaguin BV and Green-Kelly R. "Evidence is given of the reversible character of the modification of the properties of liquids under the action of surface forces." (Lyophopic substrate, a few molecules thick.) "In other cases, e.g. water-glass, water-quartz, fatty acids-metals, the substrate alters the structure of the liquid and the properties depending on it to a depth of many tens or hundreds of monolayers." (Lyophilic substrate). (the electroviscous effect, proportional to the square of the zeta-potential).
Fed Proc Transl Suppl. 1965 24(3):431-3, Effect of constant magnetic field on motor activity of birds, El'darov AL & Kholodov YA.
Physics A: Statistical and Theoretical Physics 172 (1-2), 161-173. The structure and properties of vicinal water: Lessons from statistical geometry, Etzler FM, Ross RF, Halcomb RA, (3% greater density, 25% greater heat capacity.
Dokl. Akad. Nauk. SSSR 165 (1965): 878, Fedyakin N.N.
FEBS Lett. 367 (1995): 53-55, Changes in the state of water, induced by radiofrequency electromagnetic fields, Fesenko EE and Gluvstein A.Ya.
D. Green-Kelly, B.V. Derjaguin, Research in Surface Forces vol. 2, p. 117, Consultants Bureau, NY (1966). (Birefringence of water near surfaces, in layers up to 200 A thick. Also birefringence of the boundary layers of benzene derivatives.)
Nature (submitted 1969) Hazlewood CF, Nichols BL, Chamberlain NF.
Science 164 (1969), p. 1482, Lippincott ER.
Med. Hypotheses 66 (2006) 518-526, Cell hydration as the primary factor in carcinogenesis: A unifying concept, McIntyre GI.
Med. Hypothese 69 (2007): 1127-1130, Increased cell hydration promotes both tumor growth and metastasis: A biochemical mechanism concsistent with genetic signatures, McIntyre, GI.
J Chem Phys 123, 174708, 2005, Stability of Ca-montmorillonite hydrates: A computer simulation study, Odriozola G & JF Aguilar JF.
Tranropesactions of the Faraday Society, vol. XLII B, 1946, "The composition and swelling properties of haemoglobin crystals," Perutz M.
Science 171(3967), 170-172, "Polywater" and sweat: Similarities between the infrared spectra, D.L. Rousseau,
Biochim Biophys Acta 1975; 403(1):89-97, Synchronous reversible alterations in enzymatic activity (conformational fluctuations) in actomyosin and creatine kinase preparations,Shnoll SE, Chetverikova EP.
Szent-Gyorgyi, A., 1957, Bioenergetics, Academic Press, Inc. New York.
Prog. Polym. Sci. 20 (1995): 1121-1163, High and low-density water in gels, Wiggins PM.
Nature 222, 159-161, 1969, "Anomalous" Water, Willis E, GK Rennia, C Smart BA Pethica.

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A R T I C L E

Protective CO2 and aging

The therapeutic effects of increasing carbon dioxide are being more widely recognized in recent years. Even Jane Brody, the NY Times writer on health topics, has favorably mentioned the use of the Buteyko method for asthma, and the idea of permissive hypercapnia during mechanical ventilation, to prevent lung damage from excess oxygen, has been discussed in medical journals. But still very few biologists recognize its role as a fundamental, universal protective factor. I think it will be helpful to consider some of the ways carbon dioxide might be controlling situations that otherwise are poorly understood.

The brain has a high rate of oxidative metabolism, and so it forms a very large proportion of the carbon dioxide produced by an organism. It also governs, to a great extent, the metabolism of other tissues, including their consumption of oxygen and production of carbon dioxide or lactic acid. Within a particular species, the rate of oxygen consumption increases in proportion to brain size, rather than body weight. Between very different species, the role of the brain in metabolism is even more obvious, since the resting metabolic rate corresponds to the size of the brain. For example, a cats brain is about the size of a crocodiles, and their oxygen consumption at rest is similar, despite their tremendous difference in body size.

Stress has to be understood as a process that develops in time, and the brain (especially the neocortex and the frontal lobes) organizes the adaptive and developmental processes in both the spatial and temporal dimensions. The meaning of a situation influences the way the organism responds. For example, the stress of being restrained for a long time can cause major gastrointestinal bleeding and ulcerization, but if the animal has the opportunity to bite something during the stress (signifying its ability to fight back, and the possibility of escape) it can avoid the stress ulcers.

The patterning of the nervous activity throughout the body governs the local ability to produce carbon dioxide. When the cortex of the brain is damaged or removed, an animal becomes rigid, so the cortex is considered to have a tonic inhibitory action on the body. But when the nerves are removed from a muscle (for example, by disease or accident), the muscle goes into a state of constant activity, and its ability to oxidize glucose and produce carbon dioxide is reduced, while its oxidation of fatty acids persists, increasing the production of toxic oxidative fragments of the fatty acids, which contributes to the muscles atrophy.

The organisms intentions, expectations, or plans, are represented in the nervous system as a greater readiness for action, and in the organs and tissues controlled by the nerves, as an increase or decrease of oxidative efficiency, analogous to the differences between innervated and denervated muscles. This pattern in the nervous system has been called the acceptor of action, because it is continually being compared with the actual situation, and being refined as the situation is evaluated. The state of the organism, under the influence of a particular acceptor of action, is called a functional system, including all the components of the organism that participate most directly in realizing the intended adaptive action.

The actions of nerves can be considered anabolic, because during a stressful situation in which the catabolic hormones of adaption, e.g., cortisol, increase, the tissues of the functional system are protected, and while idle tissues may undergo autophagy or other form of involution, the needs of the active tissues are supplied with nutrients from their breakdown, allowing them to change and, when necessary, grow in size or complexity.

The brains role in protecting against injury by stress, when it sees a course of action, has a parallel in the differences between concentric (positive, muscle shortening) and eccentric (negative, lengthening under tension) exercise, and also with the differences between innervated and denervated muscles. In eccentric exercise and denervation, less oxygen is used and less carbon dioxide is produced, while lactic acid increases, displacing carbon dioxide, and more fat is oxidized. Prolonged stress similarly decreases carbon dioxide and increases lactate, while increasing the use of fat.

Darkness is stressful and catabolic. For example, in aging people, the morning urine contains nearly all of the calcium lost during the 24 hour period, and mitochondria are especially sensitive to the destructive effects of darkness. Sleep reduces the destructive catabolic effects of darkness. During the rapid-eye-movement (dreaming) phase of sleep, breathing is inhibited, and the level of carbon dioxide in the tissues accumulates. In restful sleep, the oxygen tension is frequently low enough, and the carbon dioxide tension high enough, to trigger the multiplication of stem cells and mitochondria.

Dreams represent the acceptor of action operating independently of the sensory information that it normally interacts with. During dreams, the brain (using a system called the Ascending Reticular Activating System) disconnects itself from the sensory systems. I think this is the nervous equivalent of concentric/positive muscle activity, in the sense that the brain is in control of its actions. The active, dreaming phase of sleep occurs more frequently in the later part of the night, as morning approaches. This is the more stressful part of the night, with cortisol and some other stress hormones reaching a peak at dawn, so it would be reasonable for the brains defensive processes to be most active at that time. The dreaming process in the brain is associated with deep muscle relaxation, which is probably associated with the trophic (restorative) actions of the nerves.

In ancient China the Taoists were concerned with longevity, and according to Joseph Needham (Science and Civilization in China) their methods included the use of herbs, minerals, and steroids extracted from the urine of children. Some of those who claimed extreme longevity practiced controlled breathing and tai chi (involving imagery, movement, and breating), typically in the early morning hours, when stress reduction is most important. As far as I know, there are no studies of carbon dioxide levels in practitioners of tai chi, but the sensation of warmth they typically report suggests that it involves hypoventilation.

In the 1960s, a Russian researcher examined hospital records of measurements of newborn babies, and found that for several decades the size of their heads had been increasing. He suggested that it might be the result of increasing atmospheric carbon dioxide.

The experiences and nutrition of a pregnant animal are known to affect the expression of genes in the offspring, affecting such things as allergies, metabolic rate, brain size, and intelligence. Miles Storfer (1999) has reviewed the evidence for epigenetic environmental control of brain size and intelligence. The main mechanisms of epigenetic effects or imprinting are now known to involve methylation and acetylation of the chromosomes (DNA and histones).

Certain kinds of behavior, as well as nutrition and other environmental factors, increase the production and retention of carbon dioxide. The normal intrauterine level of carbon dioxide is high, and it can be increased or decreased by changes in the mothers physiology. The effects of carbon dioxide on many biological processes involving methylation and acetylation of the genetic material suggest that the concentration of carbon dioxide during gestation might regulate the degree to which parental imprinting will persist in the developing fetus. There is some evidence of increased demethylation associated with the low level of oxygen in the uterus (Wellman, et al., 2008). A high metabolic rate and production of carbon dioxide would increase the adaptability of the new organism, by decreasing the limiting genetic imprints.

A quick reduction of carbon dioxide caused by hyperventilation can provoke an epileptic seizure, and can increase muscle spasms and vascular leakiness, and (by releasing serotonin and histamine) contribute to inflammation and clotting disorders. On a slightly longer time scale, a reduction of carbon dioxide can increase the production of lactic acid, which is a promoter of inflammation and fibrosis. A prolonged decrease in carbon dioxide can increase the susceptibility of proteins to glycation (the addition of aldehydes, from polyunsaturated fat peroxidation or methylglyoxal from lactate metabolism, to amino groups), and a similar process is likely to contribute to the methylation of histones, a process that increases with aging. Histones regulate genetic activity.

With aging, DNA methylation is increased (Bork, et al., 2009). I suggest that methylation stabilizes and protects cells when growth and regeneration arent possible (and that its likely to increase when CO2 isnt available). Hibernation (Morin and Storey, 2009) and sporulation (Ruiz-Herrera, 1994; Clancy, et al., 2002) appear to use methylation protectively.
Parental stress, prenatal stress, early life stress, and even stress in adulthood contribute to imprinting of the genes, partly through methylation of DNA and the histones.

Methionine and choline are the main dietary sources of methyl donors. Restriction of methionine has many protective effects, including increased average (42%) and maximum (44%) longevity in rats (Richie, et al., 1994). Restriction of methyl donors causes demethylation of DNA (Epner, 2001). The age accelerating effect of methionine might be related to disturbing the methylation balance, inappropriately suppressing cellular activity. Besides its effect on the methyl pool, methionine inhibits thyroid function and damages mitochondria.

The local concentration of carbon dioxide in specific tissues and organs can be adjusted by nervous and hormonal activation or inhibition of the carbonic anhydrase enzymes, that accelerate the oonversion of CO2 to carbonic acid, H2CO3. The activity of carbonic anhydrase can determine the density and strength of the skeleton, the excitability of nerves, the accumulation of water, and can regulate the structure and function of the tissues and organs.
Ordinarily, carbon dioxide and bicarbonate are thought of only in relation to the regulation of pH, and only in a very general way. Because of the importance of keeping the pH of the blood within a narrow range, carbon dioxide is commonly thought of as a toxin, because an excess can cause unconsciousness and acidosis. But increasing carbon dioxide doesnt necessarily cause acidosis, and acidosis caused by carbon dioxide isnt as harmful as lactic acidosis.

Frogs and toads, being amphibians, are especially dependent on water, and in deserts or areas with a dry season they can survive a prolonged dry period by burrowing into mud or sand. Since they may be buried 10 or 11 inches below the surface, they are rarely found, and so havent been extensively studied. In species that live in the California desert, they have been known to survive 5 years of burial without rainfall, despite a moderately warm average temperature of their surroundings. One of their known adaptations is to produce a high level of urea, allowing them to osmotically absorb and retain water. (Very old people sometimes have extremely high urea and osmotic tension.)

Some laboratory studies show that as a toad burrows into mud, the amount of carbon dioxide in its tissues increases. Their skin normally functions like a lung, exchanging oxygen for carbon dioxide. If the toads nostrils are at the surface of the mud, as dormancy begins its breathing will gradually slow, increasing the carbon dioxide even more. Despite the increasing carbon dioxide, the pH is kept stable by an increase of bicarbonate (Boutilier, et al., 1979). A similar increase of bicarbonate has been observed in hibernating hamsters and doormice.
Thinking about the long dormancy of frogs reminded me of a newspaper story I read in the 1950s. Workers breaking up an old concrete structure found a dormant toad enclosed in the concrete, and it revived soon after being released. The concrete had been poured decades earlier.

Although systematic study of frogs or toads during their natural buried estivation has been very limited, there have been many reports of accidental discoveries that suggest that the dormant state might be extended indefinitely if conditions are favorable. Carbon dioxide has antioxidant effects, and many other stabilizing actions, including protection against hypoxia and the excitatory effects of intracellular calcium and inflammation (Baev, et al., 1978, 1995; Bari, et al., 1996; Brzecka, 2007; Kogan, et al., 1994; Malyshev, et al., 1995).

When mitochondria are uncoupled, they produce more carbon dioxide than normal, and the mitochondria produce fewer free radicals. Animals with uncoupled mitochondria live longer than animals with the ordinary, more efficient mitochondria, that produce more reactive oxidative fragments. One effect of the high rate of oxidation of the uncoupled mitochondria is that they can eliminate polyunsatured fatty acids that might otherwise be integrated into tissue structures, or function as inappropriate regulatory signals.

Birds have a higher metabolic rate than mammals of the same size, and live longer. Their tissues contain fewer of the highly unsaturated fatty acids. Queen bees, which live many times longer than worker bees, have mainly monounsaturated fats in their tissues, while the tissues of the short-lived worker bees, receiving a different diet, within a couple of weeks of hatching will contain highly unsaturated fats.

Bats have a very high metabolic rate, and an extremely long lifespan for an animal of their size. While most animals of their small size live only a few years, many bats live a few decades. Bat caves usually have slightly more carbon dioxide than the outside atmosphere, but they usually contain a large amount of ammonia, and bats maintain a high serum level of carbon dioxide, which protects them from the otherwise toxic effects of the ammonia.

The naked mole rat, another small animal with an extremely long lifespan (in captivity they have lived up to 30 years, 9 or 10 times longer than mice of the same size) has a low basal metabolic rate, but I think measurements made in laboratories might not represent their metabolic rate in their natural habitat. They live in burrows that are kept closed, so the percentage of oxygen is lower than in the outside air, and the percentage of carbon dioxide ranges from 0.2% to 5% (atmospheric CO2 is about 0.038). The temperature and humidity in their burrows can be extremely high, and to be very meaningful their metabolic rate would have to be measured when their body temperature is raised by the heat in the burrow.

When they have been studied in Europe and the US, there has been no investigation of the effect of altitude on their metabolism, and these animals are native to the high plains of Kenya and Ethiopia, where the low atmospheric pressure would be likely to increase the level of carbon dioxide in their tissues. Consequently, I doubt that the longevity seen in laboratory situations accurately reflects the longevity of the animals in their normal habitat.

Besides living in a closed space with a high carbon dioxide content, mole rats have another similarity to bees. In each colony, there is only one female that reproduces, the queen, and, like a queen bee, she is the largest individual in the colony. In beehives, the workers carefully regulate the carbon dioxide concentration, which varies from about 0.2% to 6%, similar to that of the mole rat colony. A high carbon dioxide content activates the ovaries of a queen bee, increasing her fertility.

Since queen bees and mole rats live in the dark, I think their high carbon dioxide compensates for the lack of light. (Both light and CO2 help to maintain oxidative metabolism and inhibit lactic acid formation.) Mole rats are believed to sleep very little. During the night, normal people tolerate more CO2, and so breathe less, especially near morning, with increased active dreaming sleep.

A mole rat has never been known to develop cancer. Their serum C-reactive protein is extremely low, indicating that they are resistant to inflammation. In humans and other animals that are susceptible to cancer, one of the genes that is likely to be silenced by stress, aging, and methylation is p53, a tumor-suppressor gene.

If the intrauterine experience, with low oxygen and high carbon dioxide, serves to reprogram cells to remove the accumulated effects of age and stress, and so to maximize the developmental potential of the new organism, a life thats lived with nearly those levels of oxygen and carbon dioxide might be able to avoid the progressive silencing of genes and loss of function that cause aging and degenerative diseases.

Several diseases and syndromes are now thought to involve abnormal methylation of genes. Prader-Willi sydrome, Angelmans syndrome, and various autistic spectrum disorders, as well as post-traumatic stress disorder and several kinds of cancer seem to involve excess methylation.

Moderate methionine restriction (for example, using gelatin regularly in the diet) might be practical, but if increased carbon dioxide can activate the demethylase enzymes in a controlled way, it might be a useful treatment for the degenerative diseases and for aging itself.
The low carbon dioxide production of hypothyroidism (e.g., Lee and Levine, 1999), and the respiratory alkalosis of estrogen excess, are often overlooked. An adequate supply of calcium, and sometimes supplementation of salt and baking soda, can increase the tissue content of CO2.
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Cell Metab. 2007 Jan;5(1):21-33. A central thermogenic-like mechanism in feeding regulation: an interplay between arcuate nucleus T3 and UCP2. Coppola A, Liu ZW, Andrews ZB, Paradis E, Roy MC, Friedman JM, Ricquier D, Richard D, Horvath TL, Gao XB, Diano S.
Ter Arkh. 1995;67(3):23-6. [Changes in the sensitivity of leukocytes to the inhibiting effect of CO2 on their generation of active forms of oxygen in bronchial asthma patients] Daniliak IG, Kogan AKh, Sumarokov AV, Bolevich S.
Cell Metab. 2007 Dec;6(6):497-505. Respiratory uncoupling in skeletal muscle delays death and diminishes age-related disease. Gates AC, Bernal-Mizrachi C, Chinault SL, Feng C, Schneider JG, Coleman T, Malone JP, Townsend RR, Chakravarthy MV, Semenkovich CF.
Endocr Pract. 2009 Jun 2:1-13. Fibrotic Appearance of Lungs in Severe Hypothyroidism is Reversible with Thyroxine Replacement. George JT, Thow JC, Rodger KA, Mannion R, Jayagopal V.
J Bioenerg Biomembr. 2009 Jun;41(3):309-21. Epub 2009 Jul 25. Effect of methionine dietary supplementation on mitochondrial oxygen radical generation and oxidative DNA damage in rat liver and heart. Gomez J, Caro P, Sanchez I, Naudi A, Jove M, Portero-Otin M, Lopez-Torres M, Pamplona R, Barja G.
Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7612-7. Increased tricarboxylic acid cycle flux in rat brain during forepaw stimulation detected with 1H[13C]NMR. Hyder F, Chase JR, Behar KL, Mason GF, Siddeek M, Rothman DL, Shulman RG.
Can J Neurol Sci. 1979 May;6(2):105-12. The effects of partial chronic denervation on forearm metabolism. Karpati G, Klassen G, Tanser P.
Biull Eksp Biol Med. 1994 Oct;118(10):395-8. [CO2--a natural inhibitor of active oxygen form generation by phagocytes] Kogan AKh, Manuilov BM, Grachev SV, Bolevich S, Tsypin AB, Daniliak IG.
Izv Akad Nauk Ser Biol. 1997 Mar-Apr;(2):204-17. [Carbon dioxide--a universal inhibitor of the generation of active oxygen forms by cells (deciphering one enigma of evolution)] Kogan AKh, Grachev SV, Eliseeva SV, Bolevich S.
Vopr Med Khim. 1996 Jul-Sep;42(3):193-202. [Ability of carbon dioxide to inhibit generation of superoxide anion radical in cells and its biomedical role] Kogan AKh, Grachev SV, Eliseeva SV, Bolevich S.
Dokl Akad Nauk. 1996 May;348(3):413-6. [New evidence for the inhibitory action of CO2 on generation of superoxide anion radicals by phagocytes in various tissues. (Mechanism of bio- and eco-effects of CO2)] Kogan AKh, Grachev SV, Bolevich S, Eliseeva SV.
Biull Eksp Biol Med. 1996 Apr;121(4):407-10. [Carbon dioxide gas inhibition of active forms of oxygen generation by cells in the internal organs and its biological significance] Kogan AKh, Grachev SV, Eliseeva SV.
Fiziol Cheloveka. 1995 Jul-Aug;21(4):128-36. [CO2--a natural inhibitor of the generation of active species of oxygen in phagocytes] Kogan AKh, Manuilov BM, Grachev SV, Bolevich S, Tsypin AB, Daniliak IG.
Patol Fiziol Eksp Ter. 1995 Jul-Sep;(3):34-40. [Comparative study of the effect of carbon dioxide on the generation of active forms of oxygen by leukocytes in health and in bronchial asthma] Kogan AKh, Bolevich S, Daniliak IG.
Can J Anaesth. 1999 Feb;46(2):185-9. Acute respiratory alkalosis associated with low minute ventilation in a patient with severe hypothyroidism. Lee HT, Levine M.Tl128@columbia.edu PURPOSE: Patients with severe hypothyroidism present unique challenges to anesthesiologists and demonstrate much increased perioperative risks. Overall, they display increased sensitivity to anesthetics, higher incidence of perioperative cardiovascular morbidity, increased risks for postoperative ventilatory failure and other physiological derangements. The previously described physiological basis for the increased incidence of postoperative ventilatory failure in hypothyroid patients includes decreased central and peripheral ventilatory responses to hypercarbia and hypoxia, muscle weakness, depressed central respiratory drive, and resultant alveolar hypoventilation. These ventilatory failures are associated most frequently with severe hypoxia and carbon dioxide (CO2) retention. The purpose of this clinical report is to discuss an interesting and unique anesthetic presentation of a patient with severe hypothyroidism. CLINICAL FEATURES: We describe an unique presentation of ventilatory failure in a 58 yr old man with severe hypothyroidism. He had exceedingly low perioperative respiratory rate (3-4 bpm) and minute ventilation volume, and at the same time developed primary acute respiratory alkalosis and associated hypocarbia (P(ET)CO2 approximately 320-22 mmHg). CONCLUSION: Our patient's ventilatory failure was based on unacceptably low minute ventilation and respiratory rate that was unable to sustain adequate oxygenation. His profoundly lowered basal metabolic rate and decreased CO2 production, resulting probably from severe hypothyroidism, may have resulted in development of acute respiratory alkalosis in spite of concurrently diminished minute ventilation.
Anal Bioanal Chem. 2008 Jan;390(2):679-88. Epub 2007 Oct 27. The structural modification of DNA nucleosides by nonenzymatic glycation: an in vitro study based on the reactions of glyoxal and methylglyoxal with 2'-deoxyguanosine. Li Y, Cohenford MA, Dutta U, Dain JA.
Biull Eksp Biol Med. 1995 Jun;119(6):590-3. [Adaptation to high altitude hypoxia facilitates a limitation of lipid peroxidation activation in inflammation and stress] [Article in Russian]Malyshev VV, Vasil'eva LS, Belogorov SB, Nefedova TV.
Am J Physiol Regul Integr Comp Physiol. 2007 Sep;293(3):R1159-68. Epub 2007 Jun 20.Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS production. Muller FL, Song W, Jang YC, Liu Y, Sabia M, Richardson A, Van Remmen H.
Radiobiologiia. 1984 Jan-Feb;24(1):29-34. [Enzyme activity of glutamic acid metabolism and the Krebs cycle in the brain of rats laser-irradiated against a background of altered adrenoreceptor function] [Article in Russian] Pikulev AT, Dzhugurian NA, Zyrianova TN, Lavrova VM, Mostovnikov VA.
Rejuvenation Res.2007 Dec12; :18072884, Exploring Overlooked Natural Mitochondria-Rejuvenative Intervention: The Puzzle of Bowhead Whales and Naked Mole Rats. Prokopov A.F.
Proceedings of the Japan Academy. Ser. B: Physical and Biological Sciences Vol.78, No.10(2002)pp.293-298. DNA methylation and Lamarckian inheritance, Sano H.
Biol Chem. 2009 Nov;390(11):1145-53. The epigenetic bottleneck of neurodegenerative and psychiatric diseases. Sananbenesi F, Fischer A. The orchestrated expression of genes is essential for the development and survival of every organism. In addition to the role of transcription factors, the availability of genes for transcription is controlled by a series of proteins that regulate epigenetic chromatin remodeling. The two most studied epigenetic phenomena are DNA methylation and histone-tail modifications. Although a large body of literature implicates the deregulation of histone acetylation and DNA methylation with the pathogenesis of cancer, recently epigenetic mechanisms have also gained much attention in the neuroscientific community. In fact, a new field of research is rapidly emerging and there is now accumulating evidence that the molecular machinery that regulates histone acetylation and DNA methylation is intimately involved in synaptic plasticity and is essential for learning and memory. Importantly, dysfunction of epigenetic gene expression in the brain might be involved in neurodegenerative and psychiatric diseases. In particular, it was found that inhibition of histone deacetylases attenuates synaptic and neuronal loss in animal models for various neurodegenerative diseases and improves cognitive function. In this article, we will summarize recent data in the novel field of neuroepigenetics and discuss the question why epigenetic strategies are suitable therapeutic approaches for the treatment of brain diseases.
Ukr Biokhim Zh 1994 Jan-Feb;66(1):109-12. [Protective effect of sodium bicarbonate in nitrite ion poisoning]. Shugalei IV, L'vov SN, Baev VI, Tselinskii IV
Am J Respir Crit Care Med. 2000 Mar;161(3 Pt 1):891-8. Modulation of release of reactive oxygen species by the contracting diaphragm. Stofan DA, Callahan LA, DiMarco AF, Nethery DE, Supinski GS.
Ecology: Vol. 50, No. 3, pp. 492-494. Carbon Dioxide Retention: A Mechanism of Ammonia Tolerance in Mammals. Studier EM and Fresquez AA.
Sci Signal. 2009 Mar 31;2(64): pe17. Reversing DNA methylation: new insights from neuronal activity-induced Gadd45b in adult neurogenesis. Wu H, Sun YE. Neurogenesis in the adult mammalian brain involves activity-dependent expression of genes critical for the proliferation of progenitors and for neuronal maturation. A recent study suggests that the stress response gene Gadd45b (growth arrest and DNA-damage-inducible protein 45 beta) can be transiently induced by neuronal activity and may promote adult neurogenesis through dynamic DNA demethylation of specific gene promoters in adult hippocampus. These results provide evidence supporting the provocative ideas that active DNA demethylation may occur in postmitotic neurons and that DNA methylation-mediated dynamic epigenetic regulation is involved in regulating long-lasting changes in neural plasticity in mammalian brains.
Patol Fiziol Eksp Ter. 2005 Apr-Jun;(2):13-5. [The effect of the NMDA-receptor blocker MK-801 on sensitivity of the respiratory system to carbon dioxide] Tarakanov IA, Dymetska A, Tarasova NN.
Life Sci. 1997;61(5):523-35. Effect of acidotic challenges on local depolarizations evoked by N-methyl-D-aspartate in the rat striatum. Urenjak J, Zilkha E, Gotoh M, Obrenovitch TP. Hypercapnia reduced NMDA-evoked responses in a concentration-dependent manner, with 7.5 and 15 % CO2 in the breathing mixture reducing the depolarization amplitude to 74 % and 64 % of that of the initial stimuli, respectively. Application of 50 mM NH4+ progressively reduced dialysate pH, and a further acidification was observed when NH4+ was discontinued. Perfusion of NMDA after NH4+ application evoked smaller depolarizations (56 % of the corresponding control, 5 min after NH4+ removal), and this effect persisted for over 1 h. Together, these results demonstrate that extracellular acidosis, such as that associated with excessive neuronal activation or ischemia, inhibits NMDA-evoked responses in vivo.
Arch Int Physiol Biochim. 1977 Apr;85(2):295-304. Glutamate and glutamine in the brain of the neonatal rat during hypercapnia. Van Leuven F, Weyne J, Leusen I.
Pediatrics 1995 Jun;95(6):868-874. Carbon dioxide protects the perinatal brain from hypoxic-ischemic damage: an experimental study in the immature rat. Vannucci RC, Towfighi J, Heitjan DF, Brucklacher RM
Pediatr Res 1997 Jul;42(1):24-29. Effect of carbon dioxide on cerebral metabolism during hypoxia-ischemia in the immature rat. Vannucci RC, Brucklacher RM, Vannucci SJ
Sci. Signal., 31 March 2009 Vol. 2, Issue 64, p. pe17, Reversing DNA Methylation: New Insights from Neuronal Activity-Induced Gadd45b in Adult Neurogenesis Wu H, Sun YI

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A R T I C L E

Genes, Carbon Dioxide and Adaptation

"Over the oxygen supply of the body carbon dioxide spreads its protecting wings."
- Friedrich Miescher, Swiss physiologist, 1885

To reach useful simplicities, we usually have to sift through the accumulated rationalizations previous generations have produced to justify doing things their way. If we could start with an accurate understanding of what life is, and what we are doing here, science could be built up deductively as well as by the accumulation of evidence. But the fact that we have grown up amid false and unworkable models of what life is, means that we have to lean heavily on evidence, building up new models inductively, imaginatively, and scientifically. Textbooks and professional journals can be useful if they are seen as monuments to past beliefs, and not as authorities to be accepted. Examining the dogmatic models of life and the world in which life exists, we can better understand the nature of the existing barriers to constructive work.

The Central Dogma of the molecular geneticists, in their own words, was that information flows only from DNA to RNA, and from RNA to protein, never in the other direction. The Central Dogma was formulated to suppress forever the Lamarckian idea of the inheritance of acquired characters, that Weismann's amputation of the tails of a multitude of mice had attempted to deal with earlier in the history of genetics.

The Central Dogma continues to be influential, even after a series of revisions. Until the 1990s, the only "practical" fruit of genetics had been genocide, but now it has become possible to insert genes into bacteria, and to use the bacteria to produce industrial quantities of specific proteins. In principle, that could be useful, although bovine growth hormone poses a threat to the health of both people and cows, human growth hormone poses a threat to athletes and old people, and human insulin could increase the number of treated diabetics. A deranged culture will put anything cheap to bad use. The ability to make organisms produce foreign proteins confirms that information can flow from DNA to protein, but as that technology was being developed, the discovery of retroviruses showed that the Central Dogma of molecular genetics was wrong, RNA is a very significant template for the production of DNA. And the scrapie prion shows that proteins can be infectious, passing along information without nucleic acids as the agent of transmission. The directed mutations demonstrated by John Cairns and others have thoroughly destroyed the Central Dogma of molecular genetics, even as it applied to the simplest organisms, but molecular genetics survives as an industrial and forensic technology.

Although evidence suggests that about 2% of human diseases involve the inheritance of an abnormal protein, the exact way the disease develops is never as clear as the geneticists would imply. And the major diseases, cancer, diabetes, heart disease, Alzheimer's, epilepsy, depression, etc., that are so often blamed on "genes," are so poorly understood that it is arbitrary and crazy to talk about the way genes "cause" them. People who had never had a problem with diabetes in their culture, very soon suffered from the same rate of diabetes as their neighbors when they immigrated into Israel and began eating the European style diet. The interesting thing about the genetic explanation for disease is how its proponents can believe what they are saying. If you read Konrad Lorenz's writings on racial hygiene, you can imagine that he might have really come to believe what he was saying, even if it was an invention that earned him personal prestige and revenge against people who were reluctant to accept his ideas of cultural excellence and inferiority. When I listened to Gunther Stent praising the doctrine he had taken straight from Konrad Lorenz's original genocide papers, I wondered how a German who had escaped the holocaust with his Jewish family when he was nine years old could talk about those doctrines without anger, and without pointing out the purpose for which they had been created. In the audience, a professor who had been a refugee from Hungary defended the doctrine, saying that a man and his work have nothing to do with each other, though the whole content of the doctrine was that a man and his work are identical, because his behavior is determined by his genes. These were mature, internationally known intellectuals, who made the most amazingly self-contradictory statements without embarrassment, because they were committed, for some deep, mysterious reason, to the doctrine of genetic determinism. If these refugees could espouse the rationale for "racial hygiene" as their own, I suppose it isn't so hard to understand that people can devote their life to studying the genetics of diabetes, even though diabetes has appeared suddenly in one generation of immigrants when their diet was suddenly changed, a massive fact that bluntly contradicts the genetic doctrine. There is something very deep in our culture that loves genetics.

One of the cultural trends that makes genetic determinism attractive is the theory of radical individualism, something that has grown up with protestant christianity, according to some historians. Roger Williams' work in nutrition seemed to be powered by this idea of individual genetic uniqueness, and in his case, the idea led him to some useful insights--he suggested that the environment could be adjusted to suit the highly specific needs of the individual. This idea led to the widespread belief that nutritional supplements might be needed by a large part of the population. Extreme nurturing of the deviant individual is the opposite extreme from the Lorenzian-Hitlerian solution, of eliminating everyone who wasn't a perfect Aryan specimen.

But Williams' genetic doctrine assumed that our nutritional needs were primarily inborn, determined by our unique genes. However, there is a famous experiment in which rats were made deficient in riboflavin, and when their corneal tissue showed evidence of the vitamin deficiency, they were given a standard diet. However, the standard diet no longer met the needs of their eye tissue, and during the remainder of the observation period, only a dose of riboflavin several times higher than normal would prevent the signs of deficiency. A developmental change had taken place in the cornea, making its vitamin B2 requirement abnormally high. If we accept the epigenetic, developmental idea of metabolic requirements, our idea of nurturing environmental support would consider the long-range effects of environmental adequacy, and would consider that much disease could be prevented by prenatal support, and by avoiding extreme deficiencies at any time. Williams himself emphasized the importance of prenatal nutrition in disease prevention, so he wasn't a genetic totalitarian; combining the idea of unique genetic individuality with the recognition that malnutrition causes disease, led him to believe in the necessity for nutitional adequacy, rather than to the extermination of the sick, weak, or different individuals.

The idea of "genetic determinism" says that our traits are the result of the specific proteins that are produced by our specific genes. The doctrine allows for some gradations, such as "half a dose" of a trait, but in practice it becomes a purely subjective accounting for everything in terms of mysterious degrees of "penetrance" of genes, and interactions with unknown factors. Proteins, that supposedly express our genetic constitution, include enzymes, structural proteins, antibodies, and a variety of protein hormones and peptide regulatory molecules. Every protein, including the smallest peptide (except certain cyclic peptides), contains at least one amine group, and usually several. Amine groups react spontaneously with carbon dioxide, to form carbamino groups, and they can also react, nonenzymically, with sugars, in the reaction called glycation or glycosylation. These chemical changes alter the functions of the proteins, so that hormones and their "receptors," tubules and filaments, enzymes and synthetic systems, all behave differently under their influences. (The proteins' electrical charge, relationship to water and fats, and shape, change quickly and reversibly as the concentration of carbon dioxide changes; in the absence of carbon dioxide, these properties tend to change irreversibly under the influence of metabolic stress.)

This is the clearest, and the most powerful, instance of metabolic influence on biological structure. That makes it very remarkable that it has been the subject of so few publications. I think the absence of discussion of this fundamental biological principle can be understood only in relation to the great importance it has for a new understanding of development and inheritance--it is an easily documented process that will invalidate some of the most deeply held beliefs of most of the people who are influential in science and politics.

I will continue discussing some of these implications in newsletters on imprinting, degenerative diseases, heart attacks, high blood pressure, and other special biological questions, but I think the most important work that remains to be done is to work out the exact mechanisms by which metabolic energy, expressed largely by factors such as the ratio of carbon dioxide to lactic acid, guides both development and evolution. These ideas will have to take into account the actual resources of the world, as well as the internal processes and resources of the organism. Each development in the organism, whether it leads to maturation or to degeneration, consists of responses to and interactions with specific environments.

Curiosity, esthetics, creativity, and stimulation are necessarily and deeply linked to metabolic efficiency and structural-anatomical development. For example, the known effects of stimulation and success (or isolation and depression) on brain anatomy and function should be linked meaningfully with metabolic, hormonal and dietary processes. There is a large amount of information available that could be put to practical use, but there are still important ideological barriers to be overcome. Marshalling the information needed to optimize our own development runs counter to the program of our technical-scientific culture, which prefers to believe that degeneration is programmed, while emergent evolution is unforeseeable. But, if an optimization project is presented as a way to forestall the "programmed degeneration," it might succeed in becoming part of the culture.

Vernadsky's idea of the Noosphere differs from the Gaia hypothesis (that the world is a self-regulating organism-like system) in the intrinsic directionality of Vernadsky's Noosphere, which makes the course of human society crucial for the fate of the planet. It proposes that planets, like organisms, are going somewhere. The Gaia hypothesis is increasingly being interpreted as a justification for feeling no responsibility for the effects of technology on the environment, and some people are expressing that view of the world as essentially a justification for any vandalism that may come along. Kary Mullis, for example, says that mass extinctions of organisms have occurred in the past, and so it's just natural for species to become extinct, and it isn't appropriate to be concerned about the extinctions that are being caused by civilization's technological depredations.

In the Noosphere, global warming and increased carbon dioxide would represent an advance toward a higher state of "metabolism" of the world, and this would support the emergence of new biological forms from those existing. But if whole systems of life are destroyed before that happens, the biological achievements of the past could be lost irretrievably; there is no guarantee that the system will continue to work, if major sectors are deleted from the interacting systems. Even in terms of the Gaia conception, that the earth is like an organism, consider what the loss of genetic complexity means for an organism. Sometimes, for example, things that happen to an individual lead to sterility several generations later, although the procedure didn't seem lethal for the individual or its immediate descendants.

The whole idea of "evolution" is that the past is preserved within the present, or that the present is built upon the accomplishments of the past. The idea that evolution has been "random," and that the world is simply self-regulating, might seem liberating to those who hate the idea that they might be intrinsically responsible for anything outside of themselves, but it is liberating only in the way that a vandal's manifesto might be, declaring the world to be their playground.

The problem with such a manifesto of irresponsibility is simply that it is built upon the same system of cultural assumptions that produced Nazi eugenics, and that those assumptions are false. The political assumptions of the people who controlled scientific institutions were built into a set of pseudo-scientific doctrines, which continue to be valued for their political and philosophical implications.

For hundreds or thousands of years, the therapeutic value of carbonated mineral springs has been known. The belief that it was the water's lively gas content that made it therapeutic led Joseph Priestley to investigate ways to make artificially carbonated water, and in the process he discovered oxygen. Carbonated water had its medical vogue in the 19th century, but the modern medical establishment has chosen to define itself in a way that glorifies "dangerous," "powerful" treatments, and ridicules "natural" and mild approaches. The motivation is obvious--to maintain a monopoly, there must be some reason to exclude the general public from "the practice of medicine." Witch doctors maintained their monopoly by working with frightening ghost-powers, and modern medicine uses its technical mystifications to the same purpose.vAlthough the medical profession hasn't lost its legal monopoly on health care, corporate interests have come to control the way medicine is practiced, and the way research is done in all the fields related to medicine.

The fact that carbon dioxide therapy is extremely safe has led to the official doctrine that it can't be effective. The results reviewed by Yandell Henderson in the Cyclopedia of Medicine in 1940 were so impressive that carbon dioxide therapy would have been as commonly used and as well known as oxygen therapy, radiation treatments, sulfa drugs, barbiturates, and digitalis, but it was completely lacking in the thrilling mystique of those dangerous treatments.

Henderson assumed that carbon dioxide use was becoming a permanent part of medicine, to be used with anesthesia to prevent cessation of spontaneous breathing, during recovery from surgery to prevent shock and pneumonia, for stimulating respiration in newborns, and for resuscitating drowning or suffocation victims, as well as for treatment of heart disease and some neurological conditions (see below). However, its use in surgery and resuscitation has probably decreased since he wrote, despite occasional publications pointing out the dangers involved in the use of oxygen without carbon dioxide.

REFERENCES

O. Rahn, "Protozoa need carbon dioxide for growth," Growth 5, 197-199, 1941. "

On page 113 of this volume, the statement of Valley and Rettger that all bacteria need carbon dioxide for growth had been shown to apply to young as well as old cells." "...it is possible...to remove it as rapidly as it is produced, and under these circumstances, bacteria cannot multiply."

Y. Henderson, "Carbon Dioxide," Cyclopedia of Medicine, 1940. "

Before considering these matters, it will be best that the mind be cleared of certain deep rooted misconceptions that have long opposed the truth and impeded its applications. It will be seen that carbon dioxide is truly the breath of life."

"The human mind is inherently inclined to take a moralistic view of nature. Prior to the modern scientific era, which only goes back a generation or two, if indeed it can be said as yet even to have begun in popular thought, nearly every problem was viewed as an alternative between good and evil, righteousness and sin, God and the Devil. This superstitious slant still distorts the conceptions of health and disease; indeed, it is mainly derived from the experience of physical suffering. Lavoisier contributed unintentionally to this conception when he defined the life supporting character of oxygen and the suffocating power of carbon dioxide. Accordingly, for more than a century after his death, and even now in the field of respiration and related functions, oxygen typifies the Good and carbon dioxide is still regarded as a spirit of Evil. There could scarcely be a greater misconception of the true biological relations of these gases." "Carbon dioxide is the chief hormone of the entire body; it is the only one that is produced by every tissue and that probably acts on every organ. In the regulation of the functions of the body, carbon dioxide exerts at least 3 well defined influences: (1) It is one of the prime factors in the acid-base balance of the blood. (2) It is the principal control of respiration. (3) It exerts an essential tonic influence upon the heart and peripheral circulation."

"A frog's muscle will contract effectively and repeatedly under suitable stimulation in an atmosphere of pure nitrogen. In contraction, a muscle produces lactic acid, partly by reconversion into sugar. In other words, oxygen is not one of the primary factors in muscular work. The reserve store of oxygen in the body is small. Vigorous breathing does not take place before an exertion; the exertion is first made and then the oxygen needed to clear the system in preparation for another exertion is absorbed. The demand for oxygen for this scavenging of waste and restoration of power is termed by A.V. Hill the "oxygen deficit" of exercise."

"On the other hand, present knowledge indicates that carbon dioxide is an absolutely essential component of protoplasm. It is one of the factors in the balance of alkali and acid for the maintenance of the normal pH of the tissues. Acapnia, that is diminution of the normal content of carbon dioxide, involves therefore, a disturbance of one of the fundamental conditions of life."

"These observations upon the circulation showed also that in animals reduced to a state of shock the carbon dioxide of the blood, or as it now be generally termed, the "alkaline reserve," is greatly reduced. This experimental result was later confirmed by the observations of Cannon upon wounded soldiers during the war."

"Catatonia.---Finally, mention may be made of the extraordinary observations reported by the late A.S. Lovenhart, in which he found that inhalation of carbon dioxide to cases of catatonia induced a temporary restoration of intelligence and mental responsiveness. The simplest explanation of the results in these cases is attained by postulating an habitual contraction of blood-vessels in the brain of the catatonic patient, similar to that in the heart and limbs of the cases discussed in the previous section. If this view is correct, the beneficial effects of the inhalation are due to improvement in the circulation in the brain under the influence of carbon dioxide upon the finer blood vessels."

Vojnosanit Pregl 1996 Jul-Aug;53(4):261-74. [Carbon dioxide inhibits the generation of active forms of oxygen in human and animal cells and the significance of the phenomenon in biology and medicine]. Boljevic S, Kogan AH, Gracev SV, Jelisejeva SV, Daniljak IG

Carbon dioxide (CO2) influence in generation of active oxygen forms (AOF) in human mononuclear cells (blood phagocytes and alveolar macrophages) and animal cells (tissue phagocytes, parenchymal and interstitial cells of liver, kidney, lung, brain and stomach) was investigated. The AOF generation was examined by the methods of chemiluminiscence (CL) using luminol, lucigenin and NBT (nitro blue tetrazolium) reaction. It was established that CO2 in concentrations similar to those in blood (5.1%, pCO2 37.5 mmHg) and at high concentrations (8.2%, pCO2 60 mmHg; 20%, pCO2 146 mmHg) showed pronounced inhibitory effect on the AOF generation in all the studied cells (usually reducing it 2 to 4 times). Those results were obtained not only after the direct contact of isolated cells with CO2, but also after the whole body exposure to CO2. Besides, it was established that venous blood gas mixture (CO2 - 45 mmHg, +O2 - 39 mmHg, + N2 - 646 mmHg) inhibited the AOF generation in cited cells more than the arterial blood gas mixture (CO2 - 40 mmHg, + O2 - 95 mmHg, + N2 - 595 mmHg). Carbon dioxide action mechanism was developed partially through the inhibition of the OAF generation in mitochondria and through deceleration of NADPH oxidative activity. Finally, it was established that CO2 led to the better coordination of oxidation and phosphorylation and increased the phosphorylation velocity in liver mitochondria. The results clearly confirmed the general property of CO2 to inhibit significantly the AOF generation in all the cell types. This favors the new explanation of the well-known evolutionary paradox: the Earth life and organisms preservation when the oxygen, that shows toxic effects on the cells through the AOF, occurs in the atmosphere. The results can also be used to explain in a new way the vasodilating effect of CO2 and the favorable hypercapnotherapy influence on the course of some bronchial asthma forms. The results are probably significant for the analysis of important bio-ecological problem, such as the increase of CO2 concentration in the atmosphere and its effect on the humans and animals.

Aviakosm Ekolog Med 1997;31(6):56-9. [Functional activity of peripheral blood neutrophils of rats during combined effects of hypoxia, hypercapnia and cooling]. Baev VI, Kuprava MV

Functional activity of neutrophilic leukocytes was studied in blood of rats immediately following single and repeated gradual increase in carbon dioxide and decrease in oxygen concentrations with the ambient temperature at 2 to 3 degrees C. Phagocytic activity was shown to alter as the number of phagocyticneutrophilic granulocytes, absorptivity or the phagocytic index, and the coefficient of phagocytosis completeness were elevated and levels of oxygen-dependent and oxygen-independent metabolism were reduced.

Izv Akad Nauk Ser Biol 1997 Mar-Apr;(2):204-17. [Carbon dioxide--a universal inhibitor of the generation of active oxygen forms by cells]. Kogan AKh, Grachev SV, Eliseeva SV, Bolevich S

Studies were carried out on blood phagocytes and alveolar macrophages of 96 humans, on the cells of the viscera and tissue phagocytes (liver, brain, myocardium, lungs, kidneys, stomach, and skeletal muscle), and liver mitochondria of 186 random bred white mice. Generation of the active oxygen forms was determined using different methods after direct effect of CO2 on the cells and biopsies and indirect effect of CO2 on the integral organism. The results obtained suggest that CO2 at a tension close to that observed in the blood (37.0 mm Hg) and high tensions (60 or 146 mm Hg) is a potent inhibitor of generation of the active oxygen forms by the cells and mitochondria of the human and tissues. The mechanism of CO2 effect appears to be realized, partially, through inhibition of the NADPH-oxidase activity. The results are important for deciphering of a paradox of evolution, life preservation upon appearance of oxygen in the atmosphere and succession of anaerobiosis by aerobiosis, and elucidation of some other problems of biology and medicine, as well as analysis of the global bioecological problem, such as ever increasing CO2 content in the atmosphere.

Ukr Biokhim Zh 1978 Mar-Apr;50(2):150-4.. [Content of adenine nucleotides and creatinephosphate in brain, myocardium, liver and skeletal muscle under combined action of hypercapnia, hypoxia and cooling]. Baev VI, Drukina MA

Cooling of rats under conditions of hypercapina and hypoxia induced no changes in the content of adenine nucleotides in the brain and skeletal muscles and decreased their concentration in the liver and myocardium. The content of creatine phosphate increased in the brain, but had no changes in the other tissues. 48 hours after cooling the amount of adenine nucleotides in the brain was higher as compared with the initial values, that was due to an increase in the ATP concentration; in the other tissues the contents of adenine nucleotides did not differ from that of the intact rats. The repeated action (48 hours after the first influences) caused no changes in the contents of adenine nucleotides in skeletal muscles and decreased them in the myocardium and liver. In the brain their amount and the content of creatinephosphate were increased as related to the intact rats. In the brain and myocardium the level of NADPH decreased after the first action and 48 hours after impact it restored up to the inital values. After repeated impact the level of NADPH in the brain restored up to initial values, in the myocardium it was increased.

Fiziol Zh SSSR 1978 Oct;64(10):1456-62. [Role of CO2 fixation in increasing the body's resistance to acute hypoxia]. Baev VI, Vasil'ev VV, Nikolaeva EN

In rats, the phenomenon of considerable increase in resistance to acute hypoxia observed after 2-hour stay under conditions of gradually increasing concentration of CO2, decreasing concentration of O2, And external cooling at 2--3 degrees seems to be based mainly on changes in concentration of CO2 (ACCORDINGLY, PCO2 and other forms of CO2 in the blood). The high resistance to acute hypoxia develops as well after subcutaneous or i.v. administration of 1.0 ml of water solution (169.2 mg/200 g) NaHCO2, (NH4)2SO4, MgSO4, MnSO4, and ZnSO4 (in proportion: 35 : 5 : 2 : 0.15 : 0.15, resp.) or after 1-hour effect of increased hypercapnia and hypoxia without cooling.

Vopr Med Khim 1976 Jan-Feb;22(1):37-41 [Pyridine nucleotide content in the brain and myocardium of rats under combined effect of hypercapnia, hypoxia and cooling]. Baev VI, Drukina MA

In experiments with rats, subjected to single and repeated simultaneous effect of hypercapnia, hypoxia and cooling, contents of pyridine nucleotides (NAD, NADP, NAD-H2 and NADP-H2) and macroergic substances were studied and also the activity of dehydrogenases of the pentose pathway was determined in brain and myocardium. In brain NADP was not practically determined and in heart its content was increased after the first and the second treatments. Content of NADP-H2 was distinctly decreased in both tissues after the single treatment. NAD was not altered in the tissues in all the periods studied. The amount of NAD-H2 was decreased in brain after the single treatment and it was increased in myocardium after the repeated one. In the activity of dehydrogenases marked alterations were not observed. Total macroergic substances were not altered in brain after the single treatment and after the repeated one they were increased mainly due to the ATP increase. In myocardium total macroergic substances were decreased after the both treatments.

ASTHMA: Buteyko's Cure.

© Ray Peat Ph.D. 2012. All Rights Reserved. www.RayPeat.com

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A R T I C L E

Serotonin, depression, and aggression: The problem of brain energy

Extremely serious mistakes about the nature of the solar system didn't matter too much until interplanetary travel became a possibility. Extremely serious mistakes about brain "transmitters" and "receptors" didn't matter too much until the drug industry got involved.

"Three years before Prozac received approval by the US Food and Drug Administration in late 1987, the German BGA, that country's FDA equivalent, had such serious reservations about Prozac's safety that it refused to approve the antidepressant based on Lilly's studies showing that previously nonsuicidal patients who took the drug had a fivefold higher rate of suicides and suicide attempts than those on older antidepressants, and a threefold higher rate than those taking placebos."

"Using figures on Prozac both from Lilly and independent research, however, Dr. David Healy, an expert on the brain's serotonin system and director of the North Wales Department of Psychological Medicine at the University of Wales, estimated that "probably 50,000 people have committed suicide on Prozac since its launch, over and above the number who would have done so if left untreated."

The Boston Globe, 2000.

Anyone who has been reading the mass media and watching television in recent decades is familiar with the use of tryptophan as an antidepressant. Tryptophan is easily converted to serotonin and melatonin in the body. The most popular kind of antidepressant, the serotonin reuptake inhibitor, is said to act by increasing the action of serotonin in the brain. Many people have read articles in popular science magazines explaining that a deficiency of serotonin can cause depression, suicide, and aggression. Estrogen is often said to achieve its wonderful effects by increasing the effects of serotonin.

Reserpine is an ancient tranquilizer, derived from a plant used in India for centuries. It has a powerful tranquilizing action, has been used to treat hypertension, and was found to be an antidepressant (Davies and Shepherd, 1955). It lowers the concentration of serotonin in the brain and other tissues. Isoniazid, an antidepressant that came into use in the 1950s, is effective, but it probably has no effect on serotonin. When those drugs were popular, serotonin wasnt recognized as a neurotransmitter. It wasnt until the 1960s that our present set of doctrines regarding serotonins effects on mood and behavior came into being.

Serotonin research is relatively new, but it rivals estrogen research for the level of incompetence and apparent fraudulent intent that can be found in professional publications.

This is partly because of the involvement of the drug industry, but the U.S. government also played a role in setting a pattern of confused and perverse interpretation of serotonin physiology, by its policy of denigrating and incriminating LSD, a powerful serotonin (approximate) antagonist, by any means possible, for example claiming that it causes genetic damage and provokes homicidal or suicidal violence. The issue of genetic damage was already disproved in the 1960s, but this was never publicly acknowledged by the National Institutes of Mental Health or other government agency. The governments irresponsible actions helped to create the drug culture, in which health warnings about drugs were widely disregarded, because the government had been caught in blatant fraud. In more recent years, government warnings about tryptophan supplements have been widely dismissed, because the government has so often lied. Even when the public health agencies try to do something right, they fail, because they have done so much wrong.

In animal studies LSD, and other anti-serotonin agents, increase playfulness and accelerate learning, and cause behavioral impairment only at very high doses. While reserpine was used medically for several decades, and was eventually found to have harmful side effects, medical research in LSD was stopped before its actual side effects could be discovered. The misrepresentations about LSD, as a powerful antiserotonin agent, allowed a set of cultural stereotypes about serotonin to be established. Misconceptions about serotonin and melatonin and tryptophan, which are metabolically interrelated, have persisted, and it seems that the drug industry has exploited these mistakes to promote the new generation of psychoactive drugs as activators of serotonin responses. If LSD makes people go berserk, as the government claimed, then a product to amplify the effects of serotonin should make people sane.

The serotonin reuptake inhibitors are called the third generation of antidepressants. The monoamine oxidase (MAO) inhibitors, that came into use in the 1950s, are called the first generation. When their patents expire on a generation of drugs, the drug companies find reasons for claiming that the new drugs are better. Every doctor in the country seems to know that the old MAO-inhibitors are dangerous because they can raise blood pressure if you eat certain kinds of cheese while taking them. In fact, statistics show that they are safer than the new generation of antidepressants. It is hardly possible for a physician to prescribe the most appropriate drug, because the medical licensing boards are thoroughly indoctrinated by the drug companies, to believe that the safest and most effective drugs are those whose patents are still in force.

While it is true that the newer antidepressants increase the actions of serotonin, it is not true that this explains their antidepressant action. This is a culturally conditioned promotional construction. Since different antidepressants increase, decrease, or dont affect the actions of serotonin, a radically new kind of theory of depression and the antidepressants is needed. Theories based on transmitter substances and receptors are favored by the drug industry, but that kind of thinking is hardly better than the belief in demons and their exorcism. If an herbal tea cures depression because the demon doesnt like its smell, at least the patient never has to abandon a remedy because a tea patent has expired.

In the world of neurotransmitters and receptors, there is ample room for the development of speculative mechanisms of drug action. Serotonin is regulated by the rate of its synthesis and degradation, by its uptake, storage, and release, and by its transporters, and its effects are modified by a great variety of receptors, by the number of these receptors, and by their binding affinities and competitive binders. Different receptors are defined by the effects of chemicals other than serotonin; this means that serotonin itself hypothetically gains some of the properties of every substance that shows some binding competition with serotonin. This complexity*note 1 has made it possible to argue that a given condition is caused by either an excess or a deficiency of serotonin.

The drug companies like to call some of their new products SSRI, selective serotonin reuptake inhibitors, meaning that they dont indiscriminately increase all the biogenic amines, the way the old MAO inhibitors supposedly did. Every drug does many things, each a little differently, so its technically true to say that they selectively do this or that. But the term antidepressant, as distinguished from tranquilizer, says that the drug is intended to relieve depression. Injecting serotonin never does that, but sometimes adrenalin or dopamine does, and these SSRI drugs increase the activities of those other amines enough that those changes could explain the altered mood, if it werent for the need to speak of a new generation of drugs. Injecting serotonin, or increasing its activity, can cause sedation, helplessness, or apathy, but these drugs have that effect only some of the time. Therefore, they arent called tranquilizers. If they were really selective for serotonin, they just wouldnt be antidepressants. And chemicals that antagonize serotonin do seem to function as antidepressants (Martin, et al., 1992). When an SSRI is used to treat irritability and aggression, it is appropriate to call it a tranquilizer. When drugs are used empirically, without really understanding the disease or the drug, classifications, descriptions, and names are subjective. The serotonin situation reminds me of the history of DES: For almost twenty years, this synthetic estrogen was marketed for the prevention of abortions; then it came out as the morning after contraception/abortion pill. If increasing serotonin isnt the cure, then maybe decreasing serotonin will be the cure.

To begin to understand serotonin, its necessary to step back from the culture of neurotransmitters, and to look at the larger biological picture.

Serotonin and estrogen have many systematically interrelated functions, and women are much more likely to suffer from depression than men are. Serotonin and histamine are increased by estrogen, and their activation mimics the effects of estrogen. Serotonin is closely involved in mood disorders, but also in a great variety of other problems that affect women much more frequently than men. These are probably primarily energy disorders, relating to cellular respiration and thyroid function. Liver disease and brain disease, e.g., Alzheimers disease, are both much more common in women than in men, and serotonin and estrogen strongly affect the energetic processes in these organs. Liver disease can increase the brains exposure to serotonin, ammonia, and histamine. It isnt just a coincidence that these three amines occur together and are neurotoxic; they are all stress-related substances, with natural roles in signaling and regulation.

There are good reasons for thinking that serotonin contributes to the nerve damage seen in multiple sclerosis and Alzheimers disease.

The high incidence of multiple sclerosis in women, and its onset during their reproductive years, is well known. The number of brain lesions is associated with the ratio of estrogen to progesterone. Estrogen activates mast cells to release histamine and serotonin, and activated mast cells can produce brain edema and demyelination. Blood clots have been microscopically associated with brain lesions like those in multiple sclerosis, and the platelets in clots release neurotoxic serotonin.

In Parkinsons disease, the benefits seen from increasing the concentration of dopamine could result from dopamines antagonism to serotonin; anti-serotonin drugs can alleviate the symptoms, and 5-hydroxytryptophan can worsen the symptoms (Chase, et al., 1976). Other movement disorders, including akathisia and chorea, can be produced by serotonin. In autism, repetitive motions are a common symptom, and serotonin is high in the blood serum and platelets of autistic children and their relatives. Irritable bowel syndrome, another kind of movement disorder, can be treated effectively with anti-serotonin agents. This syndrome is very common in women, with premenstrual exacerbations, when estrogen is highest. One of the side effects of oral contraceptives is chorea, uncontrollable dancing movements. Some research has found increased serotonin in people with Huntingtons chorea (Kish, et al., 1987), and positive results with bromocriptine have been reported (Agnoli, et al., 1977).

The neurosteroid, allopregnanolone, for which progesterone is the precursor, facilitates the inhibitory action of GABA, which is known to be deficient in some disorders of mood and movement. This suggests that progesterone will be therapeutic in the movement disorders, as it is in various mood problems. Progesterone has some specific antiserotonin actions (e.g., Wu, et al., 2000).

The serotonin reuptake inhibitors are presumed to have the same effect on the brain that they have on blood platelets. They inhibit the ability of platelets to retain and concentrate serotonin, allowing it to stay in the plasma. This uptake-inhibited condition is a model of the platelet behavior seen in multiple sclerosis and Alzheimers disease.

Serotonin and its derivative, melatonin, are both involved in the biology of torpor and hibernation. Serotonin inhibits mitochondrial respiration. Excitoxic death of nerve cells involves both the limitation of energy production, and increased cellular activation. Serotonin has both of these actions.

In hibernating animals, the stress of a declining food supply causes increased serotonin production. In humans and animals that dont hibernate, the stress of winter causes very similar changes. Serotonin lowers temperature by decreasing the metabolic rate. Tryptophan and melatonin are also hypothermic. In the winter, more thyroid is needed to maintain a normal rate of metabolism.

Increased serotonin interferes with the consolidation of learning. Hypothermia has a similar effect. Since estrogen increases serotonergia, and decreases body temperature, these effects help to explain the long-observed interference of estrogen with learning.

Although ammonia, produced by fatigue or liver inefficiency, creates torpor, it can also cause convulsions. It synergizes with serotonin, and both of these promote excitotoxicity.

Serotonins other names include thrombotonin, thrombocytin, enteramine, and 5-HT, its chemical name (5-hydroxytryptamine). These historical names derive from its role in the intestine and in blood vessels. In 1951, it was discovered that enteramine and thrombotonin were a single substance, and its involvement in circulatory disease, especially hypertension and vascular spasms, was the focus of research. (The increase in the number of cardiovascular events recently seen in the study of women using estrogen is what might be expected from something which increases serotonin dominance.) It causes vasoconstriction and vasospasm, and promotes clotting, when its released from platelets. Especially when it is released from mast cells, it is considered to be an inflammatory mediator, along with histamine. Edema, bronchoconstriction, immunosuppression, and joint swelling are produced by the release of serotonin from platelets or other cells. As inflammatory mediators, serotonin and histamine are directly involved in asthma, hives, gastrointestinal damage from alcohol, nerve cell damage, edema, and shock.

The broadly protective effects of antihistamine drugs have been energetically exploited by the drug industry for fifty years. Why havent antiserotonin drugs been similarly emphasized?

Research on LSD and its derivatives led to drugs such as bromocriptine, which oppose the effects of histamine and estrogen. Some of bromocriptines effects are clearly antagonistic to serotonin, though bromocriptine is usually called a dopamine agonist; dopamine is pretty generally a serotonin antagonist. Methysergide, a related drug with antiserotonin activity, is effective in protecting the brain from the effects of strokes. But there is a general disinclination to understand the broad biological meaning of these effects.

I think the corrupt campaign against LSD played a large role in this: If the therapeutic value of LSD and related drugs (e.g., methysergide) with expired patents,*note2 used as antiserotonin agents, became widely known, the existing system of power and profit would be threatened. The war on drugs has always had its ulterior motives,including justifying domestic and foreign interventions in issues that have nothing to do with drugs. And in the case of the serotonin/antiserotonin mythology, this war has been rewarding to the drug industry--Lilly makes over $2 billion annually on Prozac. Each suicide caused by Prozac would appear to be balanced by several hundred thousand dollars earned by the corporation. If the war on drugs were serious, this would be a good place to start. And in weighing what corporate punishments might be appropriate, this corporations financial support for universal capital punishment should be taken into account. Many experiments have shown that estrogen is very important for aggressive behavior in animals, and estrogen promotes serotonins actions. Some research shows that increased serotonin is associated with certain types of increased aggressiveness, and antiserotonin agents decrease aggresiveness (Ieni, et al., 1985; McMillen, et al., 1987) but the clearest research has to do with the crucial role of serotonin in learned helplessness. Learned helplessness is a biological condition that is created by inescapable stress. In this state, animals that would normally swim for hours will stop swimming after a few minutes and allow themselves to drown. They simply dont have enough mental or physical energy to overcome challenges.

In learned helplessness, the level of serotonin is high, and an excess of serotonin helps to create the state of learned helplessness.

Serotonin activates glycolysis, forming lactic acid. Excess lactic acid tends to decrease efficient energy production by interfering with mitochondrial respiration.

Heart failure, hypertension, muscle hyperalgesia (Babenko, et al., 2000), some panic reactions, and other maladaptive biological events associated with problems of energy metabolism, are promoted by excessive serotonin.

Autistic children and their relatives have high concentrations of serotonin in their serum and platelets. Members of a family tend to eat the same foods and to share other environmental conditions. Prenatal hypothyroidism and various kinds of imprinting, including hyperestrogenism, could account for this. Some studies have reported that thyroid supplements help autistic children, and anti-serotonin drugs have caused improvement in both children and adults.

Serotonin tends to cause hypoglycemia, and hypoglycemia inhibits the conversion of thyroxine into the active T3 hormone. Hypoglycemia and hypothyroidism increase noradrenaline, and autistic people have been found to have more noradrenaline than normal. These changes, along with the general hypometabolism caused by excess serotonin, seem to justify the use of a thyroid supplement in autism and other serotonin-excess syndromes.

Overdose with the serotonin reuptake inhibitors, or with 5-hydroxytryptophan, which has effects similar to serotonin, can cause the sometimes fatal "serotonin syndrome." Symptoms can include tremors, altered consciousness, poor coordination, cardiovascular disturbances, and seizures. Treatment with anti-serotonin drugs can alleviate the symptoms and usually can prevent death.

The serotonin syndrome has been reported in users of St. Johns wort as an antidepressant. Since the other large neutral amino acids compete with tryptophan for entry into cells, the branched chain amino acids have some anti-serotonin activity, and this could be a justification for their use by athletes, since tryptophan and serotonin decrease glycogen stores and reduce endurance.

The only amino acid that has ever been found to be carcinogenic is tryptophan. Its ability to mimic estrogen in promoting the release of prolactin is probably responsible.

A large carbohydrate meal increases the ratio of tryptophan to the competing amino acids, and it has been proposed that this can shift the bodys balance toward increased serotonin. In an animal study, bromocriptine, which shifts the balance away from serotonin, reduced obesity and insulin and free fatty acids, and improved glucose tolerance.

All of these observations are easiest to understand in terms of the suppression of cellular energy. Serotonin, like estrogen, lowers cellular ATP and interferes with oxidative metabolism.

Serotonin, like histamine, has its proper physiological functions, but it is a mediator of stress that has to be systematically balanced by the systems that support high energy respiratory metabolism. The use of supplements of tryptophan, hydroxytryptophan, or of the serotonin promoting antidepressant drugs, seems to be biologically inappropriate.

Many of the symptoms produced by excess serotonin are also the symptoms of hypothyroidism. Thyroid, progesterone, and high quality protein nutrition are central to protection against the serotonin syndromes. (Progesterone, like LSD, can inhibit the firing of serotonergic nerves, but an overdose, unlike LSD, never produces hallucinations.)

One of the many actions of the "SSRI" (such as fluoxetine, Prozac), which arent related to their effect on serotonin, is to increase the concentration of allopregnanolone in the brain, imitating the action of increased progesterone. Following this discovery, Lilly got Prozac approved as a treatment for premenstrual syndrome. Since the production of allopregnanolone and progesterone depends on the availability of pregnenolone and cholesterol, a low cholesterol level would be one of the factors making this an inappropriate way to treat PMS.

If we think biologically, starting with the role of serotonin as a damage-induced inflammatory mediator, we can speculate that an infinite number of irritating substances will be serotonin reuptake inhibitors. The particular history of the third generation antidepressants is one that should disturb our tranquility.

SOME NOTES AND SOURCES

*Note 1: I dont want to imply that the receptor theory is wrong just because it allows for the introduction of innumerable experimental artifacts; it is primarily wrong because it is tied to the profoundly irrelevant membrane theory of cell regulation.
*Note 2: Preparation for Lysergic Acid Amides: United States Patent Office 2,736,728 Patented February 28, 1956 Richard P. Pioch, Indianapolis, Indiana, assignor, to Eli Lilly and Co., Indianapolis, Indiana, a corporation of Indiana. No drawing. Application December 6, 1954, Serial No. 473,443. 10 claims. (Cl. 260-285.5)
From the PDR on Prozac: Pharmacodynamics: The antidepressant and antiobsessive-compulsive action of fluoxetine is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine.
The Lancet 269 (1955): 11720. Reserpine in the Treatment of Anxious and Depressed Patients, Davies DL and Shepherd M.
Gen Pharmacol 1994 Oct;25(6):1257-1262. Serotonin-induced decrease in brain ATP, stimulation of brain anaerobic glycolysis and elevation of plasma hemoglobin; the protective action of calmodulin antagonists. Koren-Schwartzer N, Chen-Zion M, Ben-Porat H, Beitner R Department of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. 1. Injection of serotonin (5-hydroxytryptamine) to rats, induced a dramatic fall in brain ATP level, accompanied by an increase in P(i). Concomitant to these changes, the activity of cytosolic phosphofructokinase, the rate-limiting enzyme of glycolysis, was significantly enhanced. Stimulation of anaerobic glycolysis was also reflected by a marked increase in lactate content in brain. 2. Brain glucose 1,6-bisphosphate level was decreased, whereas fructose 2,6-bisphosphate was unaffected by serotonin. 3. All these serotonin-induced changes in brain, which are characteristic for cerebral ischemia, were prevented by treatment with the calmodulin (CaM) antagonists, trifluoperazine or thioridazine. 4. Injection of serotonin also induced a marked elevation of plasma hemoglobin, reflecting lysed erythrocytes, which was also prevented by treatment with the CaM antagonists. 5. The present results suggest that CaM antagonists may be effective drugs in treatment of many pathological conditions and diseases in which plasma serotonin levels are known to increase.
J Neural Transm 1998;105(8-9):975-86. Role of tryptophan in the elevated serotonin-turnover in hepatic encephalopathy. Herneth AM, Steindl P, Ferenci P, Roth E, Hortnagl H Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Vienna, Austria. The increase of the brain levels of 5-hydroxyindoleacetic acid (5-HIAA) in hepatic encephalopathy (HE) suggests an increased turnover of serotonin (5-HT). To study the role of tryptophan on the increased brain 5-HT metabolism in HE, we attempted to monitor brain levels of tryptophan in rats with thioacetamide-induced acute liver failure by intravenous infusion of branched-chain amino acids (BCAA). The effect of this treatment on 5-HT synthesis and metabolism was investigated in five brain areas. BCAA-infusions (1 and 2 gm/kg/24 h) increased the ratio BCAA/aromatic amino acids in plasma two- and fourfold, respectively, and lowered both plasma and brain levels of tryptophan. At the higher BCAA-dose all parameters suggesting an altered brain 5-HT metabolism (increased brain levels of 5-HT and 5-HIAA, increased 5-HIAA/5-HT ratio) were almost completely normalized. These results provide further evidence for the role of tryptophan in the elevation of brain 5-HT metabolism and for a potential role of BCAA in the treatment of HE.
Tugai VA; Kurs'kii MD; Fedoriv OM. [Effect of serotonin on Ca2+ transport in mitochondria conjugated with the respiratory chain]. Ukrainskii Biokhimicheskii Zhurnal, 1973 Jul-Aug, 45(4):408-12.
Kurskii MD; Tugai VA; Fedoriv AN. [Effect of serotonin and calcium on separate components of respiratory chain of mitochondria in some rabbit tissues]. Ukrainskii Biokhimicheskii Zhurnal, 1970, 42(5):584-8.
Watanabe Y; Shibata S; Kobayashi B. Serotonin-induced swelling of rat liver mitochondria. Endocrinologia Japonica, 1969 Feb, 16(1):133-47.
Mahler DJ; Humoller FL. The influence of serotonin on oxidative metabolism of brain mitochondria. Proceedings of the Society for Experimental Biology and Medicine, 1968 Apr, 127(4):1074-9.
Eur J Pharmacol 1994 Aug 11;261(1-2):25-32. The effect of alpha 2-adrenoceptor antagonists in isolated globally ischemic rat hearts. Sargent CA, Dzwonczyk S, Grover G.J. The alpha 2-adrenoceptor antagonist, yohimbine, has been reported to protect hypoxic myocardium. Yohimbine has several other activities, including 5-HT receptor antagonism, at the concentrations at which protection was found. Pretreatment with yohimbine (1-10 microM) caused a concentration-dependent increase in reperfusion left ventricular developed pressure and a reduction in end diastolic pressure and lactate dehydrogenase release. The structurally similar compound rauwolscine (10 microM) also protected the ischemic myocardium. In contrast, idozoxan (0.3-10 microM) or tolazoline (10 microM) had no protective effects. The cardioprotective effects of yohimbine were partially reversed by 30 microM 5-HT. These results indicate that the mechanism for the cardioprotective activity of yohimbine may involve 5-HT receptor antagonistic activity.
Zubovskaia AM. [Effect of serotonin on some pathways of oxidative metabolism in the mitochondria of rabbit heart muscle]. Voprosy Meditsinskoi Khimii, 1968 Mar-Apr, 14(2):152-7.
Warashina Y. [On the effect of serotonin on phosphorylation of rat liver mitochondria]. Hoppe-Seylers Zeitschrift fur Physiologische Chemie, 1967 Feb, 348(2):139-48.
Eur Neuropsychopharmacol 1997 Oct;7 Suppl 3:S323-S328. Prevention of stress-induced morphological and cognitive consequences. McEwen BS, Conrad CD, Kuroda Y, Frankfurt M, Magarinos AM, McKittrick C, Laboratory of Neuroendocrinology, Rockefeller University, New York, NY 10021, USA. Atrophy and dysfunction of the human hippocampus is a feature of aging in some individuals, and this dysfunction predicts later dementia. There is reason to believe that adrenal glucocorticoids may contribute to these changes, since the elevations of glucocorticoids in Cushing's syndrome and during normal aging are associated with atrophy of the entire hippocampal formation in humans and are linked to deficits in short-term verbal memory. We have developed a model of stress-induced atrophy of the hippocampus of rats at the cellular level, and we have been investigating underlying mechanisms in search of agents that will block the atrophy. Repeated restraint stress in rats for 3 weeks causes changes in the hippocampal formation that include suppression of 5-HT1A receptor binding and atrophy of dendrites of CA3 pyramidal neurons, as well as impairment of initial learning of a radial arm maze task. Because serotonin is released by stressors and may play a role in the actions of stress on nerve cells, we investigated the actions of agents that facilitate or inhibit serotonin reuptake. Tianeptine is known to enhance serotonin uptake, and we compared it with fluoxetine, an inhibitor of 5-HT reuptake, as well as with desipramine. Tianeptine treatment (10 mg/kg/day) prevented the stress-induced atrophy of dendrites of CA3 pycamidal neurons, whereas neither fluoxetine (10 mg/kg/day) nor desipramine (10 mg/kg/day) had any effect. Tianeptine treatment also prevented the stress-induced impairment of radial maze learning. Because corticosterone- and stress-induced atrophy of CA3 dendrites is also blocked by phenytoin, an inhibitor of excitatory amino acid release and actions, these results suggest that serotonin released by stress or corticosterone may interact pre- or post-synaptically with glutamate released by stress or corticosterone, and that the final common path may involve interactive effects between serotonin and glutamate receptors on the dendrites of CA3 neurons innervated by mossy fibers from the dentate gyrus. We discuss the implications of these findings for treating cognitive impairments and the risk for dementia in the elderly.
J Mol Cell Cardiol 1985 Nov;17(11):1055-63. Digitoxin therapy partially restores cardiac catecholamine and brain serotonin metabolism in congestive heart failure. Sole MJ, Benedict CR, Versteeg DH, de Kloet ER. The effect of therapeutic doses of digitalis in modifying neural activity has been the subject of considerable controversy. In earlier studies we reported an increase both in serotonergic activity in the posterior hypothalamus and pons-medulla and in cardiac sympathetic tone in the failing cardiomyopathic hamster. In this study we examine the effects of doses of digitoxin, known to be therapeutic for hamster heart failure, on monoamine neurotransmitter metabolism in the brain and heart during the cardiomyopathy. Both digitoxin and ASI-222, a polar amino-glycoside which does not cross the blood-brain barrier, given either acutely (6 mg/kg ip) or chronically (2 mg/kg/day ip for 10 days), normalized the failure-induced increase in serotonin turnover in the pons-medulla but had no effect on the changes in the posterior hypothalamus. Digitoxin therapy also reduced cardiac and adrenal sympathetic activity partially restoring cardiac catecholamine stores. In order to more clearly define the pathways involved we measured serotonin (microgram/g protein) in 18 brain nuclei after 10 days of digitoxin or vehicle treatment. Heart failure was associated with an increase in serotonin in five nuclei: the mammillary bodies, ventromedial, periventricular and paraventricular nuclei of the hypothalamus, and the centralis superior nucleus of the raphe. Digitoxin therapy completely normalized the changes in the centralis superior and ventromedialis nuclei; neither congestive heart failure nor digitoxin affected serotonin levels in other nuclei. We conclude that there is an increase in activity in specific brain serotonergic nuclei in congestive heart failure. Digitalis reduces cardiac sympathetic tone and restores the changes in two of these nuclei: the ventromedial and the centralis superior.+2
Brain Res 2000 Jan 24;853(2):275-81. Duration and distribution of experimental muscle hyperalgesia in humans following combined infusions of serotonin and bradykinin. Babenko V, Svensson P, Graven-Nielsen T, Drewes AM, Jensen TS, Arendt-Nielsen L.
Eur J Pharmacol 1992 Feb 25;212(1):73-8. 5-HT3 receptor antagonists reverse helpless behaviour in rats. Martin P, Gozlan H, Puech AJ Departement de Pharmacologie, Faculte de Medecine Pitie-Salpetriere, Paris, France. The effects of the 5-HT3 receptor antagonists, zacopride, ondansetron and ICS 205-930, were investigated in an animal model of depression, the learned helplessness test. Rats previously subjected to a session of 60 inescapable foot-shocks exhibited a deficit of escape performance in three subsequent shuttle-box sessions. The 5-HT3 receptor antagonists administered i.p. twice daily on a chronic schedule (zacopride 0.03-2 mg/kg per day; ondansetron and ICS 205-930: 0.125-2 mg/kg per day) reduced the number of escape failures at low to moderate daily doses. This effect was not observed with the highest dose(s) of zacopride, ondansetron and ICS 205-930 tested. These results indicate that 5-HT3 antagonists may have effects like those of conventional antidepressants in rats.
Neuropharmacology 1992 Apr;31(4):323-30. Presynaptic serotonin mechanisms in rats subjected to inescapable shock. Edwards E, Kornrich W, Houtten PV, Henn FA. After exposure to uncontrollable shock training, two distinct groups of rats can be defined in terms of their performance in learning to escape from a controllable stress. Learned helpless rats do not learn to terminate the controllable stress, whereas non-learned helpless rats learn this response as readily as naive control rats do. These results implicate presynaptic serotonin mechanisms in the behavioral deficit caused by uncontrollable shock. In addition, a limbic-hypothalamic pathway may serve as a control center for the behavioral response to stress.
Neurochem Int 1992 Jul;21(1):29-35. In vitro neurotransmitter release in an animal model of depression. Edwards E, Kornrich W, van Houtten P, Henn FA. Sprague-Dawley rats exposed to uncontrollable shock can be separated by a subsequent shock escape test into two groups: a "helpless" (LH) group which demonstrates a deficit in escape behavior, and a "nonlearned helpless" (NLH) group which shows no escape deficit and acquires the escape response as readily as naive control rats (NC) do. The major finding concerned a significant increase in endogenous and K(+)-stimulated serotonin (5-HT) release in the hippocampal slices of LH rats. There were no apparent differences in acetylcholine, dopamine and noradrenaline release in the hippocampus of LH rats as compared to NLH and NC rats. These results add further support to previous studies in our laboratory which implicate presynaptic 5-HT mechanisms in the behavioral deficit caused by uncontrollable shock.
Psychiatry Res 1994 Jun;52(3):285-93. In vivo serotonin release and learned helplessness. Petty F, Kramer G, Wilson L, Jordan S Mental Health Clinic, Dallas Veterans Affairs Medical Center, TX. Learned helplessness, a behavioral depression caused by exposure to inescapable stress, is considered to be an animal model of human depressive disorder. Like human depression, learned helplessness has been associated with a defect in serotonergic function, but the nature of this relationship is not entirely clear. We have used in vivo microdialysis brain perfusion to measure serotonin (5-hydroxytryptamine, 5HT) in extracellular space of medial frontal cortex in conscious, freely moving rats. Basal 5HT levels in rats perfused before exposure to tail-shock stress did not themselves correlate with subsequent learned helplessness behavior. However, 5HT release after stress showed a significant increase with helpless behavior. These data support the hypothesis that a cortical serotonergic excess is causally related to the development of learned helplessness.
Pharmacol Biochem Behav 1994 Jul;48(3):671-6. Does learned helplessness induction by haloperidol involve serotonin mediation? Petty F, Kramer G, Moeller M Veterans Affairs Medical Center, Dallas 75216. Learned helplessness (LH) is a behavioral depression following inescapable stress. Helpless behavior was induced in naive rats by the dopamine D2 receptor blocker haloperidol (HDL) in a dose-dependent manner, with the greatest effects seen at 20 mg/kg (IP). Rats were tested 24 h after injection. Haloperidol (IP) increased release of serotonin (5-HT) in medial prefrontal cortex (MPC) as measured by in vivo microdialysis. Perfusion of HDL through the probe in MPC caused increased cortical 5-HT release, as did perfusion of both dopamine and the dopamine agonist apomorphine. Our previous work found that increased 5-HT release in MPC correlates with the development of LH. The present work suggests that increased DA release in MPC, known to occur with both inescapable stress and with HDL, may play a necessary but not sufficient role in the development of LH. Also, this suggests that increased DA activity in MPC leads to increased 5-HT release in MPC and to subsequent behavioral depression.
Stroke 1991 Nov;22(11):1448-51. Platelet secretory products may contribute to neuronal injury. Joseph R, Tsering C, Grunfeld S, Welch KM Department of Neurology, Henry Ford Hospital and Health Sciences Center, Detroit, MI 48202. BACKGROUND: We do not fully understand the mechanisms for neuronal damage following cerebral arterial occlusion by a thrombus that consists mainly of platelets. The view that certain endogenous substances, such as glutamate, may also contribute to neuronal injury is now reasonably well established. Blood platelets are known to contain and secrete a number of substances that have been associated with neuronal dysfunction. Therefore, we hypothesize that a high concentration (approximately several thousand-fold higher than in plasma, in our estimation) of locally released platelet secretory products derived from the causative thrombus may contribute to neuronal injury and promote reactive gliosis. SUMMARY OF COMMENT: We have recently been able to report some direct support for this concept. When organotypic spinal cord cultures were exposed to platelet and platelet products, a significant reduction in the number and the size of the surviving neurons occurred in comparison with those in controls. We further observed that serotonin, a major platelet product, has neurotoxic properties. There may be other platelet components with similar effect. CONCLUSIONS: The hypothesis of platelet-mediated neurotoxicity gains some support from these recent in vitro findings. The concept could provide a new area of research in stroke, both at the clinical and basic levels.
J. Clin Psychopharmacol 1991 Aug; 11(4):277-9. Disseminated intravascular coagulation and acute myoglobinuric renal failure: a consequence of the serotonergic syndrome. Miller F, Friedman R, Tanenbaum J, Griffin A. Letter
Chronobiol Int 2000 Mar;17(2):155-72. Association of the antidiabetic effects of bromocriptine with a shift in the daily rhythm of monoamine metabolism within the suprachiasmatic nuclei of the Syrian hamster. Luo S, Luo J, Cincotta AH. Bromocriptine, a dopamine D2 agonist, inhibits seasonal fattening and improves seasonal insulin resistance in Syrian hamsters. Compared with control values, bromocriptine treatment significantly reduced weight gain (14.9 vs. -2.9 g, p < .01) and the areas under the GTT glucose and insulin curves by 29% and 48%, respectively (p < .05). Basal plasma insulin concentration was markedly reduced throughout the day in bromocriptine-treated animals without influencing plasma glucose levels. Bromocriptine reduced the daily peak in FFA by 26% during the late light span (p < .05). Thus, bromocriptine-induced resetting of daily patterns of SCN neurotransmitter metabolism is associated with the effects of bromocriptine on attenuation of the obese insulin-resistant and glucose-intolerant condition. A large body of corroborating evidence suggests that such bromocriptine-induced changes in SCN monoamine metabolism may be functional in its effects on metabolism.
Eur J Pharmacol 1982 Jul 30;81(4):569-76. Actions of serotonin antagonists on dog coronary artery. Brazenor RM, Angus JA. Serotonin released from platelets may initiate coronary vasospasm in patients with variant angina. If this hypothesis is correct, serotonin antagonists without constrictor activity may be useful in this form of angina. We have investigated drugs classified as serotonin antagonists on dog circumflex coronary artery ring segments in vitro. Ergotamine, dihydroergotamine, bromocriptine, lisuride, ergometrine, ketanserin, trazodone, cyproheptadine and pizotifen caused non-competitive antagonism of serotonin concentration-response curves. In addition, ketanserin, trazodone, bromocriptine and pizotifen inhibited noradrenaline responses in concentrations similar to those required for serotonin antagonism. All drugs with the exception of ketanserin, cyproheptadine and pizotifen showed some degree of intrinsic constrictor activity. Methysergide antagonized responses to serotonin competitively but also constricted the coronary artery. The lack of a silent competitive serotonin antagonist precludes a definite characterization of coronary serotonin receptors at this time. However, the profile of activity observed for the antagonist drugs in the coronary artery differs from that seen in other vascular tissues. Of the drugs tested, ketanserin may be the most useful in variant angina since it is a potent 5HT antagonist, lacks agonist activity and has alpha-adrenoceptor blocking activity.
Eur J Pharmacol 1985 May 8;111(2):211-20. Maternal aggression in mice: effects of treatments with PCPA, 5-HTP and 5-HT receptor antagonists. Ieni JR, Thurmond JB. Drug treatments which influence brain serotonergic systems were administered to lactating female mice during the early postpartum period, and their effects on aggressive behavior, locomotor activity and brain monoamines were examined. P-chlorophenylalanine (200 and 400 mg/kg) and 5-hydroxytryptophan (100 mg/kg) inhibited fighting behavior of postpartum mice toward unfamiliar male intruder mice. These drug-treated postpartum females showed increased latencies to attack male intruders and also reduced frequencies of attack. In addition, postpartum mice treated with the serotonin receptor antagonists, mianserin (2 and 4 mg/kg), methysergide (4 mg/kg) and methiothepin (0.25 and 0.5 mg/kg), displayed significantly less aggressive behavior than control mice, as measured by reduced number of attacks. Whole brain monoamine and monoamine metabolite levels were measured after drug treatments. The behavioral results are discussed in terms of drug-induced changes in brain chemistry and indicate a possible role for serotonin in the mediation of maternal aggressive behavior of mice.
Naunyn Schmiedebergs Arch Pharmacol 1987 Apr;335(4):454-64. Effects of gepirone, an aryl-piperazine anxiolytic drug, on aggressive behavior and brain monoaminergic neurotransmission. McMillen BA, Scott SM, Williams HL, Sanghera MK. Gepirone (BMY 13805), a buspirone analog, was used to determine the antianxiety mechanism of the arylpiperazine class of drugs. Because of the weak effects of these drugs on conflict behavior, isolation-induced aggressive mice were used as the antianxiety model. Gepirone, like buspirone, potently inhibited attacks against group housed intruder mice (ED50 = 4.5 mg/kg i.p.) without causing sedation or ataxia. Inhibition of aggression was potentiated by co-administration of 0.25 mg/kg methiothepin or 2.5 mg/kg methysergide. Gepirone had variable effects on dopamine metabolism and reduced 5-hydroxytryptamine (5HT) metabolism about one third after a dose of 2.5 mg/kg. In contrast to buspirone, which markedly increased dopaminergic impulse flow, gepirone inhibited the firing of most cells recorded from the substantia nigra zona compacta in doses of 2.3-10 mg/kg i.v. and the effects were reversible by administration of haloperidol. The common metabolite of buspirone and gepirone, 1-(2-pyrimidinyl)-piperazine, caused increased firing rates only. Gepirone potently inhibited serotonergic impulse flow recorded from the dorsal raphe nucleus (88.3% after 0.04 mg/kg) and this effect was partially reversed by serotonergic antagonists. Both buspirone and gepirone displaced [3H]-5HT from the 5HT1a binding site in the hippocampus with IC50 values of 10 and 58 nM, respectively. Non-alkyl substituted aryl-piperazines displaced [3H]-5HT from both 5HT1a and 5HT1b binding sites. Thus, although gepirone may be a weak postsynaptic 5HT agonist, its primary effect is to decrease 5HT neurotransmission. In support of this conclusion was the observed potentiation of antiaggressive effects by blocking 5HT receptors wit small doses of methiothepin or methysergide, which would exacerbate the decreased release of 5HT caused by gepirone. These results are in harmony with reports that decreased serotonergic activity has anxiolytic-like effects in animal models of anxiety.
Farmakol Toksikol 1975 Mar-Apr;38(2):148-51. [Participation of the serotonin-reactive brain structure in certain forms of behavior in golden hamsters]. Popova NK, Bertogaeva VD. A viviacious play of young hamsters is shown to be accompanied by a drop of the serotonin level in the brain stem and the subsequent slumber - by its rise, while the corticosteroids content of the peripheral blood with the playful behavior experiences no changes. Iprazid and 5-oxytryptophan inhibit the playful activity, while dioxyphenylalanina (DOPA) does not influence it. A similar depression of the serotonin level in the brain stem was also noted in an aggressive behavior and stress conditions arising when adult male-hamsters are grouped together. A conclusion is drawn to the effect that changes in the content of serotonin in the brain stem are not associated with the emotional colouration of the condition, but rather reflect the transition from the somnolence to a highly active behavior.
Biol Psychiatry 1985 Sep;20(9):1023-5 Triiodothyronine-induced reversal of learned helplessness in rats. Martin P, Brochet D, Soubrie P, Simon P.

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Academic authoritarians, language, metaphor, animals, and science

Academic authoritarians, language, metaphor, animals, & science

A few years ago a group of researchers in Scotland studying learning in apes did some experiments (involving opening boxes to get a piece of candy inside) that showed that chimpanzees learn in a variety of flexibly adaptive ways, and that 3 year old children being presented with a similar task most often did it in ways that appear to be less intelligent than the apes. They suggest that the difference in performance of chimpanzees and children may be due to a greater susceptibility of children to cultural conventions. (Horner and Whiten, 2005; Whiten, et al., 2004).

In my newsletter on puberty, I described some of the effects of foods and hormones on intelligence. Here, I want to consider the effects of culture on the way people learn and think. Culture, it seems, starts to make us stupid long before the metabolic problems appear.

For many years I described culture as the perceived limits of possibility, but people usually prefer to think of it as the learned rules of conduct in a society. In the late 1950s I was talking with a psychologist about the nature of mental maps, and I said that I found my way around campus by reference to mental pictures of the locations of things, and he said that his method was to follow a series of rules, go out the front door and turn left, turn left at the first corner, walk three blocks and turn right, ....up the stairs, turn right, fourth office on the left. He had been studying mental processes for about 40 years, so his claim made an impression on me.

I thought this style of thinking might have something to do with the growing technological preference for digital, rather than analog, devices. The complexity and continuity of the real world is made to seem more precise and concrete by turning it into rules and numbers.

Around the same time, I found that some people dream in vivid images, while others describe dreams as listening to someone tell a story.

Several years later, a graduate student of language philosophy from MIT told me that I was just confused if I believed that I had mental images that I could use in thinking. His attitude was that language, in its forms and in the ways it could convey meaning, was governed by rules. He was part of an effort to define consciousness in terms of rules that could be manipulated formally. This was just a new variation on the doctrine of an ideal language that has concerned many philosophers since Leibniz, but now its main use is to convince people that cultural conventions and authority are rooted in the nature of our minds, rather than in particular things that people experience and the ways in which they are treated.

George Orwell, whose novels showed some of the ways language is used to control people, believed that language should be like a clear window between minds, but knew that it was habitually used to distort, mislead, and control. Scientific and medical practices often follow the authority of culture and indoctrination, instead of intelligently confronting the meaning of the evidence, the way chimpanzees are able to do.

Not so many years ago, people believed that traits were determined by genes, and that the development of an organism was the result of--was caused by--the sequential expression of genes in the nucleus of the fertilized egg. When B.F. Skinner in the 1970s said a gestating baby isn't influenced by what happens to its mother, he was expressing a deeply rooted bio-medical dogma. Physicians insisted that a baby couldn't be harmed by its mother's malnutrition, as long as she lived to give birth. People could be quite vicious when their dogma was challenged, but their actions were systematically vicious when they weren't challenged.

An ovum doesn't just grow from an oocyte according to instructions in its genes, it is constructed, with surrounding nurse cells adding substances to its cytoplasm. Analogously, the fertilized egg doesn't just grow into a human being, it is constructed, by interactions with the mother's physiology. At birth, the environment continues to influence the ways in which cells develop and interact with each other.

Even during adulthood, the ways in which our cells--in the brain, immune system, and other organs--develop and interact are shaped by the environment. When Skinner was writing, many biologists still believed that each synapse of a nerve was directed by a gene, and couldn't be influenced by experience.

Our brain grows into our culture, and the culture lives in our nervous system. If a person grows up without hearing people speak, he will have grown a special kind of brain, making it difficult to learn to speak. (Genie, wolf boy, Kaspar Hauser, for example.)

When we ask a question and find an answer, we are changed. Thinking with learning is a developmental process. But many people learn at an early age not to question. This changes the nature of subsequent learning and brain development.

In the 1960s, many textbooks were published that claimed to use scientific language theory to improve the instruction of English, from grade school level to college level. They didn't work, and at the time they were being published they appeared fraudulent to people who didn't subscribe to the incipient cults of Generative Grammar and Artificial Intelligence that later developed into Cognitive Science.

At the time that Artificial Intelligence was coming to the attention of investors and academicians, Neodarwinism had already cleansed the university biology departments of its opponents who advocated more holistic views, and the idea of a brain that was hard-wired according to genetic instructions had entered both neurology and psychology. The field concept was disappearing from developmental biology, as Gestalt psychology was disappearing from the universities and journals.

In the humanities and social sciences, a fad appeared in the 1960s, in which a theory of grammar advocated by Noam Chomsky of MIT was said to explain human thinking and behavior, and specialists in anthropology, psychology, literature, rhetoric, sociology, and other academic fields, claimed that it informed their work in an essential way. The rapid spread of a doctrine for which there was essentially no evidence suggests that it was filling a need for many people in our culture. This doctrine was filling some of the gaps left by the failure of genetic determinism that was starting to be recognized. It gave new support to the doctrine of inborn capacities and limitations, in which formulaic indoctrination can be justified by the brain's natural structure.

Chomsky was committed to an idealistic, rationalist doctrine of innate ideas, and to argue for that doctrine, which held that there are transcendent forms (or deep structures) that control mind, he disposed of the opposing empiricist approach to mind by claiming that children simply learn language so rapidly that it would be impossible to explain on the basis of learning from experience. Separating vocabulary from grammar, he acknowledged that each language is different, and can be learned as easily by the children of immigrants of different ethnicity as by children whose ancestors spoke it, but that all humans have a genetically encoded universal grammar, a language organ. It is this inborn grammar that allows children to learn what he said would be inconceivable to learn so quickly from experience.

The abstract, computational nature of the inborn functions of the language organ would make a nice program for a translating machine, and the absence of such a useful program, after more than 50 years of trying to devise one, argues against the possibility of such a thing.

Since Plato's time, some people have believed that, behind the changing irregularities of real languages, there is a timeless, context-free language. In the late 1950s, when I was studying language and the ideal languages of the philosophers, I realized that George Santayana was right when he pointed out that each time an artificial language is used by real people in real situations, it is altered by the experience that accrues to each component, from the context in which it is used. If real language were the model for mathematics, then the values of numbers would change a little with every calculation.

Adults are usually slower than children at learning a new language, but they can make the process much quicker by memorizing paradigms. With those models, they can begin speaking intelligible sentences when they know only a few words. These basics of grammar are often outlined in just a few pages, but listing irregularities and exceptions can become very detailed and complex. The grammar that children use isn't as subtle as the grammar some adults use, and college freshmen are seldom masters of the grammar of their native language.

There have been various studies that have investigated the number of words understood by children at different ages.

The Virginia Polytechnic Institute website says that

By age 4 a person probably knows 5,600 words

By age 5 a person probably knows 9,600 words

By age 6 a person probably knows 14,700 words

By age 7 a person probably knows 21,200 words

By age 8 a person probably knows 26,300 words

By age 9 a person probably knows 29,300 words

By age 10 a person probably knows 34,300 words

By age 20 a college sophomore probably knows 120,000 words

A dictionary with 14,000 words is a substantial book. The grammar used by a 6 year old person isn't very complex, because at that age a person isn't likely to know all of the subtleties of their language. There is no reason to assume that a mind that can learn thousands of words and concepts in a year can't learn the grammatical patterns of a language--a much smaller number of patterns and relationships--in a few years.

Idioms and clichés are clusters of words that are frequently used together in the same pattern to express a stereotyped meaning. There are thousands of them in English, and some of them have existed for centuries, while others are regional and generational. It is possible to speak or write almost completely in clichés, and they are such an important part of language that their acquisition along with the basic vocabulary deserves more attention than linguists have given it. A mind that can learn so many clichés can certainly learn the relatively few stereotypical rules of phrasing that make up the grammar of a language. In fact, a grammar in some ways resembles a complex cliché.

Recognition of patterns, first of things that are present, then of meaningful sequences, is what we call awareness or consciousness. There is biological evidence, from the level of single cells through many types of organism, both plant and animal, that pattern recognition is a basic biological function. An organism that isn't oriented in space and time isn't an adapted, adapting, organism. Environments change, and the organization of life necessarily has some flexibility.

A traveling bird or dog can see a pattern once, and later, going in the opposite direction, can recognize and find specific places and objects. An ant or bee can see a pattern once, and communicate it to others.

If dogs and birds lived in colonies or cities, as bees and ants do, and carried food home from remote locations, they might have a need to communicate their knowledge. The fact that birds and dogs use their vocal organs and brains to communicate in ways that people have seldom cared to study doesn't imply that their brains differ radically from human brains in lacking a language organ.

People whose ideology says that animals use instinct rather than intelligence, and that they lack the language instinct, refuse to perceive animals that are demonstrating their ability to generalize or to understand language.

Organisms have genes, so a person could say that pattern recognition is genetically determined, but it would be a foolish and empty thing to say. (Nevertheless, people do say it.) The people who believe that there are genes for grammar believe that these mind-controlling genes give us the ability to generalize, and therefore say that animals aren't able to generalize, though their instinctive behaviors might sometimes seem to involve generalization.

In language, patterns are represented symbolically by patterned sounds, and some of those symbolically represented patterns are made up of other patterns. Different languages have different ways of representing different kinds of patterns.

Things are recognizable when they are far or near, moving or still, bright or dark, or upside down, because the recognition of a pattern is an integration involving both spatial and temporal components. The recognition of an object involves both generalization and concreteness.

Things that are very complex are likely to take longer to recognize, but the nature of any pattern is that it is a complex of parts and properties.

A name for a thing is a name for a pattern, a set of relationships.

The method of naming or identifying a relationship can make use of any way of patterning sound that can be recognized as making distinctions. Concepts and grammar aren't separable things, semantics and syntax are just aspects of a particular language's way of handling meaning.

As a child interacts with more and more things, and learns things about them, the patterns of familiar things are compared to the patterns of new things, and differences and similarities are noticed and used to understand relationships. The comparison of patterns is a process of making analogies, or metaphors. Similarities perceived become generalizations, and distinctions allow things to be grouped into categories.

When things are explored analogically, the exploration may first identify objects, and then explore the factors that make up the larger pattern that was first identified, in a kind of analysis, but this analysis is a sort of expansion inward, in which the discovered complexity has the extra meaning of the larger context in which it is found.

When something new is noticed, it excites the brain, and causes attention to be focused, in the orienting reflex. The various senses participate in examining the thing, in a physiological way of asking a question. Perception of new patterns and the formation of generalizations expands the ways in which questions are asked. When words are available, questions may be verbalized. The way in which questions are answered verbally may be useful, but it often diverts the questioning process, and provides rules and arbitrary generalizations that may take the place of the normal analogical processes of intelligence. The vocabulary of patterns no longer expands spontaneously, but tends to come to rest in a system of accepted opinions.

A few patterns, formulated in language, are substituted for the processes of exploration through metaphorical thinking. In the first stages of learning, the process is expansive and metaphorical. If a question is closed by an answer in the form of a rule that must be followed, subsequent learning can only be analytical and deductive.

Learning of this sort is always a system of closed compartments, though one system might occasionally be exchanged for another, in a conversion experience.

The exploratory analogical mind is able to form broad generalizations and to make deductions from those, but the validity of the generalization is always in a process of being tested. Both the deduction and the generalization are constantly open to revision in accordance with the available evidence.

If there were infallible authorities who set down general rules, language and knowledge could be idealized and made mathematically precise. In their absence, intelligence is necessary, but the authorities who would be infallible devise ways to confine and control intelligence, so that, with the mastery of a language, the growth of intelligence usually stops.

In the 1940s and '50s, W.J.J. Gordon organized a group called Synectics, to investigate the creative process, and to devise ways to teach people to solve problems effectively. It involved several methods for helping people to think analogically and metaphorically, and to avoid stereotyped interpretations. It was a way of teaching people to recover the style of thinking of young children, or of chimps, or other intelligent animals.

When the acquisition of language is burdened by the acceptance of clichés, producing the conventionalism mentioned by Horner and Whiten, with the substitution of deductive reasoning for metaphorical-analogical thinking, the natural pleasures of mental exploration and creation are lost, and a new kind of personality and character has come into existence.

Bob Altemeyer spent his career studying the authoritarian personality, and has identified its defining traits as conventionalism, submission to authority, and aggression, as sanctioned by the authorities. His last book, The Authoritarians (2006) is available on the internet.

Altemeyer found that people who scored high on his scale of authoritarianism tended to have faulty reasoning, with compartmentalized thinking, making it possible to hold contradictory beliefs, and to be dogmatic, hypocritical, and hostile.

Since he is looking at a spectrum, focusing on differences, I think he is likely to have underestimated the degree to which these traits exist in the mainstream, and in groups such as scientists, that have a professional commitment to clear reasoning and objectivity. With careful training, and in a culture that doesn't value creative metaphorical thinking, authoritarianism might be a preferred trait.

Konrad Lorenz (who with Niko Tinbergen got the Nobel Prize in 1973) believed that specific innate structures explained animal communication, and that natural selection had created those structures. Chomsky, who said that our genes create an innate Language Acquisition Device, distanced himself slightly from Lorenz's view by saying that it wasn't certain that natural selection was responsible for it. However, despite slightly different names for the hypothetical innate devices, their views were extremely similar.

Both Lorenz and Chomsky, and their doctrine of innate rule-based consciousness, have been popular and influential among university professors. When Lorenz wrote a book on degeneration, which was little more than a revised version of the articles he had written for the Nazi party's Office for Race Policy in the late 1930s and early 1940s, advocating the extermination of racial mongrels such as jews and gypsies, most biologists in the US praised it. Lorenz identified National Socialism with evolution as an agent of racial purification. His lifelong beliefs and activities--the loyalty to a strong leader, advocating the killing of the weak--identified Lorenz as an extreme authoritarian.

When a famous professor went on a lecture tour popularizing and affirming the scientific truth and importance of those publications, and asserting that all human actions and knowledge, language, work, art, and belief, are specified and determined by genes, he and his audience (which, at the University of Oregon, included members of the National Academy of Sciences and Jewish professors who had been refugees from Nazism, who listened approvingly) were outraged when a student mentioned the Nazi origin and intention of the original publications.

They said you can't say that a man's work has anything to do with his life and political beliefs, but in fact the lecturer had just finished saying that everything a person does is integral to that person's deepest nature, just as Lorenz said that a goose with a pot belly and odd beak, or a person with non-nordic physical features and behavior and cultural preferences--should be eliminated for the improvement of the species. Not a single professor in the audience questioned the science that had justified Hitler's racial policies, and some of them showed great hostility toward the critic.

In the 1960s, a professor compared graduate students' scores on the Miller Analogies Test, which is a widely used test of analogical thinking ability, to their academic grades. She found that the students who scored close to the average on the test had the highest grades and the greatest academic success, and those who deviated the most from the average on that test, in either direction, had the worst academic grades. If the ability to think analogically is inversely associated with authoritarianism, then her results would indicate that graduate schools select for authoritarianism. (If not, then they simply select for mediocrity.)

Although Bob Altemeyer's scale mainly identified right-wing, conservative authoritarians, he indicated that there could be left-wing authoritarians, too. Noam Chomsky is identified with left-wing political views, but his views of genetic determinism and a nativist view of language learning, and his anti-empiricist identification of himself as a philosophical Rationalist, have a great correspondence to the authoritarian character. The nativist rule-based nature of Cognitive Science is just the modern form of an authoritarian tradition that has been influential since Plato's time.

The first thing a person is likely to notice when looking at Chomsky's work in linguistics is that he offers no evidence to support his extreme assertions. In fact, the main role evidence plays in his basic scheme is negative, that is, his doctrine of Poverty of the Stimulus asserts that children aren't exposed to enough examples of language for them to be able to learn grammar--therefore, grammar must be inborn.

I think Chomsky discovered long ago that the people around him were sufficiently authoritarian to accept assertions without evidence if they were presented in a form that looked complexly technical. Several people have published their correspondence with him, showing him to be authoritarian and arrogant, even rude and insulting, if the person questioned his handling of evidence, or the lack of evidence.

For example, people have argued with him about the JFK assassination, US policy in the Vietnam war, the HIV-AIDS issue, and the 9/11 investigation. In each case, he accepts the official position of the government, and insults those who question, for example, the adequacy of the Warren Commission report, or who believe that the pharmaceutical industry would manipulate the evidence regarding AIDS, or who doubt the conclusions of the 9/11 Commission investigation.

He says that investigation of such issues is diverting people from serious issues, as if those aren't serious issues. And even if it's true that the government was involved in the 9/11 terrorism, who cares? I mean, it doesn't have any significance. I mean it's a little bit like the huge amount of energy that's put out on trying to figure out who killed John F. Kennedy. I mean, who knows, and who caresplenty of people get killed all the time. Why does it matter that one of them happens to be John F. Kennedy?"

"If there was some reason to believe that there was a high level conspiracy" in the JFK assassination, "it might be interesting, but the evidence against that is just overwhelming." "And after that it's just a matter of, uh, if it's a jealous husband or the mafia or someone else, what difference does it make?" "It's just taking energy away from serious issues onto ones that don't matter. And I think the same is true here," regarding the events of 9/11. These reactions seem especially significant, considering his reputation as America's leading dissenter.

The speed with which Chomskyism spread through universities in the US in the 1960s convinced me that I was right in viewing the instruction of the humanities and social sciences as indoctrination, rather than objective treatment of knowledge. The reception of the authoritarian ideas of Lorenz and his apologists in biology departments offered me a new perspective on the motivations involved in the uniformity of the orthodox views of biology and medicine.

In being introduced into a profession, any lingering tendency toward analogical-metaphoric thinking is suppressed. I have known perceptive, imaginative people who, after a year or two in medical school, had become rigid rule-followers.

One of the perennial questions people have asked when they learn of the suppression of a therapy, is if the doctors are doing it to defend the profitable old methods, how can they refuse to use the better method even for themselves and their own family? The answer seems to be that their minds have been radically affected by their vocational training.

For many years, cancer and inflammation have been known to be closely associated, even to be aspects of a single process. This was obvious to analog minded people, but seemed utterly improbable to the essentialist mentality, because of the indoctrination that inflammation is a good thing, that couldn't coexist with a bad thing like cancer.

The philosophy of language might seem remote from politics and practical problems, but Kings and advertisers have understood that words and ideas are powerfully influential in maintaining relationships of power.

Theories of mind and language that justify arbitrary power, power that can't justify itself in terms of evidence, are more dangerous than merely mistaken scientific theories, because any theory that bases its arguments on evidence is capable of being disproved.

In the middle ages, the Divine Right of Kings was derived from certain kinds of theological reasoning. It has been replaced by newer ideologies, based on deductions from beliefs about the nature of mind and matter, words and genes, Computational Grammar, or numbers and quantized energy, but behind the ideology is the reality of the authoritarian personality.

I think if we understand more about the nature of language and its acquisition we will have a clearer picture of what is happening in our cultures, especially in the culture of science.

REFERENCES

New Yorker, April 16, 2007, The Interpreter: Has a remote Amazonian tribe upended our understanding of language? by John Colapinto. Dan Everett believes that Pirahã undermines Noam Chomsky's idea of a universal grammar.

Language & Communication Volume 23, Issue 1, January 2003, Pages 1-43. Remarks on the origins of morphophonemics in American structuralist linguistics, E. F. K. Koerner. Chomsky has led the public to believe that he originated things which he borrowed from earlier linguists.

Science. 2008 Feb 1;319(5863):569; author reply 569. Comparing social skills of children and apes. De Waal FB, Boesch C, Horner V, Whiten A. Letter

Curr Biol. 2007 Jun 19;17(12):1038-43. Epub 2007 Jun 7. Transmission of multiple traditions within and between chimpanzee groups. Whiten A, Spiteri A, Horner V, Bonnie KE, Lambeth SP, Schapiro SJ, de Waal FB. Centre for Social Learning and Cognitive Evolution and Scottish Primate Research Group, School of Psychology, University of St Andrews, St Andrews KY16 9JP, United Kingdom. A.whiten@st-andrews.ac.uk Field reports provide increasing evidence for local behavioral traditions among fish, birds, and mammals. These findings are significant for evolutionary biology because social learning affords faster adaptation than genetic change and has generated new (cultural) forms of evolution. Orangutan and chimpanzee field studies suggest that like humans, these apes are distinctive among animals in each exhibiting over 30 local traditions. However, direct evidence is lacking in apes and, with the exception of vocal dialects, in animals generally for the intergroup transmission that would allow innovations to spread widely and become evolutionarily significant phenomena. Here, we provide robust experimental evidence that alternative foraging techniques seeded in different groups of chimpanzees spread differentially not only within groups but serially across two further groups with substantial fidelity. Combining these results with those from recent social-diffusion studies in two larger groups offers the first experimental evidence that a nonhuman species can sustain unique local cultures, each constituted by multiple traditions. The convergence of these results with those from the wild implies a richness in chimpanzees' capacity for culture, a richness that parsimony suggests was shared with our common ancestor.

J Comp Psychol. 2007 Feb;121(1):12-21. Learning from others' mistakes? limits on understanding a trap-tube task by young chimpanzees (Pan troglodytes) and children (Homo sapiens). Horner V, Whiten A. Centre for Social Learning and Cognitive Evolution, School of Psychology, University of St Andrews, Fife, Scotland, UK. Vhorner@rmy.emory.edu A trap-tube task was used to determine whether chimpanzees (Pan troglodytes) and children (Homo sapiens) who observed a model's errors and successes could master the task in fewer trials than those who saw only successes. Two- to 7-year-old chimpanzees and 3- to 4-year-old children did not benefit from observing errors and found the task difficult. Two of the 6 chimpanzees developed a successful anticipatory strategy but showed no evidence of representing the core causal relations involved in trapping. Three- to 4-year-old children showed a similar limitation and tended to copy the actions of the demonstrator, irrespective of their causal relevance. Five- to 6-year-old children were able to master the task but did not appear to be influenced by social learning or benefit from observing errors.

Proc Biol Sci. 2007 Feb 7;274(1608):367-72. Spread of arbitrary conventions among chimpanzees: a controlled experiment. Bonnie KE, Horner V, Whiten A, de Waal FB. Living Links, Yerkes National Primate Research Center, Atlanta, GA 30329, USA. Kebonni@emory.edu Wild chimpanzees (Pan troglodytes) have a rich cultural repertoire--traditions common in some communities are not present in others. The majority of reports describe functional, material traditions, such as tool use. Arbitrary conventions have received far less attention. In the same way that observations of material culture in wild apes led to experiments to confirm social transmission and identify underlying learning mechanisms, experiments investigating how arbitrary habits or conventions arise and spread within a group are also required. The few relevant experimental studies reported thus far have relied on cross-species (i.e. human-ape) interaction offering limited ecological validity, and no study has successfully generated a tradition not involving tool use in an established group. We seeded one of two rewarded alternative endpoints to a complex sequence of behaviour in each of two chimpanzee groups. Each sequence spread in the group in which it was seeded, with many individuals unambiguously adopting the sequence demonstrated by a group member. In one group, the alternative sequence was discovered by a low ranking female, but was not learned by others. Since the action-sequences lacked meaning before the experiment and had no logical connection with reward, chimpanzees must have extracted both the form and benefits of these sequences through observation of others.

Proc Natl Acad Sci U S A. 2006 Sep 12;103(37):13878-83. Faithful replication of foraging techniques along cultural transmission chains by chimpanzees and children. Horner V, Whiten A, Flynn E, de Waal FB. Centre for Social Learning and Cognitive Evolution, School of Psychology, University of St. Andrews, Fife KY16 9JP, United Kingdom. Observational studies of wild chimpanzees (Pan troglodytes) have revealed population-specific differences in behavior, thought to represent cultural variation. Field studies have also reported behaviors indicative of cultural learning, such as close observation of adult skills by infants, and the use of similar foraging techniques within a population over many generations. Although experimental studies have shown that chimpanzees are able to learn complex behaviors by observation, it is unclear how closely these studies simulate the learning environment found in the wild. In the present study we have used a diffusion chain paradigm, whereby a behavior is passed from one individual to the next in a linear sequence in an attempt to simulate intergenerational transmission of a foraging skill. Using a powerful three-group, two-action methodology, we found that alternative methods used to obtain food from a foraging device ("lift door" versus "slide door") were accurately transmitted along two chains of six and five chimpanzees, respectively, such that the last chimpanzee in the chain used the same method as the original trained model. The fidelity of transmission within each chain is remarkable given that several individuals in the no-model control group were able to discover either method by individual exploration. A comparative study with human children revealed similar results. This study is the first to experimentally demonstrate the linear transmission of alternative foraging techniques by non-human primates. Our results show that chimpanzees have a capacity to sustain local traditions across multiple simulated generations.

Nature. 2005 Sep 29;437(7059):737-40. Conformity to cultural norms of tool use in chimpanzees. Whiten A, Horner V, de Waal FB. Centre for Social Learning and Cognitive Evolution, School of Psychology, University of St Andrews, St Andrews, Fife, KY16 9JP, UK. A.whiten@st-and.ac.uk Rich circumstantial evidence suggests that the extensive behavioural diversity recorded in wild great apes reflects a complexity of cultural variation unmatched by species other than our own. However, the capacity for cultural transmission assumed by this interpretation has remained difficult to test rigorously in the field, where the scope for controlled experimentation is limited. Here we show that experimentally introduced technologies will spread within different ape communities. Unobserved by group mates, we first trained a high-ranking female from each of two groups of captive chimpanzees to adopt one of two different tool-use techniques for obtaining food from the same 'Pan-pipe' apparatus, then re-introduced each female to her respective group. All but two of 32 chimpanzees mastered the new technique under the influence of their local expert, whereas none did so in a third population lacking an expert. Most chimpanzees adopted the method seeded in their group, and these traditions continued to diverge over time. A subset of chimpanzees that discovered the alternative method nevertheless went on to match the predominant approach of their companions, showing a conformity bias that is regarded as a hallmark of human culture.

Anim Cogn. 2005 Jul;8(3):164-81. Causal knowledge and imitation/emulation switching in chimpanzees (Pan troglodytes) and children (Homo sapiens). Horner V, Whiten A. Centre for Social Learning and Cognitive Evolution, School of Psychology, University of St Andrews, St Andrews, KY16 9JU, UK. Vkh1@st-andrews.ac.uk This study explored whether the tendency of chimpanzees and children to use emulation or imitation to solve a tool-using task was a response to the availability of causal information. Young wild-born chimpanzees from an African sanctuary and 3- to 4-year-old children observed a human demonstrator use a tool to retrieve a reward from a puzzle-box. The demonstration involved both causally relevant and irrelevant actions, and the box was presented in each of two conditions: opaque and clear. In the opaque condition, causal information about the effect of the tool inside the box was not available, and hence it was impossible to differentiate between the relevant and irrelevant parts of the demonstration. However, in the clear condition causal information was available, and subjects could potentially determine which actions were necessary. When chimpanzees were presented with the opaque box, they reproduced both the relevant and irrelevant actions, thus imitating the overall structure of the task. When the box was presented in the clear condition they instead ignored the irrelevant actions in favour of a more efficient, emulative technique. These results suggest that emulation is the favoured strategy of chimpanzees when sufficient causal information is available. However, if such information is not available, chimpanzees are prone to employ a more comprehensive copy of an observed action. In contrast to the chimpanzees, children employed imitation to solve the task in both conditions, at the expense of efficiency. We suggest that the difference in performance of chimpanzees and children may be due to a greater susceptibility of children to cultural conventions, perhaps combined with a differential focus on the results, actions and goals of the demonstrator.

Learn Behav. 2004 Feb;32(1):36-52. How do apes ape? Whiten A, Horner V, Litchfield CA, Marshall-Pescini S. Centre for Social Learning and Cognitive Evolution, Scottish Primate Research Group, School of Psychology, University of St. Andrews, St. Andrews, Fife, Scotland. A.whiten@st-and.ac.uk In the wake of telling critiques of the foundations on which earlier conclusions were based, the last 15 years have witnessed a renaissance in the study of social learning in apes. As a result, we are able to review 31 experimental studies from this period in which social learning in chimpanzees, gorillas, and orangutans has been investigated. The principal question framed at the beginning of this era, Do apes ape? has been answered in the affirmative, at least in certain conditions. The more interesting question now is, thus, How do apes ape? Answering this question has engendered richer taxonomies of the range of social-learning processes at work and new methodologies to uncover them. Together, these studies suggest that apes ape by employing a portfolio of alternative social-learning processes in flexibly adaptive ways, in conjunction with nonsocial learning. We conclude by sketching the kind of decision tree that appears to underlie the deployment of these alternatives.

http://www.ucc.vt.edu/stdysk/vocabula.html

© Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com

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<span class="koboSpan" id="kobo.1.1">Adaptive substance, creative regeneration: Mainstream science, repression, and creativity</span> A R T I C L E

Adaptive substance, creative regeneration: Mainstream science, repression, and creativity

"I intend to show you how neo-Darwinism has been invalidated within science itself, as an explanation of how life on earth has evolved and is evolving. It is nevertheless still perpetrated by the academic establishment, if only because it serves so well to promote genetic engineering, a technology that has the potential to destroy all life on earth. Furthermore, neo-Darwinism reinforces a worldview that undermines all moral values and prevents us from the necessary shift to holistic, ecological sciences that can truly regenerate the earth and revitalize the human spirit." Mae-Wan Ho http://www.i-sis.org.uk/paris.php

===========================

More than 50 years have been wasted in one of the most important and fundamental branches of science and medicine, for reasons that are highly ideological and political. Rather than studying the regeneration of organs and tissues, and recognizing its obvious importance in healing as well as in understanding the nature of life, much of the last century was devoted to the defamation of the researchers who were making real process in the field. Despite many demonstrations that regeneration can occur in adult mammals, students were taught that it happens only in lower vertebrates. I think it's important to look closely at the ideology responsible for this great loss.

Warburg and Szent-Gyorgyi, in thinking about cancer, emphasized that growth is the primordial function of all cells, and that the differentiated functions of complex organisms involve restraints of that primitive function, imposed by a system that has developed through time.

Seen with this orientation, regeneration is the spontaneous result of the disappearance of restraint. The reproduction of a whole plant from a twig, or clone, was a process known for thousands of years. Any part of the plant contains the information needed for making a whole plant. More than thirty years ago, cells from a tumor were added to the cells of a normal embryo, and the animal that matured from the embryo-tumor mix was normal, and had traits of both lineages, showing that the tumor cells had retained the genetic information of a complete healthy organism, and just needed a different environment in which to realize their full potential.

One of the currents of medical thinking, from classical times through Paracelsus to homeopathy and naturopathy, has been a confidence in the capacity of the organism to heal itself. But "modern" medicine has arrogated to itself the "healing power," with terrible results, mitigated only by their occasional reluctant acceptance of fragments of sane organismic thinking, such as recognizing the importance of nutrition, or of keeping sewage out of the drinking water. Research into methods to support the organism's natural restorative powers has been ridiculed and suppressed.

We are immersed in the propaganda of modern medicine, and part of that propaganda involves the confabulation of a history of science that supports their practice and their ideology. The real history of science won't be found in science textbooks.

"I intend to show you how neo-Darwinism has been invalidated within science itself, as an explanation of how life on earth has evolved and is evolving. It is nevertheless still perpetrated by the academic establishment, if only because it serves so well to promote genetic engineering, a technology that has the potential to destroy all life on earth. Furthermore, neo-Darwinism reinforces a worldview that undermines all moral values and prevents us from the necessary shift to holistic, ecological sciences that can truly regenerate the earth and revitalize the human spirit." Mae-Wan Ho http://www.i-sis.org.uk/paris.php

Mainstream medical treatments are based on some fundamentally absurd scientific ideas. The advent of experimental animal cloning and the industrialization of genetic engineering have undercut the most important biological doctrines of the 20th century, but the processes of critical thinking haven't made headway against most of the traditional medical stereotypes. Cloning shows that all cells are potential "stem cells," but this fact co-exists with the Hayflick doctrine, that says, essentially, that no cell is a stem cell.

The ideology of culturally significant "intellectuals"--scientists, professors, neurobiologists, linguists, philosophers, oncologists, geneticists--in the US is deeply influenced by the dualism and mechanistic materialism of Rene DesCartes.

The denial that animals can think or understand language, the claim that babies or animals don't feel pain, or that heart cells and brain cells can't divide, or that somatic cells lack the genetic capacity to be cloned, or that they are intrinsically mortal, limited to a maximum of 50 cell divisions--these absurdities of 20th century biology and medicine all resulted from an abject commitment to the mechanistic doctrine of matter and life promoted or invented by DesCartes.

I doubt that DesCartes really invented anything, because, by the evidence of his writing, he wasn't an intelligent man, but he placed himself politically in such a way that his arguments were acceptable to many influential people, and they continue to be acceptable to authoritarian and elitist factions even today.

In the 16th and 17th century the cultures of England, Holland, and France were increasingly dominated by business interests. People who had money to invest wanted to see the world as an orderly, predictable place, and they found that many of the ideas of the ancient Greeks were useful. Mathematics was needed to calculate interest rates, insurance premiums, and, for the military, the trajectories of missiles. In an orderly world, allowance for a little random variation helped to save the perfection of the general rule.

In this environment, theological thinking began retrenching its doctrine, to make it more acceptable to the increasingly powerful commercial people. The clockwork universe of DesCartes' time, in which a perfect world that operated according to perfect natural laws had been divinely created, gradually became theologically acceptable during the 18th and 19th centuries. In the 18th century, the Deists were the most famous embodiment of the idea, and then in the 19th century their place was taken by the Catastrophists, who claimed that the fossils which seemed to show evolutionary change of species actually represented species that had been created along with those now existing, but that had been destroyed by catastrophes, such as Noah's flood. By the end of the 19th century, the president of an American university recognized that theological compromises could prevent his undergraduates from rejecting religion entirely, and forbade sermons against evolution.

There were many biologists who insisted that evolution of new species was analogous to the development of an individual, and that both revealed an adaptive capacity of the living substance. In this view, the adaptive growth of an individual in a new environment revealed novel solutions to new problems, and showed an innate inventiveness and intelligence in the process of growth and adaptation. The appearance of new species was thought to represent the same sorts of adaptive processes.

Erasmus Darwin (grandfather of Charles) was an evolutionist of this sort, but because of political and theological pressure, he kept relatively quiet about his beliefs. There was an underground culture, in which an evolutionary view of the world was accepted, but these views were seldom published, because of increasingly stringent censorship. Because of censorship, poetry, letters, and diaries, rather than academic and scholarly works, give us the true picture of 18th century and early 19th century scientific culture.

The scientists who wanted their work to be acceptable to those in power found ways to work with the Cartesian mechanical view of the world, building on the Deists' compromise, which had succeeded in removing the supernatural from nature. As the fossil evidence of evolution became inescapable, around the time of Charles Darwin's work, those who wanted to bring evolution into the mainstream of culture found that the Catastrophism of the creationists could be adapted to their purposes, with only slight modification.

The doctrine of Thomas Malthus, who argued that war, famine, and disease were beneficial for those who survived, by decreasing the competition for limited resources, became a near equivalent to the catastrophic floods that the creationists had invoked to explain the geological record that contained evidence of many extinct animals. The doctrine of Malthus, like that of the Catastrophists, made loss, deletion, and destruction into a central device for explaining the history of the world.

Both of the Darwins had accepted the idea that many biological changes were adaptive, rather than random, but the new practical compromise doctrine introduced the idea that changes were just "random variations." The essentially mechanical nature of the world was preserved, because "chance" occurrences could be dealt with, and didn't involve anything supernatural. The function of the environment wasn't to add anything to life (that would have been to assert that there were creative powers other than those of the Creator), but simply to eliminate the inferior individuals that appeared as the result of random changes.

Gregor Mendel applied the principle of chance to explaining the inheritance of certain traits, and showed that "traits" were passed on unchanged, even when they weren't visible. His ideas were published and were acceptable to the scientific mainstream of his time. Traits were determined by "factors" that were passed on, unchanged, from parents, and biological variation was explained by varied mixing of factors which in themselves were unaffected by the organism or the environment. Genetic determinism was safely compatible with creationism.

Shortly after Mendel's death, August Weismann began a campaign to put a stop to the claims of those who, like the Darwins and Lamarck, saw adaptive development of organisms as an essential part of the evolution of species.

Weismann was essentially a propagandist, and his first fame was the result of "disproving" Lamarck by cutting the tails off more than 1500 mice, and observing that their offspring were born with tails. The reason the inheritance of acquired traits was impossible, he said, was that the "germ line" was perfectly isolated from the rest of the organism. The differentiated tissues of the body were produced by the selective loss of information from the nuclei of cells in the embryo. The cells of the germ line were immortal and contained all the information needed to produce an organism, but no other cell of the organism was complete.

Complexity was produced by deletion, and this was the basis for arguing that, if even the development of an individual was nothing but a passive unfolding of inherited properties, much like unpacking a trunkful of clothes, then there could be no adaptively acquired traits, and certainly no inheritance of something which didn't exist. Changes in an individual were simply accidents, such as having a tail amputated, and so the whole issue of the origin of complexity was safely left to a primordial creation.

Weismann and his arguments were famous in Europe and the US, and formed the background for the ideas known as neo-Darwinism. His "isolation of the germ line" was the earliest version of the Central Dogma of molecular biology, namely, that information flows only from DNA to RNA to protein. His doctrine, of complexification through deletion, is the epitome of the greatest dogma of modern times, expressed in doctrines from Catastrophism through the second law of thermodynamics and the theory of the Big Bang, down to Hayflick's Doctrine of the mortality of somatic cells. All these are consequences of the Cartesian and Deistic separation of intelligence from matter.

Regeneration is one of the most vivid examples of the intelligence of living substance.

Given a natural tendency of cells to multiply, the interesting thing about regenerative healing is the question of why the new growth of tissue sometimes differentiates to fit appropriately into its surroundings, but sometimes fails to differentiate, becoming a tumor.

With aging, the regenerative process declines, and the process of tissue rebuilding slows. Against a background of reduced regenerative ability, tissue growth sometimes produces tumors, rather than renewed healthy tissue. When tumors are grafted onto the amputated tail stump of a salamander, which has good regenerative ability, the tumor is transformed into a tail, by its envirornment, or morphogenic field. The "cancer problem" is essentially the problem of understanding the organizing forces of the organism. The aging problem is another aspect of the same problem.

Traditionally, biologists had studied anatomy, physiology, embryology or development, and taxonomy or the classification of organisms. The growth of knowedge early in the 20th century was suddenly seeming to confirm the physiological, adaptive view of organisms that Lamarck had held. C.M. Child, Joseph Needham, Alexander Gurwitsch, and L.V. Polezhaev were demonstrating the primacy of a formative process in biology. Polezhaev and Vladimir Filatov were studying practical means of stimulating regeneration as a medical technique.

Until the beginning of the second world war, the study of regeneration and the pattern-forming processes in embryology were the liveliest parts of biological research. Gestalt psychology was being developed at the same time, with a similar emphasis on patterns and wholes.

But Weismannism and neo-Darwinism, largely embodied in the person of the geneticist T.H. Morgan, deliberately set out to kill that line of biological research. Gestalt psychology was similarly eliminated by the Behaviorists.

One of Morgan's closest associates, his student and colleague A.H. Sturtevant, said that "Morgan's objectives, what he was trying to get at in general in his biological work was to produce mechanistic interpretations of biological phenomena. One of the things that irritated him most was any suggestion of purpose in biological interpretation. He always had some reservations about the idea of natural selection, because it seemed to him to open the door to interpretations of biological phenomena in terms of purpose. He could be talked into the conclusion that there was nothing that wasn't strictly mechanistic about this interpretation, but he never liked it. And you had to talk him into it again every few months." (Sturtevant, A. H., Genetics, Vol. 159, 1-5, September 2001, Copyright 2001, Reminiscences of T. H. Morgan.)

Whatever his motives, Morgan was known to have prevented his students (including C.M. Child) from publishing work that supported a holistic view of the organism. After Morgan's death, there was an intense and widespread campaign to suppress any approach to biology other than the "new synthesis," neo-Darwinism, with its doctrine of mechanistic genetic determinism and its doctrine of random variation. A developmental biologist, J.M. Opitz (1985), commented that "in one of the most astounding developments in Western scientific history, the gradient-field, or epimorphic field concept, as embodied in normal ontogeny and as studied by experimental embryologists, seems to have simply vanished from the intellectual patrimony of Western biologists."

Formative processes are necessarily multidimensional, and that makes calculation and analysis very complex. To a great extent, the geneticists were motivated to study bacterial genes, rather than vertebrate embryos, by the principle that motivated the drunk to look for his car keys under the street lamp, even though that wasn't where he lost them, because the light made it easier to look there.

Bacteria are easy to study because they lack the complexity that makes it hard to study an embryo or an animal. The language used in genetics textbooks shows not only that bacteria are treated by geneticists as if they were one or two dimensional, but that the concepts developed for bacterial genetics have been extrapolated to use in describing complex organisms: "Genes interact to establish the body axis in Drosophila. Homeotic Genes control pattern formation along the anterior-posterior body axis." (Essentials of Genetics, M. Cummings and W. Klug, Prentice Hall, 2004.)

One of the basic distinctions in embryology is in the way the cells divide after the egg is fertilized. Oysters and earthworms have spiral cleavage, sea urchins and people have radial cleavage. Several decades ago an experimenter was transferring a nucleus from an egg of an animal with radial cleavage, I think a sea urchin, into the enucleated egg of a snail, with spiral cleavage. The nucleus transplanted across such a great difference in phyla didn't sustain maturation of the animal, but it did permit development to proceed for several rounds of cell division, and the pattern of cell division, or cleavage, and embryonic development always followed the pattern of the phylum to which the egg cytoplasm belonged, never the pattern of the phylum from which the nucleus was derived. The genes in the nucleus, obviously, weren't directing the basic pattern formation of the embryo.

One-dimensional bacterial genetics can be used to "explain" multidimensional systems, but it can't be expected to make useful predictions.

The idea of complexity, or of multidimensionality, has often been analyzed in terms of "fields," by analogy with a magnetic field, as some property, or properties, that extend beyond any individual part, giving some coherence to the parts. Lamarck was concerned with understanding ensembles of particles and cells, but in his time electricity and heat were the only principles that physics provided that helped to illuminate the nature of living organisms. At the end of the 19th century, though, the physicist J.C. Bose was noticing that all of the properties of life that had interested Lamarck and Buffon--irritability, sensation, contraction, memory, etc.--had their close analogs in non-living substances. Bose, who invented the radio detector that was the core of Marconi's apparatus, found that, in the presence of an electromagnetic field, particles of a substance, such as finely powdered metal filings, cohered into a unified whole. An otherwise invisible, undetectable "field" which in Lamarck's time might have been known as one of the "subtle fluids," was able to organize a myriad of inert particles into a unified whole.

In the early 1920s, Bungenberg de Jong and A.I. Oparin showed how solutions of organic substances could spontaneously organize themselves into complex systems, with differentiated parts. A Russian embryologist, Alexander Gurwitsch, found that the parts of an organ or embryo could exert their stimulating or organizing influence on other cells even through a piece of glass, and by using different types of filter, he identified ultraweak ultraviolet rays as a medium of communication between cells. F.-A. Popp and others are currently studying the integrating functions of ultraweak light signals. Guenter Albrecht-Buehler (who has an interesting website called Cell Intelligence) is investigating the role of pulsed infrared signals in cell communication.

Electrical fields produced by cells, tissues, and organisms have been shown to influence cellular metabolism and physiology, and to influence growth patterns. Closely associated with cellular electrical fields are fields or gradients of pH and osmolarity, and all of these fields are known to affect the activity of enzymes, and so to create environments or fields of particular chemical concentrations.

A phenomenon that was well known in the 1930s, when developmental fields were still a familiar part of scientific discussion, was the "cancer field." Before a cancer developed in a particular area, the area showed progessive changes, away from normal function and structure, toward the cancer physiology.

In the embryonic state, damaged tissues regenerate quickly. The metabolism of an embryo or fetus is highly oxidative, converting glucose rapidly to carbon dioxide and water. Both carbon dioxide and water are important regulators of cellular metabolism and function, and the concentrations of both of them decrease systematically with maturity and aging. Both are involved with the most basic aspects of cellular sensitivity, responsiveness, and organization.

To resume the scientific tradition that has "simply vanished," I think we have to recover our ability to think about organisms generally, leaving aside as many of the concepts of genetics as possible (such as "gene," "operon," "receptor"; "the gene" has never been more than an ideological artifact), because they so often falsify the most important issues. The organization of tissues and organs, and their functional properties, should be the focus of attention, as they were for Lamarck around 1800, and for Johanes Muller, who in 1840 saw cancer as a problem on the level of tissue, rather than cells. For Lamarck, sensitivity and movement were the essential properties of the living substance, and J. C. Bose showed reasons for believing that the characteristics of life were built on related properties of matter itself.

Sensitivity, the ability to respond appropriately to the environment, is probably a missing factor in the development of a tumor. The ability to become quiescent, to quietly participate in the ensemble of cells, is an essential feature of the sensitivity and responsiveness of the cells of complex organisms. The factors that support organized appropriate functioning are the factors that help cells to inhibit the excitatory state. If the keys of an accordion or organ didn't spring back after the musician pressed them, the instrument would be unplayable. In extreme physiological states, such as epilepsy or malignant hyperthermia, nerves or muscles become incapable of relaxing. Insomnia and muscle cramps are milder degrees of a defective relaxation process. Excitoxicity and inflammation describe less generalized cases of a similar process, in which there is an imbalance between excitation and the restorative ability to stop the excitation. Prolonged excitation, resulting in excessive fatigue, can cause a cell to disintegrate, in the process of cell death called apoptosis, "falling away."

In the experiments of Polezhaev and Filatov, the products of cell disintegration were found to stimulate the birth of new cells (possibly by blocking a signal that restrains cell division). This process has been found in every organ that has been examined appropriately. It amounts to a "streaming regeneration" of the organism, analogous to the progressive creation of Lamarck's view. G. Zajicek has demonstrated an orderly "streaming" renewal in several organs, and even the oocytes (which in the Weismannian dogma were formed at a very early stage during embryonic development, and were perfectly isolated from the cells of the mature body) have recently been shown to be continually regenerated in adult ovaries.

"Stem" cells turn out to be ubiquitous, and the failure of regeneration and restoration seems to be situational. In the 1950s a magazine article described the regeneration of a finger-tip when the wound was kept enclosed. Decades later, friends (one a child, the other a man in his forties) had accidental amputations of a finger-tip, down to the cuticle so that no visible nail remained. The boy's mother fitted his finger with the tube from a ballpoint pen, and the man used an aluminum cigar tube as his "bandage." Within a few weeks, their fingers had regenerated to their normal shape and length. I think the closed environment allows the healing tissues to be exposed to a high concentration of carbon dioxide, in equilibrium with the carbon dioxide in the capillaries, and to a humid atmosphere, regulated by the osmotic or vapor pressure of the living tissues.

Under ordinary conditions, the creation of cells and the dissolution of cells should be exactly balanced. The coordination of these processes requires a high degree of coherence in the organism.

Simple increase of water in the vicinity of a cell increases its tendency to multiply, as well as its excitability, and hypertonicity restrains cell division, and reduces excitability. Carbon dioxide, besides helping proteins to release water, appears to increase the ability of proteins and cells to respond to morphogenetic fields. Carbon dioxide is the most universal agent of relaxation, restoration, and preservation of the ability of cells to respond to signals. Progesterone is another very general agent of restorative inhibition.

The study of regeneration and "stem cells" is helping to illuminate the general process of aging, and to provide very practical solutions for specific degenerative diseases, as well as providing a context for more appropriate treatment of traumatic tissue injury.

In aging, the growth and regenerative processes are slowed. There is some evidence that even cell death is slower in old age, at least in some tissues. Since animals with the highest metabolic rate live the longest, the slowing rate of metabolism during aging probably accounts for those changes in the rate of cell renewal. The continually streaming regeneration of tissues is part of the adaptive process, and it is probably intensified by stress.

The ability to sleep deeply decreases in old age, as a generalized inflammatory, excitatory state of stress develops. With progressive weakening of restorative cellular relaxation (inhibition), cells become more susceptible to disintegration. It's well established that bone loss occurs almost entirely during the night, and since the catabolic hormones generally affect soft tissues as well as bones, the atrophy of soft tissues ("sarcopenia") of aging is also probably a process that occurs mostly during the night. Mediators of inflammation are at their highest during the night (Cutolo and Masi, 2005). But during the period of growth, the length of bones seems to increase mostly during the night (Noonan, et al., 2004). My interpretation of this is that the stress of darkness accelerates biological processes, whether the process is mainly constructive or mainly destructive.

The effect of light supports efficient oxidative energy production, which supports the protective inhibitory processes, by increasing ATP and CO2, and decreases the inflammatory mediators that intensify stress. If organized cellular luminescence is required for a proper balance, then the random luminescence produced by lipid peroxidation (which may be more intense at night--Diaz-Munoz, et al., 1985), might be an important factor in disrupting the balanced streaming of regeneration. Free radicals, whatever their source, absorb a broad spectrum of radiation, and would block luminous signals of all frequencies. Isoprene, produced mainly at night (Cailleux and Allain, 1989), is another ultraviolet absorber that might account for nocturnal regulatory disorders.

The age pigment, lipofuscin, is known to contribute to degenerative diseases, but the nature of its toxicity has never been established. Its absorptive and fluorescent properties would be very likely to interfere with mitogenetic and morphogenetic radiation. Polyunsaturated fats are the main component of lipofuscin, and these fats in themselves can absorb ultraviolet light. When those fats are present in the skin, exposure to ultraviolet light accelerates the aging of the skin. Free fatty acids often increase during the night, under the influence of hormones such as adrenaline and growth hormone.

A single night of poor sleep probably causes significant anatomical damage to the streaming cellular systems that will be repaired over the next few days if a high level of energy metabolism can be combined with a sufficient amount of deep sleep. The things that optimize energy and sleep form the background for supporting the restorative processes. Salt, glycine, carbon dioxide, progesterone, thyroid hormone and sugar all contribute to preserving the organism's energetic reserves by reducing inappropriate excitation.

Lamarck's idea that organs developed or regressed according to their use or disuse was often attacked by followers of the Weismann-Morgan genetic dogma. In their view, the influence of the environment was limited to either preventing or permitting the realization of "the genetic potential." Once that predefined potential had been unfolded, the finite and mortal nature of the somatic cells didn't allow for any significant changes, except for depletion and death. One of the high points of Weismannian biology came with the publication of an article in Science, around 1970, that proposed to explain learning in terms of the lifelong loss of brain cells, beginning in humans around the age of 18 months, with a daily loss of 100,000 cells, which would record experience by selective deletion, the way punching holes in cards had been used to enter data into computers. I was present to witness "world class biologists" taking that idea very seriously.

As Sturtevant mentioned in the quotation above, T.H. Morgan couldn't accept any attribution of purposefulness to organisms. In his genetic dogma, changes were only random, and people who denied that were denounced as "teleological" (or metaphysical) thinkers. Changes occurred by deletion, not by meaningful addition.

One of Pavlov's students, P.K. Anokhin, developed the concept of the Functional System in the 1930s, to explain the purposive behavior of animals. In the 1950s, Anokhin integrated the endocrinology of stress and adaptation into the concept, and F.Z. Meerson continued the work, concentrating on the metabolic and structural changes that protect the heart during stress. The simplest view of the conditional reflex involves the adaptation of an animal to an external signal, identifying it as the occasion for a particular action. Analyzing the Functional System starts with the need of the animal, for example for food, and examines the processes that are involved in satisfying that need, including nerve cells, a sense of hunger, knowledge of what things are edible, the muscles needed to get the food, and the digestive apparatus for assimilating it.

When an understanding of stress physiology is combined with the idea of functional systems, the adaptive meaning of the use or disuse of certain organs is given a concrete basis. Cortisol mobilizes amino acids from muscles that are idle, and makes them available for the synthesis of proteins in the muscles, nerves, or glands that are activated in adapting to the stress. The London taxi drivers whose hippocampus grows as they learn the locations of the streets are very good examples of the processes described by Meerson, Anokhin, and Lamarck, in which the use of an organ in meeting a need contributes to the development of that organ. The balance between growth and regression is shifted during adaptive behavior.

Exercise physiologists, without mentioning functional systems, have recently discovered some principles that extend the discoveries of Meerson and Anokhin. They found that "concentric" contraction, that is, causing the muscle to contract against resistance, improves the muscle's function, without injuring it. (Walking up a mountain causes concentric contractions to dominate in the leg muscles. Walking down the mountain injures the muscles, by stretching them, forcing them to elongate while bearing a load; they call that eccentric contraction.) Old people, who had extensively damaged mitochondrial DNA, were given a program of concentric exercise, and as their muscles adapted to the new activity, their mitochondrial DNA was found to have become normal.

There are probably the equivalents of constructive "concentric" activity and destructively stressful "eccentric" activity in the brain. For example, "rote learning" is analogous to eccentric muscle contraction, and learning by asking questions is "concentric." "No bird soars too high, if he soars with his own wings." Any activity that seems "programmed" probably stifles cellular energy and cellular intelligence.

When activity is meaningful, and is seen to be meeting a felt need, the catabolic and anabolic systems support and strengthen the components of the functional system that has been activated. Everything we do has an influence on the streaming renewal of the adaptive living substance.

There are many therapeutic techniques that could be improved by organized research, for example, investigating the interactions of increasing carbon dioxide, reducing atmospheric pressure, supplementing combinations of salt and other minerals, balancing amino acids and sugars, and varying light exposure and types of activity. The dramatic results that have occasionally been demonstrated (and then suppressed and forgotten) are just a hint of the possibilities.

If we keep our thoughts on the living substance, the pervasive ideologies lose their oppressive power.

REFERENCES

Chronobiol Int. 2004;21(6):937-47. Postprandial metabolic profiles following meals and snacks eaten during simulated night and day shift work. Al-Naimi S, Hampton SM, Richard P, Tzung C, Morgan LM. "We have previously shown that both simulated and real shift workers showed relatively impaired glucose and lipid tolerance if a single test meal was consumed between 00:00-02:00 h (night shift) compared with 12:00-14:00 h (day shift). The objective of the present study was to extend these observations to compare the cumulative metabolic effect of consecutive snacks/meals, as might normally be consumed throughout a period of night or day shift work." "There was a trend toward an effect of shift for plasma glucose, with higher plasma glucose at night (p = 0.08), and there was a time-shift interaction for plasma insulin levels (p < 0.01). NEFA levels were unaffected by shift." "These findings confirm our previous observations of raised postprandial TAG and glucose at night, and show that sequential meal ingestion has a more pronounced effect on subsequent lipid than carbohydrate tolerance."

Anokhin P.K. System mechanisms of higher nervous activity. Moscow, Nauka, 1979. (In Russian).

Life Sci. 1989;44(24):1877-80. Isoprene and sleep. Cailleux A, Allain P. Isoprene is one of the main constituents of endogenous origin in exhaled human breath. The concentration of isoprene seems to vary with states of sleep and wakefulness, increasing during sleep and decreasing sharply just after awakening. Thus, isoprene may be involved in in sleep upholding.

Exp Neurol. 1978 May 15;60(1):41-55. Evidence of normal mitosis with complete cytokinesis in central nervous system neurons during sustained depolarization with ouabain. Cone CD Jr, Cone CM.

Nat New Biol. 1973 Nov 28;246(152):110-1. Stimulation of DNA synthesis in CNS neurones by sustained depolarisation. Stillwell EF, Cone CM, Cone CD Jr.

J Natl Cancer Inst. 1971 Mar;46(3):655-63. Intercellular transfer of toxic components after laser irradiation. May JF, Rounds DE, Cone CD.

J Theor Biol. 1971 Jan;30(1):151-81. Unified theory on the basic mechanism of normal mitotic control and oncogenesis. Cone CD Jr.

Oncology. 1971;25(2):168-82. Control of somatic cell mitosis by simulated changes in the transmembrane potential level. Cone CD Jr, Tongier M Jr.

Acta Cytol. 1969 Oct;13(10):576-82. Autosynchrony and self-induced mitosis in sarcoma cell networks. Cone CD Jr.

Ann N Y Acad Sci. 1980;339:115-31. Ionically mediated induction of mitogenesis in CNS neurons. Cone CD Jr.

Science. 1976 Apr 9;192(4235):155-8. Induction of mitosis in mature neurons in central nervous system by sustained depolarization. Cone CD Jr, Cone CM. DNA synthesis and mitosis have been induced in vitro in fully differentiated neurons from the central nervous system by depolarization with a variety of agents that produce a sustained rise in the intracellular sodium ion concentration and a decrease in the potassium ion concentration. Depolarization was followed in less than 1 hour by an increase in RNA synthesis and in 3 hours by initiation of DNA synthesis. Apparently normal nuclear mitosis ensued, but cytokinesis was not completed in most cells; this resulted in the formation of binucleate neurons. The daughter nuclei each contained the same amount of DNA as the diploid preinduction parental neurons; this implies that true mitogenic replication was induced.

Ann N Y Acad Sci. 1974;238:420-35. The role of the surface electrical transmembrane potential in normal and malignant mitogenesis. Cone CD Jr.

Ann N Y Acad Sci. 1974;238:451-6. Panel discussion: The role of electrical potential at the cellular level in growth and development. Becker RO, Cone CD, Jaffe LF, Parsegian VA, Pohl HA, Weiss L.

J Cell Physiol. 1973 Dec;82(3):373-86. Contact inhibition of division: involvement of the electrical transmembrane potential. Cone CD Jr, Tongier M Jr.

J Theor Biol. 1971 Jan;30(1):183-94. Maintenance of mitotic homeostasis in somatic cell populations. Cone CD Jr.

Oncology. 1970;24(6):438-70. Variation of the transmembrane potential level as a basic mechanism of mitosis control. Cone CD Jr.

Trans N Y Acad Sci. 1969 Apr;31(4):404-27. Electroosmotic interactions accompanying mitosis initation in sarcoma cells in vitro. Cone CD Jr.

Rheum Dis Clin North Am. 2005 Feb;31(1):115-29, ix-x. Circadian rhythms and arthritis. Cutolo M, Masi AT.

Neuroscience. 1985 Dec;16(4):859-63. Day-night cycle of lipid peroxidation in rat cerebral cortex and their relationship to the glutathione cycle and superoxide dismutase activity. Diaz-Munoz M, Hernandez-Munoz R, Suarez J, Chagoya de Sanchez V. Lipoperoxidation, glutathione cycle components and superoxide dismutase activity show a day-night rhythm in the cerebral cortex of the rat. The highest lipoperoxidative activity is observed during the night (20.00-04.00 h). The enhancement in lipoperoxidation occurs concurrently with a decrease in glutathione peroxidase activity, an increase in superoxide dismutase activity and an increase in the double bonds in the brain cortex lipid fraction. The changes described in this paper seem to be related to a succession of light and dark periods, or to fasting and feeding periods. We propose that those fluctuations could act as a physiological oscillator with an important role in modulating the membrane properties of the nerve cell.

Brain Res. 1977 Mar 4;123(1):137-45. Daily variations of various parameters of serotonin metabolism in the rat brain. II. Circadian variations in serum and cerebral tryptophan levels: lack of correlation with 5-HT turnover. Hery F, Chouvet G, Kan JP, Pujol JF, Glowinski J. Rats submitted to regular 12 h cycles of light and darkness for three weeks were sacrificed at various times of the day. 5-HT, 5-HIAA and tryptophan levels were estimated in the fronto-parietal cerebral cortex. Tyrosine and free and total tryptophan levels in serum were estimated in parallel. Significant circadian variations in 5-HT and 5-HIAA levels were found in cerebral tissues. The peaks of 5-HIAA levels were dectected during the lignt and dark periods respectively, the maximal fluctuations being seen between 17.00 h and 21.00 h, two times separating the light off. Important significant circadian variations in free and total serum tryptophan levels were also observed. In both cases, the maximal levels were found during the middle of the dark phase after the peak of 5-HIAA levels. The circadian rhythm of tyrosine levels in serum was in opposite phase with that of tryptophan (free or total). The diurnal changes in tryptophan content in cerebral tissues seemed thus related to those found in serum. Taking in consideration results obtained in previous studies 16,17 carried out in similar experimental conditions, it was concluded that the parallel increase in serum free tryptophan and in tissues 5-HIAA levels seen during the night were not related to a stimulation of 5-HT turnover. Indeed 5-HT synthesis is minimal at this time16.

Kryukov V.I. An attention model based on the principle of dominanta // Proceedings in Nonlinear Science. Neurocomputers and Attention. I: Neurobiology, Synchronization, and Chaos. 1989. Ed. by A.Y. Holden and V.I. Kryukov, pp. 319-351.

Endocrinol Exp. 1976 Jun;10(2):131-7. Diurnal variation in the effect of melatonin on plasma and muscle free fatty acid levels in the pigeon. John TM, George JC. Pigeons maintained on standard diet and held under 12 h daily photo-period in a controlled environmental room, were given intravenous injections of melatonin. A low dose (1.25 mg/kg body weight) of melatonin when given in the middle of the scotophase, produced a significant increase in plasma FFA when estimated at 20 min and 90 min post-injection, whereas no significant change was seen with injections given in the middle of the photophase. No significant change in muscle FFA level was obtained either during the photophase or the scotophase when estimated at 90 min postinjection. With a higher dose (5 mg/kg body weight) of melatonin given in the scotophase, on the other hand, a significant increase in both plasma as well as muscle FFA levels was obtained at 90 min post-injection but there was no effect on plasma FFA at 20 min or 90 min post-injection in the photophase and at 20 min in the scotophase. It is concluded that melatonin has a lipid mobilizing action in the pigeon when administered during the scotophase.

Exp Brain Res. 2001 Feb;136(3):313-20. Enhanced neurogenesis after transient global ischemia in the dentate gyrus of the rat. Kee NJ, Preston E, Wojtowicz JM. "Certain insults such as epileptic seizures and ischemia are known to enhance the rate of neuronal production. We analyzed this phenomenon using the temporary occlusion of the two carotid arteries combined with arterial hypotension as a method to induce ischemia in rats. We measured the rate of cell production and their state of differentiation with a mitotic indicator, bromodeoxyuridine (BrdU), in combination with the immunohistochemical detection of neuronal markers. One week after the ischemic episode, the cell production in dentate gyrus was increased two- to threefold more than the basal level seen in control animals. Two weeks after ischemia, over 60% of these cells became young neurons as determined by colabeling with BrdU and a cytoplasmic protein (CRMP-4) involved in axonal guidance during development. Five weeks after the ischemia, over 60% of new neurons expressed calbindin, a calcium-binding protein normally expressed in mature granule neurons. In addition to more cells being generated, a greater proportion of all new cells remained in the differentiated but not fully mature state during the 2- to 5-week period after ischemia." "The results support the hypothesis that survival of dentate gyrus after ischemia is linked with enhanced neurogenesis. Additional physiological stimulation after ischemia may be exploited to stimulate maturation of new neurons and to offer new therapeutic strategies for promoting recovery of neuronal circuitry in the injured brain."

Am J Cardiol. 1998 Dec 17;82(12A):24U-28U; discussion 39U-41U. Clinical profiles of plain versus sustained-release niacin (Niaspan) and the physiologic rationale for nighttime dosing. Knopp RH. Niacin is the oldest and most versatile agent in use for the treatment of dyslipidemia. It has beneficial effects on low-density lipoprotein cholesterol; high-density lipoprotein cholesterol; the apolipoproteins B and A-I constituting these fractions; triglyceride; and lipoprotein(a). Together, these benefits lead to a diminished incidence of coronary artery disease among niacin users. The chief constraints against niacin use have been flushing, gastrointestinal discomfort, and metabolic effects including hepatotoxicity. Time-release niacin has been developed in part to limit flushing, and now a nighttime formulation (Niaspan) has been developed that assists in containing this untoward effect. In a pivotal metabolic study, bed-time administration of 1.5 g time-release niacin was shown to have the same beneficial effects as 1.5 g plain niacin in 3 divided doses and to be well tolerated. Previous studies suggest that bedtime niacin administration diminishes lipolysis and release of free fatty acids to the liver; this, in turn, leads to an abolition of the usual diurnal increase in plasma triglyceride, which may result in diminished formation and secretion of triglyceride in the very-low-density lipoprotein fraction.

J Pediatr Orthop. 2004 Nov-Dec;24(6):726-31. Growing pains: are they due to increased growth during recumbency as documented in a lamb model? Noonan KJ, Farnum CE, Leiferman EM, Lampl M, Markel MD, Wilsman NJ.

Cell Tissue Kinet. 1977 Nov;10(6):557-68. Circadian rhythms of presumptive stem cells in three different epithelia of the mouse. Potten CS, Al-Barwari SE, Hume WJ, Searle J.

Physiol Res. 1995;44(4):249-56. Circadian and circaannual oscillations of tissue lipoperoxides in rats. Solar P, Toth G, Smajda B, Ahlers I, Ahlersova E. Circadian and circaannual oscillations of tissue lipid peroxides (LPO) were studied in young male Wistar rats. The concentration of malondialdehyde, one of LPO degradation products, was measured at 3-h intervals during 24 hours in rats, adapted to light:dark 12:12 h regimen in the course of the year. LPO in the liver, thymus and bone marrow oscillated rhythmically in the course of the day and year. Circadian oscillations in all tissues were two-peaked, with zeniths at various times of the light and dark parts of the day. In the liver and thymus, the highest mesors were found during the winter, in the bone marrow during the spring. The same holds for amplitude values, with the exception of the bone marrow which exhibited the highest values during the summer. The reason for the LPO oscillations is probably resulting from the changing ratio of pro- and anti-oxidative capacities in various tissues during the day and the year.

Biofizika. 1976 Jul-Aug;21(4):688-91. [Circadian rhythms of ultraweak chemiluminescence of bean roots] Sul'tsman FM, Petrusevich IuM, Tarusov BN. Circadian rhythms of ultra-weak chemoluminescence of bean roots were investigated. It was found that under periodical change of light and darkness and without subsequent illumination a periodical change of spontaneous chemoluminescence of bean roots was observed. (The study of antiradical activity of the substances extracted from the root showed the dependence of this activity on illumination conditions.

Ukr Biokhim Zh. 1977 Sep-Oct;49(5):64-9. [Effect of "carbostimulin", vitamin D 3 and their mixture on bone tissue regeneration] [Article in Ukrainian] Taran TT, Guly MF, Mykhajlovskyj VO, Dvornykova PD, Fanak MM, Vorobjov NA. "Healing of the bone injury in rabbits was studied as affected by carbostimulin and its mixture with vitamin D3. Some biochemical indexes: the content of sialic acids, calcium and citric acid in blood serum of the animals, intensity of 14C incorporation from NaH14CO3 into the regenerated bone tissue and its proteins as well as histological studies, data, evidence for a positive effect of the mentioned preparations on the bone substance regeneration in the animals under experiment."

Biofizika. 1961;6(4):490-2. [Study on ultra-weak spontaneous luminescence of animal cells.] Tarusov BN, Polivoda AI, Zhuravlev AI.

Biofizika. 1961;6(4):83-5. Study of the faint spontaneous luminescence of animal cells. Tarusov BN, Polivoda AI, Zhuravlev AI.

Vopr Med Khim. 1977 May-Jun;(3):375-81. [Free fatty acids and cholesterol as possible participants in lipid oxidation radical reactions in animal tissues] [Article in Russian] Terekhova SF, Burlakova EB, Elizarova TI. Alterations in concentration of free fatty acids, free cholesterol, native antioxidants as well as in the antioxidative activity were studied in lipids of mice liver tissue and small intestinal mucosa. The intensity of free radical reactions in lipids of animal tissues was affected directly by administration of synthetic inhibitors of the reactions. The inverse correlation was observed between the alteration in concentrations of native antioxidants and free fatty acids as well as between the antioxidative activity of lipids and amount of free cholesterol in them. Free fatty acids appears to be the constant participants in the system of free radical oxidation of lipids, while cholesterol can center the system under distinct level of these reactions intensity.

Ukhtomsky A.A. Dominanta as factor of behavior // Collected works. Leningrad, 1950. Vol.1, pp.293-315.

Biofizika. 1974 Mar-Apr;19(2):295-9. [Formation of pigments of lipid nature in animal tissues during neoplastic growth and irradiation] Vertushkov VT, Ivanov II, Tarusov BN.

Biofizika. 1967 Jul-Aug;12(4):739-41. [Antioxidative activity of blood serum fractions during malignant degeneration studied by inhibition of chemiluminescence] Zakarian AE, Tarusov BN.

Biofizika. 1966;11(5):919-21. [Inhibition of chemiluminescence of the blood plasma in malignant growth] [Article in Russian] Zakarian AE, Tarusov BN.

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A R T I C L E

Calcium and Disease: Hypertension, organ calcification, & shock, vs. respiratory energy

SOME CONTEXTS
In biology and biochemistry, calcium is the substance most often studied, so it is significant that researchers still speak of a calcium paradox.
There are several such paradoxes: As bones lose calcium, the soft tissues calcify; when less calcium is eaten, blood calcium may increase, along with calcium in many organs and tissues; if an organ such as the heart is deprived of calcium for a short time, its cells lose their ability to respond normally to calcium, and instead they take up a large, toxic amount of calcium.
Magnesium deficiency and calcium deficiency have some similar symptoms (such as cramping), but magnesium is antagonistic to calcium in many systems. It is the basic protective calcium blocker.
Inflammation leads to excessive uptake of calcium by cells, and is a factor in obesity, depression, and the degenerative diseases.
Protein deficiency is an important cause of deranged calcium metabolism. Vitamins K, E, and A are important in regulating calcium metabolism, and preventing osteoporosis. Aspirin (with antiestrogenic and vitamin E-like actions) is protective against bone resorption and hypercalcemia.

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It is extremely important to realize that calcium deposits in soft tissues become worse when the diet is low in calcium. Persons suffering from arthritis, bursitis, scleroderma, hardening of the arteries and any abnormality where calcium deposits or spurs may cause pain are often afraid to eat foods rich in calcium. Actually they can never improve until their calcium and magnesium intakes are adequate. Not infrequently physicians tell individuals with kidney stones to avoid all milk, thereby causing stones to form even more rapidly. Such calcium deposits can also occur when vitamin E is undersupplied. After open-heart surgery, when both magnesium and vitamin E are drastically needed and could easily be given, the calcification of heart muscles often becomes so severe that it can cause death within a few days. Pages 171-172, Lets Eat Right to Keep Fit, Adelle Davis, Signet, 1970.

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Almost all biologists think of the organism as a machine, regulated by information according to innate programs. When it comes down to the details, their explanations sometimes make Rube Goldbergs imaginary contraptions seem elegant. At their best, they usually rely on some mysterious things called ionic pumps, that perform active transport, powered by little motors, under instructions from molecules that act on their specific receptors. When things get unmanageable, the biologists speak of paradoxes.
Calcium is the most studied of all regulatory molecules, so it isnt surprising that there is more than one calcium paradox. But there are ways of looking at the organism, focusing on energy metabolism, that dont involve the ad hoc theory of calcium pumps, and that make it easy to keep things in context.
Ionized atoms and molecules behave in orderly ways, in relation to their size and their electrical charge. Organic material, even when its dead, selectively binds certain metal ions, and excludes others. The living organism produces a stream of metabolic products, such as carbon dioxide or lactic acid, which interact specifically with each other and with the metal ions, modifying their concentrations inside cells and in the body fluids. This movement of ions can be called active transport, without invoking the mysterious machinery of membrane pumps. Chemical changes produced inside cells, for example by respiration, create different electrical charges in different compartments (inside and outside of capillaries, for example) which affect the movements of water and ions, by simple physical processes, not by molecular pumps.
The result of these passive and active processes is that each kind of ion has a characteristic concentration in each compartment, according to the metabolic energy state of the organism.
Magnesium and potassium are mainly intracellular ions, sodium and calcium are mainly extracellular ions. When cells are excited, stressed, or de-energized, they lose magnesium and potassium, and take up sodium and calcium. The mitochondria can bind a certain amount of calcium during stress, but accumulating calcium can reach a point at which it inactivates the mitochondria, forcing cells to increase their inefficient glycolytic energy production, producing an excess of lactic acid. Abnormal calcification begins in the mitochondria.
When cells are stressed or dying, they take up calcium, which tends to excite the cells at the same time that it inhibits their energy production, intensifying their stress. A cramp or a seizure is an example of uncontrolled cellular excitation. Prolonged excitation and stress contribute to tissue inflammation and fibrosis.
Gross calcification generally follows the fibrosis that is produced by inflammation.
Arteries, kidneys, and other organs calcify during aging. At the age of 90, the amount of calcium in the elastic layer of an artery is about 35 times greater than at the age of 20. Nearly every type of tissue, including the brain, is susceptible to the inflammatory process that leads through fibrosis to calcification. The exception is the skeleton, which loses its calcium as the soft tissues absorb calcium.
These observations lead to some simplifying ideas about the nature of aging and disease.
Some people who know about the involvement of calcium in aging, stress, and degeneration suggest eating a low calcium diet, but since we all have skeletons, dietary calcium restriction cant protect our cells, and in fact, it usually intensifies the process of calcification of the soft tissues. Statistics from several countries have clearly shown that the mortality rate (especially from arteriosclerotic heart disease, but also from some other diseases, including cancer) is lower than average in regions that have hard water, which often contains a very large amount of either calcium or magnesium.
Many studies have shown that dietary calcium (or vitamin D, which increases calcium absorption) can have very important antiinflammatory effects.
About 25 years ago, David McCarron noticed that the governments data on diet and hypertension showed that the people who ate the most salt had the lowest blood pressure, and those who ate the least salt had the highest pressure. He showed that a calcium deficiency, rather than a sodium excess, was the most likely nutritional explanation for hypertension.
Hans Selye found that some steroids contribute to inflammation and calcification. Animals could be sensitized to develop calciphylaxis, an intense, localized interaction of inflammation and calcification.
In the 1970s, Constance Martin pointed out that, up to that time, estrogen was known to increase soft tissue calcium, but hadnt been shown to improve bone calcification and strength.
Oxygen deprivation, cyanide poisoning, x-irradiation, and all other sorts of injury also increase the calcium content of soft tissues.
One of Selyes colleagues, G. Jasmin, showed that magnesium deficiency causes inflammation. A deficiency of either calcium or magnesium can stimulate the parathyroid glands to produce more hormone (parathyroid hormone, PTH), which increases calcium absorption, but also removes calcium from the bones. This hormone, responding to a dietary calcium or magnesium deficiency, is an important factor in causing cells to take up too much calcium, and its excess is associated with many inflammatory and degenerative diseases.
Interleukin-6 (IL-6), an inflammatory cytokine which increases with aging, is commonly considered to have an important role in the multiple processes of atrophy in old age. One of the things which can increase the production of IL-6 is the parathyroid hormone (PTH), which increases the amount of calcium circulating in the blood, partly by causing it to be removed from the bones; IL-6 stimulates the process of calcium removal from bones.
Some of the interactions of hormones and other regulatory chemicals are interesting, even though they are normally treated as if they were parts of a machine that operates according to a hidden program written in the genes. Prolactin, which is increased under the influence of estrogen or serotonin, causes the body to lose calcium (drawing it from the bones), and it stimulates the secretion of PTH, which compensates for the calcium loss by increasing its mobilization from bones. Prolactins action on bone is at least partly by increasing IL-6 formation; IL-6 stimulates the release of prolactin. Serotonin and IL-6 stimulate each others secretion, and PTH and serotonin each stimulate the others release..
PTH (like estrogen and serotonin) inhibits cellular respiration and activates glycolysis, lowering the ATP level and shifting the cells metabolism toward the production of lactic acid rather than carbon dioxide. PTH also causes bicarbonate to be lost in the urine.
Since the formation of carbon dioxide lowers the intracellular pH, and the formation of lactic acid raises it (through the reaction of NADH with pyruvate), the proteins in the cell become more strongly negatively charged under the influence of oxygen deprivation, or under the influence of these hormones. In the cell with high pH and increased negative electrical charge, the positively charged calcium ion is absorbed into the cytoplasm. The calcium can enter from the relatively concentrated external fluid, but it can also be released from acidic intracellular stores, the way serotonin is released by a disturbance of pH.
There are several other pro-inflammatory substances, such as the cytokines, that have a similar effect on cellular energy systems.
The antimetabolic actions of PTH mimic those seen in aging and diabetes, and surgical removal of the parathyroid glands has been known to eliminate diabetes. PTH can cause diuresis, leading to loss of blood volume and dehydration, hypertension, paralysis, increased rate of cell division, and growth of cartilage, bone, and other tissues.
Simply eating an adequate amount of calcium and magnesium can alleviate many problems related to stress and aging that are considered serious, such as heart arrhythmia, pancreatitis, and tissue calcification. The antiinflammatory, anti-allergy actions of calcium and magnesium are well established, and there is clear evidence that obesity and various emotional disturbances can result from their deficiency. Chronically high PTH can produce anemia, by a variety of mechanisms.
Since a very low sodium diet increases the loss of magnesium, by increasing aldosterone synthesis, simply increasing the amount of sodium in the diet can help some people to balance their minerals and minimize stress. During fasting and other intense stress, the kidneys destroy a large amount of protein to form ammonia to maintain their ability to excrete acids, so using a large amount of the alkaline minerals can reduce the protein catabolism.
A diet of milk and fruit, or milk and meat, provides a nutritional balance with generous amounts of calcium and magnesium. Leafy vegetables are a very rich source of magnesium, but they are also a potential source of large amounts of lead and other toxins. In 1960, many people, including the U.S.government, were advocating the use of a largely vegetarian diet for children, because of the amount of radioactive strontium in milk. I compared the amount of strontium in a diet of vegetables that would provide the necessary quantity of calcium and protein, and it was clear that vegetables were the worst source of radioactive strontium, because their ratio of strontium to calcium was much higher than the ratio in milk. The cows were concentrating calcium and protein from the contaminated plant foods, eliminating much of the strontium. This principle still applies to the toxins that are currently found in the U.S. food supply.
Milk has many protective effects besides providing calcium.
Many babies are being given milk substitutes (health food drinks) made from soy or rice, with terrible consequences. The same products used by adults have less disastrous effects in the short term, but are still likely to contribute to degeneration and dementia.
Much of the intracellular magnesium is complexed with ATP, and helps to stabilize that molecule. If cellular energy production is low, as in hypothyroidism, cells tend to lose their magnesium very easily, shifting the balance toward the lower energy molecule, ADP, with the release of phosphate. ADP complexes with calcium, rather than magnesium, increasing the cells calcium content.
Increased intracellular calcium, in association with excess nitric oxide and excitatory amino acids, is involved in several neurodegenerative diseases, including ALS, Alzheimers disease, Parkinsons disease, Huntingtons chorea, and epilepsy. Magnesium, nicotine, progesterone, and many other substances are known to protect against excitotoxic calcium overload, but there is no coherent effort in the health professions to make rational use of the available knowledge.
Respiration and carbon dioxide are the basic antagonists of the PTH. At birth, a baby has practically no PTH, probably because of the high intrauterine concentration of carbon dioxide, but within a few days the PTH rises.
Increased carbon dioxide favors bone formation, and decreased bicarbonate favors the loss of calcium from bone (Canzanello, et al., 1995; Bushinsky, et al, 2001). The use of sodium bicarbonate can stimulate bone formation.
A low protein diet, similar to that eaten by a large proportion of women (0.8 g/kg of body weight) increases PTH, and so probably contributes to the development of osteoporosis and the diseases of calcification. In an extreme protein deficiency, there is a shift towards inflammation, serotonin excess, and excessive clotting, which might be related to the effect of the milder, more common protein deficiency. Many people advocate a low protein diet, specifically to prevent or treat osteoporosis, but the cultures that traditionally have had extremely high protein diets, such as the Masai, are very healthy. Recent studies (see Bell and Whiting, 2002) are emphasizing the importance of animal protein in preventing osteoporosis.
Traditional meat-eating cultures efficiently use the whole animal, including blood, skin, bones, and the various organs, rather than just the muscles. That diet is favorable for calcium regulation, because it provides more vitamin A, D, E, and K, calcium, and gelatin, and less of the pro-inflammatory amino acids, tryptophan and cysteine.
Most loss of calcium from bones occurs during the night. PTH tends to cycle with prolactin, which increases during the night, along with cortisol and the other stress hormones. These nocturnal hormones probably account for the morning stiffness seen in many rheumatic conditions, connective tissue diseases, and in aging.
Progesterone, which increases the carbon dioxide content of the tissues, is remarkably able to inhibit the actions of most of the inflammatory and catabolic mediators, and to protect against degenerative calcification and osteoporosis. It also protects against abnormal clotting. PTH increases platelet calcium concentration, and under some conditions can produce inappropriate coagulation.
Aspirin inhibits the actions of PTH, helping to prevent the calcification of inflamed tissues, and it inhibits the loss of calcium from bones. Aspirin decreases the release of IL-6.
A protein called the PTH-related protein (PTHrP) has the same functions as PTH, but can be produced in any tissue. It is responsible for the hypercalcemia of cancer, and is apparently involved in the frequent metastasis of breast cancer to the bones.
With only a small change in the theory of the nature of a living organism, recognizing the importance of the interactions of metabolites and structural substances, controlled by energetic metabolism, real progress could be made in understanding disease and health. The most important calcium paradox is that medical journals (e.g., International J. of Cardiology, Dec., 2002) are still promoting the idea that eating too much calcium causes hardening of the arteries and other diseases of calcification.

REFERENCES

J Am Soc Nephrol 1994 Apr;4(10):1814-9. A role of parathyroid hormone for the activation of cardiac fibroblasts in Uremia. Amann K, Ritz E, Wiest G, Klaus G, Mall G. Thus, PTX abolished and PTH restored intermyocardiocytic changes of experimental uremia. These observations argue for a permissive role of PTH for fibroblast activation and the genesis of the cardiac fibrosis of uremia.

Clin Endocrinol (Oxf) 1976 May;5(3):291-3. Recurrent hormone dependent chorea: effects of oestrogens and progestogens. Barber PV, Arnold AG, Evans G.

Biochem Biophys Res Commun 2001 Feb 23;281(2):277-81. 17 beta-estradiol increases Ca(2+) influx and down regulates interleukin-2 receptor in mouse thymocytes. Azenabor AA, Hoffman-Goetz L.

Nutr Rev 2002 Oct;60(10 Pt 1):337-41. Elderly women need dietary protein to maintain bone mass. Bell J, Whiting SJ. Researchers who conducted a recent prospective study of older adults reported that animal protein had a protective role for bone, especially in elderly women, whereas plant protein was negatively associated with bone mineral density. Other studies confirm the beneficial effect of increasing dietary protein intake in older women to reduce bone mineral density loss and risk of fracture, suggesting that emphasis should be placed on promoting adequate protein intake in elderly women.

Am J Physiol Renal Physiol 2001 Dec;281(6):F1058-66. Metabolic, but not respiratory, acidosis increases bone PGE(2) levels and calcium release. Bushinsky DA, Parker WR, Alexander KM, Krieger NS. A decrease in blood pH may be due to either a reduction in bicarbonate concentration ([HCO(3)(-)]; metabolic acidosis) or to an increase in PCO(2) (respiratory acidosis). In mammals, metabolic, but not respiratory, acidosis increases urine calcium excretion without altering intestinal calcium absorption, indicating that the additional urinary calcium is derived from bone. In cultured bone, chronic metabolic, but not respiratory, acidosis increases net calcium efflux (J(Ca)), decreases osteoblastic collagen synthesis, and increases osteoclastic bone resorption. Metabolic acidosis increases bone PGE(2) production, which is correlated with J(Ca), and inhibition of PGE(2) production inhibits this acid-induced J(Ca). Thus metabolic, but not respiratory, acidosis induces the release of bone PGE(2), which mediates J(Ca) from bone.

J Clin Endocrinol Metab 1991 Jan;72(1):69-76. Circadian variation in ionized calcium and intact parathyroid hormone: evidence for sex differences in calcium homeostasis. Calvo MS, Eastell R, Offord KP, Bergstralh EJ, Burritt MF. Serum intact PTH levels showed a significant circadian pattern in both sexes (P less than or equal to 0.001).

J Lab Clin Med 1995 Jul;126(1):81-7. Effect of chronic respiratory acidosis on calcium metabolism in the rat. Canzanello VJ, Kraut JA, Holick MF, Johns C, Liu CC, Madias NE. Chronic metabolic acidosis typically results in hypercalciuria and negative calcium balance. The impact of chronic respiratory acidosis on calcium metabolism has been less well studied. To address this issue, metabolic balance and static bone histomorphometric data were obtained during a 14-day exposure of rats to 10% CO2 (blood pH 7.33, PaCO2 83 mm Hg) and were compared with pair-fed controls. All rats were fed a 0.8% calcium diet. Urinary calcium excretion (mg/period, mean +/- SEM) was increased during both week 1 and week 2 (16 +/- 3 vs 9 +/- 1 and 16 +/- 2 vs 9 +/- 1, CO2 group vs controls, respectively [p < 0.05]). Net intestinal calcium absorption (intake minus fecal excretion) was increased throughout the period of hypercapnia (week 1, 213 +/- 19 mg vs 135 +/- 15 mg; week 2, 135 +/- 16 mg vs 43 +/- 14 mg; and cumulatively, 344 +/- 27 mg vs 178 +/- 20 mg, CO2 group vs controls [p < 0.01]). As a consequence of the marked increment in intestinal calcium absorption during hypercapnia, mean net calcium balance was more positive than that of controls throughout the study (week 1, 197 +/- 18 mg vs 126 +/- 15 mg; week 2, 120 +/- 15 mg vs 34 +/- 15 mg; and cumulatively, 317 +/- 25 mg vs 159 +/- 20 mg, CO2 group vs controls, respectively [p < 0.01]). There were no significant differences in calcium intake, plasma total calcium, immunoreactive parathyroid hormone, 25-hydroxyvitamin D, or creatinine clearance between the two groups.

Mov Disord 1991;6(4):355-7. An unusual cause of recurrent chorea. Caviness JN, Muenter MD. Lee Silverman

Bone 2000 Jan;26(1):79-85. Correlation of estradiol, parathyroid hormone, interleukin-6, and soluble interleukin-6 receptor during the normal menstrual cycle. Chiu KM, Arnaud CD, Ju J, Mayes D, Bacchetti P, Weitz S, Keller ET. Furthermore, IL-6 correlated positively with serum Ca over the entire cycle (p = 0.0091. Serum Ca correlated positively with serum (p = 0.040) and urine (p = 0.006) Dpd. PTH was significantly higher during the FP than in the LP (p = 0.004). These data demonstrate that IL-6 and PTH fluctuate with E2, and serum II-6 is associated with PTH levels during the menstrual cycle.

J Cell Sci 2002 Feb 1;115(Pt 3):599-607. pH-dependent regulation of lysosomal calcium in macrophages. Christensen KA, Myers JT, Swanson JA. Average free calcium concentration in macrophage lysosomes was 4-6x10(-4) M, less than half of the extracellular calcium concentration, but much higher than cytosolic calcium levels. pH-dependent reductions of lysosomal calcium concentrations appeared to result from calcium movement out of lysosomes into cytoplasm, since increases in cytosolic calcium levels could be detected upon lysosome alkalinization.

Adv Neurol 1979;26:123-33. Ovarian steroid hormones and cerebral function. Cogen PH, Zimmerman EA.

J Bone Miner Res 1996 Oct;11(10):1419-29. Stimulation of neonatal mouse calvarial bone resorption by the glucocorticoids hydrocortisone and dexamethasone. Conaway HH, Grigorie D, Lerner UH. In vitro stimulation of bone resorption was observed with the glucocorticoids hydrocortisone and dexamethasone. The 45Ca release stimulated by 1 microM hydrocortisone and 0.1 microM dexamethasone was also inhibited by 10 microM progesterone in a competitive manner and by 1 microM of the antiglucocorticoid RU38486, both of which are modulators of glucocorticoid binding.

J Physiol 2002 Mar 15;539(Pt 3):791-803. MgATP counteracts intracellular proton inhibition of the sodium-calcium exchanger in dialysed squid axons. DiPolo R, Beauge L. The increase in Ca(2+)(i) affinity induced by ATP at acid pH (6.9) can be mimicked by a rise in pH(i) from 6.9 to 7.3 in the absence of the nucleotide.

J Maine Med Assoc 1977 Oct;68(10):370-1 Quadriparesis as an unusual manifestation of hypercalcemia. Dyro FM.

J Clin Endocrinol Metab 1992 Mar;74(3):487-94. Abnormalities in circadian patterns of bone resorption and renal calcium conservation in type I osteoporosis. Eastell R, Calvo MS, Burritt MF, Offord KP, Russell RG, Riggs BL. The serum osteocalcin concentration, a sensitive index of bone formation, increased by about 5% at night in both groups. Urinary deoxypyridinoline excretion, a sensitive index of bone resorption, increased by 48% at night (P less than 0.01) in the normal women, whereas in the osteoporotic women it was 62% higher overall (P less than 0.05), and the increase persisted into the morning. The serum ionized calcium concentration did not change at night in either group. There was a trend (P = 0.07) for blunting of the nocturnal increase in the serum intact PTH level in osteoporotic women. Thus, the nocturnal serum ionized calcium level is maintained by decreased urinary calcium excretion and increased bone resorption in postmenopausal normal women, but almost entirely by increased resorption in postmenopausal osteoporotic women.

Hypertension 1986 Jun;8(6):497-505. Effects of calcium infusion on blood pressure in hypertensive and normotensive humans. Ellison DH, Shneidman R, Morris C, McCarron DA. Together, these data provide evidence for interactions between dietary sodium intake and the cardiovascular response to calcium. They confirm that hypertensive subjects exhibit enhanced parathyroid gland function even when dietary factors are controlled, and they suggest that these subjects are more sensitive to the cardiovascular effects of short-term calcium infusion.

Yale J Biol Med 1996 Sep-Dec;68(5-6):215-7. Diplopia associated with hyperparathyroidism: report of a case. Forman BH, Ciardiello K, Landau SJ, Freedman JK. A patient with hypercalcemia due to primary hyperparathyroidism presented with diplopia that resolved with surgical removal of his parathyroid adenoma and normalization of his serum calcium values. No previous report of this feature of hyperparathyroidism has been reported.

J Nutr Sci Vitaminol (Tokyo) 1985 Dec;31 Suppl:S15-9. Aging and calcium as an environmental factor. Fujita T Calcium deficiency is a constant menace to land-abiding animals, including mammals. Humans enjoying exceptional longevity on earth are especially susceptible to calcium deficiency in old age. Low calcium and vitamin D intake, short solar exposure, decreased intestinal absorption, and falling renal function with insufficient 1,25(OH)2 vitamin D biosynthesis all contribute to calcium deficiency, secondary hyperparathyroidism, bone loss and possibly calcium shift from the bone to soft tissue, and from the extracellular to the intracellular compartment, blunting the sharp concentration gap between these compartments. The consequences of calcium deficiency might thus include not only osteoporosis, but also arteriosclerosis and hypertension due to the increase of calcium in the vascular wall, amyotrophic lateral sclerosis and senile dementia due to calcium deposition in the central nervous system, and a decrease in cellular function, because of blunting of the difference in extracellular-intracellular calcium, leading to diabetes mellitus, immune deficiency and others (Fig. 6)

Ann N Y Acad Sci 1990;587:371-5. Cytokines and osteoporosis. Fujita T, Matsui T, Nakao Y, Shiozawa S, Imai Y. Conditions associated with immune dysfunction such as aging, corticosteroid therapy, and rheumatoid arthritis are associated with osteoporosis, which is also more common in females than in males, like most of the autoimmune-collagen diseases. Peripheral lymphocyte subsets CD4/CD8 were higher in patients with senile osteoporosis than in the age-matched controls, and returned to normal after 1 month of 1 alpha(OH)vitamin D3 treatment. Plasma interferon reflecting macrophage function decreased with advance in age and increased in response to 1 alpha(OH)D3 treatment. As one of the immunoregulators, vitamin D tends to stimulate the macrophage-natural killer system and suppress the lymphocyte system, stimulating TGF beta and TNF alpha activity. Senile osteoporosis of low turnover thus appears to be associated with vitamin D deficiency, low macrophage function, high CD4 lymphocyte proportion, low IL-1 and high IL-2 activity, low IFN alpha and high IFN gamma activity, and low TGF beta and TNF alpha activity.

Contrib Nephrol 1991;90:206-11. Calcium, parathyroids and aging. Fujita T Calcium is unique in its distribution in living organisms with an extremely high hard and soft tissue and extra- intracellular concentration gradient. Calcium deficiency through stimulating parathyroid hormone secretion tends to blunt such a difference by paradoxically increasing the calcium concentration in the soft tissue and intracellular compartment. Since aging is associated with the progressive aggravation of calcium deficiency, such blunting also progresses with aging. The dysfunction, damage and death of cells occurring in all diseases is always associated with a blunting of the extra- and intracellular calcium components. Calcium supplement especially with highly biologically available active absorbable calcium, was associated with the suppression of parathyroid hormone secretion and the normalization of a such blunting of intercompartmental distribution of calcium examples in hypertension and diabetes mellitus with evident improvement of clinical manifestations and laboratory tests.

Presse Med 2001 Apr 7;30(13):653-8. [Hypovitaminosis D: a major worldwide public health problem] Gannage-Yared MH, Tohme A, Halaby G. Mild to moderate hypovitaminosis D causes secondary hyperparathyroidism increasing the risk of fracture, particularly femoral neck fracture. Vitamin D would also have an antiinflammatory and anticancer effect. Hypovitaminosis D is frequently observed in Europe in the elderly, particularly in the institutionalized population, but is also seen in otherwise healthy younger adults. An estimated 40% of the young European population has some degree of hypovitaminosis D. Finally, the beneficial effect of moderate sun exposure on cutaneous vitamin D synthesis (and psychological well-being) must not be overlooked.

Mol Med 1996 Mar;2(2):204-10. Parathyroid hormone-related protein is induced during lethal endotoxemia and contributes to endotoxin-induced mortality in rodents. Funk JL, Moser AH, Strewler GJ, Feingold KR, Grunfeld C. Parathyroid hormone-related protein (PTHrP) is a ubiquitous and highly conserved vasoactive peptide whose role and regulation in normal physiology remain an enigma. Recently, we demonstrated that low-dose endotoxin (LPS) induces intrasplenic, but not systemic, levels of PTHrP; and that tumor necrosis factor, a pro-inflammatory cytokine, is the major mediator of this effect. We have therefore hypothesized that, with higher, lethal doses of endotoxin, PTHrP could be induced in multiple tissues to such a degree that it could contribute to the lethality of septic shock. In response to a near-lethal dose of endotoxin, PTHrP mRNA levels increased acutely in every vital organ examined (spleen, lung, heart, kidney, and liver). Circulating levels of PTHrP also increased, peaking 2 hr after administration of high-dose endotoxin. These results suggest that PTHrP belongs to the cascade of pro-inflammatory cytokines induced during lethal endotoxemia that is responsible for the toxic effects of LPS.

J Clin Endocrinol Metab 1998 Feb;83(2):326-32. Serum soluble interleukin-6 receptor and biochemical markers of bone metabolism show significant variations during the menstrual cycle. Gorai I, Taguchi Y, Chaki O, Kikuchi R, Nakayama M, Yang BC, Yokota S, Minaguchi H. Serum soluble interleukin-6 receptor (sIL-6R) showed a significant variation; a rise during the early and late follicular periods followed by a fall during the early luteal period (P = 0.0423, P = 0.0334) and an increase during the mid and late luteal periods. The serum PTH level was significantly higher during the follicular than the luteal period (P = 0.0132).

Calcif Tissue Int 1990 May;46(5):294-9. Effective therapy of glucocorticoid-induced osteoporosis with medroxyprogesterone acetate. Grecu EO, Weinshelbaum A, Simmons R. The results lend support to the hypothesis of a progesterone-glucocorticoid competitive antagonism at the bone level, though other possibilities can be entertained, and suggest MPA as an effective therapy for glucocorticoid-induced osteoporosis in men.

Proc Soc Exp Biol Med 1986 Mar;181(3):438-42. Forskolin-induced bone resorption in neonatal mouse calvaria in vitro. Gunasekaran S, Hall GE, Kenny AD Lactic acid release was increased during the 96 hr of incubation in proportion to the calcium release in the media.

J Endocrinol 2000 Feb;164(2):129-38. Estrogen mediates the sex difference in post-burn immunosuppression. Gregory MS, Duffner LA, Faunce DE, Kovacs EJ. Previous studies in our laboratory have demonstrated that cell-mediated immune function was suppressed in female, but not male, mice at 10 days after burn injury and was mediated, in part, by increased production of interleukin-6 (IL-6). Increased circulating concentrations of E(2) corresponded with suppressed delayed-type hypersensitivity (DTH) and splenocyte-proliferative responses, and increased circulating concentrations of IL-6 in female mice after burn. Ovariectomy restored the suppressed DTH response and decreased IL-6 concentrations, and administration of exogenous E(2) to both ovariectomized females and intact male mice resulted in a suppressed DTH response. In addition, in vitro treatment with E(2) suppressed splenocyte proliferation in a macrophage-dependent manner and enhanced macrophage production of IL-6.

Calcif Tissue Int 1990 May;46(5):294-9. Effective therapy of glucocorticoid-induced osteoporosis with medroxyprogesterone acetate. Grecu EO, Weinshelbaum A, Simmons R.

Nephron 1982;30(3):237-9. Elevated thrombocyte calcium content in uremia and its correction by 1 alpha(OH) vitamin D treatment. Gura V, Creter D, Levi J.

Fortschr Med 1985 Mar 28;103(12):328-30. [Antiallergic effect of oral calcium. A clinico-experimental study] [Article in German] Haas PJ. Randomized Controlled Trial

Acta Univ Carol Med Monogr 1972;53:427-32. The possible role of platelets as trigger in intravascular coagulation associated with acute hyperparathyroidism. Hilgard P, Hohage R, Schmitt W, Minne H, Ziegler R.

Sci Total Environ 1986 Oct;54:207-16. Chemical qualities of water that contribute to human health in a positive way. Hopps HC, Feder GL. The chemical substances in water that make positive contributions to human health act mainly in two ways: (i) nutritionally, by supplying essential macro and micro elements that the diet (excluding water) may not provide in adequate amounts (for example, Mg, I and Zn); and (ii) by providing macro and micro elements that inhibit the absorbtion and/or effects of toxic elements such as Hg, Pb and Cd. In this context, the inverse relationship between hard water and cardiovascular disease will be discussed. Specific data relating hardness and Mg and Ca content of potable waters to specific geographic regions of the U.S.A. will be presented. These data show a strong positive correlation between low Mg content and decreased longevity, and between high Ca and Mg content and increased longevity. In the regions considered, increased longevity correlates strongly with decreased cardiovascular mortality, and the decreased longevity with increased cardiovascular mortality.

Calcif Tissue Res 1977 Oct 20;23(3):241-4. Proliferation of osteoclasts in rat bone following bleeding and femoral fractures. Johnell O, Hulth A This rise in the osteoclast population might be due to an increased parathyroid activity released by the trauma, but other factors may be involved. Both bleedings and fractures in rats are followed by hypercalcemia.

Brain Behav Immun 2000 Mar;14(1):49-61. Modulation of IL-6 production during the menstrual cycle in vivo and in vitro. Konecna L, Yan MS, Miller LE, Scholmerich J, Falk W, Straub RH. Premenopausal female patients with chronic inflammatory diseases demonstrate changes in disease activity during the MC. DHEA decreased LPS-induced IL-6 secretion at six of seven time points during the MC (DHEA, p = .047). In contrast, beta-estradiol and testosterone increased LPS-induced IL-6 secretion in six of seven time points during the MC (significant for testosterone, p = .005). The study demonstrates oscillation of serum IL-6 concentration during the MC and the marked MC-dependent modulation of IL-6 secretion by sex hormones.

Kidney Int Suppl 1983 Dec;16:S204-7. Pathogenesis of the anemia of uremia: role of secondary hyperparathyroidism. Massry SG PTH may participate in the genesis of the anemia of uremia through at least three pathways. These include inhibition of erythropoiesis, shortening survival of RBCs and inducing fibrosis of bone marrow cavity.

Braz J Med Biol Res 2002 Feb;35(2):229-36. Parathyroid hormone secretion in chronic human endogenous hypercortisolism. Lanna CM, Paula FJ, Montenegro RM Jr, Moreira AC, Foss MC. Osteoporosis is a common manifestation of Cushing's syndrome, but the mechanisms responsible for this abnormality have not been defined. Patients with CH showed an increased PTH response to the hypocalcemic stimulus compared to controls.

Am J Clin Nutr 2000 Jul;72(1):168-73. A threshold for low-protein-diet-induced elevations in parathyroid hormone. Kerstetter JE, Svastisalee CM, Caseria DM, Mitnick ME, Insogna KL. Elevations in PTH developed by day 4 of the diets containing 0.7 and 0.8 g protein/kg but not during the diets containing 0.9 or 1.0 g protein/kg. Our data suggest that in young healthy women consuming a well-balanced diet, the current recommended dietary allowance for protein (0.8 g/kg) results in short-term perturbations in calcium homeostasis.

J Endocrinol 1995 Sep;146(3):421-9. Effect of oral calcium supplementation on intracellular calcium and plasma renin in men. Lijnen P, Petrov V. Oral calcium supplementation in these men was also accompanied by a reduction in the plasma concentration of intact parathyroid hormone and 1,25-dihydroxyvitamin D3, an increase in 24-h urinary calcium excretion but no change in the plasma total Ca2+ concentration, serum ionized Ca2+ level and plasma phosphate or 25-hydroxyvitamin D3.

Clin Sci (Lond) 1996 Sep;91(3):313-8. Effects of mineral composition of drinking water on risk for stone formation and bone metabolism in idiopathic calcium nephrolithiasis. Marangella M, Vitale C, Petrarulo M, Rovera L, Dutto F. The increase in overall calcium intake due to different drinking water induced modest increases in calcium excretion, whereas oxalate excretion tended to decrease. The changes in oxalate excretion during any one study period compared with another were significantly related to those in calcium intake. Citrate excretion was significantly higher with the high-calcium, alkaline water. 4. Parathyroid hormone, calcitriol and markers of bone resorption increased when patients were changed from the high-calcium, alkaline to the low-calcium drinking water. 5. We suggest that overall calcium intake may be tailored by supplying calcium in drinking water. Adverse effects on bone turnover with low-calcium diets can be prevented by giving high-calcium, alkaline drinking water, and the stone-forming risk can be decreased as effectively as with low-calcium drinking water.

J Endocrinol 1998 Feb;156(2):231-5. Calcium blood level modulates endogenous nitric oxide action: effects of parathroidectomy in patients with hyperparathyroidism. Martina V, Bruno GA, Brancaleoni V, Zumpano E, Tagliabue M, Fornengo R, Gasparri G, Pescarmona GP. In primary hyperparathyroidism (H-PTH) an increase in platelet free calcium levels is present. After surgery, together with the normalization of calcium levels, NO production also returned to normal values.

Hypertension 1980 Mar-Apr;2(2):162-8. Enhanced parathyroid function in essential hypertension: a homeostatic response to a urinary calcium leak. McCarron DA, Pingree PA, Rubin RJ, Gaucher SM, Molitch M, Krutzik S. Recent reports . . . suggest that increased parathyroid gland function may be one of the more common endocrine disturbances associated with hypertension. Compared to a second age- and sex-matched normotensive population, the hypertensives demonstrated a significant (p less than 0.005) relative hypercalciuria. For any level of urinary sodium, hypertensives excreted more calcium. These preliminary data suggest that parathyroid gland function may be enhanced in essential hypertension.

Am J Med 1987 Jan 26;82(1B):27-33. The calcium paradox of essential hypertension. McCarron DA, Morris CD, Bukoski R. Three disparate observations--that calcium mediates vascular smooth muscle contraction, that calcium channel blockers lower blood pressure, and that increased dietary calcium intake can also ameliorate hypertension--constitute somewhat of a paradox. This evidence, and the paradoxical therapeutic efficacy of both calcium channel blockers and supplemental dietary calcium, can be integrated into a single theoretic construct.

Am J Hypertens 1995 Oct;8(10 Pt 1):957-64. Regulation of parathyroid hormone and vitamin D in essential hypertension. Young EW, Morris CD, Holcomb S, McMillan G, McCarron DA. The maximal stimulated PTH level was significantly higher in hypertensive than normotensive subjects in the absence of measured differences in serum ionized calcium concentration, serum 1,25(OH)2-vitamin D concentration, and creatinine clearance.

J Clin Invest 1995 Apr;95(4):1933-40. The diurnal rhythm of bone resorption in the rat. Effect of feeding habits and pharmacological inhibitors. Muhlbauer RC, Fleisch H. This paper shows that, in rats, bone mass can be increased by feeding habits per se. . . . we previously found a peak of bone resorption following food administration. We now demonstrate that dividing the solid and liquid intake into portions blunts this peak .... Whether bone mass in humans is also under the control of dietary habits is not known. If so, an increased meal frequency may be used to prevent osteoporosis.

Nephron 2001 Dec;89(4):384-90. Prolonged dietary calcium restriction: a diagnostic approach in idiopathic Hypercalciuria. Muller D, Eggert P.

Scand J Urol Nephrol 1997 Jun;31(3):275-80. Serum magnesium concentration and PTH levels. Is long-term chronic hypermagnesemia a risk factor for adynamic bone disease? Navarro JF, Macia ML, Gallego E, Mendez ML, Chahin J, Garcia-Nieto V, Garcia JJ. Interestingly, patients with low PTH had a significantly higher serum Mg concentration than patients with adequate or high PTH (2.8 +/- 0.2 mg/dl vs 2.3 +/- 0.1 mg/dl and 2.2 +/- 0.1 mg/dl, respectively, p < 0.01). Moreover, regression analysis showed a negative linear correlation between serum PTH level and plasma Mg concentration (r = -0.6059, p < 0.001).

J Appl Physiol 2001 Jun;90(6):2094-100. Effects of hypercapnia and hypocapnia on [Ca2+]i mobilization in human pulmonary artery endothelial cells. Nishio K, Suzuki Y, Takeshita K, Aoki T, Kudo H, Sato N, Naoki K, Miyao N, Ishii M, Yamaguchi K. Hypocapnic alkalosis caused a fivefold increase in [Ca2+]i compared with hypercapnic acidosis. The hypocapnia-evoked increase in [Ca2+]i was decreased from 242 +/- 56 to 50 +/- 32 nmol/l by the removal of extracellular Ca2+. The main mechanism affecting the hypocapnia-dependent [Ca2+]i increase was thought to be the augmented influx of extracellular Ca2+ mediated by extracellular alkalosis. Hypercapnic acidosis caused little change in PGI2 production, but hypocapnic alkalosis increased it markedly.

Clin Nephrol 2002 Mar;57(3):183-91.. Bone involvement in idiopathic hypercalciuria. Misael da Silva AM, dos Reis LM, Pereira RC, Futata E, Branco-Martins CT, Noronha IL, Wajchemberg BL, Jorgetti V. A negative correlation was observed between IL-6 levels and Z score of the femoral neck. Bone involvement was detected in a young population with nephrolithiasis demonstrating that a strict follow-up is necessary in order to control hypercalciuria.

Am J Physiol Heart Circ Physiol 2002 Jul;283(1):H193-203. CaMKII-dependent reactivation of SR Ca(2+) uptake and contractile recovery during intracellular acidosis. Nomura N, Satoh H, Terada H, Matsunaga M, Watanabe H, Hayashi H. In hearts, intracellular acidosis disturbs contractile performance by decreasing myofibrillar Ca(2+) response, but contraction recovers at prolonged acidosis.

J R Soc Health 1998 Apr;118(2):103-6. Lessons to be learned: a case study approach. Primary hyperparathyroidism simulating an acute severe polyneuritis. Olukoga A. The case is presented of a 65 year old lady with recent onset of neuromuscular manifestations, comprising paraparesis, areflexia and unsteady gait, along with episodes of slurring of speech and diplopia, later confirmed to be due to severe hypercalcaemia--which itself was caused by primary hyperparathyroidism.

Nippon Ronen Igakkai Zasshi 1989 May;26(3):216-22. [Calcium and magnesium metabolism in the aged] [Article in Japanese] Ouchi Y, Orimo H Although serum calcium concentration remains constant during ageing, the plasma concentration of calcium regulating hormones has been known to show dramatic change with ageing. The plasma concentration of parathyroid hormone increases with ageing, whereas plasma concentrations of calcitonin and active vitamin D metabolite decrease with ageing. On the other hand, the incidence of soft tissue calcification is known to increase with ageing.

J Clin Endocrinol Metab 1978 Sep;47(3):626-32. Calcium-regulating hormones during the menstrual cycle. Pitkin RM, Reynolds WA, Williams GA, Hargis GK. In six subjects with cycle lengths of 27-31 days, PTH levels rose progressively through the follicular phase to a peak at or slightly before the LH surge, then fell progressively through the luteal phase; peak PTH levels were 30-35% above early follicular and late luteal values. One subject experienced a prolonged (44 day) ovulatory cycle characterized by three distinct PTH peaks, each of which coincided with elevations in plasma estradiol level.

Muscle Nerve 1982 Jan;5(1):26-32. Hereditary polymyopathy and cardiomyopathy in the Syrian hamster. II. Development of heart necrotic changes in relation to defective mitochondrial function. Proschek L, Jasmin G Since the mitochondrial respiratory pattern and calcium overload parallel the cardiac degeneration, it is inferred that the cell energy depletion is a functional consequence of an abnormal calcium influx.

Eur J Endocrinol 1998 Oct;139(4):433-7. Changes in cytochrome oxidase activity in brown adipose tissue during oestrous cycle in the rat. Puerta M, Rocha M, Gonzalez-Covaleda S, McBennett SM, Andrews JF. The involvement of oestradiol in such a cycle is suggested by the fact that oestradiol treatment decreased COX activity to values similar to those found in proestrus.

Am J Hypertens 1999 Dec;12(12 Pt 1-2):1217-24. Modification of intracellular calcium and plasma renin by dietary calcium in men. Petrov V, Lijnen P. Our data show that the increase in PARA [plasma renin activity] observed in men during oral calcium supplementation is accompanied by a reduction in the intracellular free and total Ca2+ concentration in platelets and erythrocytes and by a decrease in the plasma concentration of intact parathormone and 1,25-dihydroxyvitamin D3.

Arthritis Rheum 2001 Oct;44(10):2338-41. Association of osteoporosis and cardiovascular disease in women with systemic lupus erythematosus. Ramsey-Goldman R, Manzi S. These results demonstrate an association between decreased BMD and both an increased carotid plaque index and presence of coronary artery calcification in a small cohort of young women with lupus.

Am J Hypertens 1994 Dec;7(12):1052-7. Dietary calcium reduces blood pressure, parathyroid hormone, and platelet cytosolic calcium responses in spontaneously hypertensive rats. Rao RM, Yan Y, Wu Y.

J Clin Endocrinol Metab 2002. May;87(5):2008-12 Potassium citrate prevents increased urine calcium excretion and bone resorption induced by a high sodium chloride diet. Sellmeyer DE, Schloetter M, Sebastian A.

J Allergy Clin Immunol 1990 Dec;86(6 Pt 1):881-5 1,25-Dihydroxyvitamin D3 potentiates the decreased response of lymphocytes from atopic subjects to agents that increase intracellular cyclic adenosine monophosphate. Ravid A, Tamir R, Liberman UA, Rotem C, Pick AI, Novogrodsky A, Koren R.

Eur J Endocrinol 2002 May;146(5):635-42. Diurnal rhythm of plasma 1,25-dihydroxyvitamin D and vitamin D-binding protein in postmenopausal women: relationship to plasma parathyroid hormone and calcium and phosphate metabolism. Rejnmark L, Lauridsen AL, Vestergaard P, Heickendorff L, Andreasen F, Mosekilde L. With the disclosure of a diurnal rhythm of total plasma 1,25(OH)(2)D, all major hormones and minerals related to calcium homeostasis have now been shown to exhibit diurnal variations.

Magnes Res 1999 Dec;12(4):257-67. Magnesium deficiency-induced osteoporosis in the rat: uncoupling of bone formation and bone resorption. Rude RK, Kirchen ME, Gruber HE, Meyer MH, Luck JS, Crawford DL. Magnesium (Mg) intake has been linked to bone mass and/or rate of bone loss in humans. Experimental Mg deficiency in animal models has resulted in impaired bone growth, osteopenia, and increased skeletal fragility.

Schweiz Med Wochenschr 1994 Jun 25;124(25):1122-8. [Hypercalcemia] Schmid C. Severe hypercalcemia is mainly caused by inappropriately high concentrations of compounds which promote bone resorption, in particular PTH, PTHrP, or 1,25 (OH)2D3. The major consequences are impaired central nervous system and kidney function (polyuria/dehydration); the latter, in turn, aggravate hypercalcemia via decreased fluid intake, mobility, and renal calcium clearance.

J Neurophysiol 2002 May;87(5):2209-24. Intracellular pH response to anoxia in acutely dissociated adult rat hippocampal CA1 neurons. Sheldon C, Church J. During perfusion with HCO/CO(2)- or HEPES-buffered media (pH 7.35) at 37 degrees C, 5- or 10-min anoxic insults were typified by an intracellular acidification on the induction of anoxia, a subsequent rise in pH(i) in the continued absence of O(2), and a further internal alkalinization on the return to normoxia. Reducing extracellular pH from 7.35 to 6.60, or reducing ambient temperature from 37 degrees C to room temperature, also attenuated the increases in steady-state pH(i) observed during and after anoxia and reduced rates of pH(i) recovery from acid loads imposed in the immediate postanoxic period. The results suggest that a Zn(2+)-sensitive acid efflux mechanism, possibly a H(+)-conductive pathway activated by membrane depolarization, contributes to the internal alkalinization observed during anoxia in adult rat CA1 neurons. The rise in pH(i) after anoxia reflects acid extrusion via the H(+)-conductive pathway and also Na(+)/H(+) exchange, activation of the latter being mediated, at least in part, through a cAMP-dependent signaling pathway.

Am J Physiol Heart Circ Physiol 2002 Dec;283(6):H2518-26. pH-induced changes in calcium: functional consequences and mechanisms of action in guinea pig portal vein. Smith RD, Eisner DA, Wray S. The effects of changing extracellular (pH(o)) and intracellular pH (pH(i)) on force and the mechanisms involved in the guinea pig portal vein were investigated to better understand the control of tone in this vessel. When pH(o) was altered, the effects on force and calcium were the same irrespective of whether force had been produced spontaneously by high-K depolarization or by norepinephrine; alkalinization increased tone, and acidification reduced it. Because pH(o) changes also lead to changes in pH(i), we determined whether the effects on force could be explained by these induced pH(i) changes. It was found, however, that only with spontaneous activity did intracellular alkalinization increase force. In depolarized preparations, force was decreased, and, with norepinephrine, force was initially decreased and then increased. Thus the effects of pH(o) cannot be explained solely by changes in pH(i). The role of the sarcoplasmic reticulum (SR) and surface membrane Ca(2+)-ATPase on the mechanism were investigated and shown not to be involved. Therefore, it is concluded that both pH(o) and pH(i) can have powerful modulatory effects on portal vein tone, that these effects are not identical, and that they are likely to be due to effects of pH on ion channels rather than the SR or plasma membrane Ca(2+)-ATPase.

Biochem Biophys Res Commun 2002 May 10;293(3):974-8. Arachidonic acid increases intracellular calcium in erythrocytes. Soldati L, Lombardi C, Adamo D, Terranegra A, Bianchin C, Bianchi G, Vezzoli G.. Since arachidonic acid and other polyunsaturated fatty acids influence the activities of most ion channels, we studied their effects on the erythrocyte Ca(2+) influx. AA (5-50 microM) and EPA (20-30 microM) stimulated a concentration-dependent increase in [Ca(2+)](i), deriving from extracellular calcium (1 mM), without affecting the intra- and extracellular pH and membrane voltage. We conclude that AA could activate an erythrocyte voltage-independent Ca(2+) transport via an intermediate product of cyclooxygenase pathway...

BMJ 1991 Mar 30;302(6779):762. Hormone replacement therapy induced chorea. Steiger MJ, Quinn NP. University Department of Clinical Neurology, Institute of Neurology, London.

Nippon Naibunpi Gakkai Zasshi 1991 Dec 20;67(12):1319-38. [Cation metabolism and the effects of circulating factors in pregnancy induced hypertension] Takashima M, Morikawa H, Yamasaki M, Mochizuki M. These data suggest that the increase of p-[Ca2+]i and r-[Na+]i in PIH is important in the initiation and maintenance of hypertension by influencing peripheral vascular resistance, and also various factors in the serum of PIH women may contribute to the accumulation of intracellular ionized calcium in patients with PIH.

Hear Res 2001 Apr;154(1-2):81-7. Effects of gentamicin and pH on [Ca2+]i in apical and basal outer hair cells from guinea pigs. Tan CT, Lee SY, Yao CJ, Liu SH, Lin-Shiau SY. By means of fura-2 microspectrofluorimetry, we measured the intracellular calcium concentration ([Ca2+]i) of OHCs bathed in Hanks' balanced salt solution (pH 7.40) during either a resting state or high K+-induced depolarization. While gentamicin and extracellular acidification (pH 7.14) can separately attenuate this increase in [Ca2+]i in both types of OHCs, their suppressive effects are additive in basal OHCs, but not in apical OHCs.

Biochem Pharmacol 1983 Jan 15;32(2):355-60. Induction of mast cell secretion by parathormone. Tsakalos ND, Theoharides TC, Kops SK, Askenase PW. The biologically active fragment of human parathormone (PTH) and intact bovine PTH were found to induce secretion of both serotonin and histamine from rat peritoneal mast cells in vitro. Intradermal injection of PTH induced immediate increases in vascular permeability suggesting that PTH could induce mast cell secretion in vivo. These results demonstrate that elevated levels of PTH can induce mast cell secretion in vitro and in vivo and suggest a possible role for mast cells in the pathophysiology of non-allergic disease states.

J Neurol Sci 1989 Feb;89(2-3):189-97. Hyperestrogenemia in neuromuscular diseases. Usuki F, Nakazato O, Osame M, Igata A. The cases, comprising bulbospinal muscular disease of the Kennedy-Alter-Sung type, Kugelberg-Welander disease, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy, were all euthyroid males. The baseline levels of serum estrone were significantly higher in all of the patients than in age-matched normal subjects. Serum baseline testosterone, LH and FSH levels were all essentially normal, except low FSH levels in Duchenne muscular dystrophy.

MMW Munch Med Wochenschr 1976 Oct 22;118(43):1395-8. [Oral application of calcium and vitamin D2 in allergic bronchial asthma] Utz G, Hauck AM. Within 60 minutes after application, a statistically significant reduction of airway resistance (Rt) and intrathoracic gas volume (IGV), as well as an increase of forced exspiratory one second volume (FEV1) and forced inspiratory one second volume (FIV1) was observed, in comparison with placebo. It is concluded that calcium, given orally in combination with calciferol, causes a decrease of airway obstruction in patients with allergic bronchial asthma.

J Urol 1994 Oct;152(4):1226-8. Urinary incontinence due to idiopathic hypercalciuria in children. Vachvanichsanong P, Malagon M, Moore ES. In addition to being the most common cause of microhematuria in children, our study demonstrates that idiopathic hypercalciuria is also frequently associated with urinary incontinence of all types.

Magnes Trace Elem 1991-92;10(2-4):281-6. Relation of magnesium to osteoporosis and calcium urolithiasis. Wallach S Magnesium influences mineral metabolism in hard and soft tissues indirectly through hormonal and other modulating factors, and by direct effects on the processes of bone formation and resorption and of crystallization (mineralization). Its causative and therapeutic relationships to calcium urolithiasis (CaUr) are controversial despite an association between low urinary Mg and CaUr. Recent studies have also found a tendency to low serum and/or lymphocyte Mg levels in CaUr. Despite earlier studies demonstrating an inhibitory effect of Mg supplementation on experimental CaUr in animals and in spontaneous CaUr in humans, at least two properly controlled clinical trials of Mg supplementation have failed to demonstrate a beneficial effect on CaUr frequency. With regard to the skeleton, experimental studies have shown that Mg depletion causes a decrease in both osteoblast and osteoclast activity with the development of a form of 'aplastic bone disease'. At the same time, bone salt crystallization is enhanced by Mg deficiency. Conversely, Mg excess impairs mineralization with the development of an osteomalacia-like picture, and may also stimulate bone resorption independently of parathyroid hormone. Whether or not Mg depletion may be a causal factor in human osteoporosis is also controversial, and there are conflicting reports as to the Mg content of osteoporotic bone. Small decreases in serum and/or erythrocyte Mg in osteoporotic patients have been reported, and one author has noted improved bone mineral density with a multinutrient supplement rich in Mg. The extant data are sparse and indicate a clear need for more rigorous study.

Semin Dial 2002 May-Jun;15(3):172-86 Calciphylaxis: emerging concepts in prevention, diagnosis, and treatment. Wilmer WA, Magro CM. Several recent reports demonstrate that prolonged hyperphosphatemia and/or elevated calcium x phosphorus products are associated with the syndrome. Protein malnutrition increases the likelihood of calciphylaxis, as does warfarin use and hypercoagulable states, such as protein C and/or protein S deficiency.

J Clin Lab Anal 1998;12(3):145-9. A proposal for standardizing urine collections for bone resorption markers measurement. Zaninotto M, Bernardi D, Ujka F, Bonato P, Plebani M. The findings suggest that nocturnal collection and first morning void samples provide the most reliable data on the rate of bone degradation, possibly showing bone loss not only in osteopenic patients but also in women with a low T-score.

Am J Physiol Renal Physiol 2001 Aug;281(2):F366-73. Increased CO(2) stimulates K/Rb reabsorption mediated by H-K-ATPase in CCD of potassium-restricted rabbit. Zhou X, Nakamura S, Xia SL, Wingo CS.

Sci Total Environ 1981 Apr;18:35-45 Water hardness and mortality in the Netherlands. Zielhuis RL, Haring BJ. The hypothesis that the Ca and Mg deficiency in areas with soft drinking water increases the risk of I.H.D. death rate was supported by the finding that food loses more Ca and Mg when it is cooked in soft water as compared to cooking in hard water. However, investigation of a group of 17 municipalities of which mortality and water quality data are known for three periods, 1958-1962, 1965-1970 and 1971-1977, showed that the inverse statistical relation between I.H.D. Mortality and water hardness still existed but with decreasing significance of correlation coefficients.

J Clin Endocrinol Metab 1980 Dec;51(6):1274-8. Serotonin stimulates adenosine 3',5'-monophosphate accumulation in parathyroid adenoma. Zimmerman D, Abboud HE, George LE, Edis AJ, Dousa TP. Since cAMP acts as a mediator of parathyroid hormone (PTH) release, our results suggest that serotonin could be one of the factors regulating PTH secretion and/or contributing to PTH hypersecretion in various forms of primary hyperparathyroidism.

Cas Lek Cesk 1997 Jul 30;136(15):459-63. [New drugs with positive effects on bones] [Article in Czech] Zofkova I, Kanceva RL. Magnesium influences bone in different ways. It activates osteoblasts, increases bone mineralization, and enhances the sensitivity of target tissues (incl. bone) to PTH and 1,25(OH)2 vitamin D3, Under certain conditions however, magnesium can stimulate bone resorption. A more potent factor than magnesium is stroncium, which not only activates osteoblats but decreases the number of osteoclasts, thus abolishing bone resorption and enhancing formation. Bicarbonates are also favourable for bone. NaHCO3 together with potassium citrate stimulates osteoblasts and enhances bone mineralisation.

© Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com

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<span class="koboSpan" id="kobo.1.1">Cholesterol, longevity, intelligence, and health.</span> A R T I C L E

Cholesterol, longevity, intelligence, and health.

The biological meaning of cholesterol is just starting to be explored.
Everything that doctors know about cholesterol is wrong.
New information about cholesterol is clarifying important issues in physiology and pathology.

Medical magazines and television stations like to propagate the idea that cholesterol is bad stuff, and as a result, that cliche is known to almost every American. Recent journal articles have promoted the idea that "the lower the serum cholesterol is, the better" it is for the health of the patient.

The theory that heart disease is "caused by cholesterol" has gone through several stages, and most recently the use of the "statin" drugs has revived it in a radical way. One consistent theme for fifty years has been that people should eat more polyunsaturated fat and less saturated fat, to lower their cholesterol, and to avoid butter, cream, eggs, and "red meat," because they contain both saturated fat and cholesterol. Often, medical attention is focused on the fats in the atheroma, rather than on the whole disease process, including clotting factors, vascular spasms, heart rhythm, viscosity of the blood, deposition of calcium and iron in blood vessels, and the whole process of inflammation, including the reactions to absorbed bowel toxins.

Almost 100 years ago, some experiments in Russia showed that feeding rabbits cholesterol caused them to develop atherosclerosis, but subsequent experiments showed that rabbits are unusual in responding that way to cholesterol, and that even rabbits don't develop atherosclerosis from cholesterol if they are given a supplement of thyroid (Friedland, 1933). By 1936, it was clear that hypercholesterolemia in humans and other animals was caused by hypothyroidism, and that hypothyroidism caused many diseases to develop, including cardiovascular disease and cancer. There was already more reason at that time to think that the increased cholesterol was a protective adaptation than to think that it was maladaptive.

The strange idea that cholesterol causes atherosclerosis was revived in the 1950s when the vegetable oil industry learned that their polyunsaturated oils lowered serum cholesterol. (Many other toxins lower cholesterol, but that is never mentioned.) The industry began advertising their oils as "heart protective," and they enlisted some influential organizations to help in their advertising: The American Dietetic Association, the American Heart Association, the US Dept. of Agriculture and FDA, and the AMA. Besides the early rabbit research, which didn't make their case against cholesterol and might actually have had implications harmful to their argument (since Anitschkow had used vegetable oil as solvent for his cholesterol feedings), the oil industry helped to create and promote a large amount of fraudulent and unscientific work.

The death rate from heart disease in the United States began increasing early in the twentieth century, and it reached its peak from about 1950 to 1975, and then began declining. During the decades in which the death rate was rising, consumption of animal fat was decreasing, and the use of vegetable oil was increasing. In the southern European countries that have been said to show that eating very little animal fat prevents heart disease, the trends after the second world war have been the opposite--they have been eating more animal fat without an increase in heart disease.

The correspondence between heart disease and consumption of saturated fat and cholesterol is little more than advertising copy. If people were looking for the actual causes of heart disease, they would consider the factors that changed in the US during the time that heart disease mortality was increasing. Both increases in harmful factors, and decreases in protective factors would have to be considered.

The consumption of manufactured foods, pollution of air and water, the use of lead in gasoline, cigarette smoking, increased medicalization and use of drugs, psychosocial and socioeconomic stress, and increased exposure to radiation--medical, military, and industrial--would be obvious things to consider, along with decreased intake of some protective nutrients, such as selenium, magnesium, and vitamins.

But those harmful factors all had their defenders: Who defends socioeconomic stress? All of the social institutions that fail to alleviate it. In 1847, Rudolph Virchow was sent to Poland to study the health situation there, and when he returned, the highly regarded anatomist, physiologist and pathologist announced that the Poles wouldn't have a health problem if the government would stop oppressing them, and institute economic reforms to alleviate their poverty. The reforms weren't made, and Virchow lost his job. Other harmful factors, such as seed oils, degraded foods, and radiation, have specific, very well organized and powerful lobbies to defend them.

Despite the growing knowledge about the dangers of polyunsaturated fats, many medical articles are still advocating the "official" heart protective diet (e.g., "... diets using nonhydrogenated unsaturated fats as the predominant form of dietary fat," Hu and Willet, 2002).

Some dogs alertly look at the thing a person is pointing at, other dogs just sniff the pointing finger. The publicists who disregard the complete nutritional and ecological situation, to focus on cholesterol and fat in the diet, are like the finger sniffers.

Recent articles in the medical and lipids journals are praising the 1950 work of J. W. Gofman, and the 1914 rabbit studies of N. N. Anitschkow, as the research that revealed cholesterol to be the cause of heart disease. Anitschkow and his co-workers, however, understood that their experiment hadn't explained human heart disease, and John Gofman, about 50 years after publishing his work on the lipoproteins, has done some large studies that could be crucial in disproving the doctrine that has become almost a national religion.

He has shown that mortality from both heart disease and cancer corresponds very closely to the population's exposure to medical services, and specifically to medical radiation. During the peak years of heart disease mortality, medical x-rays gave very large doses of radiation with each exposure, and the population was also exposed to radioactive fallout from atomic bomb testing (explosions from 1945 to 1963 produced a peak of heavy fallout that persisted through the 'sixties and into the 'seventies).

Around 1971, someone noticed that the commercial cholesterol being used in feeding experiments was oxidized, that is, it wasn't really cholesterol. Comparing carefully prepared, unoxidized cholesterol with the oxidized degraded material, it was found that dietary cholesterol wasn't necessarily atherogenic (Vine, et al., 1998).

Dietitians often recommend eating poached salmon, rather than "red meat," to lower cholesterol. Experimenters have measured the toxic oxidized cholesterol in different foods prepared in a variety of ways. Steaming salmon produced several times as much oxidized cholesterol as frying it, because of the longer cooking time that allowed the polyunsaturated fatty acids to break down, producing toxins such as acrolein and free radicals that oxidize the cholesterol and other components of the fish. The toxic cholesterol content of the steamed salmon was much higher than that of beef cooked at a high temperature.

When oxidized polyunsaturated oils, such as corn oil or linoleic acid, are added to food, they appear in the blood lipids, where they accelerate the formation of cholesterol deposits in arteries (Staprans, et al., 1994, 1996).

Stress accelerates the oxidation of the polyunsaturated fatty acids in the body, so people who consume unsaturated vegetable oils and fish will have some oxidized cholesterol in their tissues. The constant turnover of cholesterol in the tissues tends to lower the proportion of the toxic oxidized degradation products of cholesterol, but in hypothyroidism, the use of cholesterol is slowed, allowing the toxic forms to accumulate.

Many antioxidant nutrients act like a thyroid supplement did in the 1934 rabbit experiments, preventing atherosclerosis even when extra toxic cholesterol is given to the animals. People who eat seafood get much more selenium in their diet than people who eat nothing from the sea, and selenium is one of the extremely protective nutrients that prevent atherosclerosis in animal experiments with excess cholesterol.

It is well established that several antioxidant nutrients are protective factors in heart disease. The medical establishment has expended a great amount of money and time in the last 60 years fighting the use of vitamin E or selenium for treating or preventing heart disease, though many physicians now take vitamin E themselves. But people who study free radical chemistry recognize that polyunsaturated fats are highly susceptible to oxidation, and that saturated fats tend to slow their degradation, acting to some extent as antioxidants. Several experiments and observations have shown that cholesterol itself can protect against damaging oxidation of polyunsaturated fats, protecting DNA and other vital components of the cell. A consistent program to prevent the oxidation of cholesterol would have to include all of the vitamins and minerals that are involved in antioxidant defense, avoidance of nutrients that exacerbate the destructive oxidations, and an effort to normalize the hormones and other factors, such as carbon dioxide, that have protective effects against free radical oxidation. A low level of cholesterol might increase susceptibility to the oxidants.

The steroids in general, especially those produced in large amounts, progesterone and DHEA, are important parts of the antioxidant defenses. Cholesterol, either that produced internally by the cell, or taken in from the blood stream, is the precursor for all the steroids in the body. Several of the major steroid hormones are antiinflammatory, and cholesterol itself is antiinflammatory. (Mikko, et al., 2002; Kreines, et al., 1990). Cholesterol also protects against radiation damage, and many forms of toxin (saponins, cobra venom, chloroform--W.G. MacCallum, A Text-book of Pathology, 1937, Saunders Co.; many more recent studies show that it protects blood cells against hemolysis--breakdown of red blood cells--caused by heat and other harmful agents; e.g., Dumas, et al., 2002, Velardi, et al., 1991). Cholesterol, vitamin E, progesterone, and vitamin D are considered to be "structural antioxidants," that prevent oxidation partly by stabilizing molecular structures. One of the basic functions of cholesterol seems to be the stabilization of mitochondria, preventing their destruction by stress. Serious stress lowers ATP, magnesium, and carbon dioxide. When ATP and intracellular magnesium are decreased, cholesterol synthesis increases.

During stress, free fatty acids are released from the tissues, and circulating in the bloodstream they are highly susceptible to oxidation. They contribute to the formation of the age pigment, lipofuscin, which is an oxygen-wasting substance that's found in the atheroma plaques in the damaged blood vessels. Iron and calcium accumulation adds to the tissue damage.

The hemolysis which is promoted by polyunsaturated fats and an imbalance of antioxidants and oxidants, releases iron and heme into the blood stream. The incidence of atherosclerosis is increased when the body iron stores are high (Kiechl, et al., 1997), probably because of its role in lipid peroxidation and lipofuscin formation.

Especially when the lining of the blood vessel is too permeable, because of the influence of polyunsaturated fats, prostaglandins, estrogen, etc., the heme and iron will enter the endothelial cells, where the iron will catalyze the formation of free radicals, and the heme will be broken down by the enzyme heme oxygenase, into biliverdin, iron, and carbon monoxide, which can contribute to the oxidative stress of the cells. Carbon monoxide makes the blood vessel lining more permeable, allowing fats and fibrinogen to enter the cells (Allen, et al., 1988).

Although cholesterol is protective against oxidative and cytolytic damage, the chronic free radical exposure will oxidize it. During the low cholesterol turnover of hypothyroidism, the oxidized variants of cholesterol will accumulate, so cholesterol loses its protective functions.

When the metabolic pathways of the steroid hormones were being worked out, an experimenter perfused an isolated ovary with blood. When the amount of cholesterol in the blood pumped into the ovary was increased, the amount of progesterone in the blood leaving the ovary increased proportionately. In the healthy organism, cholesterol is constantly being synthesized, and constantly converted into steroid hormones, and, in the liver, into the bile salts that are secreted to emulsify fats in the intestine. Thyroid hormone and vitamin A are used in the process of converting cholesterol into pregnenolone, the immediate precursor of progesterone and DHEA. Anything that interfered with these processes would be disastrous for the organism. The supply of cholesterol, thyroid and vitamin A must always be adequate for the production of steroid hormones and bile salts. When stress suppresses thyroid activity, increased cholesterol probably compensates to some extent by permitting more progesterone to be synthesized.

In very young people, the metabolic rate is very high, and the rapid conversion of cholesterol into pregnenolone, DHEA, and progesterone usually keeps the level of cholesterol in the blood low. In the 1930s, a rise in the concentration of cholesterol was considered to be one of the most reliable ways to diagnose hypothyroidism (1936 Yearbook of Neurology, Psychiatry, and Endocrinology, E.L. Sevringhaus, editor, Chicago, p. 533). With aging, the metabolic rate declines, and the increase of cholesterol with aging is probably a spontaneous regulatory process, supporting the synthesis of the protective steroids, especially the neurosteroids in the brain and retina.

Many people refer to the structural importance of cholesterol for "membranes," and often imply that the membranes are just at the surface of the cell (the plasma membrane). But in fact cholesterol is found in the nucleus in the chromosomes, bound to DNA and in the nuclear matrix that governs the activation of genes, and in the mitotic spindle, which regulates separation of the chromosomes during cell division: without sufficient cholesterol, cells divide irregularly, producing aneuploid daughter cells (i.e., they have an abnormal number of chromosomes). Aneuploidy is now coming to be recognized as an essential feature of cancer cells. A significant amount of cholesterol was recently discovered to bind to hemoglobin, suggesting that it will be found in association with many other types of protein, when it occurs to anyone to look for it. Osmotic regulation, which is closely involved in cell division and other functions, appears to require cholesterol synthesis.

Around 1985, a big study in Hungary showed that lowering cholesterol with drugs caused a huge increase in the cancer death rate. Hundreds of publications appeared in the U.S. saying that wasn't possible, because low cholesterol is good, the lower the better. The extreme increase in cancer mortality in the Hungarian study was probably the result of the drug that was commonly used at that time to lower cholesterol, but the pattern of mortality in that study was approximately the same pattern seen in any group with very low cholesterol. In the last 20 years, there have been many studies showing that lowering cholesterol increases mortality, especially from cancer and suicide, and that people with naturally low cholesterol are more likely to die from cancer, suicide, trauma, and infections than people with normal or higher than average cholesterol.

The increased mortality from accidents and suicide when cholesterol is lowered is reminiscent of the problems seen in progesterone deficiency, and it's very likely that a deficiency of the neurosteroids accounts for it. A deficiency of progesterone and other neurosteroids (the steroids synthesized by the nerves themselves) causes depression of mood and impaired learning ability, among other neurological changes. As was the case with cancer, the pharmaceutical industry continues to deny that their anticholesterol drugs cause suicide, depression, and dementia, but there is a large amount of evidence from human as well as animal studies showing that mood and intelligence are depressed by lowering cholesterol. Simply injecting cholesterol into animals can improve their learning ability. In the Framingham heart study of 1894 people extending over a period of about 20 years, people with cholesterol naturally in the "desirable" range, below 200 mg.%, scored lower on "verbal fluency, attention/concentration, abstract reasoning, and a composite score measuring multiple cognitive domains" than those with higher cholesterol (Elias, et al., 2005).

After the age of fifty, low cholesterol is clearly associated with an increased risk of dying from a variety of causes. A study of old women indicated that a cholesterol level of 270 mg. per 100 ml. was associated with the best longevity (Forette, et al., 1989). "Mortality was lowest at serum cholesterol 7.0 mmol/l [=270.6 mg%], 5.2 times higher than the minimum at serum cholesterol 4.0 mmol/l, and only 1.8 times higher when cholesterol concentration was 8.8 mmol/l. This relation held true irrespective of age, even when blood pressure, body weight, history of myocardial infarction, creatinine clearance, and plasma proteins were taken into account."

The next step in studies of this sort should be to see how the combination of extra thyroid with adequate cholesterol influences longevity. The rising cholesterol that commonly occurs with aging is probably only partial compensation for declining thyroid function, and by optimizing all of the protective factors, radical changes in the aging process may be possible.

In the roundworm C. elegans, which is now a very popular animal for testing aging theories, because its genes and cells have been thoroughly "mapped," it was recently found that adding a gene that simply allows it to synthesize cholesterol, rather than depending on food for its sterols, increased its life span by as much as 131% (Lee, et al., 2005). That would be like increasing the human lifespan to about 175 years. These worms are also more resistant than normal to radiation and heat stress.

The cells of the thymus are extremely sensitive to radiation and other stressors, and their enrichment with cholesterol inhibits lipid peroxidation, DNA degradation, and death in response to radiation (Posokhov, et al., 1992).

Many high altitude regions of the world have high levels of background radiation, from minerals as well as cosmic rays, so it has been dogmatically believed that mortality from cancer and heart disease would increase with altitude, but the reverse is true. Because oxygen at lower pressure displaces less carbon dioxide from the blood, the body is able to retain more carbon dioxide at high altitude. Carbon dioxide protects against free radicals, and also helps to deliver oxygen to tissues, to maintain efficient energy production, and to prevent cellular stress. One study found 18 times higher incidence of hypertension in low altitude populations than in high altitude people (Fiori, et al., 2000). For many years, these principles have been applied in treating atherosclerosis and other degenerative diseases, in high altitude health resorts. Even a short period of hypoxic treatment can improve the body's ability to eliminate atherogenic lipid peroxides, possibly by improving the stress-resistant functions of the liver (Meerson, et al., 1988; Aleshin, et al., 1993; Kitaev, et al., 1999).

I think editors of medical journals generally see themselves as the purveyors of enlightenment, i.e., as the pushers of the stylish and prestigious doctrines. (Selectivity of evidence to serve the received doctrine is the commonest form of scientific dishonesty.) But because their mental framework is culturally narrow, they sometimes publish things which later could turn out to be embarrassing (if inconsistency could embarrass such types).

The recent discovery that the size of the LDL particle is a predominant factor in the development of atherosclerosis is one of those things that the editors and medical professors should find embarrassing.

Smaller lipoprotein particles have a greater surface area exposed to the oxidative factors in the serum, and so are more rapidly degraded into toxic substances. People with larger LDL particles are remarkably resistant to heart disease, and the drug companies are looking for a way to turn their lipoproteins into products. But the conditions that govern the size of the LDL particles are physically and chemically reasonable, and are causing confusion among the doctinaire.

There have been several studies in India showing that consumption of butter and ghee is associated with a low incidence of heart disease; for example, according to one study, people in the north eat 19 times more fat (mostly butter and ghee) than in the south, yet the incidence of heart disease is seven times higher in the south. A study in Sweden found that the fatty acids in milk products are associated with larger LDL particles (Sjogren, et al., 2004).

In a 35 day study, when butter (20% of the calories) was compared to various kinds of margarine (with more trans fatty acids) in a similar quantity, the LDL particles were bigger on the butter diet (Mauger, et al., 2003). But in a study of the habitual diet of 414 people, large LDL particles were found to be correlated with increased intake of protein, animal fat, and trans fatty acids (Kim and Campos, 2003).

In a study of the effect of dietary cholesterol on the atherogenicity of the blood lipids, 52 people were given either an egg diet (with 640 mg. of extra cholesterol per day) or a placebo diet for 30 days. Those whose LDL increased the most on the high cholesterol diet had the largest LDL particle size (Herron, et al., 2004). They concluded that "these data indicate that the consumption of a high-cholesterol diet does not negatively influence the atherogenicity of the LDL particle." A similar study in Mexico found that "Intake of 2 eggs/d results in the maintenance of LDL:HDL and in the generation of a less atherogenic LDL in this population of Mexican children" (Ballesteros, et al., 2004).

The estrogen industry tried to get into the heart disease business several times over the last half century, and they are still trying, but the issue of estrogen's harmful effects on LDL particle size is getting some attention. Estrogen clearly decreases the size of the LDL particles (Campos, et al., 1997). The LDL particles also get smaller at menopause, and in polycystic ovary syndrome, and in preeclamptic pregnancies, all of which involve a low ratio of progesterone to estrogen. But there are still journals publishing claims that estrogen will protect against heart disease, by reducing the atherogenic response in increasingly mysterious ways. Occasionally, people have argued not only that estrogen is the factor that protects women against heart attacks, but that androgens predispose men to heart disease. One of their arguments has been that androgens lower HDL, the "good" form of cholesterol. However, there are many studies that show that testosterone and DHEA (Arad, et al., 1989) are protective against atherosclerosis. The LDL particle size is increased by androgens, and postprandial triglyceridemia is decreased (Hislop, et al., 2001).

The studies in the 1930s that showed the protective effects of thyroid hormone against atherosclerosis and heart disease have sometimes been interpreted to mean that the thyroid is protective because it lowers the cholesterol, but since cholesterol is protective, rather than harmful, something else explains the protective effect. Ever since the time of Virchow, who called atherosclerosis arteritis deformans, the inflammatory nature of the problem has been clear to those who aren't crazed by the anticholesterol cult. We are all subject to a variable degree of inflammatory stimulation from the endotoxin absorbed from the intestine, but a healthy liver normally prevents it from reaching the general circulation, and produces a variety of protective factors. The HDL lipoprotein is one of these, which protects against inflammation by binding bacterial endotoxins that have reached the bloodstream. (Things that increase absorption of endotoxin--exercise, estrogen, ethanol--cause HDL to rise.) Chylomicrons and VLDL also absorb, bind, and help to eliminate endotoxins. All sorts of stress and malnutrition increase the tendency of endotoxin to leak into the bloodstream. Thyroid hormone, by increasing the turnover of cholesterol and its conversion into the protective steroids, is a major factor in keeping the inflammatory processes under control.

In hypothyroidism, the pituitary secretes more TSH to activate the thyroid gland, but TSH itself has a variety of pro-inflammatory actions. The C-reactive protein (CRP), which is recognized as a factor contributing to atherosclerosis, is increased in association with TSH. CRP activates mast cells, which are found in the atheroma plaques, to produce a variety of pro-inflammatory substances, including histamine.

The belief that cells are controlled by a plasma membrane, and that cholesterol's main function is to participate in that membrane, has led to a culture that treats cholesterol physiology with little curiosity. A different perspective on the cell starts with a recognition of the lipophilic nature of the structural proteins (not "membrane proteins," but things like cytoskeleton-cytoplasmic ground substance, spindle, centrosome-centrioles, nuclear matrix, etc.), with which lipids interact. Modifying an extremely complex system, the living substance, cholesterol participates in complexity, and must be investigated with subtlety. I suspect that the physiological meaning of cholesterol has to do with movement, stability, differentiation, memory, and sensitivity of the parts of the cells, that is, with everything physiological.

The functions of cholesterol parallel the functions of other sterols in plants and other types of organism. Its functions have been refined and extended with the development of other steroids, such as progesterone, as biological requirements have evolved, but cholesterol is still at the center of this system. To deliberately interfere with its synthesis, as contemporary medicine does, reveals a terrible arrogance.

Many participants in the cholesterol-lowering cult believe that they have succeeded in hijacking our science culture, but when the patents on another generation of their drugs have expired, the cult could begin to fade away.

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Estrogen, memory and heredity: Imprinting and the stress response

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IN OUTLINE:
Stresses, including estrogen excess, activate the Heat Shock Proteins (HSP), the stress-proteins, a primitive defense system.
Heat Shock Proteins and "hormone receptors" are closely related and interdependent.
Stress (at least partly via HSP) activates viral expression, ordinary gene expression, and destabilizes the genome, activating the "endonucleases," enzymes which break up DNA chains.
Stress increases genetic variability.
DNA chains can be chemically modified (e.g., methylated) in a way that limits enzymes' accesss, probably as protection, and to regulate gene expression.
Genes, and subsequent growth and development, are modified by the prenatal hormonal environment, that of the newborn, and even that of the parents before conception.
Genomic imprinting makes maternal genes behave differently from paternal genes.
Hormonal imprinting early in life sets the pattern of expression of genes.
"Crossing-over" intermixes the genes on the chromosomes as cells multiply.
Stresses and regulatory substances can change the patterns of gene expression that define cell types.
"Stem cells" are those capable of renewing tissues, and may be "pluripotent," able to become glial cells and neurons in the brain, or, in the bone marrow, to become red blood cells or white blood cells, depending on regulatory influences.
"Cloning" animals from body cells strongly suggests that any cell is potentially totipotent, able to differentiate into any other type of cell.
We are "imprinted" by our mothers' hormonal and nutritional conditions, but we can intervene to correct these "inherited" conditions, by maintaining optimal hormonal and nutritional balances.
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Recent work in several areas of biology is showing that heredity is not rigidly deterministic, in the way implied by traditional genetics, and it is opening the way for the development of therapies for incurable, chronic, or congenital problems, in natural and holistic ways that don't involve the mechanistic interventions of "gene therapy" or "genetic engineering." For example, nontoxic treatments for cancer that were demonstrated decades ago, were discarded because they didn't seem consistent with "genetics." Many problems that are classified as congenital or genetic, turn out to be physiological, and correctable. Even the brain and the heart, which until recently were considered to be incapable of regenerative repair, are now seen to be capable of great anatomical flexibility.

There are still great authoritarian forces opposed to recognizing, and supporting, the organism's full potential. The most useful therapies will remain in obscurity until many people see that those therapies have a firmer scientific foundation than orthodox (antiquated) medical genetics has.

Over 100 years ago, Samuel Butler had an argument with Charles Darwin, and concluded that Darwin was philosophically muddled, and dishonest. Butler was annoyed that Darwin had belittled the work of his predecessors, including his grandfather, Erasmus Darwin. Butler was defending the idea of biological intelligence, the incorporation of experience into physiology and heredity.

My parents had an old copy of one of Darwin's books, and I was impressed by the fact that in his introduction, Darwin was careful to point out that his ideas were already being misrepresented, and that he did not hold "natural selection" to be the only mechanism of evolution, but that several factors were important, including sexual selection and the inheritance of acquired traits. I suppose those remarks might have been motivated partly by knowing that Butler didn't approve of the way he was behaving, but they didn't seem to have much influence on the way history has characterized Darwin's work. All of my biology professors would have been happier if Darwin had never made those remarks. I suspect that Darwin's problem was that any theory of evolution was under such heavy attack that he couldn't devote much time to the relatively minor issue of how evolution works.
After Darwin's death, the study of heredity made some strange concessions to the culture of anti-evolutionism. As people began thinking about "particles that carry heredity," the "genes," ideas from the anti-evolutionist culture formed much of the context for understanding these "particles."

Darwin had suggested that the mature organism reconstitutes itself in the germ cells, by sending gemmules or pangens (buds or sprouts or derivatives) from its various parts, so that the parent's traits would be incorporated into the reproductive cells. This was called pangenesis, meaning that the whole organism was the source for the new offspring. This theory opened the possibility for newly acquired traits to be passed on. It grew out of the experience of animal breeders and horticulturists, who were dedicated to improving their breeds and strains, by selecting the best individuals grown under the best conditions. It was known that the miniature ponies, Shetlands for example, would grow larger each generation when bred under favorable conditions of domestication, rather than under the harsh conditions of their native island. It apparently never occurred to most plant and animal breeders that they might be able to improve a breed by subjecting it to harmful conditions.
Around the end of the 19th century, August Weismann began a systematic attack on the ideas of Darwin. As part of his campaign, he invented the doctrine that the reproductive cells are absolutely isolated from the rest of the organism, and that they are immortal. The rest of the organism is built up by the deletion of genetic information. This doctrine was very convenient for those who maintained that all organisms had been created in a single moment, and that the appearance of evolution resulted from the extinction of some species, but not the new appearance of some species. Some people, reasoning from Weismannism, suggested that evolution might have resulted without any change in the immortal genetic material, except deletion, in a manner analogous to Weismann's theory of the developing individual. Bacteria, in that view, would contain all the genes needed to make a tree or a person, and the more complex forms would have evolved through the differential loss of that primeval genetic information.

The changes produced by subtraction were compatible with the notion of fallen man in a corrupt world, while the addition of heritable traits through experience would connote a sharing in the process of creation. The hereditary particles making up Weismann's "immortal isolated germ line" connoted a single original creation.

As mutations in the genes came to be seen as a reality, experiments with X-rays suggested to some that all mutations were harmful, and this attitude blended into the stream of doctrine which insisted that no improvement could be inherited. Although many experiments showed what seemed to be meaningfully directed mutations, the doctrine held its ground, as its advocates taught that mutations were always random. (The doctrine of random change, like the idea that entropy only increases, excluded acts of creation from the fallen material world.) If a new trait appeared under new conditions, it was said to be only because an old trait was being revealed by the induced loss of another trait.

I think anyone who reads the "landmark publications" in genetics will see that genetics had very little to do with scientific method, as commonly conceived, and that it had all the traits of a cult. Analysis of the language of genetics reveals that terms have more often been used to cover up empty speculation than to clarify situations of fact.

Parallel to the way Darwin infuriated Samuel Butler by misrepresenting the origins of his theory, the neodarwinists who debate the creationists over school textbooks are ignoring the ways in which the culture of antievolutionism shaped their own view of genetics.

The discovery of enzymes that produce DNA modeled on RNA, "reverse transcriptases," began undermining traditional genetics, because it showed that new information can enter our genome.
The discovery that bacteria can pass "genes" from one individual to another, conferring antibiotic resistance upon previously sensitive strains, was a major nuisance to people working in infectious disease, since it complicates the treating of disease, but it indicated that "evolution," or genetic change, was capable of happening in non-random ways.

Early in the study of viral genetics, many people realized that "organisms" which can't reproduce without their relatively complex hosts, presented a problem for evolutionary theory. If the virus requires a cell in order to exist, it is hardly a separate organism. A few people suggested that viruses were, or were based on, functional normal parts of higher organisms. Some researchers have suggested that virus-like particles serve to carry information from one part of an organism to other parts of that organism. Mobile genetic elements are now well recognized, operating within cells, and it is common laboratory practice to use viral particles to transfer genetic material from one cell to another.

Cellular systems which cut and splice nucleic acids, creating sequences of information which don't exist in the inherited chromosomes, are now accepted parts of cell biology. Hormonal and environmental influences on the stability of messenger RNA, and on mobile genetic elements, and on genomic stability in general, are recognized. The center of gravity in the study of the nucleic acids has now shifted from heredity to development.

Almost nothing remains of Weismannism, which was the foundation of neodarwinism. The "isolation of the germline" doctrine persists in a few places, such as explaining why "the ovary runs out of eggs," despite some examples of egg-cell renewal.

But when the identity of "germline cells" is found to depend on signals from the environment, the last vestige of Weismannian germ-line doctrine disappears. The only meaning of "germline" is that some cells are destined to be germ cells, and the meaning disappears when such cells differentiate to form body parts. (see Donovan, 1998, Labosky, et al., 1994.)

The difference between primordial germ cells and embryonic cells is a matter of "imprinting," the process in which a hormone or "growth factor" or other "signal" directs a cell down a certain course of differentiation. "Imprinting" is where genetics and physiology, phylogeny and ontoneny, come together, and the new facts that are being discovered are removing the last vestige of scientific content from Weismannism/neodarwinism.

The argument between Peter Duesberg and the virus establishment, in which Duesberg argues that acquired immunodeficiency is produced by a variety of causes, including drug use, and the establishment argues that the HIV retrovirus is the only cause, becomes a little clearer when we consider it in the context of the larger debate between the genetic determinists and the Darwinian adaptationists. I will talk about that in more detail in a newsletter on immunodeficiency.

The issues of cancer, aging, and "hormone receptors," are also illuminated by seeing the organism as capable of adaptive modification of its genes.

These newer molecular approaches to the study of biology are vindicating some of the practical observations of plant and animal breeders, and terms such as telegony, heterosis, and xenia might come into common use again, along with genomic imprinting.

Here, I want to give examples of "hormonal imprinting" amd "genetic imprinting," and to show how the idea of the "retrovirus" or "mobile genetic elements" relates to practical health issues and therapies. The developing egg cell is constructed and modified in many ways during its growth. The nurse cells which surround it in the ovarian follicle inject massive quantities of material, especially RNA, into the expanding egg cell. Regulatory substances and energy production modify enzyme activities and structural proteins, which will influence the way it develops after fertilization. During the entire lifetime of the individual person, the developing egg cells are open to influences from the organism as a whole. Because of the Weismannian scientific culture, it's important to start with a few of the clearest interaction between the environment and the reproductive cell, but many other types of interaction are starting to be explored.

It has been suggested that environmental stress is responsible for viral epidemics, by activating viruses in their animal hosts, and causing them to spread to humans. Whether that's true or not, it is well recognized that stress causes increased susceptibility to the development of viral infections. It also causes increased genetic variability, which is logical in the evolutionary sense, that a species should become more variable when its environmental niche has changed. The mobile genetic elements that were first recognized by Barbara McClintock are now considered to be the most important means by which stress increases genetic variability.

In bacteria (J. Cairns; Salyers & Shoemaker, 1996), genetic changes are known to occur in response to specific substances, which lead to adaptation to that substance. The mobile elements which are responsible for the defensive adaptive response to antibiotics are similar to viruses. In these instances, the genetic dogma which has been taught very recently in the universities couldn't have been more clearly disproved. So far, the tendency in the United States is to concentrate on the details because of their technological potential (for genetic engineering of lucrative products) and to ignore the larger biological meaning of this interaction of stress with genetics.

Resistance to antibiotics is transmitted to other bacteria by "injecting," during conjugation of a resistant bacterium with a sensitive one, a small virus-like granule containing the DNA required for detoxifying the antibiotic, along with some adjoining genes. The antibiotic itself, producing stress, stimulates the formation of this genetic package. (Whole university courses used to be devoted to showing why such things couldn't happen.)

The enzymes which cut out sections of DNA are the "restrictases," which are famous for their use in identifying samples of DNA. These "endonucleases" are activated by stress. In "excitotoxicity," which kills nerve cells through a combination of intense activation with deficient energy stores (i.e., stress), these enzymes are activated.
In apoptosis, or "programmed cell death," these enzymes are activated, along with enzymes which repair the broken genes, and the resulting energy drain from an impossible repair job causes the cell's sudden dissolution. Between excitotoxicity and apoptosis, there are intermediate states, in which the dissolution is retarded or reversed.

When the stress is more generalized, so that the cells survive, the more sensitive sections of DNA are rearranged within the cell. Some of them may escape as infective particles.

Barbara McClintock wrote about the effects of stress causing genetic rearrangement, and traced the movements of the mobile genetic elements. At the same time, without knowing about her work, Leonell Strong was working with mice, exploring the role of "genetic instability" in causing cancer, and identifying estrogen and "milk particle," or "milk factor," a virus-like particle that interacted with estrogen, as causes of breast cancer.
With only the elements of stress, the endonucleases, and the mobile packets of genes, adaptively increased variability, and the spreading of genes among a population can be explained. However, there is a subtler level at which the adaptations acquired by an indiviual can be passed on to offspring. This is "imprinting."

"Genetic imprinting" is being studied mainly in terms of the covering of regions of DNA with methyl groups. This is thought to have evolved as a way to keep the endonucleases from attacking the DNA. Sections of DNA that have been methylated can be passed on to offspring in that form, and they can be traced as a pattern of gene activity or inactivity. The maternal genes function in a manner identifiably different from the paternal genes. Having passed through the mother's body, the genes have been modified.

"Hormonal imprinting" refers to the great changes in sensitivity to hormones (and related substances) that persist after exposure to that substance early in life. When the mother's hormones are imbalanced during pregnancy or nursing, the baby is "imprinted" with an altered sensitivity to hormones. Leonell Strong showed that these effects could be exaggerated generation after generation. But--strangely, considering that he was a student of T. H. Morgan, who is considered to be the founder of classical genetics-- Strong found that a single treatment, or a series of treatments, with an extract of liver, or with certain nucleosides (the units for constructing DNA), could reverse the course of generations of breeding, and eliminate the susceptibility to cancer.

In modern terms, he was probably working with a combination of genetic imprinting and hormonal imprinting. His "milk factor" very probably was one of the "endogenous retroviruses," or mobile genetic elements. (However, Gaal, et al., 1998, found that imprinting factors can be transmitted in the milk.)

Movable genetic elements appear to regulate normal developmental processes (Long, et al., 1998) and the introduction of new particles can "improve fitness." This is an aspect of the HIV controversy that has been completely ignored, as far as I can tell. Peter Duesberg argues that the presence of antibodies to the HIV indicates that the immune system is active, and that there is no evidence showing the virus to be harmful. My suggestion would be that the virus is probably present quietly in many people who have no antibodies to it, and that environmental toxins and other stressors cause it to be adaptively expressed, creating the possibility for an antibody response. The "viral particle" itself might be biologically useful, though this wouldn't exclude the possibility that an abnormal immunological response to it could have harmful repercussions.

The importance of the retroviruses in the human genome hasn't been widely appreciated. ("almost 10% . . . homology with the retroviruses," Deb, et al, 1998.)

Environmental pollution with estrogens and immunosuppressive substances, when it persists throughout the developmental period, and across generations, will be dangerous at levels much below those that show an immediate hormonal or immunosuppressive effect. Tests that determine the "mutagenicity" or "carcinogenicity" of a substance are performed within a context of a theoretical genetics which is demonstrably false; until the complexities of imprinting and transgenerational effects are taken into account, it would be wrong to accept the claim that there are "safe levels," or "thresholds of harmful effects."

When babies are imprinted by the mother's diuretics, by milk substitutes, and by industrial effluents, the worst effects are likely to be seen decades later, or even generations later.

There is a simple image that I think makes it possible to grasp as a whole the unity of things which have been described as existing on different "levels," the genetic, the metabolic, and the ecological. This is the image of an interaction between water and large molecules, such as proteins and nucleic acids, with the system--the way the large molecule is folded, and the way the water molecules are ordered--having more than one arrangement, or physical state, each state differing slightly in the amount of potential energy it contains. Then, the differences between respiratory energy (producing carbon dioxide and consuming electron-equivalents), and relatively anaerobic conditions, determine the probability that the system will return to its higher energy state after it has been perturbed.

A brief perturbation amounts to simple perception and response, reflecting the basic "irritability" of life, to use Lamarck's term. But with more intense disturbances, the structures are altered at deeper levels, and structures will be restored with different degrees of completeness, and the organism will have adapted, according to its resources, either toward increased "fitness" and sensitivity, or toward decreased sensitivity.

On the level of an individual, the movement away from fitness and sensitivity would resemble the development of aging and degenerative disease; on the level of a species, it would amount to "reverse evolution," a mammal would become more reptilian, a primate would become more rodent-like.

Protective interventions, and therapies, will consist of things which protect the structures (preserving sensitivity, while blocking excessive stimulation), and which increase the energy resources. A great variety of physiological indicators show that substances such as progesterone, thyroid and carbon dioxide are acting "universally" as protectants, in ways that make sense only with some perspective such as this, of the systematic changes in the physical state of the living substance.

REFERENCES

Taruscio D, et al., Human endogenous retroviruses and environmental endocrine disrupters: a connection worth exploring? Teratology. 1998 Aug;58(2):27-8.

Taruscio D, et al., Human endogenous retroviral sequences: possible roles in reproductive physiopathology. Biol Reprod. 1998 Oct;59(4):713-24

Genome 1998 Oct;41(5):662-8. A single-primer PCR-based retroviral-related DNA polymorphism shared by two distinct human populations. Deb P, Klempan TA, O'Reilly RL, Singh SM Department of Zoology, University of Western Ontario, London, Canada. "Almost 10% of the human genome consists of DNA sequences that share homology with retroviruses. These sequences, which represent a stable component of the human genome (although some may retain the ability to transpose), remain poorly understood." "Such novel polymorphisms should provide useful markers and permit assessment of evolutionary mechanisms associated with retroviral-related genomic evolution. "

Chromosoma 1991 Dec;101(3):141-56 Integration site preferences of endogenous retroviruses. Taruscio D, Manuelidis L. Yale Medical School, New Haven, CT 06510. "Retroviruses have the ability to integrate into the genome of their host, in many cases with little apparent sequence or site specificity.". "Retroviral elements in Alu-rich domains would be expected to be actively transcribed in all cells. Surprisingly, hybridization to blots of brain RNA showed an approximately 25 fold lower level of transcripts from these Alu associated elements than from retroviral sequences restricted to later replicating, heterochromatic domains." "Each host genome may utilize these elements for contrary, and possibly beneficial functions."

APMIS Suppl 1998;84:37-42 The potential of integrons and connected programmed rearrangements for mediating horizontal gene transfer.. Sundstrom L. "Site-specific recombination of integrons, mediates transfer of single genes in small genomes and plasmids. Recent data suggest that new genes are recruited to the cassettes--the units moved by integrons. Integrons are resident in a class of transposons with pronounced target selectivity for resolution loci in broad host range plasmids. A resulting network of programmed transfer routes, with potential offshoots reaching into eukaryotic cells, may channel genes to unexpectedly remote organisms." "It seems very clear that integrons and associated programmed transfer mechanisms have high significance for the dissemination of antibiotic resistance genes in bacteria whereas further studies are needed to assess their importance for spreading of arbitrary genes in a wider range of host systems."

Clin Infect Dis 1996 Dec;23 Suppl 1:S36-43. Resistance gene transfer in anaerobes: new insights, new problems. Salyers AA, Shoemaker NB. "Integrated gene transfer elements, called conjugative transposons, appear to be responsible for much of the transfer of resistance genes among Bacteroides species. Conjugative transposons not only transfer themselves but also mobilize coresident plasmids and excise and mobilize unlinked integrated elements." "An unusual feature of the Bacteroides conjugative transposons is that transfer of many of them is stimulated considerably by low concentrations of antibiotics. Thus, antibiotics not only select for resistant strains but also can stimulate transfer of the resistance gene in the first place."

Genetics 1991 Aug;128(4):695-701 Adaptive reversion of a frameshift mutation in Escherichia coli. Cairns J, Foster PL Department of Cancer Biology, Harvard School of Public Health, Boston, Massachusetts 02115. Mutation rates are generally thought not to be influenced by selective forces. This doctrine rests on the results of certain classical studies of the mutations that make bacteria resistant to phages and antibiotics. We have studied a strain of Escherichia coli which constitutively expresses a lacI-lacZ fusion containing a frameshift mutation that renders it Lac-. Reversion to Lac+ is a rare event during exponential growth but occurs in stationary cultures when lactose is the only source of energy. No revertants accumulate in the absence of lactose, or in the presence of lactose if there is another, unfulfilled requirement for growth. The mechanism for such mutation in stationary phase is not known, but it requires some function of RecA which is apparently not required for mutation during exponential growth.

Science 1993 Oct 15;262(5132):317-319. Whither directed mutation? Foster, P.L.

Science 1995, 268(5209):418-420. Adaptive mutation in Escherichia coli: a role for conjugation. Radicella JP, Park PU, Fox, M.S.
Nature 1998 Mar 12;392(6672):141-2 Are retrotransposons long-term hitchhikers? Burke WD, Malik HS, Lathe WC 3rd, Eickbush TH.

J Biomol Struct Dyn 1998 Feb;15(4):717-21 Mammalian retroposons integrate at kinkable DNA sites. Jurka J, Klonowski P, Trifonov EN "This suggests that during interaction with the endonucleolytic enzyme, or enzymes, DNA undergoes bending at the integration sites and kinks are formed, as initial steps in generating the nicks. Nicking at kinkable sites, particularly at TA steps, may also play a role in integration of other insertion elements."

J. Mol Evol 1997 Dec;45(6):599-609 The evolution of MHC diversity by segmental duplication and transposition of retroelements. Kulski JK, Gaudieri S, Bellgard M, Balmer L, Giles K, Inoko H, Dawkins RL.

Biochemistry (Mosc) 1997 Nov;62(11):1202-5. Telomerase is a true reverse transcriptase. A review. Cech TR, Nakamura TM, Lingner J Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of Colorado,Boulder. "We find it remarkable that the same type of protein structure required for retroviral replication is now seen to be essential for normal chromosome telomere replication in diverse eukaryotes."

Gene 1997 Dec 31;205(1-2):177-82 Mobile elements inserted in the distant past have taken on important functions. Britten RJ.

Genetika 1994 Jun;30(6):725-30 ["Adaptive transposition" of retrotransposons in the Drosophila melanogaster genome accompanying the increase in features of adaptability]. Beliaeva ES, Pasiukova EG, Gvozdev V.A. . "The transpositions were accompanied by a dramatic increase in individual fitness (competitive success)."

Genetika 1997 Aug;33(8):1083-93 [Stress induction of retrotransposon transposition in Drosophila: reality of the phenomenon, characteristic features, possible role in rapid evolution]. Vasil'eva LA, Ratner VA, Bubenshchikova EV "This stress response involved mobilization of retrotransposons." "In all these cases, stress induction of retrotransposon transpositions was mediated by molecular mechanisms of the heat shock system-the general system of cell resistance to external and physiological stress factors. From the viewpoint of evolution, stress induction of transpositions is a powerful factor generating new genetic variation in populations under stressful environmental conditions. Passing through a "bottleneck," a population can rapidly and significantly alter its population norm and become the founder of new, normal forms."

Mol Biol (Mosk) 1995 May-Jun;29(3):522-8 [Conserved regions of potential ORF1 protein products of mobile elements and retroviral proteins, encoded by the gag gene]. Kanapin AA, Ivanov VA, Il'in IuV.

Radiats Biol Radioecol 1995 May-Jun;35(3):356-63 [DNA analysis of retroposon-like genetic LINE elements in blood plasma of rats exposed to radio-diapason electromagnetic waves]. [Article in Russian] Belokhvostov AS, Osipovich VK, Veselova OM, Kolodiazhnaia VA The elevation of LINE-elements' DNA level was revealed in blood plasma of rats exposed to electromagnetic waves. The amount of full-size 5'-containing LINE-elements copies was increased especially. Connection of this effect with retrotransposon activation and genetic instability condition of organism development is supposed.

Dokl Akad Nauk 1995 Jan;340(1):138-40 [Induction of virus-like particles Tu1 by the mini-Tu1 element in the SPT3 mutant strain of Saccharomyces cerevisiae]. Reznik NL, Zolotova LI, Shuppe NG.

Dokl Akad Nauk 1994 Dec;339(6):838-41 [Extracellular virus-like particles retrotransposon Gypsy (MDG 4) as an infectivity factor]. Semin BV, Il'in IuV.

Mol Biol (Mosk) 1994 Jul-Aug;28(4):813-21. [Expression of the third open reading frame of the drosophila MDG4 retrotransposon similar to the retroviral env-genes, occurring through splicing]. Avedisov SN, Il'in IuV "The presence of a third long open reading frame (ORF3) is the common feature of a number of Drosophila retrotransposons, including MDG4 (gypsy). Thus, these elements have a strong structural resemblance to the integrated forms of vertebrate retroviruses." "The regulation at the level of splicing is supposed to be one of the most important factors controlling the transposition frequency of MDG4."

Genetika 1994 Jun;30(6):743-8 [Introduction of a single transpositionally-active copy of MDG4 into the genome of a stable line of Drosophila melanogaster causes genetic instability]. Liubomirskaia NV, Shostak NG, Kuzin AB, Khudaibergenova BM, Il'in IuV, Kim AI. "A previously described system of a Drosophila melanogaster mutative strain (MS), which originates from a stable strain (SS), is characterized by genetic instability caused by transposition of the retrotransposon gypsy. New unstable strains were obtained by microinjections of the gypsy transposable copy into SS embryos." "Genetic instability in the MS system is apparently induced by a combination of two factors: the presence of a gypsy transposable copy and mutation(s) in the gene(s) regulating its transpositions."

Genetika 1991 Mar;27(3):404-10 [Maintenance of the copy number of retrotransposon MDG3 in the Drosophila melanogaster genome]. Glushkova IV, Beliaeva ESp, Gvozdev VA The genomes of laboratory stocks and natural population of Drosophila melanogaster contain 8-12 copies of retrotransposon MDG3 detected by in situ hybridization. Construction of genotypes with decreased MDG3 copy number using X-chromosome and chromosome 3 free of MDG3 copies results in appearance of hybrid genomes carrying up to 7-10 copies, instead of 2-4 copies expected. New MDG3 copies are detected in different genome regions, including the 42B hot spot of their location. The chromosomes, where new clusters of MDG3 were observed, carry conserved "parental pattern" of MDG1 arrangement. The data obtained suggest the existence of genomic mechanism for maintenance of retrotransposon copy number on a definite level.

Biull Eksp Biol Med 1998 Jul;126(7):4-14 [The role of retroposition in the self-regulation of genome processes (do genes program the body and retroposons program genome]? Bebikhov DV, Postnov AIu, Nikonenko TA.

Genetika 1996 Jul;32(7):902-13 [Analysis of motifs of functional MDG2 sites in assuring its possible molecular functions]. Ratner VA, Amikishiev VG "Enhancers of mobile genetic elements are assumed to determine modification of adjacent genes and polygenes. Excisions and transpositions of mobile elements seem to be induced by external stress factors or physiological factors through a heat-shock system."

Genomics 1998 Dec 15;54(3):542-55 A long terminal repeat of the human endogenous retrovirus ERV-9 is located in the 5' boundary area of the human beta-globin locus control region. Long Q, Bengra C, Li C, Kutlar F, Tuan D. "Transcription of the human beta-like globin genes in erythroid cells is regulated by the far-upstream locus control region (LCR). In an attempt to define the 5' border of the LCR, we have cloned and sequenced 5 kb of new upstream DNA. We found an LTR retrotransposon belonging to the ERV-9 family of human endogenous retroviruses in the apparent 5' boundary area of the LCR." "This LTR is conserved in human and gorilla, indicating its evolutionary stability in the genomes of the higher primates. In both recombinant constructs and the endogenous human genome, the LTR enhancer and promoter activate the transcription of cis-linked DNA preferentially in erythroid cells. Our findings suggest the possibility that this LTR retrotransposon may serve a relevant host function in regulating the transcription of the beta-globin LCR." Copyright 1998 Academic Press.

Genetika 1995 Dec;31(12):1605-13 [Heterologous induction of the retrotransposon Ty1: reverse transcriptase plays a key role in initiating the retrotransposition cycle]. Reznik NL, Kidgotko OV, Zolotova LI, Shuppe NG A new method was developed to study the mechanism of initiation of the retrotransposition cycle: retrotransposons of Drosophila melanogaster, gypsy, copia, and 17.6 were expressed in yeast under the control of potent yeast promoters. Expression of retrotransposons induced formation of viruslike particles (VLPs) associated with full-length Ty1 RNA and DNA sequences. This phenomenon was termed heterologous induction. When the gene for reverse transcriptase of human immunodeficiency virus (HIV) was expressed in yeast, the same results were obtained. These data allowed us to assume the excess of active reverse transcriptase to play the central role in induction of transposition. Possible mechanisms of induction of Ty1 transposition by homologous and heterologous elements are discussed.
Hum Exp Toxicol 1998 Oct;17(10):560-3 Effect of retinoid (vitamin A or retinoic acid) treatment (hormonal imprinting) through breastmilk on the glucocorticoid receptor and estrogen receptor binding capacity of the adult rat offspring. Gaal A, Csaba G. "Hormonal imprinting occurs perinatally when the developing receptor and the appropriate hormone meet each other. The presence of related molecules in this critical period causes misimprinting. Ligands bound to a member of the steroid-thyroid receptor superfamily can disturb the normal maturation of other members of the family, which is manifested in altered binding capacity of the receptor and decreased or increased response of the receptor-bearing cell for life. Excess or absence of the hormone also can cause misimprinting." "The results of the experiment call attention to the transmission of imprinter molecules by breastmilk to the progenies, which can cause lifelong alterations at receptorial level and points to the human health aspect. Possible reasons for the differences between retinol and retinoic acid effects and in the sensitivity of receptors are discussed."

Life Sci 1998;63(6):PL 101-5 Neonatal vitamin E treatment induces long term glucocorticoid receptor changes: an unusual hormonal imprinting effect. Csaba G, Inczefi-Gonda A. "Thousandfold tocopherol did not compete with labeled dexamethasone for their receptors, suggesting that neonatal vitamin E imprinting effect was not done at direct receptorial level."

J Hypertens 1998 Jun;16(6):823-8 Female Wistar-Kyoto and SHR/y rats have the same genotype but different patterns of expression of renin and angiotensinogen genes. Milsted A, Marcelo MC, Turner ME, Ely DL "Female SHR/y rats have the parental Wistar-Kyoto rat autosomes and X chromosomes and have no chromosomes of spontaneously hypertensive rat origin; thus they are genetically equivalent to female Wistar-Kyoto rats." "The combination of removing estrogen early in development and supplementing the ovariectomized females with testosterone revealed strain differences in response of blood pressure." "Differences in regulation of renin-angiotensin system genes between strains may result from epigenetic mechanisms such as genome imprinting of these genes or of another gene that functions as a common regulator of renin and angiotensinogen."

Gen Pharmacol 1998 May;30(5):685-7 Imprinting of thymic glucocorticoid receptor and uterine estrogen receptor by a synthetic steroid hormone at different times after birth. Csaba G, Inczefi-Gonda A. 1. "Single allylestrenol treatment (hormonal imprinting) of 3-day old rats reduced the density of thymus glucocorticoid receptors and increased the density of uterus estrogen receptors at adult age." "4. The experiments demonstrate that hormonal imprinting can be provoked by allylestrenol not only pre- or neonatally, as was done in previous experiments, but also a few days later. The imprintability was lost between the 4th and 8th day of life."

Gen Pharmacol 1998 May;30(5):647-9 Fetal digoxin treatment enhances the binding capacity of thymic glucocorticoid receptors in adult female rats. Csaba G, Inczefi-Gonda A. 1. Hormonal imprinting is provoked in the perinatal critical period in the presence of the appropriate hormone or molecules similar to it. As a consequence of hormonal imprinting, the developing receptor finishes its maturation normally (in the presence of the adequate hormone) or abnormally (under the effect of foreign molecules that are able to bind to the receptor). 2. Digoxin--which has a steroid character--caused faulty imprinting by treatments at the 15th, 17th and 20th days of pregnancy. In the adult (3-month-old) animals, the density of thymic glucocorticoid receptors was significantly elevated, whereas the density of uterine estrogen receptors was not, without any change in receptor affinity. 3. The experiments call attention to the steroid receptor imprinting effect of fetal digoxin treatment that must be considered in regard to this treatment at this period and later in regard steroid treatments.

Hum Exp Toxicol 1998 Feb;17(2):88-92 Transgenerational effect of a single neonatal benzpyrene treatment on the glucocorticoid receptor of the rat thymus. Csaba G, Inczefi-Gonda A. Hormonal imprinting is provoked perinatally by the appropriate hormone on its receptor, causing a life-long adjustment of the connection between the two participants. Faulty imprinting is caused by the presence of molecules similar to the hormone in this critical period, which results in a persistent alteration of the receptor. In the present experiment the transgenerational imprinting effect of a steroid-like environmental pollutant, benzpyrene, on the receptor binding capacity of filial thymic dexamethasone and uterine estrogen receptors was studied. The receptor density (Bmax) of the thymic glucocorticoid receptors of the males was reduced up to the third (F2) generation. In females this reduction was observed only in the F1 generation of treated animals. There was no change in receptor affinity (Kd). Uterine estrogen receptors were not subjected to transgenerational imprinting. The experiments demonstrate (1) the possibility of the transgenerational transmission of imprinting effect, (2) the differences of steroid receptors in different organs, and (3) the differences of male's and female's reactions from this aspect. The results call attention to the dangers of perinatal aromatic hydrocarbon exposition to the progeny generations.

Genetika 1994 Apr;30(4):437-44 [Tv1--a new family of Drosophila virilis retrotransposons]. Andrianov BV, Shuppe NG."The method is based on the hypothesis about the universal character of retrotransposition through reverse transcription."

Genetika 1990 Mar;26(3):399-411 [Transpositional bursts and chromosome rearrangements in unstable lines of Drosophila]. Gerasimova TI, Ladvishchenko AB, Mogila VA, Georgieva SG, Kiselev SL, Maksymiv DV "The phenomenon of transpositional bursts--massive simultaneous transpositions of mobile elements belonging to different structural classes and accompanied by multiple mutagenesis were earlier described. Although the mechanisms of this phenomenon are still unclear, it is obvious now that it embraces total genome and includes not only transpositions of different mobile elements but also recombination processes--homologous recombination for LTR's and gene conversion."

Eksp Onkol 1986;8(2):29-32 [Nature of the endogenous retrovirus-like particles of the rat liver]. Korokhov NP, Pyrinova GB, Kurtsman MIa, Tomsons VP, Salganik RI.

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<span class="koboSpan" id="kobo.1.1">Estrogen, progesterone, and cancer: Conflicts of interest in regulation and product promotion.</span> A R T I C L E

Estrogen, progesterone, and cancer: Conflicts of interest in regulation and product promotion.

What is Cancer? (Johns Hopkins Univ.)

"The term cancer refers to a new growth which will invade surrounding tissues, metastasize (spread to other organs) and may eventually lead to the patient's death if untreated.

A tumor is not necessarily a cancer. The word tumor simply refers to a mass. For example, a collection of pus is by definition a tumor. A cancer is a particularly threatening type of tumor.

neoplasm- An abnormal new growth of tissue that grows more rapidly than normal cells and will continue to grow if not treated. These growths will compete with normal cells for nutrients. This is a non-specific term that can refer to benign or malignant growths. A synonym for tumor.

tumor- The more commonly used term for a neoplasm. The word tumor simply refers to a mass. This is a general term that can refer to benign or malignant growths.

benign tumor- A non-malignant/non-cancerous tumor. A benign tumor is usually localized, rarely spreads to other parts of the body and responds well to treatment. However, if left untreated, benign tumors can lead to serious disease.

malignant tumor- Cancer. A malignant tumor is resistant to treatment, may spread to other parts of the body and often recurs after removal.

cancer- A malignant tumor (a malignant neoplasm)."

http://pathology2.jhu.edu/pancreas/pc_overview.cfm

• • •

Issues that at first seem scientific too often turn out to be merely propagandistic. When a claim has no scientific value, it's necessary to directly attack that claim, but the propagandist hopes to (and often does) control the discourse, by resorting to techniques such as censorship, public relations, and financial-political power. The pharmaceutical industry uses all of those anti-scientific powers just as effectively as the military-industrial lobby does.

While Donald Rumsfeld answered the question, "where are the weapons of mass destruction?" by saying "We know where they are. They're in the area around Tikrit and Baghdad and east, west, south and north somewhat," the estrogen industry responds to the evidence that estrogen causes breast cancer, strokes, heart attacks, blood clots and Alzheimer's disease by saying "it's progesterone that is responsible."

To deal with the antiscientific fraudulent claims of the estrogen industry, it isn't necessary to search every square meter of Iraq, as it was with Rumsfeld's claim; it's enough to show that there is no science involved in their claims, by analyzing their experimental methods. But it's also important to examine some of the methods they have used to further their goals, despite the absence of any factual basis.

For more than 60 years, the estrogen industry has been using the techniques of public relations, including the placement of pseudoscientific articles in medical journals, to promote their sales. Recently, Carla Rothenberg documented a conspiracy of the estrogen industry in the 1940s to get medical and governmental approval of their products by shifting attention away from the clear evidence of estrogen's toxicity. Her paper competently reviews the subsequent history of "Hormone Replacement Therapy."
http://leda.law.harvard.edu/leda/data/711/Rothenberg05.pdf

After 2002 when the Women's Health Initiative study announced some of the harmful effects of hormone treatment, resulting in a disastrous decrease in estrogen sales, the industry has intensified and diversified its public relations efforts, and has succeeded in recovering some of their lost market. Historically, whenever some of the claimed benefits of estrogen have been disproved, the industry shifts its emphasis to new, previously unmentioned "virtues" of the product. Hundreds of different benefits claimed for estrogen in prestigious medical journals have been proven false, but until 2002, the industry's profits grew steadily. Now, compensating for the annual loss of billions of dollars, they are highly motivated.

Dozens of toxic effects of estrogen were demonstrated and never refuted, but a variety of techniques of distraction and misdirection gradually emerged, to prevent the accumulated evidence of estrogen's toxicity (and/or ineffectiveness) from interfering with the campaigns to market it for the widest possible variety of conditions.

Since the WHI study involved the use of Prempro (PREMPROTM--conjugated estrogens and medroxyprogesterone acetate), the emphasis of the industry has been to divert attention from the toxic effects of estrogen, by blaming everything on "progesterone." An intense campaign is underway to assign all of estrogen's harmful effects to progesterone.

The pharmaceutical industry has a long history of lying about natural progesterone (and many other natural substances), to promote sales of their competing products. The price ratio of retail estrogen tablets to bulk estrogen can be 1000 to 1, while the ratio for progesterone products is often less than 10 to 1. With the increased use of progesterone (its sales in the US have increased more than 100-fold), the estrogen industry has had to develop new kinds of attack. A small shift of the market away from estrogen costs the drug industry hundreds of millions of dollars. The loss of estrogen sales following the 2002 WHI study, that convincingly demonstrated its toxicity, was huge, with the decreased sales of Wyeth alone amounting to billions of dollars. Wyeth has petitioned the FDA to prevent compounding pharmacies from selling the natural hormones.

People who have made a career of research that, according to them, reveals the "benefits" of estrogen have, in recent years, expanded their work to argue that it is progesterone, rather than estrogen, that causes diabetes, heart disease, dementia, and cancer.

The EPA currently has a document draft on the internet which, in relation to the evaluation of a carcinogenic herbicide, reviews the issue of the balance between estrogen and progesterone in the development of cancer in rats, and includes the observation that progesterone is not carcinogenic to rats, and that it instead is protective against cancer, because of its antiestrogenic effects.

Recently, stores in California have placed warnings near their progesterone-containing cosmetics, saying that the State of California "knows" progesterone to be a carcinogen.

Californians often talk about their state's having the world's sixth largest economy. The state accounts for 14% of the GDP of the U.S. If the state regulates a product made in Michigan, Texas, or France, the producer is very likely to change the product to suit California.

If an industry wants to control its competitors or potential competitors, an investment in California's regulatory system can pay huge rewards.

California has listed progesterone as a carcinogen under the Safe Drinking Water and Toxic Enforcement Act, called Proposition 65. The law doesn't prevent the sale of carcinogens, it simply requires a warning. Warnings are posted in grocery stores and restaurants, on sports equipment, in beauty parlors, on apartments and parking lots, but there is so little effort spent on realistic evaluation of risks that the effect of the law is to allow the major polluters to go unnoticed among the ubiquitous warnings. But California has other laws that encourage its lawyers to sue for "unfair business practices" when they believe Prop 65 has been violated. That has resulted in a culture of vigilantism with bounty-hunting lawyers, some of whom try to enforce Prop 65 even against companies that are clearly exempt.

California's regulatory board that lists progesterone as a carcinogen cites two bodies that have evaluated carcinogens, the US National Toxicology Program (NTP), and the UN's International Agency for Research on Cancer (IARC), as authoritative sources. One of those, the US National Toxicology Program (NTP) cites the other's, the IARC's, evaluation of progesterone as the basis for its own listing of progesterone, so the opinion of IARC has been very influential.

The IARC publications discussed the toxicity of several of the synthetic progestins, and concluded that some of them are possible human carcinogens. The (1987) entry for medroxyprogesterone acetate, for example, has three sections: "A. Evidence for carcinogenicity to humans (inadequate)," "B. Evidence for carcinogenicity to animals (sufficient)," and C., that it can damage chromosomes. Eight citations, besides two IARC monographs (1974 and 1979), are given as supporting evidence.

The entry for progesterone, oddly, has only two sections, "A. Evidence for carcinogenicity to animals (sufficient)," and B, that it doesn't damage chromosomes. There is no mention of human carcinogenicity at all. Besides the IARC monographs, only one study is mentioned, a test in beagles (I'll comment on the competency of that study below). At the end of the whole section, which included eleven synthetics and progesterone, it concludes: "Overall evaluation" "Progestins are possibly carcinogenic to humans (Group 2B)," oddly neglecting to distinguish progesterone from the synthetics.

The corruption of the term "progestin" or "progestogen" by the industry and the drug regulators has been terribly consequential. The synthetic chemicals classified as progestins often have anti-progesterone actions, and shouldn't be called progestins at all, because they don't support gestation, contrary to what the term falsely implies. It is exactly their anti-progesterone/antigestational action that led to their use as contraceptives.

Since the 1987 review by IARC, it seems that their only other review of progesterone's carcinogenicity was of a single study in 1999, and that study clearly gave evidence that progesterone prevented cancer.

But California's board of "qualified experts" in the Office of Environmental Health Hazard Assessment (OEHHA) identify progesterone as known to cause cancer, and cites the group of studies listed by IARC in the medroxyprogesterone acetate report as their evidence. Rather than trying to clarify the confusions that exist in the IARC documents, this board has compounded the confusion.

In the transcript of the meeting, at which they decided to list progesterone as a carcinogen, they received testimony from only one outside expert, Richard Edgren, who answered the chairman's question, why don't you want progesterone listed, by saying, because it isn't a carcinogen. He said that the inclusion of a large number of non-carcinogenic materials "could vitiate the use of the list."

But the chairman had, early in Edgren's review of the shortcomings of animal studies of carcinogenesis, heard the word "metastasis," in connection with beagle dogs, and--although Edgren hadn't said that any metastatic cancer had been found in the progesterone test (it hadn't)--the committee's decision to list progesterone appears to have hinged on that word.

Edgren, referring to "various synthetic and semi-synthetic progestogens," said that administering them by injection "leads to the development of mammary nodules, some of which have the characteristics of malignant tumors, although these tumors rarely metastasize." A little later, Kilgore said "I mean, I heard you say that it was rare that it metastasized. I would say any kind of metastasizing is important." Edgren isn't quoted in the transcript as having attempted to explain that the malignant and metastatic cancers appeared only in beagles treated with synthetic progestins. At best, the behavior of the chairman and the committee, as reflected in that transcript, was erratic and confused, or more accurately, irrational.

The only biologist on the committee who spoke during the meeting, Dr. Spangler, expressed confusion and dissatisfaction with the evidence:

". . . in reviewing the information that was supplied to me regarding progesterone, I was confused and concerned by what appears to be a variety of discrepancies in the way the compound has been reviewed." "In one place, IARC says there is limited evidence; in another place, it says there is sufficient evidence. And NTP says there is sufficient evidence. And they cite as their sufficient evidence a variety of very convoluted experimental procedures, in which mouse mammary tumor virus positive mice were used in a study; and, in addition to that, some other carcinogen, some other potent carcinogen, was applied at the same time or after." "It was just very confusing. And I had a lot difficulty evaluating it."

The State's rules explicitly state that all the relevant evidence is to be presented to the committee for consideration, and that the evidence must show clearly, by accepted scientific methods, that a material causes cancer (i.e., malignant tumors) before it can be listed. What is clearly shown by the few papers provided to the committee is that their procedures were not followed at all. Providing publications that didn't even claim to have involved the development of cancer, and ignoring an immense amount of more relevant evidence, the committee, in a parody of legal process, didn't even get a randomly selected sampling of the relevant evidence.

In my correspondence with OEHHA, when I pressed for information regarding the criteria for selecting evidence, and the qualifications of the staff who had the responsibility of selecting "all relevant evidence," their response was that they lacked the resources to answer the question.

Edgren, who had argued that progesterone wasn't a carcinogen, didn't make a very good presentation of the case against the few studies that had been mentioned by NTP and IARC. Even if he had been able to do that, in the few minutes he had (six or seven different substances were on the agenda for consideration for listing during that meeting), it doesn't seem likely that the committee would have been interested.

In a letter he wrote to the committee before it met, Edgren said "Careful evaluation of data from a properly conducted oral study is a prerequisite before the carcinogenicity of any chemical can be adequately evaluated." The reason for that statement is that it had become clear in the 1970s and 1980s that the invasive introduction of anything into the body's tissues creates inflammation and a complex series of systemic stress reactions that affect the immune system, and that can lead to the development or promotion of cancer, no matter how inert and innocuous seeming the injected material might be. The people on the committee didn't even discuss that issue. Worse, the studies mentioned by IARC included some that hadn't met basic scientific standards of experimental design, failing to use proper experimental controls, including vehicle controls, and failing to describe the actual composition of the vehicle or solvent used for administering progesterone.

Every good high school science teacher or science student knows that the experimental variables have to be clearly defined. The United Nations' IARC, the US's NTP, and California's Panel of Qualified Experts chose to draw conclusions on some studies that don't meet any standards for testing carcinogens, such as those published by the US government. And while disregarding basic standards of experimental design, their review of the literature had an even more serious flaw--it "cherry-picked" the published evidence that they apparently preferred, ignoring the studies which, over a period of more than 20 years, showed that progesterone prevents and/or cures tumors. And in an extremely unrepresentative selection of studies on the subject of progesterone's carcinogenicity, the selected studies presented some clear evidence of some of progesterone's anticarcinogenic effects, along with some results that can't be interpreted clearly.

One of the early papers listed as evidence of progesterone's carcinogenicity in animals actually concluded that their experiments completely failed "to produce any beneficial effect by the administration of progesterone on the mammary cancer in mice," and cautioned that their results showed "the need for care in attempting to generalize results even in different strains of the same species and emphasizes the difficulty of attempting to carry over results obtained in experimental animals to human pathology." (Burrows and Hoch- Ligeti, 1946).

The work (demonstrations of the anti-tumor effect of progesterone) that they were not able to confirm had included explicit observations that intermittent injections of progesterone were not effective in preventing tumors or causing them to regress, and emphasized the importance of continuous exposure. Knowing that, the Burrows and Hoch-Ligeti publication appears to have been designed propagandistically to oppose the work that was demonstrating the anti-tumor actions of progesterone, since they--without explanation--used the already discredited method of giving periodic injections of progesterone dissolved in peanut oil.

Without reading the article, people seeing it included on the agencies' list of studies supposedly providing evidence of progesterone's carcinogenicity would assume that it provided such evidence. It didn't. If the agencies cite this study, why didn't they mention any of the numerous studies showing that progesterone prevents tumors or causes them to regress? The reason this study was done was to argue against the studies that had demonstrated progesterone's protective effects, so anyone reading it had to know of those other studies' existence, as well as knowing that this study itself provided no evidence at all of carcinogenicity.

Reproducibility is the essence of science, and the anti-tumor effects of progesterone were repeatedly demonstrated by different investigators. The single study by Burrows and Hoch-Ligetti has never been replicated, and the reason for its failure to show an anti-tumor effect was already explained by the other workers.

Since the 1920s, many studies had demonstrated that "spontaneous" cancers increase in proportion to the quantity of polyunsaturated fat (especially linoleic acid) in the diet. By the end of the 1960s, the carcinogenicity of vegetable oils, or at least their "co-carcinogenicity" or "tumor promoting" effects had become widely known, and one of the World Health Organization publications observed that progesterone carcinogenicity studies using vegetable oil as the vehicle couldn't be recognized as valid.

More recently, ethanol has been found to antagonize progesterone's anticancer and anti-proliferative actions.

Studies using implanted pellets or plastic tubes containing a solution of progesterone sometimes neglected to even mention the nature of the solvent used. Since implanted pieces of inert materials, such as disks of plastic, could be carcinogenic, it was recognized that a proper control for a hormone-containing pellet or tube would require the implantation of a pellet or tube without the hormone. Sometimes, instead of actually implanting the object, sham surgery, similar to that involved in implantation of the pellet, would be used, in recognition that the surgical trauma itself could have far reaching effects on the organism.

Any tissue damage or irritation causes the release of cytokines and mediators of inflammation, which are known to be involved in tissue growth and cancer. When injected, even plain water and other normally harmless things are carcinogenic.

The need for proper experimental controls when using implanted devices is shown by a study that analyzed the fibrotic tumors that had grown around implanted plastic tubes. Crystals of talc were found in the tumor, that were assumed to have originated from the surgical gloves used during the operation. Talc is now widely recognized as a carcinogen, and is suspected of causing ovarian cancer.

Overlooked variables are the reason for the essentiality of repeatability and confirmation in science.

In the 1970s, a new method for suspending or dissolving oily chemicals in water was being explored. A cyclic carbohydrate, cyclodextrin, makes it possible to wet substances that are insoluble in water, such as progesterone, even if the substance remains in a solid crystalline form. Several companies were promoting the use of these for the administration of hydrophobic drugs.

In 1976, D.W. Frank reported that the cyclodextrins produced nephrosis in rats. In 1978, a study by Perrin, et al., reported its toxicity to the kidneys. Twenty years later, Horsky and Pitha at NIH reported that the cyclodextrins can synergize with carcinogens, and in 1982 a group in Japan reported that cyclodextrins can increase the production of kidney cancers by another carcinogen (Hiasa, et al.). The intrinsic carcinogenicity of a more water soluble cyclodextrin, that was considered "more toxicologically benign," was found to cause pathological changes in lungs, liver, and kidney, and to increase the formation of tumors in the pancreas and intestines of rats (Gould and Scott, 2005).

In 1974, D. W. Frank and others at Upjohn had begun testing the effects of progesterone and medroxyprogesterone acetate in beagle dogs, using an "aqueous suspension." Their 1979 publication describing that four year study didn't mention the way in which the "aqueous solution" had been made, and didn't mention cyclodextrins at all. Frank's published observation during the beagle study that cyclodextrins are toxic to the kidneys suggests that someone at Upjohn had noticed a problem with the "wetting agent" that was already in use in the beagle study.

Another remarkable feature of the four year beagle study was that, of 140 dogs that began the intended 7 year study, 28 had died by the time they published the report, and none died of cancer, but the causes of death were not reported. The only experimental group in which there were no deaths by the end of four years was the low dose progesterone group. The dogs in the high dose progesterone group received weekly intramuscular injections of 1140 mg of progesterone suspended in 11.4 ml of "aqueous vehicle." 2345 ml of the vehicle was received by each dog during the four years. Only four dogs in that group were still alive at the time of publication, but the cause of death of the other 16 wasn't mentioned. Quarts of a toxic material that had never before been used in this way, injected into their muscles, and the unexplained deaths of so many animals, make this a unique experiment that is unlikely ever to be repeated.

Their failure to mention injection-site muscle damage is just another indication of the study's low quality.

At the time of the study, it had been known for many years that interference with the organism's detoxifying systems, especially the liver and kidneys, can contribute to the development of cancer. Although the study was planned to continue for 7 years to meet the FDA requirement, none of the eight authors ever published again on a related topic, and most of them didn't publish again at all.

When I tried to contact one of the authors, he didn't respond. I assume they were embarrassed by the shoddiness of their methods. Richard Edgren has commented, "I can't believe how fast and how completely they shut down. They fired people and retrained the rest for other areas."

But the regulatory agencies have tied their reputations to studies of that sort.

No malignant cancers were reported in this four-year beagle study. Beagles normally have a high incidence of cancer, especially mammary cancer. In a different study in which 172 beagles were treated with contraceptive hormones, nine of them developed malignant cancers, and of those, five metastasized. (This might be why the chairman of the committee was thinking about metastatic cancer, but if so, he was simply confused, because the issue they were considering was the listing of natural progesterone, which wasn't reported to have produced any malignant or metastatic tumors.)

Two other studies cited by the IARC and other agencies, by Jones and Bern, 1977, and Rebout and Pageaut, hardly seem appropriate studies to support the idea that progesterone is carcinogenic.

Jones' and Bern's paper described the production, 12 months after neonatal treatment with progesterone, of vaginal and cervical lesions, and mammary nodules, which are also referred to as tumors. "Progesterone alone induced cervical lesions in only 1 of 32 mice...and induced vaginal lesions in only 2 or 32 mice. Furthermore, progesterone given with either dose of estrogen to intact mice reduced the incidence of hyperplastic lesions, compared with intact groups treated with estrogen alone." They commented (page 74) that their results were "mammary tumor virus dependent," and that this might account for the production of "hyperplastic alveolar nodules as opposed to" tumors of possible ductal origin, that had been seen in other studies when the carcinogen DMBA was used.

In another 1977 publication, Jones, Bern, and Wong described changes seen when the mice were 1.5 to 2 years old. This later publication appears to clarify the meaning of nodules or tumors in the younger animals: "Although mammary tumors were observed neither in control nor in progesterone-treated intact mice, many of the latter group possessed hyperplastic alveolar-like mammary nodules and other dysplasias." Neither of these studies refers to the carcinogenicity of progesterone.

The 1977 study (at the University of California, Berkeley) was explicitly motivated by Jones' and Bern's concern with the risks of the medical practice of treating pregnant women with DES and a synthetic progestin, and they used mammary tumor virus-bearing mice, and they didn't continue the study to observe the incidence of actual cancers. (Their choice of infant rodents to study progesterone might be questioned, because of earlier work showing that immature rat ovaries are able to convert progesterone to estrogens, unlike the tissues of other animals or humans: Quattropani and Weisz, 1973; Weniger, et al., 1984, later reported similar results.)

Anyone working with mammary tumor virus-bearing mice in the 1970s should have been aware of the effects of sex hormones on the expression of virus and development of cancer in the infected mice, as studied by Strong, Figge, and others for about 40 years. Excess estrogen causes the virus to be expressed, progesterone opposes its expression.

Jones and Bern injected the newborn mice with 0.02 ml of sesame oil daily for five days, with or without estrogen and progesterone. A newborn mouse weighs a little over a gram. On a weight and volume basis, this would be like injecting an adult human with more than a quart of sesame oil daily for five days. The proportionate weight of progesterone in an adult human would be several grams per day.

This amount of progesterone is far more than the anesthetic dose. Since the authors didn't mention anesthesia, very little of the progesterone could have been absorbed, meaning that deposits of crystals would have remained in their tissues.

Tissue irritation from foreign bodies and from vegetable oil, even in relatively small amounts, can produce severe systemic reactions, because of the reactive production of nitric oxide, prostanoids, and a great variety of pro-inflammatory and tumor-promoting cytokines.

This study might have had the formal appearance of a scientific experiment, but the unfamiliarity of the men with the material they were using, their use of mice carrying the mammary tumor virus, and, more importantly, the extremely complex reactions produced when extraneous materials are injected into the tissues, make this a useless experiment. The value of Richard Edgren's statement about the need to test carcinogens orally, rather than by injection, is becoming clearer all the time, as the role of irritation in cancer development is being better understood.

In their second 1977 study, Jones, Bern and Wong reported that at the age of 1.5 to 2 years, nearly two thirds of the progesterone treated mice had genital tract lesions. In another study published in 1977 (Iguchi and Takasugi) neonatal mice were given the same daily amount of progesterone, but for ten days rather than five, giving them twice the dose. These authors reported that there were no permanent changes in the vaginal and uterine epithelium. This study wasn't mentioned by any of the agencies, but it calls the results of the California study into question.

In a 1973 study by Rebout and Pageaut, progesterone was administered in a pellet, the composition of which was not mentioned, and there was no vehicle control at all. Each mouse received 45 mg of progesterone. The average mouse weighs about 30 grams. Invasive squamous carcinomas were produced by the carcinogen 20-methylcholanthrene, and these were more numerous in the progesterone treated mice. Methylcholanthrene is an extremely hydrophobic, highly irritating hydrocarbon which has often been used to create experimental cancers. The method of administering the carcinogen isn't clearly described: "Local exposure of carcinogen ... in the cervical canal for 9 weeks ... induced one invasive carcinoma in the vagina-exocervix and five in the endocervix." It was introduced into the cervical canal, but in what form and how often isn't described. Methylcholanthrene has some estrogenic properties.

Estrogen increases the production of mucus in the cervix and vagina, and increases its water content and mobility. Abundant and fluid mucus has a cleaning action, eliminating bacteria and other material. Progesterone makes the mucus more viscous and less hydrophilic, and when it dominates the reproductive physiology, it effectively creates a plug in the cervix that prevents the entry of sperms.

The choice of the cervix and vagina suggests that the authors were "engineering" the experimental outcome, because the effect of progesterone on cervical mucus is very well known. To apply the irritant to an area where it would normally be washed away by the mucus, but where it is kept in place by hormonally altering the mucus, is really a way of manipulating how much exposure to the irritating chemical the tissue will receive. It's analogous to studying the "toxicity" of an antihistamine, by applying a toxin to the nasal membrane of a person with a cold, and then administering the antihistamine to stop the flow of mucus, allowing the membrane to fully absorb the applied dose of toxin.

A different chemical carcinogen, 7,12-dimethylbenz(a)anthracene was used in another 1973 study (Jabara, et al.), in combination with progesterone. In this experiment, the carcinogen was administered to rats in one dose by stomach tube, dissolved in corn oil. The progesterone was injected subcutaneously in 3 mg doses in corn oil three times per week. Unfortunately, there was no control group in which the corn oil was injected alone.

The progesterone was supposedly dissolved in the corn oil, one tenth ml per dose. That amount of progesterone (3% weight/volume) will dissolve in hot corn oil, but as the oil cools, the progesterone crystallizes and precipitates. That creates doubt regarding what the animals were actually receiving.

Corn oil is one of the most effective vegetable oil tumor promoters/carcinogens, and it's now considered improper to use it as a solvent for testing even oral carcinogens, since some chemicals that are carcinogenic in the oil are relatively harmless when administered without the corn oil. The animals got 2 ml of corn oil in the stomach feeding with the carcinogen. One of the groups (group 5) received, in addition, more than 6 ml of corn oil in the injections. The experiment lasted only 135 days, and in the group that received only the carcinogen, the mortality was only 5%, and that death occurred shortly after the carcinogen was administered. All of the groups receiving the corn oil and progesterone injections had higher mortality, two with 25%, one with 37.5% mortality. Despite the unexplained general problem with prematurely dying rats, the authors found that "The relative incidence rates indicated that pretreatment with progesterone inhibited tumorigenesis, except in the group (5) in which progesterone treatment was continued for the duration of the experiment." Without progesterone, it is almost certain that the additional corn oil injected would have increased tumorigenesis in all experimental groups.

Without that vehicle control group, the experiment can just as well be described as a test of corn oil, rather than of progesterone. If you claim to be testing the capacity of a substance to promote tumors, it shouldn't be administered in a standard tumor promoter.

A 1968 publication by Glucksmann and Cherry was included in the documents offered as evidence of progesterone's carcinogenicity. Unfortunately, they neglected to identify the vehicle used for giving twice weekly intramuscular injections of 1 mg of progesterone, and they didn't have a vehicle control for the progesterone injections. At that time, the most common vehicle was a mixture of 9% benzyl alcohol and oil, usually sesame or peanut oil. Benzyl alcohol by itself is quite toxic, and was responsible for the death or brain damage of thousands of babies in hospitals, even in the small amounts that remained as residue in tubing after they had been rinsed with "bacteriostatic water," which contains 0.9% benzyl alcohol, and which is still used as the vehicle for many injections, such as penicillin and vitamin B12. The antitoxic (or "catatoxic") action of progesterone greatly reduces the toxicity of benzyl alcohol.

In discussing the effects of hormones on the induction of sarcomas, Glucksmann and Cherry comment that "The rate of induction of sarcomas in intact rats was slowed down slightly by treatment with progesterone and not significantly increased in spayed animals...."

In their Discussion section, they mention several previous studies in relation to their own results, and comment, regarding other studies, that "The effect of progesterone on the type of induced cervical cancer in mice consists in increasing the columnar component of mixed carcinomas in castrates . . . without materially affecting the induction period and tumour yield. Thus the experimental evidence in rats and mice is not as clearly antitumorigenic as that of Lipschutz (1950) for guinea pigs and the clinical observations (Ulfelder, 1962; Jolles, 1962)."

Comparing this study to that of Burrows and Hoch-Ligetti, the dose of 2 mg per week per rat is lower, on a body-weight basis, than the earlier study's dose of 1 mg per week in mice, but the greater frequency came a little closer to the continuous treatment that Lipschutz said was necessary. This could account for the fact that some of their results were intermediate between those of the Lipschutz group and those of Burrows and Hoch-Ligetti.

In Glucksmann's and Cherry's results, progesterone retarded one type of tumor and appeared to promote another (an epithelial tumor, which wasn't described as malignant or cancerous), but if the progesterone was dissolved in a tumor promoting solvent, it's impossible to ascribe the effect to progesterone. Vegetable oil applied to epithelium that has been exposed to a carcinogen such as the DMBA they used will typically increase the growth of the tumors. Without information about the vehicle, it's impossible to interpret that part of their results clearly, but anyway, they didn't describe any carcinogenic effect of progesterone; they did, however, describe a clearly anticarcinogenic action.

A 1962 study, by Capel-Edwards, et al., was intended to compare the effects of prolonged administration of high doses of progesterone with the known toxic effects of synthetic progestagens. They didn't find any malignant tumors, so the study can't be taken as evidence of the carcinogenicity of progesterone. The vehicle used for dissolving the progesterone consisted of benzyl alcohol, ethanol, and ethyl oleate. Some of the solutions contained more than 10% progesterone. When this sort of solution interacts with water in the tissues, it causes the progesterone to crystallize out of solution. The authors reported that "subcutaneous tissue reactions developed at injection sites," and that these "occurred in all animals, including controls, and were apparent for several days after the injection." These injection-site lesions sometimes developed into "sterile abscesses which eventually ulcerated and healed." The only dog that died during the study was in the control group, and although there were "a number of pathologic findings," the exact nature of that dog's sickness couldn't be determined. The injections were given daily, for a total of 518 injections in each animal, and each injection contained as much as 4 ml of the vehicle. Almost an ounce per week of this material, combined with the massive irritation produced by crystallization at hundreds of injection sites, would be the most likely explanation for the various inflammatory changes they saw, including osmotic fragility of red blood cells, and as much as a 50% enlargement of liver and kidneys.

Although some of the basic ideas about canine physiology that were held when the Capel-Edwards study was designed have been found to be mistaken, and the toxicity of their vehicle can now be seen, and they didn't conclude that progesterone was carcinogenic, their study wasn't the worst of those that have been presented as evidence of progesterone's carcinogenicity.

When an experimenter doesn't yet have a clear hypothesis, it's reasonable to do some exploratory tests, just to get an orientation to the possibilities so that it's possible to form a well defined hypothesis, before designing an experiment that will test the hypothesis. Sometimes an experimenter and journal editors will allow a merely exploratory experiment to be published. If they don't draw inappropriate conclusions from the ambiguous results, the publication can be justified, simply because it might stimulate others to investigate the subject more thoroughly.

But often editors allow the author to draw conclusions from the experiment that are not directly implied by the data, especially when those conclusions support the editor's prejudices. A conclusion may be consistent with, though not implied by, the results of the experiment. These publications may be effective propaganda, but they aren't good science.

But California's OEHHA identifies those eight publications as "the relevant evidence that clearly shows through scientifically valid testing according to generally accepted principles that progesterone causes cancer."

In 2004, the agency was petitioned to remove progesterone from the list. In the document rejecting that petition, they mentioned that IARC in 1999 had reviewed newer evidence confirming the carcinogenicity of progesterone. After months of asking the man in charge of rejecting the petition to identify that very important new data, I hadn't received an answer, so I wrote to IARC, and the man in charge there responded:

"The IARC (1999) review is actually an IARC Monographs volume (Vol.72) . . . . This volume focuses on contraception and post-menopausal therapy. Progesterone is not used for these indications and, hence, after a quick search in the book I found only one reference that clearly reports an experiment with progesterone." [Wednesday, October 04, 2006 12:44 AM]

That article (Grubbs CJ, Peckham JC & McDonough KD (1983) Effect of ovarian hormones on the induction of 1-methyl-1-nitrosourea-induced mammary cancer. Carcinogenesis 4(4):495-497) reported that progesterone reduced the incidence of mammary cancers caused by a carcinogen administered in vegetable oil.

I don't think it's possible that anyone could read articles like this, that don't even claim to show that progesterone causes cancer, and conclude that they provide evidence of progesterone's carcinogenicity. The choice of "evidence" seems to have been a selection of titles of unread articles. And even the title of the 1999 IARC volume would have suggested to most people that it wasn't a review of progesterone.

The lack of vehicle controls in some of the studies, the use of an unnamed vehicle in one beagle study, and the use of tumor-promoting vehicles in most if not all of the studies, means that no scientifically competent or valid studies have been cited by IARC, NTP, or the California state bureaucracy, OEHHA, to support California's claim that they know progesterone is a carcinogen.

In their 2004 document, OEHHA mentioned 17 articles that had been submitted regarding progesterone's protective effects. Some of these were identified; two were egregiously misrepresented in a single sentence:

Plu-Bureau, et al., were said to have reported "no association between breast cancer risk and progesterone topically applied for the treatment of mastalgia and benign breast disease..." What Plu-Bureau, et al., said immediately following that was "Although the combined treatment of oral progestogens with percutaneous progesterone significantly decreased the risk of breast cancer (RR = 0.5; 95% confidence interval 0.2-0.9) as compared with nonusers, there was no significant difference in the risk of breast cancer in percutaneous progesterone users versus nonusers among oral progestogen users." (RR means "relative risk," or "risk ratio," and 0.5 means a 50% reduction in risk.)

Cowan, et al. (1981), according to the OEHHA document, reported "reduced premenopausal breast cancer in women who had a history of progesterone deficiency." What they actually said was "These women were categorized as to the cause of infertility into 2 groups, those with endogenous progesterone deficiency (PD) and those with nonhormonal causes (NH). Women in the PD group had 5.4 times the risk of premenopausal breast cancer as compared to women in the NH group. This excess risk could not be explained by differences between the 2 groups in age at menarche or age at menopause, history of oral contraceptive use, history of benign breast diseases, or age at 1st birth. Women in the PD group also experienced a 10-fold increase in deaths from all malignant neoplasm compared to the NH group."

Ending the paragraph that mentioned those studies, the California document continues: "However, there is also evidence that progesterone may have a mitogenic effect. For example, Soderqvist et al. (1997) found that in breast cells of healthy women, cell proliferation was correlated with serum progesterone levels, thereby suggesting a proliferative action of progesterone."

Such a suggestion is not made by that "correlation." The authors said, "Our objective was to assess proliferation in normal breast epithelial cells from healthy women during the follicular and luteal phases of the menstrual cycle." At the beginning of the luteal phase, both estrogen and progesterone normally rise several-fold, so the small increase in proliferative rate also correlates with estrogen levels. A "defective luteal phase" is common, in which the ratio of estrogen to progesterone is high, and in that case progesterone's well established antiproliferative, differentiative effect will be overridden by estrogen's proliferative stimulation.

The state's reviewers didn't comment on the studies which showed that progesterone, besides inhibiting proliferation, also inhibits an "oncogene" which is associated with cancer, rather than just with proliferation. Instead, they cited a meaningless "correlation" as if it were some kind of argument against progesterone's anticancer effects. The authors of this document don't seem to know very much about the biology of cancer, but maybe they know too much about the issue of the proliferation of breast epithelium.

In a paragraph "rebutting" the petitioner's point that "This new research supports that exogenous progesterone actually reduces the risk of breast cancer in humans," the authors don't mention that point at all, but instead refer to cancer treatment and to the various claims relating to progesterone's carcinogenicity, ending with the mention of "studies that suggest progesterone stimulates cell proliferation (e.g., Soderqvist et al., 1997)." Apparently the authors had no answer to the petitioners' point, and preferred to talk about proliferation of breast cells.

Nearing the end of the document, the authors say "The NCI also reports on other studies of estrogens with progestins, which would suggest that progesterone increases the risk of human breast cancer," and then quotes comments on studies of estrogens with (synthetic) progestins. The authors cite two more studies with synthetic progestins, and then say "As discussed above, the mammary gland was a main target site in animal cancer bioassays providing the basis for the IARC and NTP identification of progesterone as carcinogenic." (The preceding discussion had mentioned the 4 year beagle study--which ended the careers of the researchers--and a 1993 publication by Kordon, et al., which had no control group for reference, and instead compared progesterone with different doses of medroxyprogesterone acetate, finding that the fewest tumors occurred in the progesterone group.*)

The techniques of distortion, diversion and evasion in this document are so obvious that any college composition teacher would have returned it to the student for revision. The document says much more about its authors than about its subject.

I think this bureaucratic behavior is understandable only if you know the composition of the group that is responsible for the progesterone listing, because the proliferation of breast cells has become an important issue for the group around USC professor Malcolm Pike.

Around 1980, Malcolm Pike, a statistician from South Africa, working in epidemiology, began arguing that the use of oral contraceptives prevented cancer. This epidemiologist, unfamiliar with steroid physiology except as it filtered through the oral contraceptive industry, decided that progesterone was the primary cause of breast cancer, by stimulating cell division and increasing the tissue density of the breast.

This line of reasoning gained adherents in the USC Keck School of Medicine, despite an overwhelming amount of contrary evidence, accumulated over more than 50 years, that progesterone protects against breast cancer, partly by inhibiting cell division, and that increased breast density is significantly associated with breast mitogens, such as serum insulin-like growth factor-I (IGF), prolactin, and estrogens, rather than with progesterone.

Breast mitogens correspond to both breast density and the risk of breast cancer (Boyd), but progesterone (antimitogen) corresponds to factors associated with low risk of breast cancer. Progesterone may reduce breast density by inhibiting some growth factors, including IGF, NO (nitric oxide), VEGF (vascular endothelial growth factor), bcl-2 (a protein that inhibits apoptosis), polyamines, and prostaglandins.

Much of the research at USC's Keck School has been generously funded by pharmaceutical companies with huge interest in estrogen-related products. The medical school website has articles by their faculty that give the impression that they are often more concerned with the fate of the estrogen market than with the science they claim to be doing. For example, commenting on the WHI evidence showing that estrogen helps to cause Alzheimer's disease, professor B.E. Henderson said "I continue to believe that estrogen therapy may help reduce a woman's risk of developing Alzheimer's disease . . . ." I noticed that there were hundreds of other estrogen-related items on the USC website.

The medical school, some of its professors, government agencies, and private companies are involved in some very complex, overlapping activities that give the impression of what used to be called "conflicts of interest."

The Keck School (a private institution), and the company, Balance Pharmaceuticals, Inc., controlled by three of their professors, participate in the business promotion organization operated by the State of California, Larta Institute, which manages Project T2, which is part of a "commercialization" system, involving awards of federal government money: "The organization will provide the awardees with assistance in all aspects of commercialization, including business development, funding and capital acquisition, government regulatory processes, intellectual property protection, licensing strategies, and merger and acquisition opportunities. SBIR Phase II is the research and development stage of the well-known program, with award sizes typically starting at $750,000 each." "Working with one of the Federal government's largest and most important agencies to assist SBIR awardees on the cusp of commercialization is a natural extension of everything we've done for the past ten years," said Larta Institute CEO Rohit Shukla.

Besides the issue of giving public money to private groups to commercialize ideas, many of which were developed using government-funded research, adding assistance with "government regulatory processes" to the help given to private corporations should arouse suspicions. The idea of "privatization" is given a new dimension: It's all for the insiders, without the usual lip-service paid to "competition."

On California's committee that chooses chemicals to put on their list of "known carcinogens" is Juliet Singh, who is the chief executive of Trans Pharma Corporation, a company that is developing transdermal drug delivery systems, for example for giving hormones by applying them to the skin. Under California's law, chemicals on the carcinogen list may to sold as drugs without a warning.

On the committee with Singh are Anna Wu and Thomas Mack, who co-authored several papers with Malcolm Pike, who was the most visible promoter of the campaign against progesterone, and who with two other USC professors controls Balance Pharmaceuticals, Inc., which is being promoted by Larta Institute, and that's planning to market a contraceptive based on the idea of suppressing progesterone. Three USC professors are on California's carcinogen committee, more than from any of the other universities in the state.

In a jury trial, I think this would look like a tainted jury.

Comparing the California agency's parody of legitimate process in this instance with its reconsideration in 2002 of its listing of saccharin as a carcinogen is illuminating. In that case, there was at least a pretense that the staff had made an attempt to provide "all relevant scientific evidence" for the committee to review, as specified by the agency's regulations. And in its decision, the State's Qualified Experts made a point of declaring, according to the language of the law, that in the opinion of the state's qualified experts it had not been "clearly shown through scientifically valid testing according to generally accepted principles to cause cancer." The Committee found that, in this case, it had to use a "'weight of evidence' approach to evaluate the body of information available...."

Unfortunately, the committee allowed some bizarre speculations about calcium phosphate to outweigh the fact that saccharin is a mild carcinogen, and in evaluating the rat experiments they were in such a hurry to remove saccharin from the list that they neglected to notice that calcium phosphate precipitation isn't unique to rat urine, but very commonly occurs in human urine. Their decision to remove it from the list rested on that non-fact.

Although the agency cited 150 studies, and went through the formality of describing some of them in their document, anyone reading the document justifying the delisting of saccharin, and the document rejecting the delisting of progesterone, will find it hard to see a principle of law that could justify removing a carcinogen from the list, because of uncertainty regarding the mechanism by which it causes cancer, and keeping progesterone on the list, despite overwhelming evidence that it protects against cancer, and a great amount of evidence regarding the mechanisms through which the protection occurs.

The committee of experts who "weighed" speculations about calcium phosphate in the 2002 saccharin document, chose not to consider, either in 1987 or 2004, any of the hundreds of empirical studies showing progesterone's protective anticancer effects. The committee "considered" approximately half of all research publications on saccharin and cancer, and fewer than 1% of those relating to progesterone and cancer. Something other than scientific objectivity must explain those differences.

The agency in charge of those processes of evaluating evidence of carcinogenicity declines to identify the people who made those possibly biased, certainly bizarre, selections of articles, or to list their qualifications for being in the crucial position of deciding what evidence would be provided to the Scientific Advisory Panel. And in the list of studies that the committee did receive, are two (Kwapien, et al., and Yager and Yager) that are about completely different chemicals, that the agency still identifies as evidence of progesterone's carcinogenicity.

Many progesterone products have been taken off the market because of California's warning signs and labels, and as a result many women are having to rely on their physicians for progesterone. Too many physicians know only what the pharmaceutical companies want them to know about progesterone and other hormones that had been available for decades in places such as health food stores.

An article in JAMA (Marcia Stefanick, April 11, 2006) was summed up by Stefanick in a way that seems designed to encourage physicians to return to prescribing estrogen: "In the estrogen and progestin trial those women who got on the active pills, we saw an increase in breast cancer within five years. In the case of estrogen only, we not only do not see an increase by 7 years, but there's actually a suggestion of a decrease." That is a serious misrepresentation of the study.

The recently reported (December 15, 2006) decline of breast cancer incidence, coinciding with the great decrease in the use of menopausal estrogen treatments, also coincided with an increased use of natural progesterone, but if the lawyers, bureaucrats, and agents of the estrogen industry succeed in convincing the public that progesterone is carcinogenic, its use will decline, and breast cancer incidence could be expected to increase again.

The studies that show cancer prevention by progesterone have, over the years, failed to resonate in the medical culture. The confusion created by classifying the antiprogestational, carcinogenic synthetics as "progestins" is largely responsible for the failure to understand the protective nature of progesterone.

If the evidence showing that progesterone prevents or cures cancer could be weighed against the evidence purporting to show that it is carcinogenic, I think it would be clear that something like a cultural-commercial misogyny has been at work. The novelty of the newer misogyny is that it is so often led, or at least figureheaded by women.

• • •

*Note: Compare the results of Kordon, et al., 1993, with the later results of Aldaz, et al.:

Kordon, et al., reported 58% of the animals had tumors in the group receiving low dose MPA pellets, 98% in the high dose MPA group.

Aldaz, et al., 1996, wrote "The synthetic progestin medroxyprogesterone acetate (MPA) was postulated by some authors to increase mammary tumor incidence in various rodent models. However, controversy exists regarding the role of MPA in experimental and human carcinogenesis." "MPA by itself did not produce any mammary tumors."

REFERENCES from IARC and OEHHA

1. National Toxicology Program, U.S. Department of Health and Human Services, Fourth Annual Report on Carcinogens (Summary), pages 392-393, 1985.

2. International Agency for Research on Cancer, IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Volume 21, pages 491-515, 1979.

3. International Agency for Research on Cancer, IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 6, pages 135-146, 1974.

4. International Agency for Research on Cancer, IARC Monograph on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Supplement 4, pages 202-203, 1982.

5. Burrows, H. and Hoch-Ligeti, C., Effects Of Progesterone On The Development Of Mammary Cancer In C3H Mice. Cancer Research, 6:608-609, 1946.

6. Capel-Edwards, K., et al., Long-Term Administration Of Progesterone To The Female Beagle Dog. Toxicology and Applied Pharmacology 24:474-488, 1973.

7. Frank, DW, et al., Mammary Tumors And Serum Hormones In The Bitch Treated With Medroxyprogesterone Acetate Or Progesterone For Four Years. Fertility and Sterility, 31(3):340-346,1979.

8. Glucksmann, A. and Cherry, CP. The effect of oestrogens, testosterone and progesterone on the induction of cervico-vaginal tumours in intact and castrate rats. British Journal of Cancer 22(3):545-562, 1968.

9. Jabara, AG, et al., Effects Of Time And Duration Of Progesterone Administration On Mammary Tumours Induced By 7, 12-dimethylbenz(A)Anthracene In Sprague-Dawley Rats. British Journal of Cancer, 27:63-71,1973.

10. Jones, LA and Bern, HA. Long-Term Effects Of Neonatal Treatment With Progesterone, Alone And In Combination With Estrogen, On The Mammary Gland And Reproductive Tract Of Female BALB/Cfc3h Mice. Cancer Research, 37:67-75,1977, [6 pages].

11. Jones, LA, et al., Cervicovaginal And Mammary Gland Abnormalities In Old BALB/cCRGL Mice Treated Neonatally With Progesterone. Journal of Toxicology and Environmental Health, 3:360-361, 1977.

12. Kwapien, RP, et al., Malignant Mammary Tumors In Beagle Dogs Dosed With Investigational Oral Contraceptive Steroids. Journal of the National Cancer Institute, 65(1):137-144,1980.

13. Reboud, S. and Pageaut, G., Co-Carcinogenic Effect Of Progesterone On 20-Methylcholanthrene Induced Cervical Carcinoma In Mice. Nature, 241:398, 1973.

14. Yager, JD and Yager, R., Oral Contraceptive Steroids As Promoters Of Hepatocarcinogenesis In Female Sprague-Dawley Rats. Cancer Research, 40:3680-3685, 1980.

15. Letter addressed to Dr. Wendell Kilgore from Helen P. Shu, Ph.D., Syntex (U.S.A.) Inc., dated December 3, 1987.

OTHER REFERENCES

J Gynecol Obstet Biol Reprod (Paris). 1990;19(3):269-74. [The in vivo effect of the local administration of progesterone on the mitotic activity of human ductal breast tissue. Results of a pilot study] Barrat J, de Lignieres B, Marpeau L, Larue L, Fournier S, Nahoul K, Linares G, Giorgi H, Contesso G. "Mean mitotic activity was significantly lower in progesterone treated group (0.04/1,000 cells) than in placebo (0.10/1,000 cells) or in estradiol (0.22/1,000 cells) treated groups. High concentration of progesterone sustained in human breast tissue in vivo during 11 to 13 days does not increase, but actually decreases mitotic activity in normal lobular epithelial cells."

Br J Cancer. 2002 Oct 7;87(8):876-82. The association of breast mitogens with mammographic densities. Boyd NF, Stone J, Martin LJ, Jong R, Fishell E, Yaffe M, Hammond G, Minkin S.

Bull Cancer. 2006 Sep 1;93(9):847-55. [Breast density: a biomarker to better understand and prevent breast cancer] Brisson J, Berube S, Diorio C.

J Steroid Biochem Mol Biol. 2005 Jul;96(2):95-108. Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. Campagnoli C, Clavel-Chapelon F, Kaaks R, Peris C, Berrino F. "Controlled studies and most observational studies published over the last 5 years suggest that the addition of synthetic progestins to estrogen in hormone replacement therapy (HRT), particularly in continuous-combined regimen, increases the breast cancer (BC) risk compared to estrogen alone. By contrast, a recent study suggests that the addition of natural progesterone in cyclic regimens does not affect BC risk. This finding is consistent with in vivo data suggesting that progesterone does not have a detrimental effect on breast tissue. The increased BC risk found with the addition of synthetic progestins to estrogen could be due to the regimen and/or the kind of progestin used."

Climacteric. 2004 Jun;7(2):129-37. Human breast cell proliferation and its relationship to steroid receptor expression. Clarke RB.

Am J Epidemiol. 1981 Aug;114(2):209-17. Breast cancer incidence in women with a history of progesterone deficiency. Cowan LD, Gordis L, Tonascia JA, Jones GS. "Women in the PD [progesterone deficiency] group had 5.4 times the risk of premenopausal breast cancer as compared to women in the NH group." "Women in the PD group also experienced a 10-fold increase in deaths from all malignant neoplasm compared to the NH group."

Climacteric 2002 Sep;5(3):229-35. Effects of progestogens on the postmenopausal breast. de Lignieres B. The potential for an increased risk of breast cancer linked to the use of synthetic progestins combined with oral estrogens is one of the main putative reasons for discouraging postmenopausal women from using any type of hormone replacement therapy (HRT) for more than a few years. Because no definitive proof exists, the available epidemiological results can be interpreted according to what seems biologically plausible to each investigator, including potential differences between various schedules of various steroids in various species and in vitro models. More than 60 years after the discovery of progesterone, the main effects of this endogenous steroid on the physiopathology of the breast during a normal luteal phase are still controversial. The lack of consensus on such basic knowledge concerning one of the most important targets of a natural ovarian hormone discovered in 1934 is amazing. In the most cited studies, nothing has been done to measure progesterone in plasma and to correlate the extremely disparate cytological results with extremely erratic steroid levels at the time of surgical stress. In a recent study, with a better design, the physiological rise of endogenous progesterone during the luteal phase coincided with a drop in proliferation of breast epithelial cells, which appears to be only slightly delayed in comparison with what is described in the endometrium. Differences in doses and schedules of treatments with various synthetic progestins have largely contributed to the inconsistency in clinical recommendations. Based on the analysis of proliferation markers in surgical biopsies from normal human postmenopausal breast tissue, it is plausible that mitogenic activity is not identical during therapy with unopposed estrogens versus estrogens combined with progestogens, and is higher during HRT that combines oral conjugated equine estrogens with medroxyprogesterone acetate than during HRT that combines transdermal estradiol and progesterone. It is misleading to put all progestogens in the same bag irrespective of their chemical structure, and, more important, their effect may vary according to whether it is estrone or estradiol that is mainly accumulated in the breast tissue. The hypothesis of progesterone decreasing the proliferative effect of estradiol in the postmenopausal breast remains highly plausible.

Eur J Cancer. 2000 Sep;36 Suppl 4:S90-1. Progesterone receptor activation. an alternative to SERMs in breast cancer. Desreux J, Kebers F, Noel A, Francart D, Van Cauwenberge H, Heinen V, Thomas JL, Bernard AM, Paris J, Delansorne R, Foidart JM. "In postmenopausal women, adding progesterone to percutaneously administrated oestradiol significantly reduces the proliferation induced by oestradiol."

Int J Cancer. 1992 May 28;51(3):416-24. Capacity of adipose tissue to promote growth and metastasis of a murine mammary carcinoma: effect of estrogen and progesterone. Elliott BE, Tam SP, Dexter D, Chen ZQ. "Estrogen can stimulate growth of SPI in adipose tissue sites, whereas progesterone inhibits growth." "Our results are consistent with the model that adipose tissue exerts an estrogen-dependent positive regulatory effect on primary SPI tumor growth, and promotes the formation of metastases."

Br J Cancer 1981 Aug;44(2):177-81. Morphological evaluation of cell turnover in relation to the menstrual cycle in the "resting" human breast. Ferguson DJ, Anderson TJ.

Fertil Steril. 1998 May;69(5):963-9. Estradiol and progesterone regulate the proliferation of human breast epithelial cells. Foidart JM, Colin C, Denoo X, Desreux J, Beliard A, Fournier S, de Lignieres B.

Mol Cell Biochem 1999 Dec;202(1-2):53-61. Bcl-2, survivin and variant CD44 v7-v10 are downregulated and p53 is upregulated in breast cancer cells by progesterone: inhibition of cell growth and induction of apoptosis. Formby B, Wiley TS. This study sought to elucidate the mechanism by which progesterone inhibits the proliferation of breast cancer cells. Utilizing breast cancer cell lines with and without progesterone receptors (T47-D and MDA-231, respectively) in vitro, the authors looked at apoptosis (programmed cell death) in response to progesterone exposure as a possible mechanism. The genetic markers for apoptosis - p53, bcl-2 and surviving, were utilized to determine whether or not the cells underwent apoptosis. The results demonstrated that progesterone does produce a strong antiproliferative effect on breast cancer cell lines containing progesterone receptors, and induced apoptosis. The relatively high levels of progesterone utilized were similar to those seen during the third trimester of human pregnancy.

Ann Clin Lab Sci 1998 Nov-Dec;28(6):360-9. Progesterone inhibits growth and induces apoptosis in breast cancer cells: inverse effects on Bcl-2 and p53. Formby B, Wiley TS.

Mol Cell Biol. 2006 Oct;26(20):7632-44. TReP-132 Is a Novel Progesterone Receptor Coactivator Required for the Inhibition of Breast Cancer Cell Growth and Enhancement of Differentiation by Progesterone. Gizard F, Robillard R, Gross B, Barbier O, Revillion F, Peyrat JP, Torpier G, Hum DW, Staels B.

Int J Cancer. 1992 Nov 11;52(5):707-12. Breast cancer and timing of surgery during menstrual cycle. A 5-year analysis of 385 pre-menopausal women. Gnant MF, Seifert M, Jakesz R, Adler A, Mittlboeck M, Sevelda P.

Am J Epidemiol. 2005 Nov 1;162(9):826-34. Epub 2005 Sep 21. The association of endogenous sex steroids and sex steroid binding proteins with mammographic density: results from the Postmenopausal Estrogen/Progestin Interventions Mammographic Density Study. Greendale GA, Palla SL, Ursin G, Laughlin GA, Crandall C, Pike MC, Reboussin BA.

Am J Physiol Regul Integr Comp Physiol. 2001 Jul;281(1):R365-72. Moderate levels of ethanol induce expression of vascular endothelial growth factor and stimulate angiogenesis. Gu JW, Elam J, Sartin A, Li W, Roach R, Adair TH.

Cancer Research 1982 42:3232-39. Endogenous hormones as a major factor in human cancer. Henderson, B.E., R.K. Ross, M.C. Pike, and J.T. Casagrande.

Reprod Biol Endocrinol. 2003 Oct 7;1(1):73. Epub 2003 Oct 07. Estrogen, Progesterone and Epithelial Ovarian Cancer. Ho SM. "New convincing data have indicated that estrogens favor neoplastic transformation of the OSE while progesterone offers protection against OCa development. Specifically, estrogens, particularly those present in ovulatory follicles, are both genotoxic and mitogenic to OSE cells. In contrast, pregnancy-equivalent levels progesterone are highly effective as apoptosis inducers for OSE and OCa cells. In this regard, high-dose progestin may exert an exfoliation effect and rid an aged OSE of pre-malignant cells."

Breast Cancer Res. 2004;6(4):R352-65. Epub 2004 May 7. Cytochrome P450 1A2 (CYP1A2) activity and risk factors for breast cancer: a cross-sectional study. Hong CC, Tang BK, Hammond GL, Tritchler D, Yaffe M, Boyd NF.

Zhonghua Fu Chan Ke Za Zhi 2000 Jul;35(7):423-6. [The effect of progesterone on proliferation and apoptosis in ovarian cancer cell] Hu Z, Deng X. "It is suggested in the present study that progesterone can inhibit the proliferation of epithelial ovarian cancer cells in vitro and there is an accordant dose-response relationship. Its anticancer effect seems to be due to induction of apoptosis which maybe a result of down-regulation of the anti-apoptotic protein bcl-2."

Endocrinol Jpn. 1977 Aug;23(4):328-32. Occurrence of permanent changes in vaginal and uterine epithelia in mice treated neonatally with progestin, estrogen and aromatizable or non-aromatizable androgens. Iguchi T, Takasugi N. "Two other groups of female mice were given neonatal injections with 20 microgram estradiol-17beta and 100 microgram progesterone for 10 days, respectively." "Neonatal progesterone treatment failed to induce the permanent changes in the vaginal and uterine epithelia."

Gynecol Oncol 2001 Jul;82(1):116-21. Production of steroids by human ovarian surface epithelial cells in culture: possible role of progesterone as growth inhibitor. Ivarsson K, Sundfeldt K, Brannstrom M, Janson PO.

J Natl Cancer Inst. 2005 May 18;97(10):755-65. Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). Kaaks R, & 40 co-authors, Nutrition and Hormones Group, International Agency for Research on Cancer (IARC-WHO), Lyon, France. "The absolute risk of breast cancer for women younger than 40 followed up for 10 years was estimated at 2.6% for those in the highest quartile of serum testosterone versus 1.5% for those in the lowest quartile; for the highest and lowest quartiles of progesterone, these estimates were 1.7% and 2.6%, respectively."

Cancer Epidemiol Biomarkers Prev. 2002 Dec;11(12):1531-43. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Kaaks R, Lukanova A, Kurzer MS. Hormones and Cancer Group, International Agency for Research on Cancer, 69372 Lyon, France. kaaks@iarc.fr "These relationships can all be interpreted in the light of the 'unopposed estrogen' hypothesis, which proposes that endometrial cancer may develop as a result of the mitogenic effects of estrogens, when these are insufficiently counterbalanced by progesterone." "After the menopause, when progesterone synthesis has ceased altogether, excess weight may continue increasing risk through elevated plasma levels of androgen precursors, increasing estrogen levels through the aromatization of the androgens in adipose tissue."

J Steroid Biochem Mol Biol. 2000 Jun;73(3-4):171-81. Progesterone effect on cell growth, ultrastructural aspect and estradiol receptors of normal human breast epithelial (HBE) cells in culture. Malet C, Spritzer P, Guillaumin D, Kuttenn F. "Cells exhibited a proliferative appearance after E2 treatment, and returned to a quiescent appearance when P was added to E2. In both studies, P proved to be as efficient as the synthetic progestin R5020. Moreover, the immunocytochemical study of E2 receptors indicated that E2 increases its own receptor level whereas P and R5020 have the opposite effect, thus limiting the stimulatory effect of E2 on cell growth. In the HBE cell culture system and in long-term treatment, P and R5020 appear predominantly to inhibit cell growth, both in the presence and absence of E2."

Ann Endocrinol (Paris). 1986;47(3):179-87. [Estradiol-progesterone interaction in normal and pathological human breast cells] Mauvais-Jarvis P, Kuttenn F, Gompel A, Malet C, Fournier S. "The antiestrogenic activity of P is carried out through the decrease of ER resynthesis and stimulation of 17 beta-hydroxysteroid dehydrogenase enzyme activity, which transforms E2 into its less active metabolite estrone (E1) in the target cells. These biochemical events are well documented concerning the endometrium. They have also been observed in normal mammary cells in primary cultures as well as in breast fibroadenomas with high epithelial cellularity. Moreover, data from literature indicate that E2 could be both a direct and indirect factor of cell multiplication in cancerous cell lines. P as well as progestins have the opposite effect. Recent results from this laboratory indicate that E2 and P also have antagonistic effects on the cell multiplication of normal human mammary cells in primary culture. Therefore, the hypothesis that a lack of P during a long period of the female genital like could be a factor in the promotion of breast cancer must be considered."

Horm Res. 1987;28(2-4):212-8. Antiestrogen action of progesterone in breast tissue. Mauvais-Jarvis P, Kuttenn F, Gompel A.

Cancer Lett. 2005 Apr 18;221(1):49-53. Effects of progesterone on ovarian tumorigenesis in xenografted mice. McDonnel AC, Van Kirk EA, Isaak DD, Murdoch WJ. "We report that the tumorigenic capacity of human ovarian carcinoma (SKOV-3) cells inoculated into the peritoneal cavity of athymic mice is suppressed by pretreatment with subcutaneous progesterone-releasing pellets." "Progesterone prevented tumors from forming on the liver. Life spans of progesterone-treated animals were prolonged." "Our findings implicate a role for progesterone in ovarian cancer prophylaxis."

J Natl Cancer Inst. 1986 Sep;77(3):617-20. Endogenous sex hormones, prolactin, and mammographic features of breast tissue in premenopausal women. Meyer F, Brisson J, Morrison AS, Brown JB.

Int J Cancer. 2004 Nov 1;112(2):312-8. Endogenous sex hormones and subsequent breast cancer in premenopausal women. Micheli A, Muti P, Secreto G, Krogh V, Meneghini E, Venturelli E, Sieri S, Pala V, Berrino F. "Compared to controls, BC cases had shorter cycles and intervals between blood sampling and bleeding, and lower LH and FSH. FT was significantly associated with BC risk: relative risk (RR; adjusted for age, body mass index and ovarian cycle variables) of highest vs. lowest tertile was 2.85 [95% confidence interval (CI) = 1.11-7.33, p for trend = 0.030]. Progesterone was inversely associated with adjusted RR for highest vs. lowest tertile of 0.40 (95% CI = 0.15-1.08, p for trend = 0.077), significantly so in women with regular menses, where adjusted RR was 0.12 (95% CI = 0.03-0.52, p for trend = 0.005). These findings support the hypothesis that ovarian hyperandrogenism associated with luteal insufficiency increases the risk of BC in premenopausal women."

Endocrinology 2002 Sep;143(9):3671-80. Ovarian hyperstimulation by LH leads to mammary gland hyperplasia and cancer predisposition in transgenic mice. Milliken EL, Ameduri RK, Landis MD, Behrooz A, Abdul-Karim FW, Keri RA.

J Steroid Biochem Mol Biol 2000 Nov 30;74(5):357-64. Estrogens in the causation of breast, endometrial and ovarian cancers - evidence and hypotheses from epidemiological findings. Persson I. "Estrogens cause endometrial cancer, an effect that can be reduced, prevented or reversed by progesterone/progestin - if allowed to act for a sufficiently long period of each cycle."

Endocrinology. 1973 Dec;93(6):1269-76. Conversion of progesterone to estrone and estradiol in vitro by the ovary of the infantile rat in relation to the development of its interstitial tissue. Quattropani SL, Weisz J.

Ann Oncol. 1991 Apr;2(4):269-72. Timing of breast cancer surgery within the menstrual cycle: influence on lymph-node involvement, receptor status, postoperative metastatic spread and local recurrence. Rageth JC, Wyss P, Unger C, Hochuli E.

Cancer Res. 1984 Feb;44(2):841-4. High testosterone and low progesterone circulating levels in premenopausal patients with hyperplasia and cancer of the breast. Secreto G, Recchione C, Fariselli G, Di Pietro S.

Cancer Res. 1984 Feb;44(2):841-4. High testosterone and low progesterone circulating levels in premenopausal patients with hyperplasia and cancer of the breast. Secreto G, Recchione C, Fariselli G, Di Pietro S.

J Natl Cancer Inst Monogr. 1994;(16):85-90. Menstrual timing of treatment for breast cancer. Senie RT, Kinne DW.

Cancer Causes Control. 2004 Feb;15(1):45-53. Serum levels of sex hormones and breast cancer risk in premenopausal women: a case-control study (USA). Sturgeon SR, Potischman N, Malone KE, Dorgan JF, Daling J, Schairer C, Brinton LA. "For luteal progesterone, the RR for the highest versus lowest tertile was 0.55 (0.2-1.4)."

Biomed Pharmacother 1984;38(8):371-9. Breast cancer and oral contraceptives: critique of the proposition that high potency progestogen products confer excess risk. Sturtevant FM A recent report by Pike et al. from the U. S. A. concluded on the basis of epidemiologic evidence that an increased risk of breast cancer was manifested by young women who had used combination oral contraceptives (OC) with a high "potency" of progestogen over a prolonged period. This conclusion is criticized in the present article, centering on three cardinal defects in the Pike study: (1) The assigned potencies of OC's are fiction and were derived from out-dated delay-of-menses data; (2) Well-known risk factors for breast cancer were ignored; (3) The method assumed no error of recall of OC brand, dose and duration of use occurring many years before telephone interviews. Noting that others have not been able to confirm these findings, it is concluded that there is no scientific basis for accepting the suggestion of Pike et al.

Pathol Oncol Res. 2006;12(2):69-72. Epub 2006 Jun 24. Leptin--from regulation of fat metabolism to stimulation of breast cancer growth. Sulkowska M, Golaszewska J, Wincewicz A, Koda M, Baltaziak M, Sulkowski S.

Cancer Res. 2004 Nov 1;64(21):7886-92. Reduction of human metastatic breast cancer cell aggressiveness on introduction of either form a or B of the progesterone receptor and then treatment with progestins. Sumida T, Itahana Y, Hamakawa H, Desprez PY.

Acta Pharmacol Toxicol (Copenh). 1983 Apr;52(4):298-304. Local muscle damage and oily vehicles: a study on local reactions in rabbits after intramuscular injection of neuroleptic drugs in aqueous or oily vehicles. Svendsen O.

Jpn J Cancer Res 1998 Dec;89(12):1334-42. Effects of sex steroids and growth factors on invasive activity and 5'-deoxy-5-fluorouridine sensitivity in ovarian adenocarcinoma OMC-3 cells. Ueda M, Fujii H, Yoshizawa K, Kumagai K, Ueki K, Terai Y, Yanagihara T, Ueki M. "The inhibitory effect of Prog on tumor cell invasion may depend on its inhibitory action on the motility of tumor cells."

Endocrinology. 1965 Oct;77(4):735-44. Estrogen and androgen production in vitro from 7-3-H-progesterone by normal and polycystic rat ovaries. Weisz J, Lloyd CW.

J Steroid Biochem. 1984 Sep;21(3):347-9. Conversion of testosterone and progesterone to oestrone by the ovary of the rat embryo in organ culture. Weniger JP, Chouraqui J, Zeis A.

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<span class="koboSpan" id="kobo.1.1">Natural Estrogens</span> A R T I C L E

Natural Estrogens

The fact that an extremely large number of naturally occurring compounds, and an unlimited number of synthetic compounds, have an estrogen-like activity has been exploited by the drug companies to produce patented proprietary drugs, especially the contraceptives.

The promotion of natural estrogens is a new marketing strategy that capitalizes on the immense promotional investment of the drug companies in the concept of estrogen replacement as therapy.

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Whether weak or strong, the estrogenic response of a chemical, if not overcome, will add extra estrogenic burden to the system. At elevated doses, natural estrogens and environmental estrogen-like chemicals are known to produce adverse effects. The source of extra or elevated concentration of estrogen could be either endogenous or exogenous. The potential of exposure for humans and animals to environmental estrogen-like chemicals is high.

D. Roy, et al., 1997

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Estrogen marketing has entered a new phase, based on the idea of specific estrogen-receptor modulators, the idea that a molecule can be designed which has estrogen's good qualities without its bad qualities. This specific molecule will be good for the bones, the heart, and the brain, without causing cancer of the breast and uterus, according to the estrogen industry. Meanwhile, soybeans are said to contain estrogens that meet that goal, and it is often said that natural estrogens are better than synthetic estrogens because they are balanced.

Estrogen's effects on cells are immediate and profound, independent of the estrogen receptors.

Japanese women's relative freedom from breast cancer is independent of soy products: traditional soy foods aren't the same as those so widely used in the US, for example, soy sauce doesn't contain the so-called soy estrogens, and tea is used much more commonly in Japan than in the US, and contains health protective ingredients. The estrogenic and antioxidant polyphenolic compounds of tea are not the protective agents (they raise the level of estrogen), but tea's caffeine is a very powerful and general anti-cancer protectant. The influential article in Lancet (D. Ingram, Lancet 1997;350:990-994. Phytoestrogens and their role in breast cancer, Breast NEWS: Newsletter of the NHMRC National Breast Cancer Centre, Vol. 3, No. 2, Winter 1997) used a method known to produce false results, namely, comparing the phytoestrogens (found in large amounts in soybeans) in the urine of women with or without breast cancer. For over fifty years, it has been known that the liver excretes estrogens and other toxins from the body, and that when (because of liver inertia) estrogen isn't excreted by the liver and kidneys, it is retained in the body. This process was observed in both animals and humans decades ago, and it is also well established that estrogen itself suppresses the detoxifying systems, causing fewer carcinogens to be excreted in the urine. Ingram's evidence logically would suggest that the women who have cancer are failing to eliminate estrogens, including phytoestrogens, at a normal rate, and so are retaining a higher percentage of the chemicals consumed in their diets. Flavonoids and polyphenols, like our own estrogens, suppress the detoxifying systems of the body.

Our bodies produce estrogen in a great variety of tissues, not just in the ovaries. Fat cells are a major source of it. The tendency to gain weight after puberty is one of the reasons that women's estrogen levels rise with aging throughout the reproductive years, though this isn't the basic reason for estrogen's lifelong growing influence, even in men.

Our diets provide very significant, if not always dangerous, amounts of estrogen. Weak estrogens generally have the full range of harmful estrogenic effects, and often have additional toxic effects. American women who eat soy products undergo changes that appear to predispose them to cancer, making their tissues even more unlike those of the relatively breast-cancer resistant Japanese than they were before eating the soy foods.

People under stress, or who have a thyroid deficiency, or who don't eat enough protein, typically have elevated estrogen levels. The accumulation of the essential fatty acids, the polyunsaturated oils, in the tissues promotes the action of estrogen in a variety of ways, and this effect of diet tends to be cumulative, and to be self-accelerating.

Science is a method that helps us to avoid believing things that are wrong, but there is a distinct herd instinct among people who work in science, which makes it easy to believe whatever sounds plausible, if a lot of other people are saying it is true. This is just as evident in physics as it is in medicine. Sometimes powerful economic interests help people to change their beliefs, for example as the insurance industry helped to convince the public of the dangers of smoking. Two of the biggest industries in the world, the estrogen industry and the soy bean industry, spend vast amounts of money helping people to believe certain plausible-sounding things that help them sell their products. Sometimes they can achieve great things just by naming the substance.

Estrogenicity can be defined most simply as acting the way estrogen does, (originally, the term estrogen meant producing estrus, the female readiness to mate) and since our natural estrogen does many things, the definition is often, for practicality, based on the rapid changes produced in certain female organs by estradiol, specifically, the enlargement of the uterus by first taking up a large amount of water, and secondarily by the multiplication of cells and the production of specific proteins. A similar process occurring in the breast is also recognized as an important feature of the estrogen reaction, but as we try to define just what estrogenicity is, we see that there is something deeply wrong with this method of defining a hormone, because we are constantly learning more about the actions of estrogen, or of a specific form of the molecule. Calling it the female hormone distracted attention from its many functions in the male, and led to great confusion about its antifertility actions and its other toxicities. Many biologists called it folliculin, because of the ovarian follicle's significant role in its production, but the pharmaceutical industry succeeded in naming it in relation to one of its functions, and then in extending that idea of it as the producer of female receptivity to the even more misleading idea that it is the female hormone. But when people speak about the estrogenicity of a substance, they mean that it has properties that parallel those of folliculin, the particular group of ovarian hormones that includes estradiol, estrone, and estriol.

Over the last 100 years, thousands of publications about estrogen's toxicity have created a slight resistance to the consumption of the major estrogen products. One ploy to overcoming this resistance is to call certain products natural estrogen, as distinguished from synthetic estrogens. The three main estrogens in our bodies are estradiol, estrone, and estriol, though there are many other minor variants on the basic molecule. These three estrogens, singly or in combinations, are being sold as natural estrogens, with their virtues explained in various ways. Implicit in many of these explanations, is the idea that these are safer than synthetics. They are sometimes contrasted to the horse estrogen in Premarin, as if they are better because they are like the estrogens that people produce. But it was exactly the normal human estrogens, produced by the ovaries, that led to the basic discoveries about the toxicity of estrogen, its ability to produce cancer in any organ, to cause seizures, blood clots, birth defects, accelerated aging, etc.

Although I would suppose that a hormone from a horse might be more natural for a person's body than a hormone from a plant, the word natural as used in the phrases natural food store, or natural medicine, has come to be associated strongly with things derived from plants. The health food industry, now largely taken over by giant corporations to sell products that weren't producing as much revenue when sold in supermarkets and drugstores, has helped to create a culture in which botanical products are thought to be especially good and safe. Naturally grown free-range chickens used to be favored, because they could eat anything they wanted, but now eggs laid by factory chickens, eating an industrial corn-and-soy diet, are from vegetarian chickens, because the marketers know the public will favor eggs that have the vegetarian mystique.

Biologically active molecules have both general and specific properties. Estrogenicity is a general property, but all molecules which have that property also have some other specific properties. Estriol is a little more water soluble than estrone, so it interacts with every body system in a slightly different way, entering oily environments with slightly less ease, etc.

The estrogen which occurs in yeasts, estradiol, is identical to the major human estrogen, and it is thought to have a reproductive function in yeasts, though this isn't really understood. A feature of this molecule, and of all other molecules that act like estrogen, is the phenolic function, an oxygen and hydrogen group attached to a resonant benzene ring. Phenol itself is estrogenic, and the phenolic group is so extremely common in nature that the number of existing estrogenic substances is great, and the number of potential molecules with estrogen-function is practically infinite.

The phenolic group has many biological functions. For example, it commonly functions as an antioxidant, though something which functions as an antioxidant in one situation is often a pro-oxidant in another situation. The molecule can have catalytic, germicidal, aromatic, neurotropic, and other functions. But it also always has, to some degree, the estrogenic function. This overlap of functions probably accounts for why so many plants have significant estrogenic activity. (Natural estrogens, like other phenolics, including the flavonoids, are also mutagenic.)

The estrogenic properties of legumes were studied when sheep farmers found that their sheep miscarried when they ate clover. (I think it's interesting how this terribly toxic effect has been neglected in recent decades.) All legumes have this property, and all parts of the plant seem to contain some of the active chemicals. In beans, several substances have been found to contribute to the effect. The estrogenic effects of the seed oils and the isoflavones have been studied the most, but the well-known antithyroid actions (again, involving the oils, the isoflavones, and other molecules found in legumes) have an indirect estrogen-promoting action, since hypothyroidism leads to hyperestrogenism. (Estrogens are known to be thyroid suppressors, so the problem tends to be self-accelerating.)

The various specific actions of the many estrogenic substances in beans and other legumes haven't been throughly studied, but there is evidence that they are also--like estrogen itself--both mutagenic and carcinogenic.

The estrogen-promoting actions of soy oil apply to all of the commonly used polyunsaturated fatty acids. The same fatty acids that suppress thyroid function, have estrogenic effects.

The isoflavones (many of which are now being promoted as antioxidants and cancer preventives) are toxic to many organs, but they have clear estrogenic effects, and are active not only immediately in the mature individual, but when they are present prenatally, they cause feminization of the male genitalia and behavior, and early maturation of the female offspring, with the tissue changes that are known to be associated with increased incidence of cancer.

There are interesting associations between vegetable fiber and estrogens. Because of my own experience in finding that eating a raw carrot daily prevented my migraines, I began to suspect that the carrot fiber was having both a bowel-protective and an antiestrogen effect. Several women who suffered from premenstrual symptoms, including migraine, had their serum estrogen measured before and after the carrot diet, and they found that the carrot lowered their estrogen within a few days, as it relieved their symptoms.

Undigestible fiber, if it isn't broken down by bowel bacteria, increases fecal bulk, and tends to speed the transit of material through the intestine, just as laxatives do. But some of these fiber materials, e.g., lignin, are themselves estrogenic, and other fibers, by promoting bacterial growth, can promote the conversion of harmless substances into toxins and carcinogens. When there is a clear antiestrogen effect from dietary fiber, it seems to be the result of accelerated transit through the intestine, speeding elimination and preventing reabsorption of the estrogen which has been excreted in the bile. Laxatives have this same effect on the excretion of estradiol.

Some of the isoflavones, lignins, and other phytoestrogens are said to prevent bowel cancer, but some of them, e.g., lignin, appear to sometimes increase its likelihood.

The phytoestrogens appear to pose a risk to organs besides the breast and uterus, for example the liver, colon, and pancreas, which isn't surprising, since estrogen is known to be carcinogenic for every tissue. And carcinogenesis, like precancerous changes, mutations, and reduced repair of DNA, is probably just an incidental process in the more general toxic effect of acceleration of aging.

REFERENCES & ABSTRACTS

"Stimulatory influence of soy protein isolate on breast secretion in pre- and postmenopausal women," Petrakis NL; Barnes S; King EB; Lowenstein J; Wiencke J; Lee MM; Miike R; Kirk M; Coward L Department of Epidemiology and Biostatistics, University of California, San Francisco 94143-0560, USA. Cancer Epidemiol Biomarkers Prev, 1996 Oct, 5:10, 785-94 "Soy foods have been reported to have protective effects against premenopausal breast cancer in Asian women. No studies have been reported on potential physiological effects of dietary soy consumption on breast gland function. We evaluated the influence of the long-term ingestion of a commercial soy protein isolate on breast secretory activity. We hypothesized that the features of nipple aspirate fluid (NAF) of non-Asian women would be altered so as to resemble those previously found in Asian women. At monthly intervals for 1 year, 24 normal pre- and postmenopausal white women, ages 30 to 58, underwent nipple aspiration of breast fluid and gave blood and 24-h urine samples for biochemical studies. No soy was administered in months 1-3 and 10-12. Between months 4-9 the women ingested daily 38 g of soy protein isolate containing 38 mg of genistein. NAF volume, gross cystic disease fluid protein (GCDFP-15) concentration, and NAF cytology were used as biomarkers of possible effects of soy protein isolate on the breast. In addition, plasma concentrations of estradiol, progesterone, sex hormone binding globulin, prolactin, cholesterol, high density lipoprotein-cholesterol, and triglycerides were measured. Compliance was assessed by measurements of genistein and daidzein and their metabolites in 24-h urine samples. Excellent compliance with the study protocol was obtained. Compared with NAF volumes obtained in months 1-3, a 2-6-fold increase in NAF volume ensued during months 4-9 in all premenopausal women. A minimal increase or no response was found in postmenopausal women. No changes were found in plasma prolactin, sex hormone binding globulin, cholesterol, high density lipoprotein cholesterol, and triglyceride concentrations. Compared with concentrations found in months 1-3 (no soy), plasma estradiol concentrations were elevated erratically throughout a "composite" menstrual cycle during the months of soy consumption. No significant changes were seen in plasma progesterone concentrations. No significant changes were found in plasma estrogen levels in postmenopausal women. A moderate decrease occurred in the mean concentration of GCDFP-15 in NAF in premenopausal women during the months of soy ingestion. Of potential concern was the cytological detection of epithelial hyperplasia in 7 of 24 women (29.2%) during the months they were consuming soy protein isolate. The findings did not support our a priori hypothesis. Instead, this pilot study indicates that prolonged consumption of soy protein isolate has a stimulatory effect on the premenopausal female breast, characterized by increased secretion of breast fluid, the appearance of hyperplastic epithelial cells, and elevated levels of plasma estradiol. These findings are suggestive of an estrogenic stimulus from the isoflavones genistein and daidzein contained in soy protein isolate.

J Clin Endocrinol Metab 1995 May;80(5):1685-1690 Dietary intervention study to assess estrogenicity of dietary soy among postmenopausal women. Baird DD, Umbach DM, Lansdell L, Hughes CL, Setchell KD, Weinberg CR, Haney AF, Wilcox AJ, Mclachlan JA. National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA. We tested the hypothesis that postmenopausal women on a soy-supplemented diet show estrogenic responses. Ninety-seven postmenopausal women were randomized to either a group that was provided with soy foods for 4 weeks or a control group that was instructed to eat as usual. Changes in urinary isoflavone concentrations served as a measure of compliance and phytoestrogen dose. Changes in serum FSH, LH, sex hormone binding globulin, and vaginal cytology were measured to assess estrogenic response. The percentage of vaginal superficial cells (indicative of estrogenicity) increased for 19% of those eating the diet compared with 8% of controls (P = 0.06 when tested by ordinal logistic regression). FSH and LH did not decrease significantly with dietary supplementation as hypothesized, nor did sex hormone binding globulin increase. Little change occurred in endogenous estradiol concentration or body weight during the diet. Women with large increases in urinary isoflavone concentrations were not more likely to show estrogenic responses than were women with more modest increases. On the basis of published estimates of phytoestrogen potency, a 4-week, soy-supplemented diet was expected to have estrogenic effects on the liver and pituitary in postmenopausal women, but estrogenic effects were not seen. At most, there was a small estrogenic effect on vaginal cytology.

Oncol Rep 1998 May-Jun;5(3):609-16 Maternal genistein exposure mimics the effects of estrogen on mammary gland development in female mouse offspring. Hilakivi-Clarke L, Cho E, Clarke R Lombardi Cancer Center, Research Bldg., Room W405, Georgetown University, 3970 Reservoir Road, NW, Washington, DC, 20007-2197, USA. Human and animal data indicate that a high maternal estrogen exposure during pregnancy increases breast cancer risk among daughters. This may reflect an increase in the epithelial structures that are the sites for malignant transformation, i.e., terminal end buds (TEBs), and a reduction in epithelial differentiation in the mammary gland. Some phytoestrogens, such as genistein which is a major component in soy-based foods, and zearalenone, a mycotoxin found in agricultural products, have estrogenic effects on the reproductive system, breast and brain. The present study examined whether in utero exposure to genistein or zearalenone influences mammary gland development. Pregnant mice were injected daily with i) 20 ng estradiol (E2); ii) 20 microg genistein; iii) 2 microg zearalenone; iv) 2 microg tamoxifen (TAM), a partial estrogen receptor agonist; or v) oil-vehicle between days 15 and 20 of gestation. E2, genistein, zearalenone, and tamoxifen all increased the density of TEBs in the mammary glands. Genistein reduced, and zearalenone increased, epithelial differentiation. Zearalenone also increased epithelial density, when compared with the vehicle-controls. None of the treatments had permanent effects on circulating E2 levels. Maternal exposure to E2 accelerated body weight gain, physical maturation (eyelid opening), and puberty onset (vaginal opening) in the female offspring. Genistein and tamoxifen had similar effects on puberty onset than E2. Zearalenone caused persistent cornification of the estrus smears. These findings indicate that maternal exposure to physiological doses of genistein mimics the effects of E2 on the mammary gland and reproductive systems in the offspring. Thus, our results suggest that genistein acts as an estrogen in utero, and may increase the incidence of mammary tumors if given through a pregnant mother. The estrogenic effects of zearalenone on the mammary gland, in contrast, are probably counteracted by the permanent changes in estrus cycling.

[The effects on the thyroid gland of soybeans administered experimentally in healthy subjects] Ishizuki Y; Hirooka Y; Murata Y; Togashi K Nippon Naibunpi Gakkai Zasshi, 1991 May 20, 67:5, 622-9 To elucidate whether soybeans would suppress the thyroid function in healthy adults, we selected 37 subjects who had never had goiters or serum antithyroid antibodies. They were given 30g of soybeans everyday and were divided into 3 groups subject to age and duration of soybean administration. In group 1, 20 subjects were given soybeans for 1 month. Groups 2 and 3 were composed of 7 younger subjects (mean 29 y.o.) and 10 elder subjects (mean 61 y.o.) respectively, and the subjects belonging to these groups received soybeans for 3 months. The Wilcoxon-test and t-test were used in the statistical analyses. In all groups, the various parameters of serum thyroid hormones remained unchanged by taking soybeans, however TSH levels rose significantly although they stayed within normal ranges. The TSH response after TRH stimulation in group 3 revealed a more significant increase than that in group 2, although inorganic iodide levels were lowered during the administration of the soybeans. We have not obtained any significant correlation between serum inorganic iodide and TSH. Hypometabolic symptoms (malaise, constipation, sleepiness) and goiters appeared in half the subjects in groups 2 and 3 after taking soybeans for 3 months, but they disappeared 1 month after the cessation of soybean ingestion. These findings suggested that excessive soybean ingestion for a certain duration might suppress thyroid function and cause goiters in healthy people, especially elderly subjects.

Exp Clin Endocrinol Diabetes 1996;104 Suppl 4:41-5 Iodolactones and iodoaldehydes--mediators of iodine in thyroid autoregulation. Dugrillon A Central Clinical Laboratory, University of Heidelberg, Germany. Within the last decades multiple iodolipid-classes have been identified in thyroid tissue. For a long time they have been supposed to be involved in thyroid autoregulation, but for the time being no specific compounds could be isolated. A new approach was stimulated by the finding that thyroid cells were able to iodinate polyunsaturated fatty acids to form iodolactones and by the identification of alpha-iodohexadecanal (alpha-IHDA) as the major compound of an iodolipid fraction.

Plasma free fatty acids, inhibitor of extrathyroidal conversion of T4 to T3 and thyroid hormone binding inhibitor in patients with various nonthyroidal illnesses. Suzuki Y; Nanno M; Gemma R; Yoshimi T Endocrinol Jpn, 1992 Oct, 39:5, 445-53.

[Endemic goiter in Austria. Is iodine deficiency the primary cause of goiter?] Grubeck-Loebenstein B; Kletter K; Kiss A; Vierhapper H; Waldhäusl W Schweiz Med Wochenschr, 1982 Oct 30, 112:44, 1526-30 In spite of government-regulated iodide admixture to table salt, the incidence of goiter is still high in Austria. Iodine excretion and thyroid function were therefore investigated in 80 patients suffering from ordinary goiter in whom thyroid size and resulting symptoms had increased lately. 25 euthyroid non-goitrous subjects served as controls. 48% of the goitrous patients investigated presented with iodine excretion of less than 70 micrograms/24 h, suggesting an insufficient iodine supply. Thyroid I131 uptake, basal and TRH-stimulated plasma TSH concentrations, and serum T3 levels were higher, whereas serum T4 levels were lower in these patients than in goitrous patients with higher iodine excretion and non-goitrous controls. Iodine deficiency thus appears to be of pathogenetic relevance in about half of the goitrous Austrian population. Other factors enhancing goiter development seem to assume particular importance in goitrous patients with a sufficient iodine supply.

Biochemical and molecular changes at the cellular level in response to exposure to environmental estrogen-like chemicals. Roy D; Palangat M; Chen CW; Thomas RD; Colerangle J; Atkinson A; Yan ZJ Environmental Toxicology Program, University of Alabama, Birmingham 35294, USA. J Toxicol Environ Health, 1997 Jan, 50:1, 1-29. Estrogen-like chemicals are unique compared to nonestrogenic xenobiotics, because in addition to their chemical properties, the estrogenic property of these compounds allows them to act like sex hormones. Whether weak or strong, the estrogenic response of a chemical, if not overcome, will add extra estrogenic burden to the system. At elevated doses, natural estrogens and environmental estrogen-like chemicals are known to produce adverse effects. The source of extra or elevated concentration of estrogen could be either endogenous or exogenous. The potential of exposure for humans and animals to environmental estrogen-like chemicals is high. Only a limited number of estrogen-like compounds, such as diethylstilbestrol (DES), bisphenol A, nonylphenol, polychlorinated biphenyls (PCBs), and dichlorodiphenyltrichloroethane (DDT), have been used to assess the biochemical and molecular changes at the cellular level. Among them, DES is the most extensively studied estrogen-like chemical, and therefore this article is focused mainly on DES-related observations. In addition to estrogenic effects, environmental estrogen-like chemicals produce multiple and multitype genetic and/or nongenetic hits. Exposure of Syrian hamsters to stilbene estrogen (DES) produces several changes in the nuclei of target organ for carcinogenesis (kidney): (1) Products of nuclear redox reactions of DES modify transcription regulating proteins and DNA; (2) transcription is inhibited; (3) tyrosine phosphorylation of nuclear proteins, including RNA polymerase II, p53, and nuclear insulin-like growth factor-1 receptor, is altered; and (4) DNA repair gene DNA polymerase beta transcripts are decreased and mutated. Exposure of Noble rats to DES also produces several changes in the mammary gland: proliferative activity is drastically altered; the cell cycle of mammary epithelial cells is perturbed; telomeric length is attenuated; etc. It appears that some other estrogenic compounds, such as bisphenol A and nonylphenol, may also follow a similar pattern of effects to DES, because we have recently shown that these compounds alter cell cycle kinetics, produce telomeric associations, and produce chromosomal aberrations. Like DES, bisphenol A after metabolic activation is capable of binding to DNA. However, it should be noted that a particular or multitype hit(s) will depend upon the nature of the environmental estrogen-like chemical. The role of individual attack leading to a particular change is not clear at this stage. Consequences of these multitypes of attack on the nuclei of cells could be (1) nuclear toxicity/cell death; (2) repair of all the hits and then acting as normal cells; or (3) sustaining most of the hits and acting as unstable cells. Proliferation of the last type of cell is expected to result in transformed cells.

Potential adverse effects of phytoestrogens. Whitten PL; Lewis C; Russell E; Naftolin F Department of Anthropology, Emory University, Atlanta, GA 30322. J Nutr, 1995 Mar, 125:3 Suppl, 771S-776S Evaluation of the potential benefits and risks offered by naturally occurring plant estrogens requires investigation of their potency and sites of action when consumed at natural dietary concentrations. Our investigations have examined the effects of a range of natural dietary concentrations of the most potent plant isoflavonoid, coumestrol, using a rat model and a variety of estrogen-dependent tissues and endpoints. Treatments of immature females demonstrated agonistic action in the reproductive tract, brain, and pituitary at natural dietary concentrations. Experiments designed to test for estrogen antagonism demonstrated that coumestrol did not conform to the picture of a classic antiestrogen. However, coumestrol did suppress estrous cycles in adult females. Developmental actions were examined by neonatal exposure of pups through milk of rat dams fed a coumestrol, control, or commercial soy-based diet during the critical period of the first 10 postnatal days or throughout the 21 days of lactation. The 10-day treatment did not significantly alter adult estrous cyclicity, but the 21-day treatment produced in a persistent estrus state in coumestrol-treated females by 132 days of age. In contrast, the 10-day coumestrol treatments produced significant deficits in the sexual behavior of male offspring. These findings illustrate the broad range of actions of these natural estrogens and the variability in potency across endpoints. This variability argues for the importance of fully characterizing each phytoestrogen in terms of its sites of action, balance of agonistic and antagonistic properties, natural potency, and short-term and long-term effects.

Am J Obstet Gynecol 1987 Aug;157(2):312-317 Age-related changes in the female hormonal environment during reproductive life. Musey VC, Collins DC, Musey PI, Martino-Saltzman D, Preedy JR. Previous studies have indicated that serum levels of follicle-stimulating hormone rise with age during the female reproductive life, but the effect on other hormones is not clear. We studied the effects of age, independent of pregnancy, by comparing serum hormone levels in two groups of nulliparous, premenopausal women aged 18 to 23 and 29 to 40 years. We found that increased age during reproductive life is accompanied by a significant rise in both basal and stimulated serum follicle-stimulating hormone levels. This was accompanied by an increase in the serum level of estradiol-17 beta and the urine levels of estradiol-17 beta and 17 beta-estradiol-17-glucosiduronate. The serum level of estrone sulfate decreased with age. Serum and urine levels of other estrogens were unchanged. The basal and stimulated levels of luteinizing hormone were also unchanged. There was a significant decrease in basal and stimulated serum prolactin levels. Serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate decreased with age, but serum testosterone was unchanged. It is concluded that significant age-related changes in the female hormonal environment occur during the reproductive years.

Rodriguez, P; Fernandez-Galaz, C; Tejero, A. Controlled neonatal exposure to estrogens: A suitable tool for reproductive aging studies in the female rat. Biology of Reproduction, v.49, n.2, (1993): 387-392. The present study was designed to determine whether the modification of exposure time to large doses of estrogens provided a reliable model for early changes in reproductive aging. Silastic implants containing estradiol benzoate (EB) in solution were placed into 5-day-old female Wistar rats and removed 1 day (Ei1 group) or 5 days (Ei5) later. In addition, 100 mu-g EB dissolved in 100 mu-l corn oil was administered s.c. to another group (EI). Control rats received either vehicle implants or 100 mu-l corn oil. Premature occurrence of vaginal opening was observed in all three estrogenized groups independently of EB exposure. However, females bearing implants for 24 h had first estrus at the same age as their controls and cycled regularly, and neither histological nor gonadal alterations could be observed at 75 days.. Interestingly, they failed to cycle regularly at 5 mo whereas controls continued to cycle. On the other hand, the increase of EB exposure (Ei5, EI) resulted in a gradual and significant delay in the onset of first estrus and in a high number of estrous phases, as frequently observed during reproductive decline. At 75 days, the ovaries of these last two groups showed a reduced number of corpora lutea and an increased number of large follicles. According to this histological pattern, ovarian weight and progesterone (P) content gradually decreased whereas both groups showed higher estradiol (E-2) content than controls. This resulted in a higher E-2:P ratio, comparable to that observed in normal aging rats. The results allow us to conclude that the exposure time to large doses of estrogens is critical to the gradual enhancement of reproductive decline. Furthermore, exposures as brief as 24 h led to a potential early model for aging studies that will be useful to verify whether neuroendocrine changes precede gonadal impairment.

Cancer Lett 1992 Oct 30;67(1):55-59 Evidence of hypothalamic involvement in the mechanism of transplacental carcinogenesis by diethylstilbestrol. Smith DA, Walker BE Anatomy Department, Michigan State University, East Lansing 48824-1316. Disruption of hypothalamic sex differentiation in the fetus is one hypothesis to explain female reproductive system anomalies and cancer arising from prenatal exposure to diethylstilbestrol (DES). To further test this hypothesis, breeding performance and behavior were monitored in a colony of mice exposed prenatally to DES, using a schedule previously shown to produce anomalies and cancer of the female reproductive system. Fertility decreased with age more rapidly in DES-exposed females than in control females. DES-exposed females were less accepting of the male than control females. These observations support the hypothesis of abnormal hypothalamic sex differentiation as a basic mechanism in DES transplacental carcinogenesis.

Int J Cancer 1980 Aug;26(2):241-6 The influence of the lipid composition of the feed given to mice on the immunocompetence and tumour resistance of the progeny. Boeryd B, Hallgren B. In inbred CBA mice, the immunocompetence of adult progeny from breeding pairs fed three different diets was compared. Substitution of soy oil for animal fat in the feed of the mice during gestation or lactation significantly decreased the PFC response to SRBC in the adult offspring. Addition of 2-methoxy-substituted glycerol ethers to the feed of mothers deprived of animal fat during lactation partly restored the PFC response of the male offspring. In the adult mice fed differently pre- and perinatally the resistance to a transplanted syngeneic sarcoma was similar. The growth of offspring from mice fed the three diets was similar. In mice deprived of animal fat at weaning and for the following 21 days the immune reactivity to SRBC, tested about 3 months after stopping the diet, was not influenced. However, the resistance to a transplanted tumour in similarly fed mice was increased and this resistance was brought approximately to the control level by methoxy-substituted glycerol ethers.

Cancer Res 1987 Mar 1;47(5):1333-8. Effects of dietary fats and soybean protein on azaserine-induced pancreatic carcinogenesis and plasma cholecystokinin in the rat. Roebuck BD, Kaplita PV, Edwards BR, Praissman M Both dietary unsaturated fat and raw soybean products are known to enhance pancreatic carcinogenesis when fed during the postinitiation phase. A comparison of these two dietary components was made to evaluate the relative potency of each ingredient for enhancing pancreatic carcinogenesis and to determine if this enhancement was correlated with an increase in plasma cholecystokinin (CCK) levels. Male Wistar rats were initiated with a single dose of azaserine (30 mg/kg body weight) at 14 days of age. The rats were weaned to test diets formulated from purified ingredients. Dietary protein at 20% by weight was either casein or soy protein isolate (heat treated or raw).. Corn oil was the unsaturated fat of major interest and it was fed at either 5 or 20% by weight. Pancreases were quantitatively evaluated for carcinogen-induced lesions at 2- and 4-month postinitiation. In a second experiment designed to closely mimic the above experiment, rats were implanted with cannulae which allowed plasma to be repetitively sampled over a 2.5-week period during which the test diets were fed. Plasma was collected both prior to introduction of the test diets and afterwards. Plasma CCK was measured by a specific radioimmunoassay. Both the 20% corn oil diet and the raw soy protein isolate diet enhanced pancreatic carcinogenesis. The effects of the raw soy protein isolate on the growth of the carcinogen-induced lesions were significantly greater than the effects of the 20% corn oil diet. Plasma CCK values were not elevated in the rats fed the 20% corn oil diet, but they were significantly elevated in the rats fed the raw soy protein isolate. Heat-treated soy protein isolate neither enhanced carcinogenesis nor elevated the plasma CCK level. This study demonstrates that certain plant proteins enhance the growth of carcinogen-induced pancreatic foci and that this effect is considerably greater than the enhancement by high levels of dietary unsaturated fat. Furthermore, the enhancement by the raw soy protein isolate may be mediated by CCK; but this does not appear to be the mechanism by which the unsaturated fat, corn oil, enhances pancreatic carcinogenesis.

J Biol Chem 1988 Mar 15;263(8):3639-3645 Dynamic pattern of estradiol binding to uterine receptors of the rat. Inhibition and stimulation by unsaturated fatty acids. Vallette G, Christeff N, Bogard C, Benassayag C, Nunez E

J Biol Chem 1986 Feb 25;261(6):2954-2959 Modifications of the properties of human sex steroid-binding protein by nonesterified fatty acids. Martin ME, Vranckx R, Benassayag C, Nunez EA The effect of unsaturated and saturated nonesterified fatty acids (NEFAs) on the electrophoretic, immunological, and steroid-binding properties of human sex hormone-binding protein (SBP) were investigated. Tests were carried out on whole serum from pregnant women and on purified SBP using polyacrylamide gel electrophoresis, crossed immunoelectrophoresis with autoradiography, and equilibrium dialysis. All three methods showed that NEFAs influence the binding of sex steroids to SBP both in whole serum and with the purified protein. Saturated NEFAs caused a 1.5-2-fold increase in binding of dehydrotestosterone, testosterone, and estradiol to SBP, while unsaturated NEFAs, such as oleic (18:1) and docosahexaenoic (22:6) acids inhibited the binding of these steroids to SBP. Thus, unsaturated NEFAs in the concentration range 1-100 microM are more inhibitory for estradiol binding than for testosterone or dehydrotestosterone binding. In addition to these binding changes, polyacrylamide gel electrophoresis and immunoelectrophoretic studies revealed a shift in SBP from the slow-moving active native form to a fast-moving inactive one. There was also a reduction in the apparent SBP concentration by Laurell immunoelectrophoresis in the presence of unsaturated NEFA (5.5 nmol of NEFA/pmol of protein). These studies indicate that unsaturated NEFAs induce conformational changes in human SBP which are reflected in its electrophoretic, immunological, and steroid-binding properties. They suggest that the fatty acid content of the SBP environment may result in lower steroid hormone binding and thus increased free hormone levels.

J Biol Chem 1986 Feb 25;261(6):2954-2959 Modifications of the properties of human sex steroid-binding protein by nonesterified fatty acids. Martin ME, Vranckx R, Benassayag C, Nunez EA The effect of unsaturated and saturated nonesterified fatty acids (NEFAs) on the electrophoretic, immunological, and steroid-binding properties of human sex hormone-binding protein (SBP) were investigated. Tests were carried out on whole serum from pregnant women and on purified SBP using polyacrylamide gel electrophoresis, crossed immunoelectrophoresis with autoradiography, and equilibrium dialysis. All three methods showed that NEFAs influence the binding of sex steroids to SBP both in whole serum and with the purified protein. Saturated NEFAs caused a 1.5-2-fold increase in binding of dehydrotestosterone, testosterone, and estradiol to SBP, while unsaturated NEFAs, such as oleic (18:1) and docosahexaenoic (22:6) acids inhibited the binding of these steroids to SBP. Thus, unsaturated NEFAs in the concentration range 1-100 microM are more inhibitory for estradiol binding than for testosterone or dehydrotestosterone binding. In addition to these binding changes, polyacrylamide gel electrophoresis and immunoelectrophoretic studies revealed a shift in SBP from the slow-moving active native form to a fast-moving inactive one. There was also a reduction in the apparent SBP concentration by Laurell immunoelectrophoresis in the presence of unsaturated NEFA (5.5 nmol of NEFA/pmol of protein). These studies indicate that unsaturated NEFAs induce conformational changes in human SBP which are reflected in its electrophoretic, immunological, and steroid-binding properties. They suggest that the fatty acid content of the SBP environment may result in lower steroid hormone binding and thus increased free hormone levels.

J Steroid Biochem 1986 Feb;24(2):657-659 Free fatty acids: a possible regulator of the available oestradiol fractions in plasma. Reed MJ, Beranek PA, Cheng RW, James VH Consumption of dietary fats has been linked to the high incidence of breast cancer found in Western women. In vitro studies we have carried out show that unsaturated free fatty acids can increase the biologically available oestradiol fractions in plasma. It is possible therefore that the increased risk for breast cancer associated with a diet high in fats may be related to an elevation in the biologically available oestradiol fractions in plasma.

Endocrinology 1986 Jan;118(1):1-7 Potentiation of estradiol binding to human tissue proteins by unsaturated nonesterified fatty acids. Benassayag C, Vallette G, Hassid J, Raymond JP, Nunez EA Nonesterified fatty acids (NEFAs) have been recently shown in the rat to be involved in steroid hormone expression, having effects on plasma transport and intracellular activity. This study examines the influence of saturated and unsaturated NEFAs on estradiol (E2) binding to cytosol from human uterus, breast, and melanoma. Binding was analyzed after separation with dextran-coated charcoal or hydroxylapatite and by sucrose density gradient centrifugation. Unsaturated NEFAs induced a 2- to 10-fold increase (P less than 0.001) in E2 binding to cytosol from normal, fibromatous, and neoplastic uteri, while saturated NEFAs had a slight inhibitory effect (P less than 0.05). Similar effects were seen with cytosol from metastatic melanoma lymph nodes and neoplastic breast tissues. By contrast, unsaturated NEFAs did not increase E2 binding to serum from these patients. Density gradient centrifugation indicated that the increased binding was associated with the proteins present in the 2- to 4 S region. Analysis of E2 metabolites in the presence of unsaturated NEFAs showed the formation of water-soluble derivatives. Seventy percent of these E2 derivatives were trichloracetic acid precipitable, suggesting a covalent link between the steroid and a protein. The existence of such water-soluble metabolites could be erroneously interpreted as a true binding to soluble cytoplasmic receptors.

Ann N Y Acad Sci 1988;538:257-264 Possible relevance of steroid availability and breast cancer. Bruning PF, Bonfrer JM Netherlands Cancer Institute (Antoni van Leeuwenhoekhuis), Amsterdam. The as yet circumstantial evidence for a central role of estrogens in the promotion of human breast cancer is supported by many data. However, it has not been possible to identify breast cancer patients or women at risk by abnormally elevated estrogen levels in plasma. The concept of available, i.e., non-SHBG bound sex steroid seems to offer a better understanding than total serum steroid levels do. We demonstrated that sex steroid protein binding is decreased by free fatty acids.

J Surg Oncol 1993 Feb;52(2):77-82. The effect of the fiber components cellulose and lignin on experimental colon neoplasia. Sloan DA, Fleiszer DM, Richards GK, Murray D, Brown RA Department of Surgery, University of Kentucky College of Medicine, Lexington. Sixty Sprague-Dawley rats were pair-fed one of three nutritionally identical diets. One diet contained "low-fiber" (3.8% crude fiber); the others contained "high fiber" (28.7% crude fiber) composed of either cellulose or lignin. Although both "high fiber" diets had similar stool bulking effects, only the cellulose diet was associated with a reduction in 1,2-dimethylhydrazine (DMH)-induced colon neoplasms. The cellulose diet was also associated with distinct changes in the gut bacterial profile and with a lowered serum cholesterol.

Nutr Cancer 1984;6(2):77-85 Enhancement of 1,2-dimethylhydrazine-induced large bowel tumorigenesis in Balb/c mice by corn, soybean, and wheat brans. Clapp NK, Henke MA, London JF, Shock TL This study was designed to determine the effects of four well-characterized dietary brans on large bowel tumorigenesis induced in mice with 1,2-dimethylhydrazine (DMH). Eight-week-old barrier-derived male Balb/c mice were fed a semisynthetic diet with 20% bran added (either corn, soybean, soft winter wheat, or hard spring wheat) or a no-fiber-added control diet. Half of each group was given DMH (20 mg/kg body weight/week, subcutaneously for 10 weeks) beginning at 11 weeks of age. Surviving mice were killed 40 weeks after the first DMH injection. Tumors were not found in mice not subjected to DMH. In DMH-treated mice, tumors were found almost exclusively in the distal colon. Tumor incidences were as follows: controls, 11%; soybean group, 44%; soft winter wheat group, 48%; hard spring wheat group, 58%; and corn group, 72%. Tumors per tumor-bearing mouse ranged from 1.4 to 1.6, except in the corn group, which had 2.1. A positive correlation was found between percentage of neutral detergent fiber in the brans and tumor incidences but not between the individual components of cellulose, hemicellulose, or lignin. The enhancement of DMH-induced large bowel tumorigenesis by all four bran types may reflect a species and/or mouse strain effect that is bran-source related. These data emphasize the importance of using well-defined bran in all "fiber" studies.

Prev Med 1987 Jul;16(4):540-4 Fiber, stool bulk, and bile acid output: implications for colon cancer risk. McPherson-Kay R Dietary fiber has direct effects on stool bulk and bile acid output that may be of relevance in the etiology of colon cancer. Most types of fiber increase the total volume of stool and reduce the concentration of specific substances, including bile acids, that are in contact with the bowel wall. However, fibers differ in their effect on stool bulk, with wheat fiber being a more effective stool bulking agent than fruit and vegetable fibers. In addition, the extent to which a specific fiber reduces bile acid concentration will be modified by its concomitant effects on total fecal sterol excretion. Whereas wheat bran reduces fecal bile acid concentration, pectin, lignin, and oat bran do not. These three fibers significantly increase total bile acid output. Bile acids act as promoters of colonic tumors in mutagenesis assay systems and in various animal models. Human epidemiological studies show a relationship between various dietary variables, including fat and fiber intake, fecal concentration of bile acids, and colon cancer risk.

Eur J Gastroenterol Hepatol 1998 Jan;10(1):33-9 Intestinal absorption of oestrogen: the effect of altering transit-time. Lewis SJ, Oakey RE, Heaton KW University Department of Medicine, Bristol Royal Infirmary, UK. OBJECTIVE: The mechanism by which a high fibre diet may reduce serum oestrogens is unknown. We hypothesized that time is a rate-limiting factor in oestrogen absorption from the colon so that changes in colonic transit-rate affect the proportion of oestrogen that is deconjugated and/or absorbed. AIM: To determine if alteration of intestinal transit rate would influence the absorption of an oral dose of oestradiol glucuronide. PARTICIPANTS: Twenty healthy postmenopausal women recruited by advertisement. SETTING: Department of Medicine, Bristol Royal Infirmary. METHODS: Volunteers consumed, in turn, wheat bran, senna, loperamide and bran shaped plastic flakes, each for 10 days with a minimum 2 week washout period between study periods, dietary intake being unchanged. Before and in the last 4 days of each intervention whole-gut transit-time, defecation frequency, stool form, stool beta-glucuronidase activity, stool pH and the absorption of a 1.5 mg dose of oestradiol glucuronide were measured. RESULTS: Wheat bran, senna and plastic flakes led to the intended reduction in whole-gut transit-time, increase in defecatory frequency and increase in stool form score. Loperamide caused the opposite effect. The length of time the absorbed oestrogen was detectable in the serum fell with wheat bran and senna, although this was only significant for oestradiol. Oestrone, but not oestradiol, was detectable for a longer time with loperamide. Plastic flakes had no effect on either oestrogen. Areas under the curve did not change significantly but tended to fall with the three transit-accelerating agents and to rise with loperamide. CONCLUSION: Our data indicate there is likely to be an effect of intestinal transit on the absorption of oestrogens but more refined techniques are needed to characterize this properly.

Br J Cancer 1997;76(3):395-400. Lower serum oestrogen concentrations associated with faster intestinal transit. Lewis SJ, Heaton KW, Oakey RE, McGarrigle HH University Department of Medicine, Bristol Royal Infirmary, UK. Increased fibre intake has been shown to reduce serum oestrogen concentrations. We hypothesized that fibre exerts this effect by decreasing the time available for reabsorption of oestrogens in the colon. We tested this in volunteers by measuring changes in serum oestrogen levels in response to manipulation of intestinal transit times with senna and loperamide, then comparing the results with changes caused by wheat bran. Forty healthy premenopausal volunteers were placed at random into one of three groups. The first group took senna for two menstrual cycles then, after a washout period, took wheat bran, again for two menstrual cycles. The second group did the reverse. The third group took loperamide for two menstrual cycles. At the beginning and end of each intervention a 4-day dietary record was kept and whole-gut transit time was measured; stools were taken for measurement of pH and beta-glucuronidase activity and blood for measurement of oestrone and oestradiol and their non-protein-bound fractions and of oestrone sulphate. Senna and loperamide caused the intended alterations in intestinal transit, whereas on wheat bran supplements there was a trend towards faster transit. Serum oestrone sulphate fell with wheat bran (mean intake 19.8 g day(-1)) and with senna; total- and non-protein-bound oestrone fell with senna. No significant changes in serum oestrogens were seen with loperamide. No significant changes were seen in faecal beta-glucuronidase activity. Stool pH changed only with senna, in which case it fell. In conclusion, speeding up intestinal transit can lower serum oestrogen concentrations.

J Steroid Biochem Mol Biol 1991 Aug;39(2):193-202 Influence of wheat bran on NMU-induced mammary tumor development, plasma estrogen levels and estrogen excretion in female rats. Arts CJ, de Bie AT, van den Berg H, van 't Veer P, Bunnik GS, Thijssen JH TNO Toxicology and Nutrition Institute, The Netherlands. In our animal experiments the hypothesis was tested that a high-fiber (HF) diet reduces tumor promotion by interruption of the enterohepatic circulation resulting in lowered estrogen exposure of the estrogen-sensitive tissue. In the first experiment the development of N-nitrosomethylurea (NMU) induced mammary tumors was investigated. One group of rats (HF) was fed a HF diet (11% fiber, based on wheat bran), the other group (LF) fed a low-fiber diet (0.5% fiber, based on white wheat flour). Tumor incidence (90 and 80%, respectively) and latency (121 and 128 days, respectively) were similar in the HF and LF groups. Compared to the LF group, HF rats had lower tumor weights (0.16 vs 0.55 g; P less than 0.01) and a slightly lower tumor multiplicity (1.8 vs 2.8 tumors per tumor-bearing rat). These differences were reduced after adjustment for body weight. In a second experiment rats, not treated with the carcinogen, were kept on the same HF and LF diets. From these rats 24-h urine and feces and orbital blood samples were collected for analysis of (un)conjugated estrogens. The excretion of both free and conjugated estrogens in fecal samples was about 3-fold higher in HF rats than in LF rats. During the basal period of the cycle urinary excretion of estrone was lower in HF rats (mean 9.7 ng/day) than in LF rats (mean 13.0 ng/day; P less than 0.05). It is concluded that wheat bran interrupts the enterohepatic circulation of estrogens, but plasma levels are not affected. Whether the development of mammary tumors is reduced by the introduction of specific components of wheat bran, or by a reduced body weight due to a lower (effective) energy intake remains to be determined.

Nutr Cancer 1998;31(1):24-30 Dietary lignin, and insoluble fiber, enhance uterine cancer but did not influence mammary cancer induced by N-methyl-N-nitrosourea in rats. Birt DF, Markin RS, Blackwood D, Harvell DM, Shull JD, Pennington KL Eppley Institute for Research in Cancer and Allied Disease, University of Nebraska Medical Center, Omaha 69198, USA. Previous investigations suggested potential breast cancer-preventive properties of dietary fiber from cabbage. The purpose of the present investigation was to determine whether lignin, a component of cabbage fiber, would protect against mammary carcinogenesis by N-methyl-N-nitrosourea (MNU) in Sprague-Dawley rats. A six-week study was conducted using diets containing 0.5-5% dietary wood lignin (a readily available, purified source). These diets were well tolerated by the rats, and a carcinogenesis study using 5 mg MNU/100 g body wt i.v. at 50 days of age was conducted, with the 2.5% lignin diet fed from 6 through 8 weeks of age followed by 5% lignin diet until 20 weeks after MNU. Dietary lignin and MNU treatment increased food consumption (p < 0.05), and body weight was slightly reduced at 10 and 20 weeks after MNU in the MNU-5% lignin diet group (p < 0.05). Serum estradiol was not altered by dietary lignin or MNU treatment, but uterine weights were highest in the MNU-control diet group 4 and 12 weeks after MNU. Expression of creatine kinase B, an estrogen-responsive gene, was lower in the uteri of the MNU-lignin diet group than in other groups at 20 weeks. Mammary carcinogenesis was not altered by dietary lignin. However, uterine endometrial adenocarcinoma was observed only in the MNU-lignin diet group (4 carcinomas/40 effective rats) (p < 0.05).

Ginecol Obstet Mex 1998 Mar;66:111-8 [Estrogens of vegetable origin]. [Article in Spanish] Rubio Lotvin B Reproduccion y de Ginecologia y Obstetricia Facultad de Medicina, UNAM Depto. de Ginecologia y Obstetricia Hospital Americano, Britanico Cowdray. Mexico, D.F. In recent years, estrogens of vegetable origin have acquired some importance that justify the presentation of the available data. The compounds that have estrogenic effect when ingested as food through vegetables include isoflavones, lignines and lactones. The review comprises their chemical structure, metabolism and excretion as well as their effect on plasmatic levels of estrogens FSH, LH and SHBG as well as their activity over lipoproteins and, naturally, their action on menopause symptoms and breast cancer.

Proc Soc Exp Biol Med 1995 Jan;208(1):6-12 Chemical studies of phytoestrogens and related compounds in dietary supplements: flax and chaparral. Obermeyer WR, Musser SM, Betz JM, Casey RE, Pohland AE, Page SW Division of Natural Products, Food and Drug Administration, Washington, District of Columbia 20204. High-performance liquid chromatographic (HPLC) and mass spectrometric (MS) procedures were developed to determine lignans in flaxseed (Linum usitatissimum) and chaparral (Larrea tridentata). Flaxseed contains high levels of phytoestrogens. Chaparral has been associated with acute nonviral toxic hepatitis and contains lignans that are structurally similar to known estrogenic compounds. Both flaxseed and chaparral products have been marketed as dietary supplements. A mild enzyme hydrolysis procedure to prevent the formation of artifacts in the isolation step was used in the determination of secoisolariciresinol in flaxseed products. HPLC with ultraviolet spectral (UV) or MS detection was used as the determinative steps. HPLC procedures with UV detection and mass spectrometry were developed to characterize the phenolic components, including lignans and flavonoids, of chaparral and to direct fractionation studies for the bioassays.

Brain Res 1994 Jul 25;652(1):161-3 The 21-aminosteroid antioxidant, U74389F, prevents estradiol-induced depletion of hypothalamic beta-endorphin in adult female rats. Schipper HM, Desjardins GC, Beaudet A, Brawer JR Department of Anatomy and Cell Biology, Bloomfield Centre for Research in Aging, Jewish General Hospital, McGill University, Montreal, Que., Canada. A single intramuscular injection of 2 mg estradiol valerate (EV) results in neuronal degeneration and beta-endorphin depletion in the hypothalamic arcuate nucleus of adult female rats. We have hypothesized that peroxidase-positive astrocytes in this brain region oxidize estrogens and catecholestrogens to semiquinone radicals which mediate oxidative neuronal injury. In the present study, dietary administration of the potent antioxidant 21-aminosteroid, U-74389F, completely blocked EV-induced beta-endorphin depletion in the hypothalami of adult female rats. Neither EV nor 21-aminosteroid treatment had any effect on hypothalamic concentrations of neuropeptide Y and Met-enkephalin, confirming that the estradiol lesion is fairly selective for the beta-endorphin cell population. The present findings support the hypothesis that the toxic effect of estradiol on hypothalamic beta-endorphin neurons is mediated by free radicals.

J Steroid Biochem Mol Biol 1998 Feb;64(3-4):207-15, Effects of tea polyphenols and flavonoids on liver microsomal glucuronidation of estradiol and estrone. Zhu BT, Taneja N, Loder DP, Balentine DA, Conney AH Administration of 0.5 or 1% lyophilized green tea (5 or 10 mg tea solids per ml, respectively) as the sole source of drinking fluid to female Long-Evans rats for 18 days stimulated liver microsomal glucuronidation of estrone, estradiol and 4-nitrophenol by 30-37%, 15-27% and 26-60%, respectively. Oral administration of 0.5% lyophilized green tea to female CD-1 mice for 18 days stimulated liver microsomal glucuronidation of estrone, estradiol and 4-nitrophenol by 33-37%, 12-22% and 172-191%, respectively. The in vitro addition of a green tea polyphenol mixture, a black tea polyphenol mixture or (-)-epigallocatechin gallate inhibited rat liver microsomal glucuronidation of estrone and estradiol in a concentration-dependent manner and their IC50 values for inhibition of estrogen metabolism were approximately 12.5, 50 and 10 microg/ml, respectively. Enzyme kinetic analysis indicates that the inhibition of estrone glucuronidation by 10 microM (-)-epigallocatechin gallate was competitive while inhibition by 50 microM (-)-epigallocatechin gallate was noncompetitive. Similarly, several flavonoids (naringenin, hesperetin, kaempferol, quercetin, rutin, flavone, alpha-naphthoflavone and beta-naphthoflavone) also inhibited rat liver microsomal glucuronidation of estrone and estradiol to varying degrees. Naringenin and hesperetin displayed the strongest inhibitory effects (IC50 value of approximately 25 microM). These two hydroxylated flavonoids had a competitive mechanism of enzyme inhibition for estrone glucuronidation at a 10 microM inhibitor concentration and a predominantly noncompetitive mechanism of inhibition at a 50 microM inhibitor concentration.

Toxicology 1997 Sep 26;122(1-2):61-72, Effects of co-administration of butylated hydroxytoluene, butylated hydroxyanisole and flavonoids on the activation of mutagens and drug-metabolizing enzymes in mice. Sun B, Fukuhara M Effects of co-administration of food additives and naturally occurring food components were studied on the activation of mutagens. Male mice (ddY) were given diets containing butylated hydroxytoluene (BHT) or butylated hydroxyanisole (BHA) and flavone or flavanone (2,3-dihydroflavone) for two weeks and the ability of hepatic microsomes to activate aflatoxin B1, benzo[a]pyrene and N-nitrosodimethylamine was determined by the mutagenicity test. Co-administration of an antioxidant (0.1% BHT or 0.2% BHA in diet) and a flavonoid (0.1% flavone or 0.1% flavanone) resulted in additive effects on the activation of aflatoxin B1 and benzo[a]pyrene, while the activation of N-nitrosodimethylamine was not elevated significantly by the co-administration. To understand the mechanism for the additive effects, induction of specific isozymes of cytochrome P450 involved in the activation of the mutagens was studied. Co-administration of BHT (0.1%) and flavone (0.1%) increased markedly the levels of proteins and the activities of the enzymes related to the isozymes of CYP2A and CYP2B, while co-administration of BHA (0.2%) and flavanone (0.1%) elevated those related to CYP1A. Further, the activation of aflatoxin B1 and benzo[a]pyrene in hepatic microsomes was inhibited by the antibodies against these isozymes, which suggested that the enhanced activation of the mutagens by the co-administration might be mediated by the induction of these isozymes.

Biochem Soc Trans 1977;5(5):1489-92. Frameshift mutagenicity of certain naturally occurring phenolic compounds in the 'Salmonella/microsome' test: activation of anthraquinone and flavonol glycosides by gut bacterial enzymes. Brown JP, Dietrich PS, Brown RJ

Mutagenesis 1997 Sep;12(5):383-90 Involvement of rat cytochrome 1A1 in the biotransformation of kaempferol to quercetin: relevance to the genotoxicity of kaempferol. Silva ID, Rodrigues AS, Gaspar J, Maia R, Laires A, Rueff J. Kaempferol is a flavonoid widely distributed in edible plants and has been shown to be genotoxic to V79 cells in the absence of external metabolizing systems. The presence of an external metabolizing system, such as rat liver homogenates (S9 mix), leads to an increase in its genotoxicity, which is attributed to its biotransformation to the more genotoxic flavonoid quercetin, via the cytochrome P450 (CYP) mono-oxygenase system.

Environ Health Perspect 1997 Apr;105 Suppl 3:633-6 Dietary estrogens stimulate human breast cells to enter the cell cycle. Dees C, Foster JS, Ahamed S, Wimalasena J. "Our findings are consistent with a conclusion that dietary estrogens at low concentrations do not act as antiestrogens, but act like DDT and estradiol to stimulate human breast cancer cells to enter the cell cycle."

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<span class="koboSpan" id="kobo.1.1">Tissue-bound estrogen in aging</span> A R T I C L E

Tissue-bound estrogen in aging

The "Estrogen Replacement" industry is based on the doctrine that a woman's tissues are depleted of estrogen after menopause. This doctrine is false.

The concentration of a hormone in the blood doesn't directly represent the concentration in the various organs.

The amount of estrogen in tissue is decreased when progesterone is abundant. In the absence of progesterone, tissues retain estrogen even when there is little estrogen circulating in the blood.

Many things suggest an increased estrogenic activity at menopause. For example, melatonin decreases sharply at puberty when estrogen increases, and then it decreases again at menopause. Prolactin (stimulated by estrogen) increases around puberty, and instead of decreasing at menopause, it often increases, and its increase is associated with osteoporosis and other age-related symptoms.

Estrogen is produced in many tissues by the enzyme aromatase, even in the breast and endometrium, although these are considered "target tissues" rather than endocrine glands. Aromatase increases with aging.

Estrogen is inactivated, mainly in the liver and brain, by being made water soluble by the attachment of glucuronic acid and/or sulfuric acid.

Estrogen's concentration in a particular tissue depends on many things, including its affinity or binding strength for components of that tissue, relative to its affinity for the blood; the activity in that tissue of the aromatase enzyme, which converts androgens to estrogen; the activity of the glucuronidase enzyme, that converts water-soluble estrogen glucuronides into the oil soluble active forms of estrogen; and the sulfatases and several other enzymes that modify the activity and solubility of the estrogens. The "estrogen receptors," proteins which bind estrogens in cells, are inactivated by progesterone, and activated by many physical and chemical conditions.

Inflammation activates beta-glucuronidase, and antiinflammatory substances such as aspirin reduce many of estrogen's effects.

Doctrines are admitted into the "scientific canon" by those who have the power of censorship. In astronomy, Halton Arp's discovery of "anomalous" galactic red-shifts is practically unknown, because the journal editors say the observations are "just anomalies," or that the theories which could explain them are unconventional; but the actual problem is that they are strong evidence against The Big Bang, Hubble's Law, and the Expanding Universe. American science, since the 1940s, has probably been the most censored and doctrinaire in the world.

Gilbert Ling's revolution in cell biology remains outside the canon, despite the profound influence of MRI, which grew directly out of his view of the cell, because his work provided conclusive evidence that cells are not regulated by "semipermeable membranes and membrane pumps." Every field of science is ruled by a doctrinaire establishment.

Charles E. Brown-Séquard (1817-94) was a physiologist who pioneered scientific endocrinology, but who was ridiculed because of his claim that extracts of animal glands had an invigorating effect when injected. His place in the scientific canon is mainly as an object of ridicule, and the details of his case are perfectly representative of the way our canon has been constructed. The argument for dismissing his observations was that he used a water extract of testicles, and, according to the 20th century American biologists, testosterone is not water soluble, and so the water extract would have contained no hormone. The argument is foolish, because living organs contain innumerable substances that will solublize oily molecules, but also because Brown-Sequard was describing an effect that wasnt necessarily limited to a single chemical substance. (The transplanting of living cells to repair tissues is finally being accepted, but the pioneers in promoting tissue regeneration or repair with the transplantation of living, dead, or stressed cells--V. Filatov, L.V. Polezhaev, W.T. Summerlin, for example--were simply written out of history.)

If Brown-Séquards extract couldnt work because testosterone isnt soluble in water, then what are we to think of the thousands of medical publications that talk about free hormones as the only active hormones? (Free hormone is defined as the hormone that isnt bound to a transporting protein, with the more or less explicit idea that it is dissolved in the water of the plasma or extracellular fluid.) Brown-Séquards tissue extracts would have contained solublizing substances including proteins and phospholipids, so the oily hormones would certainly be present (and active) in his extracts. But the thousands of people who ridiculed him committed themselves to the fact that steroid hormones are insoluble in water. By their own standard, they are selling an impossibility when they do calculations to reveal the amount of free hormone, as something distinct from the protein bound hormone, in the patients blood.

The immense Hormone Replacement Therapy industry--which Brown-Séquards experiments foreshadowed--is based on the fact that the concentrations of some hormones in the blood serum decrease with aging.

At first, it was assumed that the amount of the hormone in the blood corresponded to the effectiveness of that hormone. Whatever was in the blood was being delivered to the target tissues. But as the idea of measuring protein bound iodine (PBI) to determine thyroid function came into disrepute (because it never had a scientific basis at all), new ideas of measuring active hormones came into the marketplace, and currently the doctrine is that the bound hormones are inactive, and the active hormones are free. The free hormones are supposed to be the only ones that can get into the cells to deliver their signals, but the problem is that free hormones exist only in the imagination of people who interpret certain lab tests, as I discussed in the newsletter on thyroid tests (May, 2000).

In the 1960s and 1970s, when the PBI test was disappearing, there was intense interest in--a kind of mania regarding--the role of membranes in regulating cell functions, and the membrane was still seen by most biologists as the semipermeable membrane which, obviously, would exclude molecules as large as albumin and the other proteins that carry thyroid and other hormones in the blood. (In reality, and experimental observations, albumin and other proteins enter cells more or less freely, depending on prevailing conditions.) The membrane doctrine led directly to the free hormone doctrine.

This issue, of arguing about which form of a hormone is the active form, has to do with explaining how much of the blood-carried hormone is going to get into the target tissues. If the membrane is a semipermeable barrier to molecules such as hormones, then specific receptors and transporters will be needed. If the concentration of a hormone inside the cell is higher than that in the blood, a pump will usually be invoked, to produce an active transport of the hormone against its concentration gradient.

But if the membrane regulates the passage of hormones from blood to tissue cells, and especially if pumps are needed to move the hormone into the cell, how relevant is the measurement of hormones in the blood?

Within the blood, progesterone and thyroid hormone (T3) are much more concentrated in the red blood cells than in the serum. Since it isnt likely that red blood cells are targets for the sex hormones, or for progesterone or even thyroid, their concentration against their gradient in these cells suggests that a simple distribution by solubility is involved. Oily substances just naturally tend to concentrate inside cells because of their insolubility in the watery environment of the plasma and extracellular fluid. Proteins that have oily regions effectively bind oily molecules, such as fats and steroids. Even red blood cells have such proteins.

In the case of oil soluble molecules, such as progesterone and estrogen, its important to explain that most of their binding to proteins or other oil-loving molecules is really the nearly passive consequence of the molecules being forced away from the watery phase--they are hydrophobic, and although it would take a great amount of energy to make these insoluble substances enter the watery phase, the attractive force between them and the cell is usually small. This means that they can be freely mobile, while bound or concentrated within the cell. The oxygen atoms, and especially the phenolic group of estrogen, slightly reduce the hormones affinity for simple oils, but they interact with other polar or aromatic groups, giving estrogen the ability to bind more strongly and specifically with some proteins and other molecules. Enzymes which catalyze estrogens oxidation-reduction actions are among the specific estrogen-binding proteins.

Many proteins and lipoproteins bind steroids, but some intracellular proteins bind them so strongly that they have been--in a very teleological, if not anthropomorphic, way--considered as the switch by which the hormone turns on the cellular response. In the popular doctrine of the Estrogen Receptor, a few molecules of estrogen bind to the receptors, which carry them to the nucleus of the cell, where the activated receptors turn on the genes in charge of the female response. (Or the male response, or the growth response, or the atrophy response, or whatever genetic response estrogen is producing.) Once the switch has been thrown, the estrogen molecules have fulfilled their hormonal duty, and must get lost, so that the response isnt perpetuated indefinitely by a few molecules.

Although the Estrogen Receptor doctrine is worse than silly, there are real proteins which bind estrogen, and some of these are called receptors. The uterus, breast, and brain, which are very responsive to estrogen, bind, or concentrate, estrogen molecules.

When I was working on my dissertation, I tried to extract estrogens from hamster uteri, but the chemical techniques I was using to measure estrogen werent accurate for such small quantities. A few years later, S. Batra was able to extract the estrogen from human tissue in quantities large enough for accurate analysis by radioimmunoassay. (Batra, 1976.)

His crucial observation was that the difference in estrogen concentration between tissue and blood was lowest in the luteal phase, when progesterone is high:

The tissue/plasma ratio of E2 [estradiol] ranged from 1.45 to 20.36 with very high values in early follicular phase and the lowest in mid-luteal phase. This means that progesterone prevents the tissue from concentrating estrogen. He made similar observations during pregnancy, with tissue estrogen decreasing as blood progesterone increased, so that there is less estrogen in the tissue than in the plasma. But in women who arent pregnant, and when their progesterone is low, the tissues may contain 20 to 30 times more estrogen than the plasma (in equal volumes).

In aging, the sharply decreased progesterone production creates a situation resembling the follicular phase of the menstrual cycle, allowing tissues to concentrate estrogen even when the serum estrogen may be low.

In postmenopausal women, the tissue concentration of E2 was not significantly lower than in menstruating women in follicular phase. . . . (Akerlund, et al., 1981.)

Besides the relatively direct actions of progesterone on the estrogen receptors, keeping their concentration low, and its indirect action by preventing prolactin from stimulating the formation of estrogen receptors, there are many other processes that can increase or decrease the tissue concentration of estrogen, and many of these influences change with aging.

There are two kinds of enzyme that produce estrogen. Aromatase converts male hormones into estrogen. Beta-glucuronidase converts the inactive estrogen-glucuronides into active estrogen. The healthy liver inactivates practically all the estrogen that reaches it, mostly by combining it with the sugar acid, glucuronic acid. This makes the estrogen water soluble, and it is quickly eliminated in the urine. But when it passes through inflamed tissue, these tissues contain large amounts of beta-glucuronidase, which will remove the glucuronic acid, leaving the pure estrogen to accumulate in the tissue.

Many kinds of liver impairment decrease its ability to excrete estrogen, and estrogen contributes to a variety of liver diseases. The work of the Biskinds in the 1940s showed that a dietary protein deficiency prevented the liver from detoxifying estrogen. Hypothyroidism prevents the liver from attaching glucuronic acid to estrogen, and so increases the bodys retention of estrogen, which in turn impairs the thyroid glands ability to secrete thyroid hormone. Hypothyroidism often results from nutritional protein deficiency.

Although we commonly think of the ovaries as the main source of estrogen, the enzyme which makes it can be found in all parts of the body. Surprisingly, in rhesus monkeys, aromatase in the arms accounts for a very large part of estrogen production. Fat and the skin are major sources of estrogen, especially in older people. The activity of aromatase increases with aging, and under the influence of prolactin, cortisol, prostaglandin, and the pituitary hormones, FSH (follicle stimulating hormone) and growth hormone. It is inhibited by progesterone, thyroid, aspirin, and high altitude. Aromatase can produce estrogen in fat cells, fibroblasts, smooth muscle cells, breast and uterine tissue, pancreas, liver, brain, bone, skin, etc. Its action in breast cancer, endometriosis, uterine cancer, lupus, gynecomastia, and many other diseases is especially important. Aromatase in mammary tissue appears to increase estrogen receptors and cause breast neoplasia, independently of ovarian estrogen (Tekmal, et al., 1999).

Women who have had their ovaries removed are usually told that they need to take estrogen, but animal experiments consistently show that removal of the gonads causes the tissue aromatases to increase. The loss of progesterone and ovarian androgens is probably responsible for this generalized increase in the formation of estrogen. In the brain, aromatase increases under the influence of estrogen treatment.

Sulfatase is another enzyme that releases estrogen in tissues, and its activity is inhibited by antiestrogenic hormones.

In at least some tissues, progesterone inhibits the release or activation of beta-glucuronidase (which, according to Cristofalo and Kabakjian, 1975, increases with aging). Glucaric acid, which inhibits this enzyme, is being used to treat breast cancer, and glucuronic acid also tends to inhibit the intracellular release of estrogen by beta-glucuronidase.

Although there is clearly a trend toward the rational use of antiestrogenic treatments for breast cancer, in other diseases the myth of estrogen deficiency still prevents even rudimentary approaches.

Ever since Lipshutz work in the 1940s, it has been established that the uninterrupted effect of a little estrogen is more harmful than larger but intermittent exposures. But after menopause, when progesterone stops its cyclic displacement of estrogen from the tissues, the tissues retain large amounts of estrogen continuously.

The menopause itself is produced by the prolonged exposure to estrogen beginning in puberty, in spite of the monthly protection of the progesterone produced by cycling ovaries. The unopposed action of the high concentration of tissue-bound estrogen after menopause must be even more harmful.

The decline of the antiestrogenic factors in aging, combined with the increase of pro-estrogenic factors such as cortisol and prolactin and FSH, occurs in both men and women. During the reproductive years, womens cyclic production of large amounts of progesterone probably retards their aging enough to account for their greater longevity. Childbearing also has a residual antiestrogenic effect and is associated with increased longevity.

Being aware of this pervasive increase in estrogen exposure with aging should make it possible to marshal a comprehensive set of methods for opposing that trend toward degeneration.

REFERENCES

Contraception 1981 Apr;23(4):447-55. Comparison of plasma and myometrial tissue concentrations of estradiol-17 beta and progesterone in nonpregnant women. Akerlund M, Batra S, Helm G Plasma and myometrial tissue concentrations of estradiol (E2) and progesterone (P) were measured by radioimmunoassay techniques in samples obtained from women with regular menstrual cycles and from women in pre- or postmenopausal age. In women with regular cycles, the tissue concentration of E2 ranged from 0.13 to 1.06 ng/g wet weight, with significantly higher levels around ovulation than in follicular or luteal phases of the cycle. The tissue concentration of P ranged from 2.06 to 14.85 ng/g wet weight with significantly higher level in luteal phase than in follicular phase. The tissue/plasma ratio of E2 ranged from 1.45 to 20.36 with very high values in early follicular phase and the lowest in mid-luteal phase. The ratio for P ranged from 0.54 to 23.7 and was significantly lower in the luteal phase than in other phases of the cycle. One woman in premenopausal age with an ovarian cyst was the only case with a tissue/plasma ratio of E2 Less Than 1, since her plasma E2 levels were exceptionally high. In postmenopausal women, the tissue concentration of E2 was not significantly lower than in menstruating women in follicular phase, and the tissue concentration of P was not significantly lower than in fertile women in any of the phases. Neither in these women nor in menstruating women was there a close correlation between tissue and plasma levels. The present data indicate that the myometrial uptake capacity for ovarian steroids may be saturated, and also that a certain amount of these steroids is bound to tissue even if plasma levels are low.

Biokhimiia 1984 Aug;49(8):1350-6. [The nature of thyroid hormone receptors. Translocation of thyroid hormones through plasma membranes]. Azimova ShS, Umarova GD, Petrova OS, Tukhtaev KR, Abdukarimov A The in vivo translocation of thyroxine-binding blood serum prealbumin (TBPA) was studied. It was found that the TBPA-hormone complex penetrates-through the plasma membrane into the cytoplasm of target cells. Electron microscopic autoradiography revealed that blood serum TBPA is localized in ribosomes of target cells as well as in mitochondria, lipid droplets and Golgi complex. Negligible amounts of the translocated TBPA is localized in lysosomes of the cells insensitive to thyroid hormones (spleen macrophages). Study of T4- and T3-binding proteins from rat liver cytoplasm demonstrated that one of them has the antigenic determinants common with those of TBPA. It was shown autoimmunoradiographically that the structure of TBPA is not altered during its translocation.

Biokhimiia 1985 Nov;50(11):1926-32. [The nature of thyroid hormone receptors. Intracellular functions of thyroxine-binding prealbumin] Azimova ShS; Normatov K; Umarova GD; Kalontarov AI; Makhmudova AA The effect of tyroxin-binding prealbumin (TBPA) of blood serum on the template activity of chromatin was studied. It was found that the values of binding constants of TBPA for T3 and T4 are 2 X 10(-11) M and 5 X 10(-10) M, respectively. The receptors isolated from 0.4 M KCl extract of chromatin and mitochondria as well as hormone-bound TBPA cause similar effects on the template activity of chromatin. Based on experimental results and the previously published comparative data on the structure of TBPA, nuclear, cytoplasmic and mitochondrial receptors of thyroid hormones as well as on translocation across the plasma membrane and intracellular transport of TBPA, a conclusion was drawn, which suggested that TBPA is the "core" of the true thyroid hormone receptor. It was shown that T3-bound TBPA caused histone H1-dependent conformational changes in chromatin. Based on the studies with the interaction of the TBPA-T3 complex with spin-labeled chromatin, a scheme of functioning of the thyroid hormone nuclear receptor was proposed.

Biokhimiia 1984 Sep;49(9):1478-85[The nature of thyroid hormone receptors. Thyroxine- and triiodothyronine-binding proteins of mitochondria] Azimova ShS; Umarova GD; Petrova OS; Tukhtaev KR; Abdukarimov A. T4- and T3-binding proteins of rat liver were studied. It was found that the external mitochondrial membranes and matrix contain a protein whose electrophoretic mobility is similar to that of thyroxine-binding blood serum prealbumin (TBPA) and which binds either T4 or T3. This protein is precipitated by monospecific antibodies against TBPA. The internal mitochondrial membrane has two proteins able to bind thyroid hormones, one of which is localized in the cathode part of the gel and binds only T3, while the second one capable of binding T4 rather than T3 and possessing the electrophoretic mobility similar to that of TBPA. Radioimmunoprecipitation with monospecific antibodies against TBPA revealed that this protein also the antigenic determinants common with those of TBPA. The in vivo translocation of 125I-TBPA into submitochondrial fractions was studied. The analysis of densitograms of submitochondrial protein fraction showed that both TBPA and hormones are localized in the same protein fractions. Electron microscopic autoradiography demonstrated that 125I-TBPA enters the cytoplasm through the external membrane and is localized on the internal mitochondrial membrane and matrix.

Biokhimiia 1984 Aug;49(8):1350-6. [The nature of thyroid hormone receptors. Translocation of thyroid hormones through plasma membranes] Azimova ShS; Umarova GD; Petrova OS; Tukhtaev KR; Abdukarimov A The in vivo translocation of thyroxine-binding blood serum prealbumin (TBPA) was studied. It was found that the TBPA-hormone complex penetrates-through the plasma membrane into the cytoplasm of target cells. Electron microscopic autoradiography revealed that blood serum TBPA is localized in ribosomes of target cells as well as in mitochondria, lipid droplets and Golgi complex. Negligible amounts of the translocated TBPA is localized in lysosomes of the cells insensitive to thyroid hormones (spleen macrophages). Study of T4- and T3-binding proteins from rat liver cytoplasm demonstrated that one of them has the antigenic determinants common with those of TBPA. It was shown autoimmunoradiographically that the structure of TBPA is not altered during its translocation.

Probl Endokrinol (Mosk), 1981 Mar-Apr, 27:2, 48-52. [Blood estradiol level and G2-chalone content in the vaginal mucosa in rats of different ages] Anisimov VN; Okulov VB. 17 beta-Estradiol level was higher in the blood serum of rats aged 14 to 16 months with regular estral cycles during all the phases as compared to that in 3- to 4-month-old female rats. The latter ones had a higher vaginal mucosa G2-chalone concentration. The level of the vaginal mucosa G2-chalone decreased in young rats 12 hours after subcutaneous benzoate-estradiol injection. . . .. Possible role of age-associated disturbances of the regulatory cell proliferation stimulant (estrogen) and its inhibitor (chalone) interactions in neoplastic target tissue transformation is discussed.

Clin Endocrinol (Oxf) 1979 Dec;11(6):603-10. Interrelations between plasma and tissue concentrations of 17 beta-oestradiol and progesterone during human pregnancy. Batra S, Bengtsson LP, Sjoberg NO Oestradiol and progesterone concentration in plasma, decidua, myometrium and placenta obtained from women undergoing Caesarian section at term and abortion at weeks 16-22 of pregnancy were determined. There was a significant increase in oestradiol concentration (per g wet wt) both in placenta, decidua and myometrium from mid-term to term. Both at mid-term and term oestradiol concentrations in decidua and myometrium were much smaller than those in the plasma (per ml). Progesterone concentration in placenta and in myometrium did not increase from mid-term to term where it increased significantly in decidua. Decidual and myometrial progesterone concentrations at mid-term were 2-3 times higher than those in plasma, but at term the concentrations in both these tissues were lower than in plasma. The ratio progesterone/oestradiol in plasma, decidua, myometrium and placenta at mid-term was 8.7, 112.2, 61.4 and 370.0, respectively, and it decreased significantly in the myometrium and placenta but was nearly unchanged in plasma and decidua at term. The general conclusion to be drawn from the present study is the lack of correspondence between the plasma concentrations and the tissue concentrations of female sex steroids during pregnancy.

Endocrinology 1976 Nov; 99(5): 1178-81. Unconjugated estradiol in the myometrium of pregnancy. Batra S. By chemically digesting myometrium in a mixture of NaOH and sodium dodecyl sulphate, estradiol could be recovered almost completely by extraction with ethyl acetate. The concentration of estradiol-17beta (E2) in the extracted samples could reliably be determined by radioimmunoassay. Compared to its concentration in the plasma, E2 in the pregnant human myometrium was very low, and as a result, the tissue/plasma estradiol concentration ratio was less than 0.5. In the pseudopregnant rabbit, this ratio ranged between 16 and 20.

J Steroid Biochem 1989 Jan;32(1A):35-9. Tissue specific effects of progesterone on progesterone and estrogen receptors in the female urogenital tract. Batra S, Iosif CS. The effect of progesterone administration on progesterone and estrogen receptors in the uterus, vagina and urethra of rabbits was studied. After 24 h of progesterone treatment the concentration of cytosolic progesterone receptors decreased to about 25% of the control value in the uterus, whereas no significant change in receptor concentration was observed in the vagina or the urethra. The concentration of the nuclear progesterone receptor did not change in any of the three tissues studied. The apparent dissociation constant (Kd) of nuclear progesterone receptor increased after progesterone treatment in all three tissues. Although the Kd of the cytosolic progesterone receptor also increased in all tissues, the difference was significant for only the vagina and urethra. The concentration of cytosolic estrogen receptors in the uterus decreased significantly (P less than 0.001) after progesterone treatment whereas the Kd value increased slightly (P less than 0.05). In vagina or the urethra, there was no change in either estrogen receptor concentration or Kd values after progesterone treatment. These data clearly showed that the reduction by progesterone of progesterone and estrogen receptor concentrations occurs only in the uterus and not in the vagina or the urethra.

Am J Obstet Gynecol 1980 Apr 15;136(8):986-91. Female sex steroid concentrations in the ampullary and isthmic regions of the human fallopian tube and their relationship to plasma concentrations during the menstrual cycle. Batra S, Helm G, Owman C, Sjoberg NO, Walles B. The concentrations of estradiol-17 beta (E2) and progesterone (P) were measured in the ampullary and isthmic portions of the fallopian tube of nonpregnant menstruating women and the cyclic fluctuations were related to the concentrations of these hormones in plasma. The steroid concentrations were determined by radioimmunoassays. There was no significant difference in the isthmic and ampullary concentrations of either steroid in any of the menstrual phases. The mean value for E2 was highest in the ovulatory phase and for P during the luteal phase. The tissue (per gm)/plasma (per ml) ratio for the steroid concentrations was above unity in all measurements. The ratio for E2 was highest (isthmus:12, ampulla:8) in the follicular phase and for P (isthmus:26, ampulla:18) during ovulation. Since these highest ratios were attained when plasma steroid concentrations were relatively low they were interpreted as reflections of a maximal receptor contribution.

Biol Reprod 1980 Apr;22(3):430-7. Sex steroids in plasma and reproductive tissues of the female guinea pig. Batra S, Sjoberg NO, Thorbert G.

J Steroid Biochem Mol Biol 1997 Apr;61(3-6):323-39. Steroid control and sexual differentiation of brain aromatase. Balthazart J. Together, these data indicate that the removal of estrogens caused by steroidal inhibitors decreases the synthesis of ARO, presumably at the transcriptional level.

Science, Vol. 94, No. 2446 (Nov. 1941), p. 462. Diminution in Ability of the Liver to Inactivate Estrone in Vitamin B Complex Deficiency, Biskind, M.S., and G. R. Biskind.

Am. Jour. Clin. Path., Vol. 16 (1946), No. 12, pages 737-45. The Nutritional Aspects of Certain Endocrine Disturbances, Biskind, G. R., and M. S. Biskind.

Biol Reprod, 1993 Oct, 49:4, 647-52. Pathologic effect of estradiol on the hypothalamus. Brawer JR; Beaudet A; Desjardins GC; Schipper HM. Estradiol provides physiological signals to the brain throughout life that are indispensable for the development and regulation of reproductive function. In addition to its multiple physiological actions, we have shown that estradiol is also selectively cytotoxic to beta-endorphin neurons in the hypothalamic arcuate nucleus. The mechanism underlying this neurotoxic action appears to involve the conversion of estradiol to catechol estrogen and subsequent oxidation to o-semiquinone free radicals. The estradiol-induced loss of beta-endorphin neurons engenders a compensatory increment in mu opioid binding in the medial preoptic area rendering this region supersensitive to residual beta-endorphin or to other endogenous opioids. The consequent persistent opioid inhibition results in a cascade of neuroendocrine deficits that are ultimately expressed as a chronically attenuated plasma LH pattern to which the ovaries respond by becoming anovulatory and polycystic. This neurotoxic action of estradiol may contribute to a number of reproductive disorders in humans and in animals in which aberrant hypothalamic function is a major component.

Mech Ageing Dev, 1991 May, 58:2-3, 207-20. Exposure to estradiol impairs luteinizing hormone function during aging. Collins TJ; Parkening TA Department of Anatomy and Neurosciences, University of Texas Medical Branch, Galveston 77550. This work evaluated the anterior pituitary (AP) component of the H-P axis by determining the ability of perifused AP to release LH following sustained but pulsatile LHRH stimulation. The normal dual discharge profile of LH was affected by age. The role of estradiol (E2) in AP aging was further tested as AP from ovariectomized (OVXed) mice, deprived of E2 since puberty, responded as well as the mature proestrous group. In contrast, aged mice subjected to long-term E2 exposure (cycling or OVXed plus E2 replacement) failed to produce the dual response pattern. Furthermore, E2 is a major factor in altering LH function and appears to act before middle age.

Mech Ageing Dev 1975 Jan-Feb;4(1):19-28. Lysosomal enzymes and aging in vitro: subcellular enzyme distribution and effect of hydrocortisone on cell life-span. Cristofalo VJ, Kabakjian J. The acid phosphatase and beta glucuronidase activities of four subcellular fractions (nuclear, mitochondrial-lysosomal, microsomal, supernatant) of WI-38 cells were compared during in vitro aging. All of the fractions showed an age-associated increase in activity.

Endocrinology, 1992 Nov, 131:5, 2482-4. Vitamin E protects hypothalamic beta-endorphin neurons from estradiol neurotoxicity. Desjardins GC; Beaudet A; Schipper HM; Brawer JR. Estradiol valerate (EV) treatment has been shown to result in the destruction of 60% of beta-endorphin neurons in the hypothalamic arcuate nucleus. Evidence suggests that the mechanism of EV-induced neurotoxicity involves the conversion of estradiol to catechol estrogen and subsequent oxidation to free radicals in local peroxidase-positive astrocytes. In this study, we examined whether treatment with the antioxidant, vitamin E, protects beta-endorphin neurons from the neurotoxic action of estradiol. Our results demonstrate that chronic vitamin E treatment prevents the decrement in hypothalamic beta-endorphin concentrations resulting from arcuate beta-endorphin cell loss, suggesting that the latter is mediated by free radicals. Vitamin E treatment also prevented the onset of persistent vaginal cornification and polycystic ovarian condition which have been shown to result from the EV-induced hypothalamic pathology.

Exp Gerontol, 1995 May-Aug, 30:3-4, 253-67. Estrogen-induced hypothalamic beta-endorphin neuron loss: a possible model of hypothalamic aging. Desjardins GC; Beaudet A; Meaney MJ; Brawer JR. Over the course of normal aging, all female mammals with regular cycles display an irreversible arrest of cyclicity at mid-life. Males, in contrast, exhibit gametogenesis until death. Although it is widely accepted that exposure to estradiol throughout life contributes to reproductive aging, a unified hypothesis of the role of estradiol in reproductive senescence has yet to emerge. Recent evidence derived from a rodent model of chronic estradiol-mediated accelerated reproductive senescence now suggests such a hypothesis. It has been shown that chronic estradiol exposure results in the destruction of greater than 60% of all beta-endorphin neurons in the arcuate nucleus while leaving other neuronal populations spared. This loss of opioid neurons is prevented by treatment with antioxidants indicating that it results from estradiol-induced formation of free radicals. Furthermore, we have shown that this beta-endorphin cell loss is followed by a compensatory upregulation of mu opioid receptors in the vicinity of LHRH cell bodies. The increment in mu opioid receptors presumably renders the opioid target cells supersensitive to either residual beta-endorphin or other endogenous mu ligands, such as met-enkephalin, thus resulting in chronic opioid suppression of the pattern of LHRH release, and subsequently that of LH. Indeed, prevention of the neuroendocrine effects of estradiol by antioxidant treatment also prevents the cascade of neuroendocrine aberrations resulting in anovulatory acyclicity. The loss of beta-endorphin neurons along with the paradoxical opioid supersensitivity which ensues, provides a unifying framework in which to interpret the diverse features that characterize the reproductively senescent female.

Geburtshilfe Frauenheilkd 1994 Jun; 54(6):321-31. Hormonprofile bei hochbetagten Frauen und potentielle Einflussfaktoren. Eggert-Kruse W; Kruse W; Rohr G; Muller S; Kreissler-Haag D; Klinga K; Runnebaum B. [Hormone profile of elderly women and potential modifiers]. Eggert-Kruse W, Kruse W, Rohr G, Muller S, Kreissler-Haag D, Klinga K, Runnebaum B. In 136 women with a median age of 78 (60-98) years the serum concentrations of FSH, LH, prolactin, estradiol-17 beta, testosterone and DHEA-S were determined completed by GnRH and ACTH stimulation tests in a subgroup. This resulted in median values for FSH of 15.8 ng/ml, LH 6.4 ng/ml, prolactin 6.9 ng/ml, estradiol 16 pg/ml, testosterone 270 pg/ml and 306 ng/ml for DHEA-S. No correlation with age in this population was found for gonadotropins as well as the other hormones for an age level of up to 98 years.

Acta Physiol Hung 1985;65(4):473-8. Peripheral blood concentrations of progesterone and oestradiol during human pregnancy and delivery. Kauppila A, Jarvinen PA To evaluate the significance of progesterone and estradiol in human uterine activity during pregnancy and delivery the blood concentrations of these hormones were monitored weekly during the last trimester of pregnancy and at the onset of labour in 15 women, and before and 3 hours after the induction of term delivery in 83 parturients. Neither plasma concentrations of progesterone or estradiol nor the ratio of progesterone to estradiol changed significantly during the last trimester of pregnancy or at the onset of delivery. After the induction of delivery parturients with initial progesterone dominance (ratio of progesterone to estradiol higher than 5 before induction) demonstrated a significant fall in serum concentration of progesterone and in the ratio of progesterone to estradiol while estradiol concentration rose significantly. In estrogen dominant women (progesterone to estradiol ratio equal to or lower than 5) the serum concentration of progesterone and the ratio of progesterone to estradiol rose significantly during the 3 hours after the induction of delivery. Our results suggest that the peripheral blood levels of progesterone and estradiol do not correlate with the tissue biochemical changes which prepare the uterine cervix and myometrium for delivery. The observation that the ratio of progesterone to estradiol decreased in progesterone-dominant and increased in estrogen-dominant women stresses the importance of a well balanced equilibrium of these hormones for prostaglandin metabolism during human delivery.

Am J Obstet Gynecol 1984 Nov 1;150(5 Pt 1):501-5. Estrogen and progesterone receptor and hormone levels in human myometrium and placenta in term pregnancy. Khan-Dawood FS, Dawood MY. Estradiol and progesterone receptors in the myometrium, decidua, placenta, chorion, and amnion of eight women who underwent elective cesarean section at term were determined by means of an exchange assay. The hormone levels in the peripheral plasma and cytosol of these tissues were measured by radioimmunoassays. Maternal plasma and the placenta had high concentrations of estradiol and progesterone, with the placenta having 12 times more progesterone than in maternal plasma but only half the concentrations of estradiol in maternal plasma. The decidua and placenta had detectable levels of cytosol and nuclear estradiol receptors, but the myometrium had no measurable cytosol estradiol receptors, whereas the chorion and amnion had neither cytosol nor nuclear estradiol receptors. However, the chorion and amnion had significantly higher concentrations of estradiol in the cytosol than those in the decidua and myometrium. Only the decidua and myometrium had cytosol and nuclear progesterone receptors, but the placenta, amnion, and chorion had neither cytosol nor nuclear progesterone receptors. In contrast, progesterone hormone levels were significantly higher in the placenta, amnion, and chorion than in the decidua and myometrium. The findings indicate that, in the term pregnant uterus, (1) the placenta, amnion, and chorion are rich in progesterone, estradiol, and nuclear estradiol receptors but have no progesterone receptors, (2) the decidua and myometrium have nuclear estradiol and progesterone receptors, and (3) the myometrium has a higher progesterone/estradiol ratio than that of the peripheral plasma, thus suggesting a highly progesterone-dominated uterus.

Biochem Biophys Res Commun 1982 Jan 29;104(2):570-6. Progesterone-induced inactivation of nuclear estrogen receptor in the hamster uterus is mediated by acid phosphatase. MacDonald RG, Okulicz WC, Leavitt, W.W.

Steroids 1982 Oct;40(4):465-73. Progesterone-induced estrogen receptor-regulatory factor is not 17 beta-hydroxysteroid dehydrogenase. MacDonald RG, Gianferrari EA, Leavitt WW These studies were done to determine if the progesterone-induced estrogen receptor-regulatory factor (ReRF) in hamster uterus is 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD), i.e. that rapid loss of nuclear estrogen receptor (Re) might be due to enhanced estradiol oxidation to estrone catalyzed by 17 beta-HSD. Treatment of proestrous hamsters with progesterone (approximately 25 mg/kg BW) for either 2 h or 4 h had no effect on 17 beta-HSD activity measured as the rate of conversion of [6,7-3H]estradiol to [3H]estrone by whole uterine homogenates at 35 degrees C. During this same time interval, progesterone treatment increased the rate of inactivation of the occupied form of nuclear Re as determined during a 30 min incubation of uterine nuclear extract in vitro at 36 degrees C. Since we previously demonstrated that such in vitro Re-inactivating activity represents ReRF, the present studies show that ReRF is not 17 beta-HSD or a modifier of that enzyme.

Am J Obstet Gynecol 1987 Aug; 157(2):312-317. Age-related changes in the female hormonal environment during reproductive life. Musey VC, Collins DC, Musey PI, Martino-Saltzman D, Preedy JR Previous studies have indicated that serum levels of follicle-stimulating hormone rise with age during the female reproductive life, but the effect on other hormones is not clear. We studied the effects of age, independent of pregnancy, by comparing serum hormone levels in two groups of nulliparous, premenopausal women aged 18 to 23 and 29 to 40 years. We found that increased age during reproductive life is accompanied by a significant rise in both basal and stimulated serum follicle-stimulating hormone levels. This was accompanied by an increase in the serum level of estradiol-17 beta and the urine levels of estradiol-17 beta and 17 beta-estradiol-17-glucosiduronate. The serum level of estrone sulfate decreased with age. Serum and urine levels of other estrogens were unchanged. The basal and stimulated levels of luteinizing hormone were also unchanged. There was a significant decrease in basal and stimulated serum prolactin levels. Serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate decreased with age, but serum testosterone was unchanged. It is concluded that significant age-related changes in the female hormonal environment occur during the reproductive years.

Endocrinology 1981 Dec;109(6):2273-5. Progesterone-induced estrogen receptor-regulatory factor in hamster uterine nuclei: preliminary characterization in a cell-free system. Okulicz WC, MacDonald RG, Leavitt WW. In vitro studies have demonstrated a progesterone-induced activity associated with the uterine nuclear fraction which resulted in the loss of nuclear estrogen receptor. This progesterone-dependent stimulation of estrogen receptor loss was absent when nuclear extract was prepared in phosphate buffer rather than Tris buffer. In addition, sodium molybdate and sodium metavanadate (both at 10 mM) inhibited this activity in nuclear extract. These observations support the hypothesis that progesterone modulation of estrogen action may be accomplished by induction (or activation) of an estrogen receptor-regulatory factor (Re-RF), and this factor may in turn act to eliminate the occupied form of estrogen receptor from the nucleus, perhaps through a hypothetical dephosphorylation-inactivation mechanism.

American Journal of Human Biology, v.8, n.6, (1996): 751-759. Ovarian function in the latter half of the reproductive lifespan. O'Rourke, M T; Lipson, S F; Ellison, P T. Thus, ovarian endocrine function over the course of reproductive life represents a process of change, but not one of generalized functional decline.

J Gerontol, 1978 Mar, 33:2, 191-6. Circulating plasma levels of pregnenolone, progesterone, estrogen, luteinizing hormone, and follicle stimulating hormone in young and aged C57BL/6 mice during various stages of pregnancy. Parkening TA; Lau IF; Saksena SK; Chang MC Young (3-5 mo of age) and senescent (12-15 mo of age) multiparous C57BL/6 mice were mated with young males (3-6 mo of age) and the numbers of preimplantation embryos and implantation sites determined on days 1 (day of plug), 4, 9, and 16 of pregnancy. The numbers of viable embryos were significantly lower (p less than 0.02 to p less than 0.001) in senescent females compared with young females on all days except day 1 of pregnancy. Plasma samples tested by radioimmunoassay indicated circulating estradiol-17B was significantly lower (P less than 0.05) on day 1 and higher (p less than 0.05) on day 4 in older females, whereas FSH was higher on days 4, 9, and 16 (p less than 0.02 to p less than 0.001) in senescent females when compared with samples from young females. Levels of pregnenolone, progesterone, estrone, and LH were not significantly different at any stage of pregnancy in the two age groups. From the hormonal data it did not appear that degenerating corpora lutea were responsible for the declining litter size in this strain of aged mouse.

Biol Reprod, 1985 Jun, 32:5, 989-97. Orthotopic ovarian transplantations in young and aged C57BL/6J mice. Parkening TA; Collins TJ; Elder FF. Orthotopic ovarian transplantations were done between young (6-wk-old) and aged (17-mo-old) C57BL/6J mice. The percentages of mice mating following surgery from the four possible ovarian transfer combinations were as follows: young into young, 83%; young into aged, 46%; aged into young, 83%; and aged into aged, 36%. The only statistical differences found between the transfer groups occurred in FSH concentrations. Plasma FSH was markedly elevated (P less than 0.005) in young recipients with ovaries transplanted from aged donors, in comparison to young recipients with ovaries from young donors. These data indicate that the aging ovary and uterus play a secondary role in reproductive failure and that the aging hypothalamic-hypophyseal complex is primarily responsible for the loss of fecundity in older female C57BL/6J mice.

J Endocrinol, 1978 Jul, 78:1, 147-8. Postovulatory levels of progestogens, oestrogens, luteinizing hormone and follicle-stimulating hormone in the plasma of aged golden hamsters exhibiting a delay in fertilization. Parkening TA; Saksena SK; Lau IF.

Biology of Reproduction, v.49, n.2, (1993): 387-392. Controlled neonatal exposure to estrogens: A suitable tool for reproductive aging studies in the female rat. Rodriguez, P; Fernandez-Galaz, C; Tejero, A. The present study was designed to determine whether the modification of exposure time to large doses of estrogens provided a reliable model for early changes in reproductive aging. Premature occurrence of vaginal opening was observed in all three estrogenized groups independently of EB exposure. However, females bearing implants for 24 h had first estrus at the same age as their controls and cycled regularly, and neither histological nor gonadal alterations could be observed at 75 days. Interestingly, they failed to cycle regularly at 5 mo whereas controls continued to cycle. On the other hand, the increase of EB exposure (Ei5, EI) resulted in a gradual and significant delay in the onset of first estrus and in a high number of estrous phases, as frequently observed during reproductive decline. At 75 days, the ovaries of these last two groups showed a reduced number of corpora lutea and an increased number of large follicles. According to this histological pattern, ovarian weight and progesterone (P) content gradually decreased whereas both groups showed higher estradiol (E-2) content than controls. This resulted in a higher E-2:P ratio, comparable to that observed in normal aging rats. The results allow us to conclude that the exposure time to large doses of estrogens is critical to the gradual enhancement of reproductive decline. Furthermore, exposures as brief as 24 h led to a potential early model for aging studies that will be useful to verify whether neuroendocrine changes precede gonadal impairment.

J Clin Endocrinol Metab 1996 Apr;81(4):1495-501. Characterization of reproductive hormonal dynamics in the perimenopause. Santoro N, Brown JR, Adel T, Skurnick JH. Overall mean estrone conjugate excretion was greater in the perimenopausal women compared to that in the younger women [76.9 ng/mg Cr (range, 13.1-135) vs. 40.7 ng/mg Cr (range, 22.8-60.3); P = 0.023] and was similarly elevated in both follicular and luteal phases. Luteal phase pregnanediol excretion was diminished in the perimenopausal women compared to that in younger normal subjects (range for integrated pregnanediol, 1.0-8.4 vs. 1.6-12.7 microg/mg Cr/luteal phase; P = 0.015). We conclude that altered ovarian function in the perimenopause can be observed as early as age 43 yr and include hyperestrogenism, hypergonadotropism, and decreased luteal phase progesterone excretion. These hormonal alterations may well be responsible for the increased gynecological morbidity that characterizes this period of life.

Brain Res, 1994 Jul 25, 652:1, 161-3. The 21-aminosteroid antioxidant, U74389F, prevents estradiol-induced depletion of hypothalamic beta-endorphin in adult female rats. Schipper HM; Desjardins GC; Beaudet A; Brawer JR. A single intramuscular injection of 2 mg estradiol valerate (EV) results in neuronal degeneration and beta-endorphin depletion in the hypothalamic arcuate nucleus of adult female rats. The present findings support the hypothesis that the toxic effect of estradiol on hypothalamic beta-endorphin neurons is mediated by free radicals.

Clin Exp Obstet Gynecol 2000;27(1):54-6. Hormonal reproductive status of women at menopausal transition compared to that observed in a group of midreproductive-aged women. Sengos C, Iatrakis G, Andreakos C, Xygakis A, Papapetrou P. CONCLUSION: The reproductive hormonal patterns in perimenopausal women favor a relatively hypergonadotropic hyper-estrogenic milieu.

Endocr Relat Cancer 1999 Jun;6(2):307-14. Aromatase overexpression and breast hyperplasia, an in vivo model--continued overexpression of aromatase is sufficient to maintain hyperplasia without circulating estrogens, and aromatase inhibitors abrogate these preneoplastic changes in mammary glands. Tekmal RR, Kirma N, Gill K, Fowler K To test directly the role of breast-tissue estrogen in initiation of breast cancer, we have developed the aromatase-transgenic mouse model and demonstrated for the first time that increased mammary estrogens resulting from the overexpression of aromatase in mammary glands lead to the induction of various preneoplastic and neoplastic changes that are similar to early breast cancer. Our current studies show aromatase overexpression is sufficient to induce and maintain early preneoplastic and neoplastic changes in female mice without circulating ovarian estrogen. Preneoplastic and neoplastic changes induced in mammary glands as a result of aromatase overexpression can be completely abrogated with the administration of the aromatase inhibitor, letrozole. Consistent with complete reduction in hyperplasia, we have also seen downregulation of estrogen receptor and a decrease in cell proliferation markers, suggesting aromatase-induced hyperplasia can be treated with aromatase inhibitors. Our studies demonstrate that aromatase overexpression alone, without circulating estrogen, is responsible for the induction of breast hyperplasia and these changes can be abrogated using aromatase inhibitors.

J Steroid Biochem Mol Biol 2000 Jun;73(3-4):141-5. Elevated steroid sulfatase expression in breast cancers. Utsumi T, Yoshimura N, Takeuchi S, Maruta M, Maeda K, Harada N. In situ estrogen synthesis makes an important contribution to the high estrogen concentration found in breast cancer tissues. Steroid sulfatase which hydrolyzes several sulfated steroids such as estrone sulfate, dehydroepiandrosterone sulfate, and cholesterol sulfate may be involved. In the present study, we therefore, assessed steroid sulfatase mRNA levels in breast malignancies and background tissues from 38 patients by reverse transcription and polymerase chain reaction. The levels in breast cancer tissues were significantly increased at 1458.4+/-2119.7 attomoles/mg RNA (mean +/- SD) as compared with 535.6+/-663.4 attomoles/mg RNA for non-malignant tissues (P<0.001). Thus, increased steroid sulfatase expression may be partly responsible for local overproduction of estrogen and provide a growth advantage for tumor cells.

Ann N Y Acad Sci 1986;464:106-16. Uptake and concentration of steroid hormones in mammary tissues. Thijssen JH, van Landeghem AA, Poortman J In order to exert their biological effects, steroid hormones must enter the cells of target tissues and after binding to specific receptor molecules must remain for a prolonged period of time in the nucleus. Therefore the endogenous levels and the subcellular distribution of estradiol, estrone, DHEAS, DHEA ad 5-Adiol were measured in normal breast tissues and in malignant and nonmalignant breast tumors from pre- and postmenopausal women. For estradiol the highest tissue levels were found in the malignant samples. No differences were seen in these levels between pre- and postmenopausal women despite the largely different peripheral blood levels. For estrone no differences were found between the tissues studied. Although the estradiol concentration was higher in the estradiol-receptor-positive than in the receptor-negative tumors, no correlation was calculated between the estradiol and the receptor consent. Striking differences were seen between the breast and uterine tissues for the total tissue concentration of estradiol, the ratio between estradiol and estrone, and the subcellular distribution of both estrogens. At similar receptor concentrations in the tissues these differences cannot easily be explained. Regarding the androgens, the tissue/plasma gradient was higher for DHEA than for 5-Adiol, and for DHEAS there was very probably a much lower tissue gradient. The highly significant correlation between the androgens suggests an intracellular metabolism of DHEAS to DHEA and 5-Adiol. Lower concentrations of DHEAS and DHEA were observed in the malignant tissues compared with the normal ones and the benign lesions. For 5-Adiol no differences were found and therefore these data do not support our original hypothesis on the role of this androgen in the etiology of breast abnormalities. Hence the way in which adrenal androgens express their influence on the breast cells remains unclear.

Clin Endocrinol (Oxf) 1978 Jul;9(1):59-66. Sex hormone concentrations in post-menopausal women. Vermeulen A, Verdonck L. Plasma sex hormone concentrations (testosterone, (T), androstenedione (A), oestrone (E1) and oestradiol (E2) were measured in forty post-menopausal women more than 4 years post-normal menopause. Sex hormone concentrations in this group of postmenopausal women (greater than 4YPM) did not show any variation as a function of age, with the possible exception of E2 which showed a tendency to decrease in the late post-menopause. E1 and to a lesser extent E2 as well as the E1/A ratio were significantly corelated with degree of obesity or fat mass, suggesting a possible role of fat tissue in the aromatization of androgens. Neither the T/A nor the E2/E1 ratios were correlated with fat mass, suggesting that the reduction of 17 oxo-group does not occur in fat tissue. The E1/A ratio was significantly higher than the reported conversion rate of A in E1.

J Steroid Biochem 1984 Nov;21(5):607-12. The endogenous concentration of estradiol and estrone in normal human postmenopausal endometrium. Vermeulen-Meiners C, Jaszmann LJ, Haspels AA, Poortman J, Thijssen JH The endogenous estrone (E1) and estradiol (E2) levels (pg/g tissue) were measured in 54 postmenopausal, atrophic endometria and compared with the E1 and E2 levels in plasma (pg/ml). The results from the tissue levels of both steroids showed large variations and there was no significant correlation with their plasma levels. The mean E2 concentration in tissue was 420 pg/g, 50 times higher than in plasma and the E1 concentration of 270 pg/g was 9 times higher. The E2/E1 ratio in tissue of 1.6, was higher than the corresponding E2/E1 ratio in plasma, being 0.3. We conclude that normal postmenopausal atrophic endometria contain relatively high concentrations of estradiol and somewhat lower estrone levels. These tissue levels do not lead to histological effects.

J Clin Endocrinol Metab 1998 Dec; 83(12):4474-80. Deficient 17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17beta-estradiol. Zeitoun K, Takayama K, Sasano H, Suzuki T, Moghrabi N, Andersson S, Johns A, Meng L, Putman M, Carr B, Bulun SE. Aberrant aromatase expression in stromal cells of endometriosis gives rise to conversion of circulating androstenedione to estrone in this tissue, whereas aromatase expression is absent in the eutopic endometrium. In this study, we initially demonstrated by Northern blotting transcripts of the reductive 17beta-hydroxysteroid dehydrogenase (17betaHSD) type 1, which catalyzes the conversion of estrone to 17beta-estradiol, in both eutopic endometrium and endometriosis. Thus, it follows that the product of the aromatase reaction, namely estrone, that is weakly estrogenic can be converted to the potent estrogen, 17beta-estradiol, in endometriotic tissues. It was previously demonstrated that progesterone stimulates the inactivation of 17beta-estradiol through conversion to estrone in eutopic endometrial epithelial cells. In conclusion, inactivation of 17beta-estradiol is impaired in endometriotic tissues due to deficient expression of 17betaHSD-2, which is normally expressed in eutopic endometrium in response to progesterone.

Biochem Biophys Res Commun 1999 Aug 2;261(2):499-503. Piceatannol, a stilbene phytochemical, inhibits mitochondrial F0F1-ATPase activity by targeting the F1 complex. Zheng J, Ramirez VD.

Eur J Pharmacol 1999 Feb 26;368(1):95-102. Rapid inhibition of rat brain mitochondrial proton F0F1-ATPase activity by estrogens: comparison with Na+, K+ -ATPase of porcine cortex. Zheng J, Ramirez VD. The data indicate that the ubiquitous mitochondrial F0F1-ATPase is a specific target site for estradiol and related estrogenic compounds; however, under this in vitro condition, the effect seems to require pharmacological concentrations.

J Steroid Biochem Mol Biol 1999 Jan;68(1-2):65-75. Purification and identification of an estrogen binding protein from rat brain: oligomycin sensitivity-conferring protein (OSCP), a subunit of mitochondrial F0F1-ATP synthase/ATPase. Zheng J, Ramirez VD. This finding opens up the possibility that estradiol, and probably other compounds with similar structures, in addition to their classical genomic mechanism, may interact with ATP synthase/ATPase by binding to OSCP, and thereby modulating cellular energy metabolism.

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<span class="koboSpan" id="kobo.1.1">Suitable Fats, Unsuitable Fats: Issues in Nutrition</span> A R T I C L E

Suitable Fats, Unsuitable Fats: Issues in Nutrition

For fifty years, the mass media have been making the public think about the fats in their diet, filling the culture with clichés about bad saturated animal fats that raise cholesterol, or lately the trans-fats in margarine, and images of arteries clogged by bad fats. The public instruction about the fats we should eat resembles the owner's manual for a car, that tells you what kind of motor oil and fuel and coolant to use; they are telling us that they know how our body works, and that they know what it needs. But now, even after the human genome has supposedly been partly "decoded," the biological functions of the fats have hardly begun to be investigated.

To understand the present issues regarding fats in nutrition and medicine it's helpful to look at the historical development of biochemical and physiological fat research in a variety of contexts, including agriculture and economics, as well as considering the effects of the changing ideas about cell structure, vitamins, hormones, immunology, brain development, evolution, and the growing understanding of the way physiology interacts with ecology. We need to recognize the complexity of the physiology of fats, to appreciate the complexity of the living organism.

Financial considerations have driven fat research in very obvious ways. In 1883, Mark Twain described how commercial fraud was making use of new technology to substitute cheap fats and oils for butter and olive oil.. Hard fats such as tallow, which had been used for making soap and candles, began to be widely used as a substitute for butter in the 19th century. Around 1912, chemists found economical ways to solidify (for use as a butter substitute) the very cheap liquid oils, such as cottonseed oil, linseed oil, whale oil, and fish oils, which been used mostly as fuels or varnish. The seed oils were so cheap that meat packers quickly became major producers of hydrogenated cottonseed and soy oils, to extend their limited supply of lard or tallow for sale as shortening or margarine.

Between 1912 and 1927 there were several studies that reported that animals could live on a fat-free diet, and that in fact they lived longer, and without the normal mortality from cancer. In the 1940s and 1950s, most textbooks that mentioned the idea that certain fats were essential nutrients described it as a controversial idea. But the oil industries used public relations effectively to sell the medical (heart protective) benefits of a diet containing increased amounts of linoleic and linolenic acids, which they called the essential fatty acids. They began citing a 1929 publication (by G. Burr and M. Burr) that claimed to demonstrate the essentiality of those fatty acids, while ignoring the publications that pointed in different directions.

The cheapness of the seed oils led to their use in animal feeds, to promote growth. By the 1940s, the polyunsaturated oils, including fish oils, were known to cause deterioration of the brain, muscles, and gonads in a variety of animals, and this was found to be caused mainly by their destruction of vitamin E. A little later, the disease called steatitis or yellow fat disease was found to be produced in various animals that were fed too much fish or fish oil.

The reason linseed oil and fish oil were used for making varnishes and paints was that they are "drying oils," reacting with oxygen to polymerize and harden. The physical and chemical propertiess of the oils are fairly well understood, and among the polyunsaturated fatty acids (PUFA) the omega -3 fatty acids react most easily with oxygen. Heat, light, and moisture increase their spontaneous interactions with oxygen, and besides polymerizing, these oils produce a variety of reactive particles, including acrolein, which combine with other substances, such as cellular proteins and DNA, with highly toxic effects. At low temperatures and low oxygen concentrations these oils are not highly reactive. Fats that harden at low temperatures (as saturated fats do) wouldn't be convenient for organisms that live in a cool environment, and so organisms regulate the type of fat they synthesize according to the temperature of their tissues. The fact that certain types of polyunsaturated fatty acids function nicely in fish, worms, and insects, doesn't mean that they are ideal fats for mammals.

The fact that vitamin E prevented or cured some of the major diseases in farm animals caused by excessive PUFA, and that it could retard the development of rancidity in stored oils, led quickly to the persistent belief that lipid peroxidation is the only toxic effect of the vegetable oils. However, the oils were being seen to cause other problems, including accelerated aging and obesity, but those problems weren't of interest to farmers, who wanted to sell plump young animals as cheaply and quickly as possible. Even fresh oils have toxic effects, and the oxidative damage they do is often the consequence of these other toxic actions.

Another cheap food additive, coconut oil, was found to increase feed consumption while slowing weight gain, so it wasn't popular in the meat industry. The highly unsaturated seed oils had the opposite effect, of producing a rapid fattening of the animal, while decreasing feed consumption, so by 1950 corn and soybeans were widely considered to be optimal feeds for maximizing profits in the production of meat animals. It was at this time that the industry found that it could market the liquid oils directly to consumers, as health-promoting foods, without bothering to turn them into solid shortening or margarine. Somehow, few physiologists continued to think about the implications of metabolic slowing, obesity, and the related degenerative diseases.

As vitamin research advanced in the 1940s, Roger Williams' lab at the Clayton Foundation Biochemical Institute, University of Texas at Austin, recognized the "fat deficiency disease" of the Burrs as a deficiency of vitamin B6, and showed that when they produced the condition with a diet similar to the one the Burrs had used, they could cure it by administering vitamin B6. In the early 1930s George Burr had discovered that animals on a fat free diet had an extremely high rate of metabolism, but he didn't investigate the important ramifications of that observation, such as their increased need for vitamins and minerals, in accordance with their rate of metabolism. The PUFA slowed metabolism, and that effect was good for agriculture.

The commercial pressure on fat research has created a new way of writing research reports, that several decades earlier wouldn't have been acceptable. For example, the effects of a specific fat on a few of the components of a complex process such as clotting are often described in the title, introduction, and conclusion of an article as if they were revealing a way to prevent heart disease. The effects of unsaturated fats on cells in vitro are often the opposite of their effects in living animals, but editors are allowing authors to claim that their in vitro results justify dietary or therapeutic use of the fats. Journals of medicine and nutrition are now preferred sites for commercial press releases, composed to superficially resemble scientific reports.

The suppressive effects of unsaturated fats on mitochondrial energy production have been widely investigated, since it is that effect that makes animal fattening with PUFA so economical. Rather than interpreting that as a toxic effect, using the innate structure and function of the mitochondrion as a point of reference from which to evaluate dietary components, the consumption of "good" oils is being used as the reference point from which to evaluate the meaning of metabolism ("efficiency is good," "low oxygen consumption is good"). Building on the idea that the oils are health-promoters which increase metabolic efficiency, the never-viable "rate of aging" theory was resuscitated: The anti-respiratory effect of PUFA is used (illogically) to return to the idea that aging occurs in proportion to the amount of oxygen consumed, because animals which lack the supposedly essential nutrients ("defective animals") consume oxygen rapidly--burning calories rapidly, they are supposed to be like a candle that won't last as long if it burns intensely. The old theory is simply resuscitated to explain why the anti-respiratory action of PUFA might be beneficial, justifying further promotion of their use as food and drugs.

Ordinarily, in biochemistry and physiology the inhibition of an enzyme is taken as a suggestion of toxicity, but when the point of reference is the idea of the goodness of PUFA, the activity of an intrinsic enzyme is taken to be evidence of harm, and its inhibition (by PUFA) is taken to be the proper, healthful situation. The enzyme that produces the Mead fatty acid is strongly inhibited by PUFA seed oils (less strongly by fish oils), and so the presence of the Mead acid in the tissues is taken as evidence that the animal is suffering damage resulting from the absence of PUFA. The Mead acid happens to have some valuable anti-inflammatory effects, and is associated with many biological advantages, but research in that direction is prevented by the lack of funding.

By 1920, the polyunsaturated fatty acids were recognized to inhibit proteolytic enzymes. At that time, the production of unsaturated fat was considered to be a feature of certain pathogens, able to overcome the proteolytic-phagocytic functions of the immune system.

Scattered studies have found that polyunsaturated fats inhibit the proteolytic enzymes involved in the digestion of food, in the removal of clots, in the formation of thyroid hormone, and many other essential physiological processes. But currently, the only implication being drawn from this broad class of effects of the PUFA is that some proteolytic enzymes are involved in disease processes, and consequently increased consumption of PUFA would be appropriate, because of their ability to suppress a conditionally harmful proteolytic enzyme. Since the organism consists mainly of proteins, there are complex innate systems for regulating the proteolytic enzymes, activating or inactivating them as needed, and such complexity isn't likely to depend on variable, unstable dietary factors. Exogenous substances that inhibit some proteases could create an unlimited variety of functional and anatomical irregularities.

Some of the interesting enzymes affected specifically by polyunsaturated fatty acids are those involved in hormone production. While they inhibit the formation of progesterone and androgens, they activate the synthesis of estrogen, which in turn activates the release of more free polyunsaturated fatty acids from the tissues, in a positive feedback pattern.

The inhibition of detoxification enzymes by PUFA (Tsoutsikos, et al., 2004) affects many processes, such as the elimination of estrogen, contributing to the positive feedback between estrogen and the oils. The meaning of this tends to be lost, because of the estrogen industry's effective campaigns.

Another situation in which fatty acids participate in a positive feedback system is the stress reaction, in which the released fatty acids impair mitochondrial energy production, increasing the stress and leading to further release of fatty acids.

One of the perennial theories of aging that has remained viable is the metaplasm/lipofuscin/age pigment theory, the idea that a toxic material accumulates in tissues over time. The age pigment contains proteins, cross-linked PUFA, and metals. The inhibition of proteolytic enzymes is involved in its accumulation, and the ratio of PUFA to saturated fatty acids is an important factor in its formation. Estrogen is one of the factors that can promote the formation of age pigment, probably partly because its lipolytic action increases the cells' exposure to free fatty acids. The lipofuscin contributes to inhibition of proteolysis, probably partly through increased production of free radicals and hydrogen peroxide.

The proteolytic enzymes are an essential part of innate immunity, and the highly unsaturated fatty acid, EPA, which is the most immunosuppressive of the fats, strongly inhibits proteolysis in some cells. The natural killer (NK) cells and phagocytic cells are two types of cell that are suppressed by PUFA, and they are involved in many kinds of physiological events, not just the killing of tumor cells and virus infected cells.

The immunosuppressive effects of PUFA are very general. Many metabolites that are known to have harmful effects on the immune system are increased by the PUFA (histamine [Masini, et al., 1990], serotonin, lactate, nitric oxide [Omura, et al., 2001]). These substances are also involved in tumor development.

Besides inhibiting enzymes and being converted into prostaglandins, the polyunsaturated fatty acids have direct effects, as signals (or interference with signals) on many tissues. The belief that the PUFA are essential nutrients has influenced the way cellular excitability thresholds are being interpreted. Anxiety and panic may be interpreted as alertness, calmness may be interpreted as stupidity. Specifically, long-term potentiation (LTP) may contribute to seizures, senility, and excitotoxicity, as well as to learning, but many titles and conclusions equate increased LTP with "improved LTP," implying that it has biological value to the animal.

The ability of nerve cells to become quiescent after excitation is essential to learning and perception. This ability is lost with aging, as the functional balance in the brain shifts away from GABA-ergic to glutamatergic nerves. The polyunsaturated fatty acids promote the excitatory nervous state. The combination of respiratory inhibition with excitation can produce excitotoxic cell death. If the doctrine of "essentiality of PUFA" hadn't been so influential, different interpretations of excitatory thresholds, energy metabolism, and even cell structure would have been allowed to develop more fully.

The concentration of polyunsaturated fats in the brain has led many people to say that the "nutritionally essential fatty acids," especially the omega -3 fatty acids, are essential for brain development (for the formation of nerve cell membranes), and for the formation of synapses, and that increasing the amount of those fats in the diet would be desirable. The types of argument they use simply ignore the real evidence: Cells can multiply indefinitely in culture dishes without the essential fatty acids, insects can multiply for generations on diets without the unsaturated fats, forming normal synapses and brains, and mammals fed diets with extremely small amounts of the unsaturated fats grow with perfectly normal--possibly superior--brains.

One of the fats in the omega -9 series, that the human body can synthesize, nervonic acid, is a major constituent of brain tissue, but its important functions in brain development have hardly been investigated. Unlike the unsaturated fatty acids oleic acid, linoleic acid, and eicosapentaenoic acid (EPA), nervonic acid isn't associated with the "coronary risk factors," and it has been suggested that it might be used in adults to prevent obesity-related diseases. (Oda, et al., 2005).

One major area of research that has been neglected involves the role of fats in modifying the ways in which proteins and nucleic acids interact with water--arguably the most basic of all physiological processes. Unsaturated fats are more water soluble than saturated fats, and they are involved in many problems of permeability and edema.

In aging and evolution, there are systematic changes in tissue water content that appear to correspond to changes in rate of metabolism, to the degree of unsaturation of cellular fats, and to thyroid function and temperature. Metabolic intensity and longevity can be modified by changing the degree of saturation of fats in the diet and tissues, but--despite almost a century of sporadic investigations--no one has yet worked out in detail the most appropriate way to do this. But it has become clear that the "uncoupled" mitochondrion, that "wastes oxygen and calories," is protective against free radicals, cancer, and aging. Thyroid hormone and the absence of PUFA are important factors in supporting the "wasteful" mitochondrion.

Although the complex interactions of anatomy, energy, temperature, fat nutrition, tissue water content, and hormones haven't been systematically investigated, some of the principles regarding the biological suitability of specific fats are already being applied in the limited context of therapy.

At present, the most important issue is to recognize the dangers presented by the intrusion of corporate power into science, especially as it relates to nutrition and medicine, and to consider the implications of the known effects of the PUFA on all of our biological systems.

The food-derived polyunsaturated fatty acids play important roles in the development of all of the problems associated with aging--reduced immunity, insomnia, decreased learning ability, substitution of fat for muscle, susceptibility to tissue peroxidation and inflammation, growth of tumors, etc., and are probably involved in most other health problems, even in children. If research hadn't been guided by the economic interests of the seed oil industry, many of those problems would have been solved by now.

The influence of the mass media on science can be seen in two issues that are currently well known.

A popular test used for evaluating diabetes is the measurement of glycated hemoglobin, the attachment of a sugar-like fragment to the protein of hemoglobin. This is used to judge whether blood sugar is being controlled adequately. The glycation of proteins is widely believed to be a central process in aging, and is often used to argue that people should reduce their sugar consumption.

Another well publicized problem supposedly involving the reaction between sugars and proteins has to do with the discovery of the carcinogen, acrylamide, in breads and french fries. The Whole Foods Market was sued in California for selling whole wheat bread without a warning that it contained a carcinogen.

But the changes in proteins that occur in diabetes are mainly produced by the breakdown products of polyunsaturated fatty acids. Acrylamide is produced largely by the reaction of PUFA with proteins.

Sugar, by reducing the level of free fatty acids in the body, actually tends to protect against these toxic effects of the PUFA. Diabetes, like cancer, has been known for a long time to be promoted by unsaturated oils in the diet, rather than by sugar. The seed oil industry has been more effective than the sugar industry in lobbying and advertising, and the effects can be seen in the assumptions that shape medical and biological research.

REFERENCES

Biochem Pharmacol. 1990 Mar 1;39(5):879-89. Histamine release from rat mast cells induced by metabolic activation of polyunsaturated fatty acids into free radicals. Masini E, Palmerani B, Gambassi F, Pistelli A, Giannella E, Occupati B, Ciuffi M, Sacchi TB, Mannaioni PF.

Int Heart J. 2005 Nov;46(6):975-85. Relationships between serum unsaturated fatty acids and coronary risk factors: negative relations between nervonic acid and obesity-related risk factors. Oda E, Hatada K, Kimura J, Aizawa Y, Thanikachalam PV, Watanabe K. "The objective of the present study was to analyze the relationships between serum USFA and CRF [coronary risk factors]." "Oleic acid (OA), linoleic acid (LA), and eicosapentaenoic acid (EPA) were positively related to coronary risk factors (total CRFS = 2, 3, and 4, respectively), while nervonic acid (NA) exerted negative effects on these risk factors (total CRFS = -6 ). It is concluded NA may have preventive effects on obesity-related metabolic disorders."

FEBS Lett. 2001 Jan 5;487(3):361-6. Eicosapentaenoic acid (EPA) induces Ca(2+)-independent activation and translocation of endothelial nitric oxide synthase and endothelium-dependent vasorelaxation. Omura M, Kobayashi S, Mizukami Y, Mogami K, Todoroki-Ikeda N, Miyake T, Matsuzaki M. "EPA stimulated NO production even in endothelial cells in situ loaded with a cytosolic Ca(2+) chelator . . . which abolished the [Ca(2+)]i elevations induced by ATP and EPA."

Biochem Pharmacol. 2004 Jan 1;67(1):191-9. Evidence that unsaturated fatty acids are potent inhibitors of renal UDP-glucuronosyltransferases (UGT): kinetic studies using human kidney cortical microsomes and recombinant UGT1A9 and UGT2B7. Tsoutsikos P, Miners JO, Stapleton A, Thomas A, Sallustio BC, Knights KM.

Lipids. 1997 Dec;32(12):1265-70. Dietary fatty acid profile affects endurance in rats. Ayre KJ, Hulbert AJ. "The diets comprised an essential fatty acid-deficient diet (containing mainly saturated fatty acids); a diet high in n-6 fatty acids, High n-6; and a diet enriched with n-3 fatty acids, High n-3. Submaximal endurance in rats fed the High n-3 diet was 44% less than in rats fed the High n-6 diet (P < 0.02). All rats were then fed a standard commercial laboratory diet for a 6-wk recovery period, and their performances were reevaluated. Although endurance in all groups was lower then at 9 wk, it was again significantly 50% lower in the High n-3 group than the High n-6 group (P < 0.005). Although n-3 fats are considered beneficial for cardiovascular health, they appear to reduce endurance times, and their side effects need to be further investigated."

Ann Biol Clin (Paris) 2000 Sep-Oct;58(5):595-600. [Studies on the genotoxic effects of crude liver oils from 3 species of Mediterranean sharks by means of in vitro micronucleus test using human lymphocytes] Bartfai E, Orsiere T, Duffaud F, Villani P, Pompili J, Botta A. "The results of this experimental study show that the crude liver oils of three species of sharks are genotoxic and confirm a high carcinogenic risk."

Vaccine. 2002 Jan 31;20(9-10):1435-44. Long-term influence of lipid nutrition on the induction of CD8(+) responses to viral or bacterial antigens. Bassaganya-Riera J, Hontecillas R, Zimmerman DR, Wannemuehler MJ.

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J Anim Sci, 1984 Apr, 58:4, 971-8. Essential fatty acid status and characteristics associated with colostrum-deprived gnotobiotic and conventional lambs. Growth, organ development, cell membrane integrity and factors associated with lower bowel function. Bruckner G; Grunewald KK; Tucker RE; Mitchell GE Jr "The absence of dietary linoleic acid decreased liver and spleen weights and, in general, suppressed development of organs except the brain." "The results indicate that neonatal colostrum-deprived lambs have an EFA requirement, as evidenced by decreased growth and performance characteristics in the GN linoleic deficient vs GN supplemented group, and suggests that the required level is in excess of .32% of the total caloric intake as linoleic acid."

Crit Care Med. 1996 Jul;24(7):1129-36. An increase in serum C18 unsaturated free fatty acids as a predictor of the development of acute respiratory distress syndrome. Bursten SL, Federighi DA, Parsons P, Harris WE, Abraham E, Moore EE Jr, Moore FA, Bianco JA, Singer JW, Repine JE.

Free Radic Biol Med. 1999 Jul;27(1-2):51-9. Arachidonic acid interaction with the mitochondrial electron transport chain promotes reactive oxygen species generation. Cocco T, Di Paola M, Papa S, Lorusso M. It is shown that arachidonic acid causes an uncoupling effect under state 4 respiration of intact mitochondria as well as a marked inhibition of uncoupled respiration. While, under our conditions, the uncoupling effect is independent of the fatty acid species considered, the inhibition is stronger for unsaturated acids. Experiments carried out with mitochondrial particles indicated that the arachidonic acid dependent decrease of the respiratory activity is caused by a selective inhibition of Complex I and III. It is also shown that arachidonic acid causes a remarkable increase of hydrogen peroxide production when added to mitochondria respiring with either pyruvate+malate or succinate as substrate.

Antioxid Redox Signal. 2005 Jan-Feb;7(1-2):256-68. Lipid peroxidation in diabetes mellitus. Davi G, Falco A, Patrono C.

Naunyn Schmiedebergs Arch Pharmacol. 2005 Mar;371(3):202-11. Epub 2005 Apr 15. Antiarrhythmic and electrophysiological effects of long-chain omega-3 polyunsaturated fatty acids. Dhein S, Michaelis B, Mohr FW. Atrioventricular conduction time was slowed only by DHA and EPA. Regarding antiarrhythmic activity we found that the threshold for elicitation of a ventricular extrasystole was concentration-dependently enhanced by DHA and EPA, but not by ALA. DHA dose-dependently reduced longitudinal propagation velocity V(L) and to a lower extent transverse velocity V(T).

J Biol Chem. 2002 Oct 18;277(42):39368-78. The mechanism of docosahexaenoic acid-induced phospholipase D activation inhuman lymphocytes involves exclusion of the enzyme from lipid rafts. Diaz O, Berquand A, Dubois M, Di Agostino S, Sette C, Bourgoin S, Lagarde M, Nemoz G, Prigent AF. Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid that inhibits T lymphocyte activation, has been shown to stimulate phospholipase D (PLD) activity in stimulated human peripheral blood mononuclear cells (PBMC). This PLD activation might be responsible for the immunosuppressive effect of DHA because it is known to transmit antiproliferative signals in lymphoid cells.

Nutrition. 2003 Feb;19(2):144-9. Diets rich in polyunsaturated fatty acids: effect on hepatic metabolism in rats. Gaiva MH, Couto RC, Oyama LM, Couto GE, Silveira VL, Ribeiro EB, Nascimento CM. Male Wistar rats, just weaned, were fed ad libitum for 8 wk with one of the following diets: rat chow (C), rat chow containing 15% (w/w) soybean oil (S), rat chow containing 15% (w/w) fish oil (F), and rat chow containing 15% soy bean and fish oil (SF; 5:1, w/w). Body weight gain was higher in F and SF than in C and S rats. Liver weight, lipid content, and lipogenesis rate increased in F and SF rats, although adenosine triphosphate citrate lyase activity decreased. Glycogen concentration decreased in S, F, and SF rats compared with C rats.

Br J Nutr. 2001 Sep;86(3):371-7. Polyunsaturated fatty acid-rich diets: effect on adipose tissue metabolism in rats. Gaiva MH, Couto RC, Oyama LM, Couto GE, Silveira VL, Riberio EB, Nascimento CM. Wistar rats were fed ad libitum, for 8 weeks with one of the following diets: C, rat chow; S, rat chow containing 15 % (w/w) soyabean oil; F, rat chow containing 15 % (w/w) fish oil; SF, rat chow containing 15 % (w/w) soyabean and fish oil (5:1, w/w). "Energy intake was reduced while carcass lipid content was increased in the three fat-fed groups." "These results indicate that enrichment of the diet with polyunsaturated fatty acids causes changes in adipose tissue metabolism that favour fat deposition. Different metabolic pathways were preferentially affected by each type of fatty acid used."

Adv Exp Med Biol 266:3-15, 1989, "Lipofuscin and ceroid formation: the cellular recycling system," Harman, D.

Mech Ageing Dev 2001 Apr 15;122(4):427-43. Effect of the degree of fatty acid unsaturation of rat heart mitochondria on their rates of H2O2 production and lipid and protein oxidative damage. Herrero A, Portero-Otin M, Bellmunt MJ, Pamplona R, Barja G. "Previous comparative studies have shown that long-lived animals have lower fatty acid double bond content in their mitochondrial membranes than short-lived ones. In order to ascertain whether this trait protects mitochondria by decreasing lipid and protein oxidation and oxygen radical generation, the double bond content of rat heart mitochondrial membranes was manipulated by chronic feeding with semi-purified AIN-93G diets rich in highly unsaturated (UNSAT) or saturated (SAT) oils. UNSAT rat heart mitochondria had significantly higher double bond content and lipid peroxidation than SAT mitochondria. They also showed increased levels of the markers of protein oxidative damage malondialdehyde-lysine, protein carbonyls, and N(e)-(carboxymethyl)lysine adducts." "These results demonstrate that increasing the degree of fatty acid unsaturation of heart mitochondria increases oxidative damage to their lipids and proteins, and can also increase their rates of mitochondrial oxygen radical generation in situations in which the degree of reduction of Complex III is higher than normal. These observations strengthen the notion that the relatively low double bond content of the membranes of long-lived animals could have evolved to protect them from oxidative damage."

Biochem J. 1994 May 15;300 ( Pt 1):251-5. Regulation of fibrinolysis by non-esterified fatty acids. Higazi AA, Aziza R, Samara AA, Mayer M. "Examination of the fatty acid specificity showed that a minimal chain length of 16 carbon atoms and the presence of at least one double bond, preferably in a cis configuration, were required for inhibition of the fibrinolytic activity of plasmin."

B. A. Houssay and C. Martinez, "Experimental diabetes and diet," Science 105, 548-549, 1947.

J Theor Biol. 2005 May 21;234(2):277-88. On the importance of fatty acid composition of membranes for aging. Hulbert AJ.

Mech Ageing Dev. 2006 Apr 16; Extended longevity of wild-derived mice is associated with peroxidation-resistant membranes. Hulbert AJ, Faulks SC, Harper JM, Miller RA, Buffenstein R. "Muscle and liver phospholipids from these long-living mice lines have a reduced amount of the highly polyunsaturated omega-3 docosahexaenoic acid compared to the DC mice, and consequently their membranes are less likely to peroxidative damage. The relationship between maximum longevity and membrane peroxidation index is similar for these mice lines as previously observed for mammals in general. It is suggested that peroxidation-resistant membranes may be an important component of extended longevity."

Virchows Arch B Cell Pathol. 1975 Nov 21;19(3):239-54. [Ultrastructure and morphogenesis of ceroid pigment. II. Late changes of lysosomes in Kupffer cells of rat liver after phagocytosis of unsaturated lipids] Kajihara H, Totovic V, Gedigk P. "These lipids, which have been changed in their molecular structure, cannot be hydrolized by lysosomal enzymes. They remain as an indigestible material, as a waste product in lysosomal residual bodies. Both lipofuscin and ceroid are lysosomal structures containing oxidized and polymerized lipids."

Reprod Nutr Dev. 1998 Jan-Feb;38(1):31-7. Effect of a high linoleic acid diet on delta 9-desaturase activity, lipogenesis and lipid composition of pig subcutaneous adipose tissue. Kouba M, Mourot J.

Gerontology 1993;39(1):7-18. Modulation of membrane phospholipid fatty acid composition by age and food restriction. Laganiere S, Yu BP. H.M. "Phospholipids from liver mitochondrial and microsomal membrane preparations were analyzed to further assess the effects of age and lifelong calorie restriction on membrane lipid composition." "The data revealed characteristic patterns of age-related changes in ad libitum (AL) fed rats: membrane levels of long-chain polyunsaturated fatty acids, 22:4 and 22:5, increased progressively, while membrane linoleic acid (18:2) decreased steadily with age. Levels of 18:2 fell by approximately 40%, and 22:5 content almost doubled making the peroxidizability index increase with age." "We concluded that the membrane-stabilizing action of long-term calorie restriction relates to the selective modification of membrane long-chain polyunsaturated fatty acids during aging."

Free Radic Biol Med 1999 Feb;26(3-4):260-5. Modulation of cardiac mitochondrial membrane fluidity by age and calorie intake. Lee J, Yu BP, Herlihy JT. "The fatty acid composition of the mitochondrial membranes of the two ad lib fed groups differed: the long-chain polyunsaturated 22:4 fatty acid was higher in the older group, although linoleic acid (18:2) was lower. DR eliminated the differences." "Considered together, these results suggest that DR maintains the integrity of the cardiac mitochondrial membrane fluidity by minimizing membrane damage through modulation of membrane fatty acid profile."

Lipids 2001 Jun;36(6):589-93. Effect of dietary restriction on age-related increase of liver susceptibility to peroxidation in rats. Leon TI, Lim BO, Yu BP, Lim Y, Jeon EJ, Park DK.

Lipids 22(3), 133-6, 1987. Effects of parenteral nutrition with high doses of linoleate on the developing human liver and brain, Martinez, M., and A. Ballabriga.

J Pharmacol Exp Ther. 1995 Jan;272(1):469-75. Acetic acid-induced colitis in normal and essential fatty acid deficient rats. Mascolo N, Izzo AA, Autore G, Maiello FM, Di Carlo G, Capasso F.

Biochem Pharmacol. 1990 Mar 1;39(5):879-89. Histamine release from rat mast cells induced by metabolic activation of polyunsaturated fatty acids into free radicals. Masini E, Palmerani B, Gambassi F, Pistelli A, Giannella E, Occupati B, Ciuffi M, Sacchi TB, Mannaioni PF.

J Nutrit 10:63(1935). The effect of retarded growth upon length of the life span and upon the ultimate body size. McCay, CM., Crowell, MF., and Maynard, LA.

McCollum EV. 1957. A History of Nutrition. Boston: Houghton Mifflin. p 374.

J Biol Chem. 2003 Oct 24;278(43):42012-9. Pyridoxamine traps intermediates in lipid peroxidation reactions in vivo: evidence on the role of lipids in chemical modification of protein and development of diabetic complications. Metz TO, Alderson NL, Chachich ME, Thorpe SR, Baynes JW.

FEBS Lett. 1998 Oct 16;437(1-2):24-8. Generation of protein carbonyls by glycoxidation and lipoxidation reactions with autoxidation products of ascorbic acid and polyunsaturated fatty acids. Miyata T, Inagi R, Asahi K, Yamada Y, Horie K, Sakai H, Uchida K, Kurokawa K.

Naunyn Schmiedebergs Arch Pharmacol. 1996 Jul;354(2):109-19. Exposure to the n-3 polyunsaturated fatty acid docosahexaenoic acid impairs alpha 1-adrenoceptor-mediated contractile responses and inositol phosphate formation in rat cardiomyocytes. Reithmann C, Scheininger C, Bulgan T, Werdan K. The results presented show that chronic n-3 polyunsaturated fatty acid pretreatment of rat cardiomyocytes leads to a marked impairment of alpha 1-adrenoceptor-induced positive inotropic effects and induction of arrhythmias concomitant with a n-3 fatty acid-induced decrease in IP3 formation.

Nutrition. 2000 Jan;16(1):11-4. Effects of eicosapentaenoic acid intake on plasma fibrinolytic and coagulation activity by using physical load in the young. Sakamoto N, Nishiike T, Iguchi H, Sakamoto K. Thus, as determined by the load, a small amount of daily EPA intake clearly decreased fibrinolytic activity and increased coagulation activity.

Diabetes. 2005 Aug;54(8):2314-9. Insulin resistance and type 2 diabetes in high-fat-fed mice are linked to high glycotoxin intake. Sandu O, Song K, Cai W, Zheng F, Uribarri J, Vlassara H. These results demonstrate that the development of insulin resistance and type 2 diabetes during prolonged high-fat feeding are linked to the excess AGEs/advanced lipoxidation end products inherent in fatty diets.

Nutr Cancer 1998;30(2):137-43. Effects of dietary n-3-to-n-6 polyunsaturated fatty acid ratio on mammary carcinogenesis in rats. Sasaki T, Kobayashi Y, Shimizu J, Wada M, In'nami S, Kanke Y, Takita T. "Dietary fat was fed to the rats as 10% of the total feed weight, starting two weeks before the initiation. An increase in the n-3/n-6 ratio did not suppress the incidence or reduce the latency of mammary tumor development. The number and weight of mammary tumors per tumor-bearing rat tended to be large in the group with an n-3/n-6 ratio of 7.84 compared with those in the other groups. As the n-3/n-6 ratios were elevated, the total number and weight of tumors increased gradually." "These results suggested that the increase in the n-3/n-6 ratio of dietary fat with the fixed PUFA-to-saturated fatty acid ratio cannot suppress the mammary carcinogenesis but can promote development of tumors, despite reduced PGE2 concentration in the tumor."

J Cardiovasc Pharmacol. 2006 Mar;47(3):493-9. Mildronate, a novel fatty acid oxidation inhibitor and antianginal agent, reduces myocardial infarct size without affecting hemodynamics. Sesti C, Simkhovich BZ, Kalvinsh I, Kloner RA. "Mildronate is a fatty acid oxidation inhibitor approved as an antianginal drug in parts of Europe."

J Nutr 2000 Dec;130(12):3028-33. Polyunsaturated (n-3) fatty acids susceptible to peroxidation are increased in plasma and tissue lipids of rats fed docosahexaenoic acid-containing oils. Song JH, Fujimoto K, Miyazawa T.. "Thus, high incorporation of (n-3) fatty acids (mainly DHA) into plasma and tissue lipids due to DHA-containing oil ingestion may undesirably affect tissues by enhancing susceptibility of membranes to lipid peroxidation and by disrupting the antioxidant system."

Diabetes Nutr Metab. 2002 Aug;15(4):205-14. Long-term effect of fish oil diet on basal and stimulated plasma glucose and insulin levels in ob/ob mice. Steerenberg PA, Beekhof PK, Feskens EJ, Lips CJ, Hoppener JW, Beems RB. We have investigated, in comparison to low and high fat diets, the effect of a fish oil diet on basal and stimulated plasma glucose and insulin levels in male and female ob/ob mice. Intercurrent deaths were found especially in the fish oil diet group. Compared to the other diet groups, plasma insulin levels of the fish oil diet group were significantly increased 3 months after the start of the diet and remained higher for another 3 months. At 12 months, microscopy revealed an increased severity of hepatic brown pigment accumulation and extramedullary haematopoiesis in the spleen of mice fed with fish oil. Fish oil diet also increased intercurrent mortality. However, a consistent course of death could not be established using morphological parameters.

J Biol Chem. 2002 Feb 15;277(7):5692-7. Unsaturated fatty acids inhibit cholesterol efflux from macrophages by increasing degradation of ATP-binding cassette transporter A1. Wang Y, Oram JF. These findings raise the possibility that an increased supply of unsaturated fatty acids in the artery wall promotes atherogenesis by impairing the ABCA1 cholesterol secretory pathway in macrophages.

J Biol Chem. 2005 Oct 28;280(43):35896-903. Epub 2005 Aug 23. Unsaturated fatty acids phosphorylate and destabilize ABCA1 through a phospholipase D2 pathway. Wang Y, Oram JF. "ATP-binding cassette transporter ABCA1 mediates the transport of cholesterol and phospholipids from cells to HDL apolipoproteins and thus modulates HDL levels and atherogenesis. Unsaturated fatty acids, which are elevated in diabetes, impair the ABCA1 pathway in cultured cells by destabilizing ABCA1 protein." "Unsaturated but not saturated fatty acids stimulated phospholipase D (PLD) activity, the PLD inhibitor 1-butanol prevented the unsaturated fatty acid-induced reduction in ABCA1 levels, and the PLD2 activator mastoparan markedly reduced ABCA1 protein levels, implicating a role for PLD2 in the ABCA1 destabilizing effects of fatty acids." "These data provide evidence that intracellular unsaturated acyl-CoA derivatives destabilize ABCA1 by activating a PLD2 signaling pathway."

Isr J Med Sci. 1996 Nov;32(11):1134-43. Diet and disease--the Israeli paradox: possible dangers of a high omega-6 polyunsaturated fatty acid diet. Yam D, Eliraz A, Berry EM. Thus, rather than being beneficial, high omega-6 PUFA diets may have some long-term side effects, within the cluster of hyperinsulinemia, atherosclerosis and tumorigenesis.

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<span class="koboSpan" id="kobo.1.1">The Great Fish Oil Experiment</span> A R T I C L E

The Great Fish Oil Experiment

Reading medical journals and following the mass media, it's easy to get the idea that fish oil is something any sensible person should use. It's rare to see anything suggesting that it could be dangerous.

During the recent years in which the U.S. government has gone from warning against the consumption of too much of these omega-3 oils ("to assure that the combined daily intake of two fatty acids that are components" "(i.e., eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) would not exceed 3 grams per person per day (g/p/d)") to sponsoring biased industry claims, there has been considerable accumulation of information about the dangers of fish oils and omega-3 fatty acids. But there has been an even greater increase in the industry's promotional activities.

The US government and the mass media selectively promote research that is favorable to the fish oil industry. The editorial boards of oil research journals often include industry representatives, and their editorial decisions favor research conclusions that promote the industry, in the way that editorial decisions in previous decades favored articles that denied the dangers of radiation and reported that estrogen cures almost everything. Marcia Angell, former editor of the NEJM, has observed that the "significant results" reported in published studies can be properly interpreted only by knowing how many studies reporting opposite results were rejected by the editors.

One way to evaluate published studies is to see whether they tell you everything you would need to know to replicate the experiment, and whether the information they provide is adequate for drawing the conclusions they draw, for example whether they compared the experimental subjects to proper control subjects. With just a few minimal critical principles of this sort, most "scientific" publications on nutrition, endocrinology, cancer and other degenerative diseases are seen to be unscientific. In nutritional experiments with fish oil, controls must receive similar amounts of vitamins A, D, E, and K, and should include fat free or "EFA" deficient diets for comparison.

In declaring EPA and DHA to be safe, the FDA neglected to evaluate their antithyroid, immunosuppressive, lipid peroxidative (Song et al., 2000), light sensitizing, and antimitochondrial effects, their depression of glucose oxidation (Delarue et al., 2003), and their contribution to metastatic cancer (Klieveri, et al., 2000), lipofuscinosis and liver damage, among other problems.

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"Houston-based Omega Protein Inc.'s bottom line may get a little fatter.

The publicly traded company, which produces an Omega-3 fatty acid product called OmegaPure, has signed an agreement to provide its fish oil in school lunches in 38 school districts in South Texas beginning this month.

The 500-person company, which has ties to former President George Bush's Zapata Corp., will distribute the product through an agreement with Mercedes-based H&H Foods.

Although the dollar amount of the contract between Omega Protein and H&H Foods hinges on future sales, the company is poised to cash in as school administrators and parents refocus their attention on the nutritional content of student diets.

Omega Protein President and CEO Joseph von Rosenberg says the company's recent investment of $16.5 million for a fish oil refinery in Reedville, Va., scheduled for completion in May, and an increased awareness of the benefits of Omega-3 in human food, positions Omega to capitalize on predicted demand."

Jenna Colley
Houston Business Journal

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Andrew Weil was on the radio recently recommending DHA (usually found in fish oil*) to treat depression, and I think that means that a lot of people are buying it and eating it. A few years ago the government declared that it was "generally regarded as safe" and approved its use in baby formula, and a few months ago Texas school districts contracted with Omega Protein (which grew out of the Bush family's Zapata Corporation) to provide menhaden fish oil for school lunches. Between the 1950s and the 1970s, people were assured that eating polyunsaturated seed oils would protect them against heart disease. There's no evidence that the bad outcome of that campaign decreased the gullibility of the public. They are happily joining in the latest public health experiment.

*Weil recommends eating "oily fish"--"wild Alaskan salmon, mackerel, sardines, or herring"--. "If you do take supplements, fish oil is a better source of DHA than algae"

When a group of people in government and industry decide on a policy, they can use carrots (good jobs, grants, and prestige) and sticks (loss of jobs and grants, organized slander, and worse) to make their guidelines clear, and most people will choose to follow those cues, even if they know that the policy is wrong. Historically, policy makers have told the public that "radiation is good for you," "estrogen will make you fertile (or safely infertile) and feminine and strong and intelligent," "starchy foods will prevent diabetes and obesity," "using diuretics and avoiding salt will make pregnancy safer," and that the polyunsaturated fatty acids are "nutritionally essential, and will prevent heart disease."

The original "essential fatty acids" were linoleic, linolenic, and arachidonic acids. Now that the toxic effects of those are coming to be recognized, new "essential fatty acids," the omega-3 fatty acids, including those with long chains, found in fish oils, are said to make babies more intelligent, to be necessary for good vision, and to prevent cancer, heart disease, obesity, arthritis, depression, epilepsy, psychosis, dementia, ulcers, eczema and dry skin.
With just a normal amount of vitamin E in the diet, cod liver oil is certain to be highly oxidized in the tissues of a mammal that eats a lot of it, and an experiment with dogs showed that it could increase their cancer mortality from the normal 5% to 100%. Although fish oils rapidly destroy vitamin E in the body, some of them, especially the liver oils, can provide useful vitamins, A and D. In studies comparing fish oil diets with standard diets, these nutrients, as well as any toxins besides fatty acids (Huang, et al., 1997; Miyazaki, et al., 1998) in either type of oil, should be taken into account, but they seldom are.

Despite the nutritional value of those vitamins, fish oils are generally much more immunosuppressive than the seed oils, and the early effects of fish oil on the "immune system" include the suppression of prostaglandin synthesis, because the more highly unsaturated long chain fats interfere with the conversion of linoleic acid into arachidonic acid and prostaglandins. The prostaglandins are so problematic that their suppression is helpful, whether the inhibition is caused by aspirin or vitamin E, or by fish oil.

Some of the important antiinflammatory effects of fish oil result from the oxidized oils, rather than the unchanged oils (Sethi, 2002; Chaudhary, et al., 2004). These oils are so unstable that they begin to spontaneously oxidize even before they reach the bloodstream.

In experiments that last just a few weeks or months, there may not be time for cancers to develop, and on that time scale, the immunosuppressive and antiinflammatory effects of oxidized fish oil might seem beneficial. For a few decades, x-ray treatments were used to relieve inflammatory conditions, and most of the doctors who promoted the treatment were able to retire before their patients began suffering the fatal effects of atrophy, fibrosis, and cancer. (But a few people are still advocating x-ray therapy for inflammatory diseases, e.g., Hildebrandt, et al., 2003.) The fish oil fad is now just as old as the x-ray fad was at its peak of popularity, and if its antiinflammatory actions involve the same mechanisms as the antiinflammatory immunosuppressive x-ray treatments, then we can expect to see another epidemic of fibrotic conditions and cancer in about 15 to 20 years.
Around 1970 researchers reported that animals given fish oil in their food lived longer than animals on the standard diet. Alex Comfort, who was familiar with the research showing that simple reduction of food intake increased longevity, observed that the animals were very reluctant to eat the food containing smelly fish oil, and were eating so little food that their longevity could be accounted for by their reduced caloric intake. Even when "fresh" deodorized fish oil is added to the diet, its spontaneous oxidation before it reaches the animal's tissues reduces its caloric value. Without antioxidants, fish oil is massively degraded within 48 hours, and even with a huge amount of antioxidant there is still considerable degradation (Gonzalez, 1988; Klein, et al., 1990).
Fish oil has been used for hundreds of years as varnish or for fuel in lamps, and the fatty fish have been used as fertilizer and animal feed, and later the hydrogenated solid form of the oil, which is more stable, has been used in Europe as a food substitute for people. When whale hunting was reduced around 1950, fish oil was substituted for whale oil in margarine production. Like the seed oils, such as linseed oil, the fish oils were mostly replaced by petroleum derivatives in the paint industry after the 1960s.

Although by 1980 many animal diseases were known to be caused by eating oily fish, and the unsaturated oils were known to accelerate the formation of the "age pigment," lipofuscin, many "beneficial effects" of dietary fish oil started appearing in research journals around that time, and the mass media, responding to the industry's public relations campaign, began ignoring studies that showed harmful effects from eating fish oil.

When reviewers in professional journals begin to ignore valid research whose conclusions are harmful to the fish oil industry, we can see that the policy guidelines set by the industry and its agents in government have become clear. Around the end of the century, we begin to see a strange literary device appearing, in which research reports on the toxic effects of omega-3 oils are prefaced by remarks to the effect that "we all know how great these oils are for good health." I think I detect groveling and shuffling of the feet by authors who want to get their work published. If you are willing to say that your work probably doesn't mean what it seems to mean, maybe they will publish it.

For more than 50 years, the great majority of the medical publications on estrogen were part of the drug industry's campaign to fraudulently gain billions of dollars, and anyone who cared to analyze them could see that the authors and editors were part of a cult, rather than seekers of useful knowledge. Likewise, the doctrine of the harmlessness of x-rays and radioactive fallout was kept alive for several decades by demonizing all who challenged it. It now looks as though we are in danger of entering another period of medical-industrial-governmental cultism, this time to promote the universal use of polyunsaturated fats as both drugs and foods.
In 2004, a study of 29,133 men reported that the use of omega-3 oil or consumption of fish didn't decrease depression or suicide, and in 2001, a study of 42,612 men and women reported that after more than 9 years the use of cod liver oil showed no protective effect against coronary heart disease (Hakkarainen, et al., 2004; Egeland, et al., 2001).

The most popular way of arguing that fish oil will prevent heart disease is to show that it lowers blood lipids, continuing the old approach of the American Heart Association's "heart protective diet." Unfortunately for that argument, it's now known that the triglycerides in the blood are decreased because of the fish oil's toxic effects on the liver (Hagve and Christophersen, 1988; Ritskes-Hoitinga, et al., 1998). In experiments with rats, EPA and DHA lowered blood lipids only when given to rats that had been fed, in which case the fats were incorporated into tissues, and suppressed mitochondrial respiration (Osmundsen, et al., 1998).

The belief that eating cholesterol causes heart disease was based mainly on old experiments with rabbits, and subsequent experiments have made it clear that it is oxidized cholesterol that damages the arteries (Stapran, et al., 1997). Since both fish oil and oxidized cholesterol damage rabbits' arteries, and since the lipid peroxides associated with fish oil attack a great variety of biological materials, including the LDL lipoproteins carrying cholesterol, the implications of the rabbit experiments now seem very different.

Another way of arguing for the use of fish oil or other omega-3 fats is to show a correlation between disease and a decreased amount of EPA, DHA, or arachidonic acid in the tissues, and to say "these oils are deficient, the disease is caused by a deficiency of essential fatty acids." Those oils are extremely susceptible to oxidation, so they tend to spontaneously disappear in response to tissue injury, cellular excitation, the increased energy demands of stress, exposure to toxins or ionizing radiation, or even exposure to light. That spontaneous oxidation is what made them useful as varnish or paint medium. But it is what makes them sensitize the tissues to injury. Their "deficiency" in the tissues frequently corresponds to the intensity of oxidative stress and lipid peroxidation; it is usually their presence, rather than their deficiency, that created the disposition for the disease.

One of the earliest harmful effects of polyunsaturated fatty acids, PUFA, to be observed was their acceleration of the formation of lipofuscin or ceroid, the "age pigment," during oxidative stress or vitamin E deficiency. Associated with the formation of lipofuscin, the PUFA were discovered to cause degeneration of the gonads and brain, and the fact that vitamin E could prevent some of their toxic effects led to the idea that vitamin E was essentially an antioxidant. Unfortunately, the protective effect of vitamin E against the PUFA is only partial (Allard, et al., 1997).

The degenerative diseases are all associated with disturbances involving fat metabolism and lipid peroxidation. Alzheimer's disease, alcoholic and nonalcoholic liver disease, retinal degeneration, epilepsy, AIDS, diabetes, and a variety of circulatory problems involve breakdown products of the PUFA. The products of PUFA decomposition include acrolein, malondialdehyde, hydroxynonenal, crotonaldehyde, ethane, pentane, and the neuroprostanes, which are prostaglandin-like molecules formed from DHA by free radical lipid peroxidation products, especially in the brain and at a higher level in Alzheimer's disease.

The reactions of three types of cell--vascular endothelium, nerve cells, and thymus cells--to the PUFA will illustrate some of the important processes involved in their toxicity.

When the body doesn't have enough glucose, free fatty acids are released from the tissues, and their oxidation blocks the oxidation of glucose even when it becomes available from the breakdown of protein caused by cortisol, which is released during glucose deprivation. Cells of the thymus are sensitive to glucose deprivation, and even in the presence of glucose, cortisol prevents them from using glucose, causing them to take up fatty acids. The thymic cells die easily when exposed either to excess cortisol, or deficient glucose. The polyunsaturated fatty acids linoleate, arachidonate, and eicosapentaenoic, are especially toxic to thymic cells by preventing their inactivation of cortisol, increasing its action. (Klein, et al., 1987, 1989, 1990). Lymphocytes from people with AIDS and leukemia are less able to metabolize cortisol. An extract of serum from AIDS patients caused lymphocytes exposed to cortisol to die 7 times faster than cells from healthy people. AIDS patients have high levels of both cortisol and free polyunsaturated fatty acids (Christeff, et al., 1988).
The cytotoxicity caused by EPA and its metabolites (15 mg. of EPA per liter killed over 90% of a certain type of macrophage) isn't inhibited by vitamin E (Fyfe and Abbey, 2000). Immunological activation tends to kill T cells that contain PUFA (Switzer, et al., 2003).

When animals are fed fish oil and then exposed to bacteria, their immunosuppressed thymic (T) cells cause them to succumb to the infection more easily than animals fed coconut oil or a fat free diet. Natural killer cells, which eliminate cancer cells and virus infected cells, are decreased after eating fish oil, and T suppressor cells are often increased. More subtle interference with immunity is produced by the actions of PUFA on the "immune synapse," a contact between cells that permits the transmission of immunological information. The immunosuppressive effect of fish oil is recognized as a useful aid in preventing the rejection of transplanted organs, but some studies are showing that survival a year after transplantation isn't improved.

Polyunsaturated fatty acids, especially those that can be turned into prostaglandins, are widely involved in causing inflammation and vascular leakiness. EPA and DHA don't form ordinary prostaglandins, though the isoprostanes and neuroprostanes they produce during lipid peroxidation behave in many ways like the more common prostaglandins, and their enzymically formed eicosanoids have some functions similar to those of the common prostaglandins. The brain contains a very high concentration of these unstable fatty acids, and they are released in synapses by ordinary excitatory process.

Chan, et al., 1983, found that polyunsaturated fats caused brain swelling and increased blood vessel permeability. In 1988, Chan's group found that DHA and other polyunsaturated fatty acids added to cultured cells from the cerebral cortex produced free radicals and stimulated production of malondialdehyde and lactate, and inhibited the uptake of glutamic acid, which suggests that they would contribute to prolonged excitation of the nerves (Yu, et al., 1986). In brain slices, the polyunsaturated fatty acids caused the production of free radicals and swelling of the tissue, and the saturated fatty acids didn't (Chan and Fishman, 1980). The PUFA inhibited the respiration of mitochondria in brain cells (Hillered and Chan, 1988), and at a higher concentration, caused them to swell (Hillered and Chan, 1989), but saturated fatty acids didn't produce edema. Free radical activity was shown to cause the liberation of free fatty acids from the cellular structure (Chan, et al., 1982, 1984). The activation of lipases by free radicals and lipid peroxides, with the loss of potassium from the cells, suggests that excitation can become a self-stimulating process, leading to cellular destruction.

DHA itself, rather than its decomposition products, facilitates excitatory (glutamate) nerve transmission (Nishikawa, et al., 1994), and that excitatory action causes the release of arachidonic acid (Pellerin and Wolfe, 1991).

Considering just one of the products of fish oil peroxidation, acrolein, and a few of its effects in cells, we can get an idea of the types of damage that could result from increasing the amount of omega-3 fats in our tissues.
The "barrier" between the brain and blood stream is one of the most effective vascular barriers in the body, but it is very permeable to oils, and lipid peroxidation disrupts it, damaging the ATPase that regulates sodium and potassium (Stanimirovic, et al., 1995). Apparently, anything that depletes the cell's energy, lowering ATP, allows an excess of calcium to enter cells, contributing to their death (Ray, et al., 1994). Increasing intracellular calcium activates phospholipases, releasing more polyunsaturated fats (Sweetman, et al., 1995) The acrolein which is released during lipid peroxidation inhibits mitochondrial function by poisoning the crucial respiratory enzyme, cytochrome oxidase, resulting in a decreased ability to produce energy (Picklo and Montine, 2001). (In the retina, the PUFA contribute to light-induced damage of the energy producing ability of the cells [King, 2004], by damaging the same crucial enzyme.) Besides inhibiting the ability of nerve cells to produce energy from the oxidation of glucose, acrolein inhibits the ability of cells to regulate the excitatory amino acid glutamate (Lovell, et al., 2000), contributing to the excitatory process. High levels of acrolein (and other products of PUFA degradation) are found in the brain in Alzheimer's disease (Lovell, et al., 2001).

The "prion" diseases, CJD and TSE/BSE (mad cow disease) have many features in common with Alzheimer's disease, and several studies have shown that the "prion" protein produces its damage by activating the lipases that release polyunsaturated fatty acids and produce lipid peroxides (Bate, et al., 2004, Stewart, et al., 2001).
Acrolein reacts with DNA, causing "genetic" damage, and also reacts with the lysine in proteins, for example contributing to the toxicity of oxidized low density lipoproteins (LDL), the proteins that carry cholesterol and that became famous because of their involvement in the development of atherosclerosis that was supposedly caused by eating saturated fats.

My newsletter on mad cow disease discussed the evidence incriminating the use of fish meal in animal feed, as a cause of the degenerative brain diseases, and earlier newsletters (glycemia, and glycation) discussed the reasons for thinking that inappropriate glycation of lysine groups in proteins, as a result of a lack of protective carbon dioxide/carbamino groups, produces the amyloid (or "prion") proteins that characterize the dementias. Acrolein, produced from the decomposing "fish oils" in the brain, is probably the most reactive product of lipid peroxidation in the brain, and so would be likely to cause the glycation of lysine in the plaque-forming proteins.
These toxic effects of acrolein in the brain are analogous to the multitude of toxic effects of the omega-3 fatty acids and their breakdown products in all of the other organs and tissues of the body. Cancer cells are unusual in their degree of resistance to the lethal actions of the lipid peroxides, but the inflammatory effects of the highly unsaturated fatty acids are now widely recognized to be essentially involved in the process of cancerization (my newsletters on cancer and leakiness discuss some of the ways the fats are involved in tumor development).
The fats that we synthesize from sugar, or coconut oil, or oleic acid, the omega-9 series, are protective against the inflammatory PUFA, in some cases more effective even than vitamin E.

In Woody Allen's 1973 movie, Sleeper, the protagonist woke up after being frozen for 200 years, to find that saturated fats were health foods. At the time the movie was made, that had already been established (e.g., Hartroft and Porta, 1968 edition of Present Knowledge in Nutrition, who showed that adequate saturated fat in the diet helped to protect against the formation of lipofuscin).

PS:
Royal Society for the Protection of Birds says 2004 has been the most catastrophic breeding season on record for seabirds along UK coasts. It says industrial fishing to supply fish meal and oil is barely sustainable and imperils the whole marine food web.
"The UK has suffered serious seabird disasters this year already. In Shetland and Orkney, entire colonies of birds failed to produce any young because of severe food shortages. "On top of that, hundreds of seabirds have been washing ashore having perished at sea. Again, lack of food is thought to be one of the reasons." The report, Assessment Of The Sustainability Of Industrial Fisheries Producing Fish Meal And Fish Oil, was compiled for the RSPB by Poseidon Aquatic Resource Management Ltd and the University of Newcastle-upon-Tyne.

REFERENCES

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A R T I C L E

Gelatin, stress, longevity

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The main bulk of an animal's body consists of water, protein, fat and bones. Fat tissue and bone are metabolically more quiescent than the protein-water systems. During stress or starvation, or even hibernation, animals lose lean mass faster than fat.

The amino acids that constitute protein have many hormone-like functions in their free state. When our glucose (glycogen) stores have been depleted, we convert our own tissue into free amino acids, some of which are used to produce new glucose. The amino acids cysteine and tryptophan, released in large quantities during stress, have antimetabolic (thyroid-suppressing) and, eventually, toxic effects. Hypothyroidism itself increases the catabolic turnover of protein, even though general metabolism is slowed.

Other amino acids act as nerve-modifiers (transmitters), causing, for example, excitation or inhibition.

Some of these amino acids, such as glycine, have a very broad range of cell-protective actions.

Their physical properties, rather than their use for production of energy or other metabolic function, are responsible for their important cytoprotective actions.

Gelatin (the cooked form of collagen) makes up about 50% of the protein in an animal, but a much smaller percentage in the more active tissues, such as brain, muscle, and liver. 35% of the amino acids in gelatin are glycine, 11% alanine, and 21% proline and hydroxyproline.

In the industrialized societies, the consumption of gelatin has decreased, relative to the foods that contain an inappropriately high proportion of the antimetabolic amino acids, especially tryptophan and cysteine.

The degenerative and inflammatory diseases can often be corrected by the use of gelatin-rich foods.

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I usually think about something for a long time before I get around to integrating it into my life, sometimes because old habits have to be changed, but usually because our social organization is set up to do things in conventional ways. Our foods reflect our social organization, enforced by laws and rules. When I first went to Mexico to study, many traditional foods were still available even in the city--fried pig skin, served crisp or boiled with a sauce, blood tacos, cartilaginous parts of various animals, chicken-foot soup, crustaceans, insects, etc. Later, when I studied biochemistry, I realized that each part of an organism has a characteristic chemistry and special nutritional value. I knew of Weston Price's research on traditional diets, and his argument that the degenerative diseases of civilization were produced by the simplified diets that are characteristic of the highly industrialized societies.

As I began to study endocrinology, I realized that there were some radical misconceptions behind the ideas of scientific nutrition. I. P. Pavlov, who had studied nutritional physiology because it constituted the animal's closest interactions with its environment, was motivated by a desire to understand life in its totality, including consciousness. But western nutritionists were nearly all committed to an ideology that forced them to think in terms of essential factors for growth, leading to ideas such as minimum daily requirement for each nutrient. Bodily bulk (especially body length) was the criterion, not the experienced quality of life. And there has been no scarcity of evidence showing that rapid bodily growth has its drawbacks (e.g., Miller, et al., 2002, Big mice die young).

One of the brightest of the genetically oriented nutritionists, Roger Williams, used the idea of genetic individuality to explain that the popular idea of a species-wide standard diet couldn't be applied to exceptional individuals, and that disease was often the result of the mismatch between special nutritional requirements and a standard diet. Linus Pauling's concept of orthomolecular medicine was a restatement of Williams' principle for the general scientific community.

But still, the emphasis was on the match between a specific chemical and the genetic constitution of the organism. Pavlov's idea of the trophic actions of nerves was discarded, and the rest of his work was relegated to a crudely caricatured branch of psychology. His therapeutic recommendation of beef broth for many ailments was ignored as having nothing to do with the caricatured Pavlovism.

If nerves are intimately involved in the processes of nutrition and development, the effects of nutrients on the nerves and their development should have a central place in nutritional research. Our appetites reflect our biochemical needs, and our unconditional reflexes are likely to be wiser than the theories that are based simply on the amount of weight a young animal gains on a particular diet.

When I began teaching endocrinology, some of my students didn't want to hear about anything except lock and key endocrinology, in which a hormone signals certain cells that have a suitable receptor for that hormone. But the studies of Hans Selye and Albert Szent-Gyorgyi made it clear that Pavlov's global, holistic approach to the organism in its environment was the soundest scientific basis for physiology, including endocrinology. A cell's response to a hormone depended on the state of the cell. Nutrients and metabolites and hormones and neurotransmitters all modify the cell's sensitivity to its surroundings. The assumptions of molecular biology, as generally understood, are fundamentally mistaken.

The idea of fixed requirements for specific nutrients, and especially the idea that rapid physical growth was the way to determine the essentiality of a substance, led to a monstrous distortion of the official dietary recommendations. Business, industry, government, and the health professions collaborated in the propagation of an ideology about nutrition that misrepresented the nature of the living organism.

Most studies of the nutritional requirements for protein have been done for the agricultural industries, and so have been designed to find the cheapest way to get the maximum growth in the shortest time. The industry isn't interested in the longevity, intelligence, or happiness of their pigs, chickens, and lambs. The industry has used chemical growth stimulants in combination with the foods that support rapid growth at least expense. Antibiotics and arsenic and polyunsaturated fatty acids have become part of our national food supply because they produce rapid weight gain in young animals.

The amino acids in proteins have been defined as essential on the basis of their contribution to growth, ignoring their role in producing long life, good brain development, and good health. The amino acid and protein requirements during aging have hardly been studied, except in rats, whose short life-span makes such studies fairly easy. The few studies that have been done indicate that the requirements for tryptophan and cysteine become very low in adulthood.

Although Clive McKay's studies of life extension through caloric restriction were done in the 1930s, only a few studies have been done to find out which nutrients' restriction contributes most to extending the life span. Restricting toxic heavy metals, without restricting calories, produces about the same life-extending effect as caloric restriction. Restricting only tryptophan, or only cysteine, produces a greater extension of the life span than achieved in most of the studies of caloric restriction. How great would be the life-span extension if both tryptophan and cysteine were restricted at the same time?

Both tryptophan and cysteine inhibit thyroid function and mitochondrial energy production, and have other effects that decrease the ability to withstand stress. Tryptophan is the precursor to serotonin, which causes inflammation, immunodepression, and generally the same changes seen in aging. Histidine is another amino acid precursor to a mediator of inflammation, histamine; would the restriction of histidine in the diet have a longevity promoting effect, too?

It happens that gelatin is a protein which contains no tryptophan, and only small amounts of cysteine, methionine, and histidine. Using gelatin as a major dietary protein is an easy way to restrict the amino acids that are associated with many of the problems of aging.

The main amino acids in gelatin are glycine and proline; alanine is also present in significant quantity. Glycine and proline are responsible for the unusual fibrous property of collagen.

An animal's body, apart from fat and water, is mostly protein, and about half of the protein in the body is collagen (which is the native, uncooked form of gelatin). Its name is derived from its traditional use as glue. It is responsible for the structural toughness of mature animal bodies.

When cells are stressed, they form extra collagen, but they can also dissolve it, to allow for tissue remodeling and growth. Invasive cancers over-produce this kind of enzyme, destroying the extracellular matrix which is needed for normal cellular differentiation and function. When collagen is broken down, it releases factors that promote wound healing and suppress tumor invasiveness. (Pasco, et al., 2003) Glycine itself is one of the factors promoting wound healing and tumor inhibition.

It has a wide range of antitumor actions, including the inhibition of new blood vessel formation (angiogenesis), and it has shown protective activity in liver cancer and melanoma. Since glycine is non-toxic (if the kidneys are working, since any amino acid will contribute to the production of ammonia), this kind of chemotherapy can be pleasant.

When we eat animal proteins in the traditional ways (for example, eating fish head soup, as well as the muscles, or head-cheese as well as pork chops, and chicken-foot soup as well as drumsticks), we assimilate a large amount of glycine and gelatin. This whole-animal balance of amino acids supports all sorts of biological process, including a balanced growth of children's tissues and organs.

When only the muscle meats are eaten, the amino acid balance entering our blood stream is the same as that produced by extreme stress, when cortisol excess causes our muscles to be broken down to provide energy and material for repair. The formation of serotonin is increased by the excess tryptophan in muscle, and serotonin stimulates the formation of more cortisol, while the tryptophan itself, along with the excess muscle-derived cysteine, suppresses the thyroid function.

A generous supply of glycine/gelatin, against a balanced background of amino acids, has a great variety of antistress actions. Glycine is recognized as an inhibitory neurotransmitter, and promotes natural sleep. Used as a supplement, it has helped to promote recovery from strokes and seizures, and to improve learning and memory. But in every type of cell, it apparently has the same kind of quieting, protective antistress action. The range of injuries produced by an excess of tryptophan and serotonin seems to be prevented or corrected by a generous supply of glycine. Fibrosis, free radical damage, inflammation, cell death from ATP depletion or calcium overload, mitochondrial damage, diabetes, etc., can be prevented or alleviated by glycine.

Some types of cell damage are prevented almost as well by alanine and proline as by glycine, so the use of gelatin, rather than glycine, is preferable, especially when the gelatin is associated with its normal biochemicals. For example, skin is a rich source of steroid hormones, and cartilage contains Mead acid, which is itself antiinflammatory.

The other well-studied inhibitory neurotransmitter is GABA, so it's significant that GABA (gamma amino butyric acid) is a close analog of glycine (alpha amino acetic acid). A synthetic molecule structurally similar to those natural inhibitory transmitters, beta amino propanoic acid, has some of the protective effects of glycine and GABA. The other molecules in the series, at least up to epsilon amino caproic acid, have some of the same antiinvasive, antiinflammatory, anti-angiogenic, properties. Alanine and proline, with cell-protecting actions, have the same basic composition, carbon (CH2 or CH) atoms separating acid and amino groups. Even the amino acids in which the lipophilic carbon atoms extend out in a branched side-chain, valine, leucine, and isoleucine, have some of the antiseizure (inhibitory) action (Skeie, et al., 1992, 1994) of GABA and glycine. Tests done with one, or a few, of the relatively lipophilic (aliphatic) amino acids prevent seizures, while the balanced mixtures of amino acids permit seizures; unfortunately, results of this sort haven't led researchers to question the idea of balance that developed within the setting of agricultural research.

The similarity between the structures and actions of glycine and GABA suggest that their receptors are similar, if not identical. For years, it has been known that progesterone and pregnenolone act on the GABA receptor, to reinforce the protective, inhibitory effects of GABA. Estrogen has the opposite effect, inhibiting GABA's action. Since GABA opposes estrogen and inhibits the growth of breast cancer, it wouldn't be surprising if glycine, alanine, etc., did the same.

Recent research shows that progesterone and its metabolites also act on the glycine receptor, increasing inhibition, and that the phytoestrogen, genistein, antagonizes the inhibitory effect of glycine.

The inhibitory systems are opposed by excitatory systems, especially by the excitatory amino acid system, activated by glutamic and aspartic acid. Progesterone and estrogen act on that system, too, decreasing and increasing excitation, respectively.

I have previously discussed the arguments for viewing progesterone as a cardinal adsorbent (as in Ling and Fu, 1987, 1988, Ling, et al., 1984, a steroid alters glycine's influence on the cell's electrical behavior) which increases the lipophilic, fat-loving property of the cytoplasm, and estrogen as having the opposite action, increasing the water-loving hydrophilic quality of the cytoplasm. If we think of the proteins known as the GABA and glycine receptors as having some regions in which the basic amine of lysine associates with the acidic group of aspartic or glutamic acid, then the action of glycine, or other amino acids would be to introduce additional lipophilic carbon atoms into those regions (with the amino acids' polar ends pairing with their opposites on the protein), where the cardinal adsorbents exert their influence.

Generally, biologists seem puzzled by such facts, because they don't fit into the lock and key model of molecular biology. But I think they make the organism easier to understand, since these constellations of facts illustrate simple and general physical principles. They suggest the idea that estrogen and progesterone and glycine, GABA, etc., will be active in any functioning cell, at a suitable concentration. It was this kind of thinking in terms of general physical principles that led Szent-Gyorgyi to investigate the effects of estrogen and progesterone on heart physiology. The old characterization of estrogen and progesterone as sex and pregnancy hormones acting on a few tissues through specific receptors never had a good basis in evidence, but the accumulated evidence has now made those ideas impossible for an informed person to accept. (Progesterone increases the heart's pumping efficiency, and estrogen is antagonistic, and can produce cardiac arrhythmia.)

In the context of the excitatory actions of estrogen, and the inhibitory action of glycine, it would be reasonable to think of glycine as one of the antiestrogenic substances. Another type of amino acid, taurine, is structurally similar to glycine (and to beta amino propanoic acid, and to GABA), and it can be thought of as antiestrogenic in this context. The specific kinds of excitation produced by estrogen that relate to reproduction occur against a background of very generalized cellular excitation, that includes increased sensitivity of sensory nerves, increased activity of motor nerves, changes in the EEG, and, if the estrogen effect is very high, epilepsy, tetany, or psychosis.

Glycine's inhibitory effects appear to oppose estrogen's actions generally, in sensory and motor nerves, in regulating angiogenesis, and in modulating the cytokines and "chemokines" that are involved in so many inflammatory and degenerative diseases, especially tumor necrosis factor (TNF), nitric oxide (NO), and prostaglandins. Exposure to estrogen early in life can affect the health in adulthood, and so can an early deficiency of glycine. The degenerative diseases can begin in the earliest years of life, but because aging, like growth, is a developmental process, it's never too late to start the corrective process.

One of estrogen's excitatory effects is to cause lipolysis, the release of fatty acids from storage fat; it directs the conversion of glucose into fat in the liver, so that the free fatty acids in the circulation remain chronically high under its influence. The free fatty acids inhibit the oxidation of glucose for energy, creating insulin resistance, the condition that normally increases with aging, and that can lead to hyperglycemia and diabetes.

Gelatin and glycine have recently been reported to facilitate the action of insulin in lowering blood sugar and alleviating diabetes. Gelatin has been used successfully to treat diabetes for over 100 years (A. Guerard, Ann Hygiene 36, 5, 1871; H. Brat, Deut. Med. Wochenschrift 28 (No. 2), 21, 1902). Glycine inhibits lipolysis (another antiexcitatory, antiestrogenic effect), and this in itself will make insulin more effective, and help to prevent hyperglycemia. (A gelatin-rich diet can also lower the serum triglycerides.) Since persistent lipolysis and insulin resistance, along with a generalized inflammatory state, are involved in a great variety of diseases, especially in the degenerative diseases, it's reasonable to consider using glycine/gelatin for almost any chronic problem. (Chicken foot soup has been used in several cultures for a variety of ailments; chicken foot powder has been advocated as a stimulant for spinal cord regeneration--Harry Robertson's method was stopped by the FDA).

Although Hans Selye observed as early as the 1930s that stress causes internal bleeding (in lungs, adrenals, thymus, intestine, salivary and tear glands, etc.), the medical establishment, which has the opportunity to see it after surgery, burns or other trauma, and following strokes and head injuries, prefers to explain it by "stomach hyperacidity," as if it were limited to the stomach and duodenum. And the spontaneous bruising, and easy bruising, that is experienced by millions of women, especially with the premenstrual syndrome, and nose bleeds, and scleral bleeding, purpura senilis, urinary bleeding, bleeding gums, and many other kinds of "spontaneous" or stress related bleeding, are treated by main-line medicine as if they had no particular physiological significance.

Stress is an energy problem, that leads to the series of hormonal and metabolic reactions that I have often written about--lipolysis, glycolysis, increased serotonin, cortisol, estrogen, prolactin, leaky capillaries, protein catabolism, etc. The capillaries are among the first tissues to be damaged by stress.

Although Selye showed that estrogen treatment mimics shock and stress, and that progesterone prevents the stress reaction, the effects of these hormones on the circulatory system have never been treated systematically. Katherina Dalton observed that progesterone treatment prevented the spontaneous bruising of the premenstrual syndrome; Soderwall observed that estrogen caused enlargement of the adrenals, sometimes with hemorrhage and necrosis; old female animals often have bleeding in the adrenals (Dhom, et al., 1981). Strangely, estrogen's induction of uterine bleeding has been compartmentalized, as if the endometrial blood vessels didn't follow the same rules as vessels elsewhere in the body. Both estrogen and cortisol are known to cause clotting disorders and to increase capillary fragility, but these steroids have been elevated to the realm of billion dollar drug products, beyond the reach of ordinary physiological thinking. Other stress-released substances that are entangled in the drug market (tryptophan, serotonin, nitric oxide, and unsaturated fats, for example) are similarly exempt from consideration as factors in circulatory, neoplastic, and degenerative diseases.

At the time Selye was observing stress-induced bleeding, standard medicine was putting gelatin to use--orally, subcutaneously, and intravenously--to control bleeding. Since ancient times, it had been used to stop bleeding by applying it to wounds, and this had finally been incorporated into medical practice.

The 1936 Cyclopedia of Medicine (G.M. Piersol, editor, volume 6) mentions the use of gelatin solution to quickly control nosebleeds, excessive menstrual bleeding, bleeding ulcers (using three doses of 18 grams as a 10% solution during one day), and bleeding from hemorrhoids and the lower bowel, and hemorrhage from the bladder. But since Selye's work relating the thrombohemorrhagic syndromes to stress wasn't known at that time, gelatin was thought of as a useful drug, rather than as having potentially far-reaching physiological effects, antagonizing some of the agents of stress-induced tissue damage.

Skin cells and nerve cells and many other cells are electrically stabilized by glycine, and this effect is currently being described in terms of a chloride current. A variety of mechanisms have been proposed for the protective effects of some of the amino acids, based on their use as energy or for other metabolic purpose, but there is evidence that glycine and alanine act protectively without being metabolized, simply by their physical properties.

A small dose of glycine taken shortly after suffering a stroke was found to accelerate recovery, preventing the spreading of injury through its inhibitory and antiinflammatory actions. Its nerve-stabilizing action, increasing the amount of stimulation required to activate nerves, is protective in epilepsy, too. This effect is important in the regulation of sleep, breathing, and heart rhythm.

Glycine's antispastic activity has been used to alleviate the muscle spasms of multiple sclerosis. It is thought to moderate some of the symptoms of schizophrenia.

A recent publication shows that glycine alleviates colitis; but the use of gelatin, especially in the form of a concentrated gelatinous beef broth, for colitis, dysentery, ulcers, celiac disease, and other diseases of the digestive system, goes far back in medical history. Pavlov's observation of its effectiveness in stimulating the secretion of digestive juices occurred because the stimulating value of broth was already recognized.

Although I pointed out a long time ago the antithyroid effects of excessive cysteine and tryptophan from eating only the muscle meats, and have been recommending gelatinous broth at bedtime to stop nocturnal stress, it took me many years to begin to experiment with large amounts of gelatin in my diet. Focusing on the various toxic effects of tryptophan and cysteine, I decided that using commercial gelatin, instead of broth, would be helpful for the experiment. For years I hadn't slept through a whole night without waking, and I was in the habit of having some juice or a little thyroid to help me go back to sleep. The first time I had several grams of gelatin just before bedtime, I slept without interruption for about 9 hours. I mentioned this effect to some friends, and later they told me that friends and relatives of theirs had recovered from long-standing pain problems (arthritic and rheumatic and possibly neurological) in just a few days after taking 10 or 15 grams of gelatin each day.

For a long time, gelatin's therapeutic effect in arthritis was assumed to result from its use in repairing the cartilage or other connective tissues around joints, simply because those tissues contain so much collagen. (Marketers suggest that eating cartilage or gelatin will build cartilage or other collagenous tissue.) Some of the consumed gelatin does get incorporated into the joint cartilage, but that is a slow process, and the relief of pain and inflammation is likely to be almost immediate, resembling the antiinflammatory effect of cortisol or aspirin.

Inflammation produces fibrosis, because stress, hypoxia, and inadequate supply of glucose stimulate the fibroblasts to produce increased amounts of collagen. In lungs, kidneys, liver, and other tissues, glycine protects against fibrosis, the opposite of what the traditional view would suggest.

Since excess tryptophan is known to produce muscle pain, myositis, even muscular dystrophy, gelatin is an appropriate food for helping to correct those problems, simply because of its lack of tryptophan. (Again, the popular nutritional idea of amino acids as simply building blocks for tissues is exactly wrong--muscle protein can exacerbate muscle disease.) All of the conditions involving excess prolactin, serotonin, and cortisol (autism, postpartum and premenstrual problems, Cushing's disease, "diabetes," impotence, etc.) should benefit from reduced consumption of tryptophan. But the specifically antiinflammatory amino acids in gelatin also antagonize the excitatory effects of the tryptophan-serotonin-estrogen- prolactin system.

In some of the older studies, therapeutic results improved when the daily gelatin was increased. Since 30 grams of glycine was commonly used for treating muscular dystrophy and myasthenia gravis, a daily intake of 100 grams of gelatin wouldn't seem unreasonable, and some people find that quantities in that range help to decrease fatigue. For a growing child, though, such a large amount of refined gelatin would tend to displace other important foods. The National Academy of Sciences recently reviewed the requirements for working adults (male and female soldiers, in particular), and suggested that 100 grams of balanced protein was needed for efficient work. For adults, a large part of that could be in the form of gelatin.

If a person eats a large serving of meat, it's probably helpful to have 5 or 10 grams of gelatin at approximately the same time, so that the amino acids enter the blood stream in balance.

Asian grocery stores are likely to sell some of the traditional gelatin-rich foods, such as prepared pig skin and ears and tails, and chicken feet.

Although the prepared powdered gelatin doesn't require any cooking, dissolving it in hot water makes it digest a little more quickly. It can be incorporated into custards, mousses, ice cream, soups, sauces, cheese cake, pies, etc., or mixed with fruit juices to make desserts or (with juice concentrate) candies.

Although pure glycine has its place as a useful and remarkably safe drug, it shouldn't be thought of as a food, because manufactured products are always likely to contain peculiar contaminants.

REFERENCES

Am J Physiol. 1990 Jul;259(1 Pt 2):F80-7. Mechanisms of perfused kidney cytoprotection by alanine and glycine. Baines AD, Shaikh N, Ho P.

Neurol. 1974; 24:392. Preliminary study of glycine administration in patients with spasticity. Barbeau A.

Virchows Arch B Cell Pathol Incl Mol Pathol. 1981;36(2-3):195-206. Peliosis of the female adrenal cortex of the aging rat. Dhom G, Hohbach C, Mausle E, Scherr O, Uebergerg H. Foci of apparent peliosis are regularly observed in the mid-zone of the adrenal cortex in female rats older than 600 days. The changes present range from ectasis of the sinusoids to extensive cystic change of the whole organ. This lesion occurs almost exclusively in female animals and was seen in only one of 50 male animals older than 600 days examined. Experimental stimulation or inhibition did not influence adrenal peliosis. Electron microscopically, there was marked pericapillary edema with collapse of the capillaries, and erythrocytes and thrombocytes were seen infiltrating the edema. Fibrin accumulated in the larger foci. Degenerative alterations were not observed either in the epithelial cells of the cortex or in mesenchymal cells. The pathogenesis is unknown, but the possible role of constant estrus in aging female rats will be discussed.

Riv Neurol. 1976 Mar-Jun;46(3):254-61. [Antagonism between focal epilepsy and taurine administered by cortical Perfusion] Durelli L, Quattrocolo G, Buffa C, Valentini C, Mutani R. The therapeutic action of taurine cortical perfusion was tested in cats affected with Premarin and cobalt cortical epileptogenic foci. In all animals taurine provoked the disappearance of EEG epileptic abnormalities. In the case of Premarin focus the effect appeared more quickly than in the cobalt one. This different time-course, according to previous reports on the antiepileptic action of the parenteral administration of the amino acid, suggests the hypothesis of a taurine direct inhibitory action against Premarin focus and, on the contrary, a mediated action towards the cobalt's. The latter might be related to the metabolic production of some taurine derivative.

Ann Neurol. 1998; 44:261-265. Beneficial effects of L-serine and glycine in the management of seizures in 3-phosphoglycerate dehydrogenase deficiency. de Kooning JT, Duran M, Dorling L, et al.

Arch Gen Psychiatry. 1999; 56:29-36. Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Heresco-Levy U, Javitt DC, Ermilov M, et al.

Free Radic Biol Med. 2001 Nov 15;31(10):1236-44. Dietary glycine inhibits activation of nuclear factor kappa B and prevents liver injury in hemorrhagic shock in the rat. Mauriz JL, Matilla B, Culebras JM, Gonzalez P, Gonzalez-Gallego J. "Feeding the rats glycine significantly reduced mortality, the elevation of plasma transaminase levels and hepatic necrosis. The increase in plasma TNFalpha and nitric oxide (NO) was also blunted by glycine feeding."

Am Fam Phys 1979 May;19(5):77-86. 'Not Cushing's syndrome'. Rincon J, Greenblatt RB, Schwartz RP Cushing's syndrome is characterized by protein wasting secondary to hypergluconeogenesis, which produces thin skin, poor muscle tone, osteoporosis and capillary fragility. These features distinguish patients with true Cushing's syndrome from those who have some of the clinical findings often associated with the syndrome, such as obesity, hypertension, striae and hirsutism. The dexamethasone suppression test helps identify patients with pseudo-Cushing's syndrome.

Carcinogenesis. 1999; 20:2075-2081. Dietary glycine prevents the development of liver tumors caused by the peroxisome proliferator WY-14, 643. Rose ML, Cattley RC, Dunn C, et al.

Carcinogenesis, Vol. 20, No. 5, 793-798, May 1999. Dietary glycine inhibits the growth of B16 melanoma tumors in mice. Rose M.L.,Madren J, Bunzendahl H., and Thurman R.G. Dietary glycine inhibited hepatocyte proliferation in response to the carcinogen WY-14,643. Since increased cell replication is associated with hepatic cancer caused by WY-14,643, glycine may have anti-cancer properties. Therefore, these experiments were designed to test the hypothesis that dietary glycine would inhibit the growth of tumors arising from B16 melanoma cells implanted subcutaneously in mice. C57BL/6 mice were fed diet supplemented with 5% glycine and 15% casein or control diet (20% casein) for 3 days prior to subcutaneous implantation of B16 tumor cells. Weight gain did not differ between mice fed control and glycine-containing diets. B16 tumors grew rapidly in mice fed control diet; however, in mice fed glycine diet, tumor size was 50-75% less. At the time of death, tumors from glycine-fed mice weighed nearly 65% less than tumors from mice fed control diet (P < 0.05). Glycine (0.01-10 mM) did not effect growth rates of B16 cells in vitro. Moreover, tumor volume and mitotic index of B16 tumors in vivo did not differ 2 days after implantation when tumors were small enough to be independent of vascularization. After 14 days, tumors from mice fed dietary glycine had 70% fewer arteries (P < 0.05). Furthermore, glycine (0.01-10 mM) inhibited the growth of endothelial cells in vitro in a dose-dependent manner (P < 0.05; IC50 = 0.05 mM). These data support the hypothesis that dietary glycine prevents tumor growth in vivo by inhibiting angiogenesis through mechanisms involving inhibition of endothelial cell proliferation.

Carcinogenesis, Vol. 20, No. 11, 2075-2081, November 1999. Dietary glycine prevents the development of liver tumors caused by the peroxisome proliferator WY-14,643. M.L.Rose, R.C.Cattley1, C.Dunn, V.Wong, Xiang Li and R.G.Thurman. Simpson RK Jr, Gondo M, Robertson CS, Goodman JC. The influence of glycine and related compounds on spinal cord injury-related spasticity. Neurochem Res. 1995; 20:1203-1210.

Neurochem Res. 1995 Oct;20(10):1203-10. The influence of glycine and related compounds on spinal cord injury-induced spasticity. Simpson RK Jr, Gondo M, Robertson CS, Goodman JC.

Neurochem Res. 1996 Oct;21(10):1221-6. Reduction in the mechanonociceptive response by intrathecal administration of glycine and related compounds. Simpson RK Jr, Gondo M, Robertson CS, Goodman JC.

Neurol Res. 1998 Mar;20(2):161-8. Glycine receptor reduction within segmental gray matter in a rat model in neuropathic pain. Simpson RK Jr, Huang W.

Neurol Res. 2000 Mar;22(2):160-4. Long-term intrathecal administration of glycine prevents mechanical hyperalgesia in a rat model of neuropathic pain. Huang W, Simpson RK.

Pharmacol Biochem Behav. 1992 Nov;43(3):669-71. Branched-chain amino acids increase the seizure threshold to picrotoxin in rats. Skeie B, Petersen AJ, Manner T, Askanazi J, Jellum E, Steen PA.

Thromb Diath Haemorrh Suppl 1968;30:165-9 [Purpura of the premenstrum and climacteric]. [Article in German] Stamm H.

Toth E, Lajtha A. Glycine potentiates the action of some anticonvulsant drugs in some seizure models. Neurochem Res. 1984; 9:1711-1718.

Sheng Li Ke Xue Jin Zhan. 2000 Jul;31(3):231-3. [The roles of estrogen and progestin in epileptogenesis and their mechanisms of action] [Article in Chinese] Wang Q.

FASEB J. 2000; 14:476-484. Glycine-gated channels in neutrophils attenuate calcium influx and superoxide production. Wheeler M, Stachlewitz RT, Yamashina S, et al.

Cell Mol Life Sci.1999; 56:843-856. Glycine: a new anti-inflammatory immunonutrient. Wheeler MD, Ikejema K, Mol Life Sci. Enomoto N, et al.

Nutr Cancer. 2001;40(2):197-204. Endothelial cells contain a glycine-gated chloride channel. Yamashina S, Konno A, Wheeler MD, Rusyn I, Rusyn EV, Cox AD, Thurman RG. "Glycine inhibited growth of B16 melanoma tumors in vivo most likely because of the inhibition of angiogenesis. Here, the hypothesis that the anticancer effect of glycine in vivo is due to expression of a glycine-gated Cl- channel in endothelial cells was tested.

Biull Eksp Biol Med. 1981 Nov;92(11):599-601. [Repair processes in wound tissues of experimental animals following administration of glycine] [Article in Russian] Zaidenberg MA, Pisarzhevskii SA, Nosova IM, Kerova AN, Dudnikova GN. A study was made of the effect of glycine given in doses approximating the physiological ones on the repair of processes in rat wound tissues. It was disclosed that in the early periods of wound healing, glycine administration leads to the increased content of cAMP and cAMP/cGMP ratio in the wound muscle and then in the granulation tissue, which appears to promote the intensification of the repair processes manifesting in the changes in tissue metabolism (DNA, collagen), in anti-inflammatory action, as well as in a more rapid maturation of the granulation tissue and wound reduction.. It was also found that the doses of glycine tested do not affect the content of insulin and hydrocortisone in the blood of experimental animals.

In recent years, evidence has mounted in favor of the antiinflammatory, immunomodulatory and cytoprotective effects of the simplest amino acid L-glycine. Glycine protects against shock caused by hemorrhage, endotoxin and sepsis, prevents ischemia/reperfusion and cold storage/reperfusion injury to a variety of tissues and organs including liver, kidney, heart, intestine and skeletal muscle, and diminishes liver and renal injury caused by hepatic and renal toxicants and drugs. Glycine also protects against peptidoglycan polysaccharide-induced arthritis... and inhibits gastric secretion ....and protects the gastric mucosa against chemically and stress-induced ulcers. Glycine appears to exert several protective effects, including antiinflammatory, immunomodulatory and direct cytoprotective actions. Glycine acts on inflammatory cells such as macrophages to suppress activation of transcription factors and the formation of free radicals and inflammatory cytokines. In the plasma membrane, glycine appears to activate a chloride channel that stabilizes or hyperpolarizes the plasma membrane potential. As a consequence, .... opening of ... calcium channels and the resulting increases in intracellular calcium ions are suppressed, which may account for the immunomodulatory and antiinflammatory effects of glycine. Lastly, glycine blocks the opening of relatively non-specific pores in the plasma membrane that occurs as the penultimate event leading to necrotic cell death.

Zhong Z, Wheeler MD, Li X, Froh M, Schemmer P, Yin M, Bunzendaul H, Bradford B, Lemasters JJ., "L-Glycine: a novel antiinflammatory, immunomodulatory, and cytoprotective agent." Curr Opin Clin Nutr Metab Care. 2003 Mar;6(2):229-40.

© Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com

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A R T I C L E

Glycemia, starch, and sugar in context

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Monosaccharide -- a simple sugar; examples, glucose, fructose, ribose, galactose (galactose is also called cerebrose, brain sugar).

Disaccharide -- two monosaccharides bound together; examples, sucrose, lactose, maltose.

Oligosaccharide -- a short chain of monosaccharides, including disaccharides and slightly longer chains.

Polysaccharide -- example, starch, cellulose, glycogen.

Glycation -- the attachment of a sugar to a protein.

Lipolysis - the liberation of free fatty acids from triglycerides, the neutral form in which fats are stored, bound to glycerine.

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In the 1920s, diabetes was thought to be a disease of insulin deficiency. Eventually, measurements of insulin showed that diabetics often had normal amounts of insulin, or above-normal amounts. There are now two kinds of diabetes, with suggestions that the disease will soon be further subdivided.

The degenerative diseases that are associated with hyperglycemia and commonly called diabetes, are only indirectly related to insulin, and as an approach to understanding or treating diabetes, the glycemic index of foods is useless. Physiologically, it has no constructive use, and very little meaning.

Insulin is important in the regulation of blood sugar, but its importance has been exaggerated because of the diabetes/insulin industry. Insulin itself has been found to account for only about 8% of the "insulin-like activity" of the blood, with potassium being probably the largest factor. There probably isn't any process in the body that doesn't potentially affect blood sugar.

Glucagon, cortisol, adrenalin, growth hormone and thyroid tend to increase the blood sugar, but it is common to interpret hyperglycemia as "diabetes," without measuring any of these factors. Even when "insulin dependent diabetes" is diagnosed, it isn't customary to measure the insulin to see whether it is actually deficient, before writing a prescription for insulin. People resign themselves to a lifetime of insulin injections, without knowing why their blood sugar is high.

Insulin release is also stimulated by amino acids such as leucine, and insulin stimulates cells to absorb amino acids and to synthesize proteins. Since insulin lowers blood sugar as it disposes of amino acids, eating a large amount of protein without carbohydrate can cause a sharp decrease in blood sugar. This leads to the release of adrenalin and cortisol, which raise the blood sugar. Adrenalin causes fatty acids to be drawn into the blood from fat stores, especially if the liver's glycogen stores are depleted, and cortisol causes tissue protein to be broken down into amino acids, some of which are used in place of carbohydrate. Unsaturated fatty acids, adrenaline, and cortisol cause insulin resistance.

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Professional opinion can be propagated about 10,000 times faster than research can evaluate it, or, as C. H. Spurgeon said, "A lie travels round the world while Truth is putting on her boots."

In the 1970s, dietitians began talking about the value of including "complex carbohydrates" in the diet. Many dietitians (all but one of the Registered Dietitians that I knew of) claimed that starches were more slowly absorbed than sugars, and so should be less disruptive to the blood sugar and insulin levels. People were told to eat whole grains and legumes, and to avoid fruit juices.

These recommendations, and their supporting ideology, are still rampant in the culture of the United States, fostered by the U.S. Department of Agriculture and the American Dietetic Association and the American Diabetes Association and innumerable university departments of home economics, dietetics, or nutrition.

Judging by present and past statements of the American Dietetic Association, I think some kind of institutional brain defect might account for their recommendations. Although the dietetic association now feebly acknowledges that sugars don't raise the blood sugar more quickly than starches do, they can't get away from their absurd old recommendations, which were never scientifically justified: Eat more starches, such as bread, cereal, and starchy vegetables--6 servings a day or more. Start the day with cold (dry) cereal with nonfat/skim milk or a bagel with one teaspoon of jelly/jam. Put starch center stage--pasta with tomato sauce, baked potato with chili, rice and stir-fried beef and vegetables. Add cooked black beans, corn, or garbanzo beans (chickpeas) to salads or casseroles.

The Dietetic Association's association with General Mills, the breakfast cereal empire, (and Kellog, Nabisco, and many other food industry giants) might have something to do with their starchy opinions. Starch-grain embolisms can cause brain damage, but major money can also make people say stupid things.

In an old experiment, a rat was tube-fed ten grams of corn-starch paste, and then anesthetized. Ten minutes after the massive tube feeding, the professor told the students to find how far the starch had moved along the alimentary canal. No trace of the white paste could be found, demonstrating the speed with which starch can be digested and absorbed. The very rapid rise of blood sugar stimulates massive release of insulin, and rapidly converts much of the carbohydrate into fat.

It was this sort of experiment that led to the concept of "glycemic index," that ranks foods according to their ability to raise the blood sugar. David Jenkins, in 1981, knew enough about the old studies of starch digestion to realize that the dietitians had created a dangerous cult around the complex carbohydrates, and he did a series of measurements that showed that starch is more glycemic than sucrose. But he simply used the amount of increase in blood glucose during the first two hours after ingesting the food sample, compared to that following ingestion of pure glucose, for the comparison, neglecting the physiologically complex facts, all of the processes involved in causing a certain amount of glucose to be present in the blood during a certain time. (Even the taste of sweetness, without swallowing anything, can stimulate the release of glucagon, which raises blood sugar.)

More important than the physiological vacuity of a simple glycemic measurement was the ideology within which the whole issue developed, namely, the idea that diabetes (conceived as chronic hyperglycemia) is caused by eating too much sugar, i.e., chronic hyperglycemia the illness is caused by the recurrent hyperglycemia of sugar gluttony. The experiments of Bernardo Houssay (1947 Nobel laureate) in the 1940s, in which sugar and coconut oil protected against diabetes, followed by Randle's demonstration of the antagonism between fats and glucose assimilation, and the growing recognition that polyunsaturated fatty acids cause insulin resistance and damage the pancreas, have made it clear that the dietetic obsession with sugar in relation to diabetes has been a dangerous diversion that has retarded the understanding of degenerative metabolic diseases.

Starting with the insulin industry, a culture of diabetes and sugar has been fabulized and expanded and modified as new commercial industries found ways to profit from it. Seed oils, fish oils, breakfast cereals, soybean products, and other things that were never eaten by any animal in millions of years of evolution have become commonplace as foods, even as health foods.

Although many things condition the rate at which blood sugar rises after eating carbohydrates, and affect the way in which blood glucose is metabolized, making the idea of a glycemic index highly misleading, it is true that blood sugar and insulin responses to different foods have some meaningful effects on physiology and health.

Starch and glucose efficiently stimulate insulin secretion, and that accelerates the disposition of glucose, activating its conversion to glycogen and fat, as well as its oxidation. Fructose inhibits the stimulation of insulin by glucose, so this means that eating ordinary sugar, sucrose (a disaccharide, consisting of glucose and fructose), in place of starch, will reduce the tendency to store fat. Eating complex carbohydrates, rather than sugars, is a reasonable way to promote obesity. Eating starch, by increasing insulin and lowering the blood sugar, stimulates the appetite, causing a person to eat more, so the effect on fat production becomes much larger than when equal amounts of sugar and starch are eaten. The obesity itself then becomes an additional physiological factor; the fat cells create something analogous to an inflammatory state. There isn't anything wrong with a high carbohydrate diet, and even a high starch diet isn't necessarily incompatible with good health, but when better foods are available they should be used instead of starches. For example, fruits have many advantages over grains, besides the difference between sugar and starch. Bread and pasta consumption are strongly associated with the occurrence of diabetes, fruit consumption has a strong inverse association.

Although pure fructose and sucrose produce less glycemia than glucose and starch do, the different effects of fruits and grains on the health can't be reduced to their effects on blood sugar.

Orange juice and sucrose have a lower glycemic index than starch or whole wheat or white bread, but it is common for dietitians to argue against the use of orange juice, because its index is the same as that of Coca Cola. But, if the glycemic index is very important, to be rational they would have to argue that Coke or orange juice should be substituted for white bread.

After decades of education to promote eating starchy foods, obesity is a bigger problem than ever, and more people are dying of diabetes than previously. The age-specific incidence of most cancers is increasing, too, and there is evidence that starch, such as pasta, contributes to breast cancer, and possibly other types of cancer.

The epidemiology would appear to suggest that complex carbohydrates cause diabetes, heart disease, and cancer. If the glycemic index is viewed in terms of the theory that hyperglycemia, by way of glucotoxicity, causes the destruction of proteins by glycation, which is seen in diabetes and old age, that might seem simple and obvious.

Fructose | 32 | 22
Lactose | 65 | 46
Honey | 83 | 58
High fructose corn syrup | 89 | 62
Sucrose | 92 | 64
Glucose | 137 | 96
Glucose tablets | 146 | 102
Maltodextrin | 150 | 105
Maltose | 150 | 105
Pineapple juice | 66 | 46
Peach, canned | 67 | 47
Grapefruit juice | 69 | 48
Orange juice | 74 | 52
Barley flour bread | 95 | 67
Wheat bread, high fiber | 97 | 68
Wheat bread, wholemeal flour | 99 | 69
Melba toast | 100 | 70
Wheat bread, white | 101 | 71
Bagel, white | 103 | 72
Kaiser rolls | 104 | 73
Whole-wheat snack bread | 105 | 74
Bread stuffing | 106 | 74
Wheat bread, Wonderwhite | 112 | 78
Wheat bread, gluten free | 129 | 90
French baguette | 136 | 95
Taco shells | 97 | 68
Cornmeal | 98 | 69
Millet | 101 | 71
Rice, Pelde | 109 | 76
Rice, Sunbrown Quick | 114 | 80
Tapioca, boiled with milk | 115 | 81
Rice, Calrose | 124 | 87
Rice, parboiled, low amylose Pelde | 124 | 87
Rice, white, low amylose | 126 | 88
Rice, instant, boiled 6 min | 128 | 90

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GLYCEMIC LIST
White Bread
Glucose Based

But there are many reasons to question that theory.

Oxidation of sugar is metabolically efficient in many ways, including sparing oxygen consumption. It produces more carbon dioxide than oxidizing fat does, and carbon dioxide has many protective functions, including increasing Krebs cycle activity and inhibiting toxic damage to proteins. The glycation of proteins occurs under stress, when less carbon dioxide is being produced, and the proteins are normally protected by carbon dioxide.

When sugar (or starch) is turned into fat, the fats will be either saturated, or in the series derived from omega -9 monounsaturated fatty acids. When sugar isn't available in the diet, stored glycogen will provide some glucose (usually for a few hours, up to a day), but as that is depleted, protein will be metabolized to provide sugar. If protein is eaten without carbohydrate, it will stimulate insulin secretion, lowering blood sugar and activating the stress response, leading to the secretion of adrenalin, cortisol, growth hormone, prolactin, and other hormones. The adrenalin will mobilize glycogen from the liver, and (along with other hormones) will mobilize fatty acids, mainly from fat cells. Cortisol will activate the conversion of protein to amino acids, and then to fat and sugar, for use as energy. (If the diet doesn't contain enough protein to maintain the essential organs, especially the heart, lungs, and brain, they are supplied with protein from the skeletal muscles. Because of the amino acid composition of the muscle proteins, their destruction stimulates the formation of additional cortisol, to accelerate the movement of amino acids from the less important tissues to the essential ones.)

The diabetic condition is similar in many ways to stress, inflammation, and aging, for example in the chronic elevation of free fatty acids, and in various mediators of inflammation, such as tumor necrosis factor (TNF).

Rather than the sustained hyperglycemia which is measured for determining the glycemic index, I think the diabetogenic or carcinogenic action of starch has to do with the stress reaction that follows the intense stimulation of insulin release. This is most easily seen after a large amount of protein is eaten. Insulin is secreted in response to the amino acids, and besides stimulating cells to take up the amino acids and convert them into protein, the insulin also lowers the blood sugar. This decrease in blood sugar stimulates the formation of many hormones, including cortisol, and under the influence of cortisol both sugar and fat are produced by the breakdown of proteins, including those already forming the tissues of the body. At the same time, adrenalin and several other hormones are causing free fatty acids to appear in the blood.

Since the work of Cushing and Houssay, it has been understood that blood sugar is controlled by antagonistic hormones: Remove the pituitary along with the pancreas, and the lack of insulin doesn't cause hyperglycemia. If something increases cortisol a little, the body can maintain normal blood sugar by secreting more insulin, but that tends to increase cortisol production. A certain degree of glycemia is produced by a particular balance between opposing hormones.

Tryptophan, from dietary protein or from the catabolism of muscles, is turned into serotonin which activates the pituitary stress hormones, increasing cortisol, and intensifying catabolism, which releases more tryptophan. It suppresses thyroid function, which leads to an increased need for the stress hormones. Serotonin impairs glucose oxidation, and contributes to many of the problems associated with diabetes.

Diabetes is often the diagnosis, when excess cortisol is the problem. The hormones have traditionally not been measured before diagnosing diabetes and prescribing insulin or other chemical to lower the blood sugar. Some of the worst effects of diabetes, including retinal damage, are caused or exacerbated by insulin itself.

Antiserotonin drugs can sometimes alleviate stress and normalize blood sugar. Simply eating sucrose was recently discovered to restrain the stress hormone system (A new perspective on glucocorticoid feedback: relation to stress, carbohydrate feeding and feeling better, J Neuroendocrinol 13(9), 2001, KD Laugero).

The free fatty acids released by the stress hormones serve as supplemental fuel, and increase the consumption of oxygen and the production of heat. (This increased oxygen demand is a problem for the heart when it is forced to oxidize fatty acids. [A. Grynberg, 2001]) But if the stored fats happen to be polyunsaturated, they damage the blood vessels and the mitochondria, suppress thyroid function, and cause glycation of proteins. They also damage the pancreas, and impair insulin secretion.

A repeated small stress, or overstimulation of insulin secretion, gradually tends to become amplified by the effects of tryptophan and the polyunsaturated fatty acids, with these fats increasing the formation of serotonin, and serotonin increasing the liberation of the fats.

The name, glycation, indicates the addition of sugar groups to proteins, such as occurs in diabetes and old age, but when tested in a controlled experiment, lipid peroxidation of polyunsaturated fatty acids produces the protein damage about 23 times faster than the simple sugars do (Fu, et al., 1996). And the oxidation of fats rather than glucose means that the proteins won't have as much protective carbon dioxide combined with their reactive nitrogen atoms, so the real difference in the organism is likely to be greater than that seen by Fu, et al.

These products of lipid peroxidation, HNE, MDA, acrolein, glyoxal, and other highly reactive aldehydes, damage the mitochondria, reducing the ability to oxidize sugar, and to produce energy and protective carbon dioxide.

Fish oil, which is extremely unstable in the presence of oxygen and metals such as iron, produces some of these dangerous products very rapidly. The polyunsaturated essential fatty acids and their products, arachidonic acid and many of the prostaglandin-like materials, also produce them.

When glucose can't be oxidized, for any reason, there is a stress reaction, that mobiles free fatty acids. Drugs that oppose the hormones (such as adrenalin or growth hormone) that liberate free fatty acids have been used to treat diabetes, because lowering free fatty acids can restore glucose oxidation.

Brief exposures to polyunsaturated fatty acids can damage the insulin-secreting cells of the pancreas, and the mitochondria in which oxidative energy production takes place. Prolonged exposure causes progressive damage. Acutely, the free polyunsaturated fatty acids cause capillary permeability to increase, and this can be detected at the beginning of insulin resistance or diabetes. After chronic exposure, the leakiness increases and albumin occurs in the urine, as proteins leak out of the blood vessels. The retina and brain and other organs are damaged by the leaking capillaries.

The blood vessels and other tissues are also damaged by the chronically increased cortisol, and at least in some tissues (the immune system is most sensitive to the interaction) the polyunsaturated fats increase the ability of cortisol to kill the cells.

When cells are stressed, they are likely to waste glucose in two ways, turning some of it into lactic acid, and turning some into fatty acids, even while fats are being oxidized, in place of the sugar that is available. Growth hormone and adrenalin, the stress-induced hormones, stimulate the oxidation of fatty acids, as well as their liberation from storage, so the correction of energy metabolism requires the minimization of the stress hormones, and of the free fatty acids. Prolactin, ACTH, and estrogen also cause the shift of metabolism toward the fatty acids.

Sugar and thyroid hormone (T3, triiodothyronine) correct many parts of the problem. The conversion of T4 into the active T3 requires glucose, and in diabetes, cells are deprived of glucose. Logically, all diabetics would be functionally hypothyroid. Providing T3 and sugar tends to shift energy metabolism away from the oxidation of fats, back to the oxidation of sugar.

Niacinamide, used in moderate doses, can safely help to restrain the excessive production of free fatty acids, and also helps to limit the wasteful conversion of glucose into fat. There is evidence that diabetics are chronically deficient in niacin. Excess fatty acids in the blood probably divert tryptophan from niacin synthesis into serotonin synthesis.

Sodium, which is lost in hypothyroidism and diabetes, increases cellular energy. Diuretics, that cause loss of sodium, can cause apparent diabetes, with increased glucose and fats in the blood. Thyroid, sodium, and glucose work very closely together to maintain cellular energy and stability.

In Houssay's experiments, sugar, protein, and coconut oil protected mice against developing diabetes. The saturated fats of coconut oil are similar to those we synthesize ourselves from sugar. Saturated fats, and the polyunsaturated fats synthesized by plants, have very different effects on many important physiological processes. In every case I know about, the vegetable polyunsaturated fats have harmful effects on our physiology.

For example, they bind to the receptor proteins for cortisol, progesterone, and estrogen, and to all of the major proteins related to thyroid function, and to the vesicles that take up nerve transmitter substances, such as glutamic acid.

They allow glutamic acid to injure and kill cells through excessive stimulation; this process is similar to the nerve damage done by cobra venom, and other toxins.

Excess cortisol makes nerve cells more sensitive to excitotoxicity, but the cells are protected if they are provided with an unusually large amount of glucose.

The cells of the thymus gland are very sensitive to damage by stress or cortisol, but they too can be rescued by giving them enough extra glucose to compensate for the cortisol. Polyunsaturated fatty acids have the opposite effect, sensitizing the thymus cells to cortisol. This partly accounts for the immunosuppressive effects of the polyunsaturated fats. (AIDS patients have increased cortisol and polyunsaturated fatty acids in their blood.[E.A. Nunez, 1988.])

Unsaturated fatty acids activate the stress hormones, sugar restrains them.

Simply making animals deficient in the unsaturated vegetable oils (which allows them to synthesize their own series of animal polyunsaturated fats, which are very stable), protects them against autoimmune diabetes, and against a variety of other immunological challenges. The essential fatty acid deficiency increases the oxidation of glucose, as it increases the metabolic rate generally.

Saturated fats improve the insulin-secreting response to glucose.

The protective effects of sugar, and the harmful effects of excessive fat metabolism, are now being widely recognized, in every field of physiology. The unsaturated vegetable fats, linoleic and linolenic acid and their derivatives, such as arachidonic acid and the long chain fish oils, have excitatory, stress promoting effects, that shift metabolism away from the oxidation of glucose, and finally destroy the respiratory metabolism altogether. Since cell injury and death generally involve an imbalance between excitation and the ability to produce energy, it is significant that the oxidation of unsaturated fatty acids seems to consume energy, lowering cellular ATP (Clejan, et al, 1986).

The bulk of the age-related tissue damage classified as glycation end-products (or advanced glycation end-products, AGE) is produced by decomposition of the polyunsaturated fats, rather than by sugars, and this would be minimized by the protective oxidation of glucose to carbon dioxide.

Protein of the right kind, in the right amount, is essential for reducing stress. Gelatin, with its antiinflammatory amino acid balance, helps to regulate fat metabolism.

Aspirin's antiinflammatory actions are generally important when the polyunsaturated fats are producing inflammatory and degenerative changes, and aspirin prevents many of the problems associated with diabetes, reducing vascular leakiness. It improves mitochondrial respiration (De Cristobal, et al., 2002) and helps to regulate blood sugar and lipids (Yuan, et al., 2001). Aspirin's broad range of beneficial effects is probably analogous to vitamin E's, being proportional to protection against the broad range of toxic effects of the polyunsaturated essential fatty acids.

REFERENCES

Diabetes Care 1993 Sep;16(9):1301-5. Metabolic effects of dietary sucrose in type II diabetic subjects. Bantle JP, Swanson JE, Thomas W, Laine DC CONCLUSIONS--A high sucrose diet did not adversely affect glycemia or lipemia in type II diabetic subjects.

Am J Physiol 1997 Nov;273(5 Pt 1):C1732-8. Glycolysis inhibition by palmitate in renal cells cultured in a two-chamber system. Bolon C, Gauthier C, Simonnet H palmitate promoted a long-term decrease in lactate production and sustained excellent cellular growth. After 4 days of contact, decreased glycolysis was maintained even in the absence of carnitine.

Diabetes 1989 Oct;38(10):1314-9. Effects of fish oil supplementation on glucose and lipid metabolism in NIDDM. Borkman M, Chisholm DJ, Furler SM, Storlien LH, Kraegen EW, Simons LA, Chesterman CN. Garvan In summary, dietary fish oil supplementation adversely affected glycemic control in NIDDM subjects without producing significant beneficial effects on plasma lipids. The effect of safflower oil supplementation was not significantly different from fish oil, suggesting that the negative effects on glucose metabolism may be related to the extra energy or fat intake. Randomized Controlled Trial

Ann Clin Lab Sci 1988 Jul-Aug;18(4):337-43. Effects of peroxidized polyunsaturated fatty acids on mitochondrial function and structure: pathogenetic implications for Reye's syndrome. Brown RE, Bhuvaneswaran C, Brewster M. Linoleic acid, a polyunsaturated fatty acid, is a constituent of margosa oil which has been implicated as a cause of Reye's syndrome (RS) in infants. Increased concentrations of polyunsaturated fatty acids have been found in sera from patients with RS. Isolated rat liver mitochondria exposed to the peroxidized (but not unperoxidized) methyl esters of linoleic (C18:2) or linolenic (C18:3) acids showed decreases in state 3 and uncoupled respiratory rates and in respiratory control and ADP/O ratios. In addition, they caused mitochondrial swelling as demonstrated spectrophotometrically. Between the two, the peroxidized methyl ester of linolenic acid was more toxic and was capable of inducing high amplitude swelling ultrastructurally similar to that seen in the hepatocytes of RS victims. The ability of rat liver mitochondria to oxidize glutamate was inversely related to the peroxide concentration in the medium.

J Neurochem 1982 Feb;38(2):525-31. Phospholipid degradation and cellular edema induced by free radicals in brain cortical slices. Chan PH, Yurko M, Fishman RA. These data suggest that lipases are activated by free radicals and lipid peroxides in the pathogenesis of cellular swelling.

J Neurochem 1988 Apr;50(4):1185-93. Induction of intracellular superoxide radical formation by arachidonic acid and by polyunsaturated fatty acids in primary astrocytic cultures. Chan PH, Chen SF, Yu AC. Other PUFAs, including linoleic acid, linolenic acid, and docosahexaenoic acid, were also effective in stimulating NBF formation in astrocytes, whereas saturated palmitic acid and monounsaturated oleic acid were ineffective. Similar effects of these PUFAs were observed in malondialdehyde formation in cells and lactic acid accumulation in incubation medium. These data indicate that both membrane integrity and cellular metabolism were perturbed by arachidonic acid and by other PUFAs.

Can J Biochem 1978 Feb;56(2):111-6. Uncoupling activity of endogenous free fatty acids in rat liver mitochondria. Chan SH, Higgins E Jr.

J Neurochem 1980 Oct;35(4):1004-7. Transient formation of superoxide radicals in polyunsaturated fatty acid-induced brain swelling. Chan PH, Fishman RA. The polyunsaturated fatty acids linoleic acid (18:2), linolenic acid (18:3), arachidonic acid (20:4), and docosahexaenoic acid (22:6) caused brain swelling concomitant with increases in superoxide and membrane lipid peroxidation. Palmitic acid (16:0) and oleic acid (18:1) had no such effect. These in vitro data support the hypothesis that both superoxide radicals and lipid peroxidation are involved in the mechanism of polyunsaturated fatty acid-induced brain edema.

Arch Biochem Biophys 1986 May 1;246(2):820-8. Effect of growth hormone on fatty acid oxidation: growth hormone increases the activity of 2,4-dienoyl-CoA reductase in mitochondria. Clejan S, Schulz H. Rates of respiration supported by polyunsaturated fatty acylcarnitines, in contrast to rates observed with palmitoylcarnitine or oleoylcarnitine, were slightly lower in hypophysectomized rats than in normal rats, but were higher in hypophysectomized rats treated with growth hormone. The effects were most pronounced with docosahexaenoylcarnitine, the substrate with the highest degree of unsaturation. Since uncoupling of mitochondria with 2,4-dinitrophenol resulted in lower rates of docosahexaenoylcarnitine-supported respiration, while substitution of ATP for ADP yielded higher rates, it appears that energy is required for the effective oxidation of polyunsaturated fatty acids. Growth hormone treatment of hypophysectomized rats caused a threefold increase in t`he activity of 2,4-dienoyl-CoA reductase or 4-enoyl-CoA reductase (EC 1.3.1.34) in mitochondria, but not in peroxisomes. Rates of acetoacetate formation from linolenoylcarnitine, but not from palmitoylcarnitine, were stimulated by glutamate in mitochondria from hypophysectomized rats and hypophysectomized rats treated with growth hormone. All data together lead to the conclusion that the mitochondrial oxidation of highly polyunsaturated fatty acids is limited by the availability of NADPH and the activity of 2,4-dienoyl-CoA reductase which is induced by growth hormone treatment.

V. Coiro, et al., "Low-dose ovine corticotropin-releasing hormone stimulation test in diabetes mellitus with or without neuropathy," Metabolism--Clinical and Experimental 44(4), 538-542, 1995. "...basal and CRH-induced cortisol levels were significantly higher in diabetics than in normal controls." "...even uncomplicated diabetes mellitus is associated with adrenal hyperfunction."

Stroke 2002 Jan;33(1):261-7. Inhibition of glutamate release via recovery of ATP levels accounts for a neuroprotective effect of aspirin in rat cortical neurons exposed to oxygen-glucose deprivation. De Cristobal J, Cardenas A, Lizasoain I, Leza JC, Fernandez-Tome P, Lorenzo P, Moro MA. Aspirin is preventive against stroke not only because of its antithrombotic properties but also by other direct effects. Aspirin inhibited OGD-induced neuronal damage at concentrations lower (0.3 mmol/L) than those reported to act via inhibition of the transcription factor nuclear factor-kappaB (which are >1 mmol/L), an effect that correlated with the inhibition caused by aspirin on glutamate release. This effect was shared by sodium salicylate but not by indomethacin, thus excluding the involvement of cyclooxygenase. A pharmacological dissection of the components involved indicated that aspirin selectively inhibits the increase in extracellular glutamate concentration that results from reversal of the glutamate transporter, a component of release that is due to ATP depletion. Moreover, aspirin-afforded neuroprotection occurred in parallel with a lesser decrease in ATP levels after OGD. Aspirin elevated ATP levels not only in intact cortical neurons but also in isolated brain mitochondria, an effect concomitant with an increase in NADH-dependent respiration by brain submitochondrial particles. Taken together, our present findings show a novel mechanism for the neuroprotective effects of aspirin, which takes place at concentrations in the antithrombotic-analgesic range, useful in the management of patients with high risk of ischemic events.

Diabetes 2002 Jun;51(6):1825-33. The composition of dietary fat directly influences glucose-stimulated insulin secretion in rats. Dobbins RL, Szczepaniak LS, Myhill J, Tamura Y, Uchino H, Giacca A, McGarry JD. Insulin responses during hyperglycemic clamps were augmented by saturated but not unsaturated fat (580 +/- 25, 325 +/- 30, and 380 +/- 50 pmol x l(-1) x min(-1) in Lard, Soy, and Low-Fat groups, respectively). These data indicate that prolonged exposure to saturated fat enhances GSIS (but this does not entirely compensate for insulin resistance), whereas unsaturated fat, given in the diet or by infusion, impairs GSIS.

C. Douillet and M. Ciavatti, "Effect of vitamin E treatment on tissue fatty acids and cholesterol content in experimental diabetes," J. Nutr. Biochem. 6(6), 319-326, 1995. "Diabetes induced a decrease of monounsaturated fatty acids and particularly palmitoleic acid in all studied tissues: liver, aorta, plasma." C18:3 n-6 and C20:4 n-6 were increased by diabetes.

Diabetologia 1992 Feb;35(2):165-72. Long-term effects of linoleic-acid-enriched diet on albuminuria and lipid levels in type 1 (insulin-dependent) diabetic patients with elevated urinary albumin excretion. Dullaart RP, Beusekamp BJ, Meijer S, Hoogenberg K, van Doormaal JJ, Sluiter WJ. We conducted a 2-year prospective randomised study to investigate the effects of a linoleic-acid-enriched diet on albuminuria and lipid levels in Type 1 (insulin-dependent) diabetic patients with elevated urinary albumin excretion (overnight urinary albumin excretion rate between 10 and 200 micrograms/min). Clinical characteristics, albuminuria, blood pressure, glomerular filtration rate, metabolic control and dietary composition were similar in the two groups at baseline. In the high linoleic acid diet group, linoleic intake rose from 7 +/- 4 to 11 +/- 2 energy % and polyunsaturated:saturated fatty acids ratio rose from 0.60 +/- 0.28 to 0.96 +/- 0.16 (p less than 0.001 compared to usual diet group). The median increase albuminuria was 58% (95% confidence interval, 13 to 109) during the first year (p less than 0.02) and 55% (95% confidence interval, 11 to 127) (p less than 0.01) during the second year.

J Biol Chem 1996 Apr 26;271(17):9982-6. The advanced glycation end product, Nepsilon-(carboxymethyl)lysine, is a product of both lipid peroxidation and glycoxidation reactions. Fu MX, Requena JR, Jenkins AJ, Lyons TJ, Baynes JW, Thorpe SR. Nepsilon-(Carboxymethyl)lysine (CML) is an advanced glycation end product formed on protein by combined nonenzymatic glycation and oxidation (glycoxidation) reactions. We now report that CML is also formed during metal-catalyzed oxidation of polyunsaturated fatty acids in the presence of protein. During copper-catalyzed oxidation in vitro, the CML content of low density lipoprotein increased in concert with conjugated dienes but was independent of the presence of the Amadori compound, fructoselysine, on the protein. CML was also formed in a time-dependent manner in RNase incubated under aerobic conditions in phosphate buffer containing arachidonate or linoleate; only trace amounts of CML were formed from oleate. After 6 days of incubation the yield of CML in RNase from arachidonate was approximately 0.7 mmol/mol lysine compared with only 0.03 mmol/mol lysine for protein incubated under the same conditions with glucose. Glyoxal, a known precursor of CML, was also formed during incubation of Rnase with arachidonate. These results suggest that lipid peroxidation, as well as glycoxidation, may be an important source of CML in tissue proteins in vivo and that CML may be a general marker of oxidative stress and long term damage to protein in aging, atherosclerosis, and diabetes.

J Nutr 2000 Oct;130(10):2503-7. A high carbohydrate versus a high monounsaturated fatty acid diet lowers the atherogenic potential of big VLDL particles in patients with type 1 diabetes. Georgopoulos A, Bantle JP, Noutsou M, Hoover HA. A high (25%) monounsaturated fatty acid (Mono) diet and a high (61%) carbohydrate (CHO) diet were provided for 4 wk in a randomized crossover design to 19 normolipidemic, nonobese patients with type 1 diabetes. The two diets were matched for protein, polyunsaturated/saturated fatty acids, cholesterol and fiber content. We conclude that a high CHO diet might be preferable to a high Mono diet, on the basis of the premise that more big VLDL particles could increase the atherosclerotic risk in patients with diabetes.

J. Girard, "Role of free fatty acids in insulin resistance of subjects with non-insulin-dependent diabetes," Diabetes Metab. 21(2), 79-88, 1995. "Studies performed in the rat suggest that impaired glucose-induced insulin secretion could also be related to chronic exposure of pancreatic beta cells to elevated plasma free fatty acid levels."

Ann Intern Med 1988 May;108(5):663-8. Adverse metabolic effect of omega-3 fatty acids in non-insulin-dependent diabetes mellitus. Glauber H, Wallace P, Griver K, Brechtel G. Increased interest in using omega-3 fatty acids led us to examine their metabolic effects in six men with type II (non-insulin-dependent) diabetes mellitus. After 1 month of a diet supplemented with these fatty acids, the patients' fasting glucose rose from 13.1 +/- 1.3 to 15.3 +/- 1.3 mmol/L (P = 0.03) and glucose area during a mixed meal profile rose by 22% (P = 0.04). After omega-3 fatty acid withdrawal, fasting glucose returned to baseline. Omega-3 fatty acid treatment in type II diabetes leads to rapid but reversible metabolic deterioration, with elevated basal hepatic glucose output and impaired insulin secretion but unchanged glucose disposal rates. Caution should be used when recommending omega-3 fatty acids in type II diabetic persons.

A. Golay, et al., "Effect of lipid oxidation on the regulation of glucose utilization in obese patients," Acta Diabetologica 32(1), 44-48, 1995. [Free fatty acids strongly and quickly depress the ability to oxidize or store glucose.]

Biol Neonate 1985;47(6):343-9. Increased maternal-fetal transport of fat in diabetes assessed by polyunsaturated fatty acid content in fetal lipids. Goldstein R, Levy E, Shafrir E. The distribution of fatty acids was determined by gas-liquid chromatography in total lipid and triglyceride fraction of extracts of several tissues of streptozotocin-diabetic rats and their fetuses on day 20 of pregnancy. In maternal rats, diabetes did not significantly affect fatty acid distribution apart from small changes in the relative content of linoleate in adipose tissue and liver. In the placenta, the fetal carcass and the fetal liver the triglyceride content increased approximately 2-fold as a result of maternal diabetes, in association with the elevation in triglycerides and free fatty acids in the maternal circulation. A pronounced increase in the relative content of linoleate was recorded in the total lipid and triglyceride extracts of placenta (35 and 59%), fetal carcass (56 and 66%) and fetal liver (100 and 205%). Small increases in arachidonate proportion were also seen in some fetal tissues. The large increase in fetal hepatic linoleate indicates that this tissue is an important uptake target of maternal lipids transported in excess into the fetus. The results confirm the previous observations on increased transplacental fat passage in diabetes by demonstrating that the increment in the essential fatty acid, linoleate, parallels the diabetes-induced triglyceride accumulation in the fetoplacental unit.

A. Gomes, et al., "Anti-hyperglycemic effect of black tea (Camellia sinensis) in rat," J. of Ethnopharmacology 45(3), 223-226, 1995. It "was found to possess both preventive and curative effects on experimentally produced diabetes in rats."

J Endocrinol 2002 Apr;173(1):73-80. Acute effects of fatty acids on insulin secretion from rat and human islets of Langerhans. Gravena C, Mathias PC, Ashcroft SJ. Long-chain fatty acids (palmitate and stearate) were more effective than medium-chain (octanoate). Saturated fatty acids (palmitate, stearate) were more effective than unsaturated (palmitoleate, linoleate, elaidate).

Diabetes Metab 2001 Nov;27(5 Pt 2):S12-9. [Modifications in myocardial energy metabolism in diabetic patients]] [Article in French] Grynberg A. Because FA is the main heart fuel (although the most expensive one in oxygen, and prompt to induce deleterious effects), this process is based on a balanced fatty acid (FA) metabolism. Several pathological situations are associated with an accumulation of FA or derivatives, or with an excessive b-oxidation. The diabetic cardiomyocyte is characterised by an over consumption of FA. The control of the FA/glucose balance clearly appears as a new strategy for cytoprotection, particularly in diabetes and requires a reduced FA contribution to ATP production. Cardiac myocytes can control FA mitochondrial entry, but display weak ability to control FA uptake, thus the fate of non beta-oxidized FA appear as a new impairment for the cell. Sudden death, hypercatecholaminemia, diabetes and heart failure have been associated with an altered PUFA content in cardiac membranes.

Diabetologia 1996 Mar;39(3):251-5. Acceleration of experimental diabetic retinopathy in the rat by omega-3 fatty Acids. Hammes HP, Weiss A, Fuhrer D, Kramer HJ, Papavassilis C, Grimminger F. Omega-3 fatty acids exert several important biological effects on factors that may predispose to diabetic retinopathy. Potential pathogenetic mechanisms include platelet dysfunction, altered eicosanoid production, increased blood viscosity in association with impaired cell deformability and pathologic leucocyte/endothelium interaction. Therefore, we tested whether a 6-month administration of fish oil (750 mg Maxepa, 5 times per week), containing 14% eicosapentaenoic acid (EPA) and 10% docosahexaenic acid, could inhibit the development of experimental retinopathy of the streptozotocin-diabetic rat. The efficiency of fish oil supplementation was evaluated by measuring EPA concentrations in total, plasma and membrane fatty acids and by measuring the generation of lipid mediators (leukotrienes and thromboxanes). Retinal digest preparations were quantitatively analysed for pericyte loss, and the formation of acellular capillaries. Omega-3 fatty acid administration to diabetic rats resulted in a twofold increase of EPA 20:5 in total fatty acids, and a reduction of the thromboxane ratio from 600 (untreated diabetic rats) to 50 (treated diabetic rats). Despite these biochemical changes, diabetes-associated pericyte loss remained unaffected and the formation of acellular, occluded capillaries was increased by 75% in the fish oil treated diabetic group (115.1 +/- 26.8; untreated diabetic 65.2 +/- 15.0 acellular capillary segments/mm2 of retinal area). We conclude from this study that dietary fish oil supplementation may be harmful for the diabetic microvasculature in the retina.

Y. Hattori, et al., "Phorbol esters elicit Ca++-dependent delayed contractions in diabetic rat aorta," Eur. J. Pharmacol. 279(1), 51-58, 1995. [Diabetic tissue is more responsive to activation of protein kinase C by phorbol esters.]

Nutr Metab 1975;18(1):41-8. Adipose tissue metabolism in essential fatty acid deficienty. Effects of prostaglandin e1, epinephrine, and ACTH. Hazinski TA, Barr M, Hertelendy F. In an effort to better define some of the metabolic changes that accompany essential fatty acid deficiency (EFAD), we studied glucose metabolism in adipose tissue of EFAD and normal mice under basal conditions and in the presence of prostaglandin E1 (PGE1), epinephrine, and ACTH1-18. Isolated fat cells were incubated in Krebs-Ringer bicarbonate medium containing glucose 1(-14C) or 6(-14C), and the incorporation of radioactive carbon into CO2, total fat, fatty acids, and glyceride-glycerol was determined. It was found that EFAD increased glucose uptake over controls which could be attributed to increased oxidation to CO2 and fatty acid synthesis. The contribution of the pentose cycle to glucose oxidation was 50-80% higher in EFAD adipocytes as compared to controls. ACTH1-18 (0.1 mug/ml) suppressed this by 18 and 30% in the control and EFAD groups, respectively, while epinephrine decreased pentose cycle activity by 83 and 55% in the two groups, respectively. PGE1 alone had no significant effect, but in combination with epinephrine it abolished the inhibitory action of the catecholamine in both groups.

J Neurosci Res 1989 Oct;24(2):247-50. Brain mitochondrial swelling induced by arachidonic acid and other long chain free fatty acids. Hillered L, Chan PH. Polyunsaturated fatty acids (PUFAs), arachidonic acid in particular, are well known, potent inducers of edema in the brain, while monounsaturated and saturated long chain fatty acids do not possess this quality. ATP-MgCl2 both prevented and reversed this swelling, while binding of the 20:4 by the addition of bovine serum albumin could only prevent but not reverse the swelling. Moreover, reversal of the swelling occurred without recovery of respiratory function.

J Neurosci Res 1988 Aug;20(4):451-6. Role of arachidonic acid and other free fatty acids in mitochondrial dysfunction in brain ischemia. Hillered L, Chan PH.

B. A. Houssay and C. Martinez, "Experimental diabetes and diet," Science 105, 548-549, 1947. [Mortality was zero on the high coconut oil diet, 100% on the high lard diet. It was 90% on the low protein diet, and 33% on the high protein diet. With a combination of coconut oil and lard, 20%.]

B. A. Houssay, et al., "Accion de la administracion prolongada de glucosa sobre la diabetes de la rata," Rev. Soc. argent. de biol. 23, 288-293, 1947.

S. Ikemoto, et al., "High fat diet-induced hyperglycemia: Prevention by low level expression of a glucose transporter (GLUT4) minigene in transgenic mice," Proc. Nat. Acad. Sci. USA 92(8), 3096-3099, 1995. "...mice fed a high-fat (safflower oil) diet develop defective glycemic control, hyperglycemia, and obesity."

M. Inaba, et al., "Influence of high glucose on 1,25-dihydroxyvitamin D-3-induced effect on human osteoblast-like MG-63 cells," J. Bone Miner. Res. 10(7), 1050-1056, 1995.

J. S. Jensen, et al., "Microalbuminuria reflects a generalized transvascular albumin leakiness in clinically healthy subjects," Clin. Sci. 88(6), 629-633, 1995.

J Am Geriatr Soc 1984 May;32(5):375-9. Low triiodothyronine and raised reverse triiodothyronine levels in patients over fifty years of age who have type II diabetes mellitus: influence of metabolic control, not age. Kabadi UM, Premachandra BN. Several studies have demonstrated that the uncontrolled diabetic state in both type I as well as type II diabetes mellitus is characterized by altered thyroid hormone metabolism, which results in the lowering of serum triiodothyronine (T3) levels and a reciprocal elevation of T3 (rT3) levels. Serum T3 levels declined and rT3 levels rose in the diabetic patients with worsening of the metabolic control.

Metabolism 1989 Mar;38(3):278-81. The effect of fatty acids on the vulnerability of lymphocytes to cortisol. Klein A, Bruser B, Malkin A. We have shown previously that cortisol-sensitive lymphocytes (thymocytes) have a much lower capacity than cortisol-resistant cells to catabolize cortisol and that linoleic acid inhibits the catabolism of cortisol by lymphocytes and modulates the sensitivity of lymphocytes to cortisol. Measuring the effect of fatty acids on cortisol catabolism by lymphocytes indicated that the polyunsaturated fatty acids, linoleate, arachidonate, and eicosapentaenoic, inhibit cortisol catabolism by lymphocytes. Examining the effect of fatty acids on the vulnerability of lymphocytes to cortisol, we noted that saturated fatty acids had no significant effect, whereas the aforementioned polyunsaturated fatty acids make lymphocytes more sensitive to cortisol.

Jpn J Pharmacol 1978 Apr;28(2):277-87. Relationship between cerebral energy failure and free fatty acid accumulation following prolonged brain ischemia. Kuwashima J, Nakamura K, Fujitani B, Kadokawa T, Yoshida K, Shimizu M. Mitochondria isolated from the ischemic brain showed an impairment of oxidative phosphorylation. The ischemic brain was also characterized by remarkable accumulation of free fatty acids known to have properties as an uncoupling factor. These results indicate that cerebral energy failure in the ischemic brain is related to the accumulation of free fatty acids, which are derived from endogenous brain lipids.

Probl Endokrinol (Mosk) 1992 Nov-Dec; 38(6):53-4. [Effect of protein content in rat diet on water-soluble vitamin metabolism in streptozotocin-induced diabetes] [Article in Russian] Kodentsova VM, Sadykova RE, Dreval' AV, Vrzhesinskaia OA, Sokol'nikov AA, Beketova NA. Water-soluble group B vitamins metabolism was studied over the course of streptozotocin-induced diabetes mellitus in rats fed semisynthetic isocaloric diets containing 18 and 50% of protein. A high-protein diet in diabetes mellitus does not influence riboflavin metabolism disordered in this disease but reduced 4-pyridoxyl acid excretion to the level characteristic of healthy animals. The observed trend to an increase of liver nicotinamide coenzymes levels and of 1-methylnicotinamide urinary excretion reflects increased niacin synthesis from the diet protein tryptophan, for niacin level is reduced in diabetes.

M. Kusunoki, et al., "Amelioration of high fat feeding-induced insulin resistance in skeletal muscle with the antiglucocorticoid RU486," Diabetes 44(6), 718-720, 1995. "These results suggest that glucocorticoids play, in a tissue-specific manner, a role in the maintenance and/or production of insulin resistance produced by high-fat feeding."

J Neuroendocrinol 2001 Sep;13(9):827-35. A new perspective on glucocorticoid feedback: relation to stress, carbohydrate feeding and feeling better. Laugero KD. In this review, I discuss findings that have led us to view glucocorticoid feedback in the HPA axis in a new light. Much of what has precipitated this view comes from a very surprising finding in our laboratory; sucrose ingestion normalizes feeding, energy balance and central corticotropin releasing factor expression in adrenalectomized (ADX) rats. Taken together, recent findings of the well-known importance of glucocorticoids to feeding and energy balance, and the modulatory actions of carbohydrate ingestion on both basal and stress-induced activity in the HPA axis, strongly suggest that many metabolic (e.g. obesity) and psychological (e.g. depression) pathologies, which often present together and have been associated with stress and HPA dysregulation, might, in part, be understood in light of our new view of glucocorticoid feedback.

Endocrinology 2001 Jul;142(7):2796-804. Sucrose ingestion normalizes central expression of corticotropin-releasing-factor messenger ribonucleic acid and energy balance in adrenalectomized rats: a glucocorticoid-metabolic-brain axis? Laugero KD, Bell ME, Bhatnagar S, Soriano L, Dallman MF. Both CRF and norepinephrine (NE) inhibit food intake and stimulate ACTH secretion and sympathetic outflow. CRF also increases anxiety; NE increases attention and cortical arousal. Adrenalectomy (ADX) changes CRF and NE activity in brain, increases ACTH secretion and sympathetic outflow and reduces food intake and weight gain; all of these effects are corrected by administration of adrenal steroids. Unexpectedly, we recently found that ADX rats drinking sucrose, but not saccharin, also have normal caloric intake, metabolism, and ACTH. Voluntary ingestion of sucrose restores CRF and dopamine-beta-hydroxylase messenger RNA expression in brain, food intake, and caloric efficiency and fat deposition, circulating triglyceride, leptin, and insulin to normal.

A. Lazarow, "Protection against alloxan diabetes," Anat. Rec. 97, 353, 1947.

A. Lazarow, "Protective effect of glutathione and cysteine against alloxan diabetes in the rat," Proc. Soc. Exp. Biol. & Med. 61, 441-447, 1946. [While certain doses of cysteine, glutathione, and thioglycolic acid completely prevented alloxan diabetes, it was interesting that all of the rats receiving ascorbic acid became diabetic. To me, this argues for the free radical cause of diabetes, rather than just the sulfhydryl oxidation. Lazarow suggested that succinic dehydrogenase, and various other sulfhydryl enzymes, including those involved in fatty acid oxidation, might be involved.]

Minerva Endocrinol 1990 Oct-Dec;15(4):273-7. [Postprandial thermogenesis and obesity: effects of glucose and fructose]. [Article in Italian] Macor C, De Palo C, Vettor R, Sicolo N, De Palo E, Federspil G. Energy expenditure was calculated both in basal conditions and during the test (resting metabolic rate: RMR) using indirect calorimetry expressed per kg of lean weight, as assessed using bioimpedance measurement techniques. Blood samples were collected to assay glycemia and insulinemia. Results show that increased RMR induced by glucose was significantly reduced in the group of obese subjects compared to controls. In the same group of obese subjects, RMR was found to be significantly higher following fructose in comparison to the glucose response but did not differ from that in controls. Data confirm the existence of reduced thermogenesis in obese subjects induced by glucose. The fact that this phenomenon was not recorded in the same subjects following the fructose tolerance test, whose metabolism is insulin-independent, supports the hypothesis that reduced glucose-induced thermogenesis in obese subjects may depend on insulin resistance.

Diabetes Care 2000 Oct;23(10):1472-7. Dietary unsaturated fatty acids in type 2 diabetes: higher levels of postprandial lipoprotein on a linoleic acid-rich sunflower oil diet compared with an oleic acid-rich olive oil diet. Madigan C, Ryan M, Owens D, Collins P, Tomkin GH.

Proc Natl Acad Sci U S A 1990 Nov;87(22):8845-9. Incorporation of marine lipids into mitochondrial membranes increases susceptibility to damage by calcium and reactive oxygen species: evidence for enhanced activation of phospholipase A2 in mitochondria enriched with n-3 fatty Acids. Malis CD, Weber PC, Leaf A, Bonventre JV. Mitochondrial site 1 (NADH coenzyme Q reductase) activity was reduced to 45 and 85% of control values in fish-oil- and beef-tallow-fed groups, respectively. Exposure to Ca2+ and reactive oxygen species enhance the release of polyunsaturated fatty acids enriched at the sn-2 position of phospholipids from mitochondria of fish-oil-fed rats when compared with similarly treated mitochondria of beef-tallow-fed rats. Phospholipase A2 activity and mitochondrial damage are enhanced when mitochondrial membranes are enriched with n-3 fatty acids.

FEBS Lett 1998 Oct 16:437(1-2):24-8. Generation of protein carbonyls by glycoxidation and lipoxidation reactions with autoxidation products of ascorbic acid and polyunsaturated fatty acids. Miyata T, Inagi R, Asahi K, Yamada Y, Horie K, Sakai H, Uchida K, Kurokawa K. In vitro incubation of proteins with ascorbic acid accelerated the production of protein carbonyls as well as CML and pentosidine, and incubation with arachidonate accelerated the production of protein carbonyls as well as CML, MDA, and HNE. By contrast, incubation of proteins with glucose resulted in the production of CML and pentosidine, but not protein carbonyls. The present study suggests that ascorbate and polyunsaturated fatty acids, but not glucose, represent potential sources of protein carbonyls, and that both the glycoxidation and lipoxidation reactions contribute to protein carbonyl formation in aging and various diseases.

Chem Phys Lipids 1996 Jan 25;79(1):47-53. Previously unknown aldehydic lipid peroxidation compounds of arachidonic acid. Mlakar A, Spiteller G. Lehrstuhl fr Organische Chemie I, Arachidonic acid was oxidized by iron ascorbate. The main aldehydic lipid peroxidation product was found to be the well-known 4-hydroxy-2-nonenal (HNE), but 2-hydroxy heptanal (HH) -- a previously unknown lipid peroxidation product of arachidonic acid -- was detected to be nearly equally abundant. Malondialdehyde (MDA), glyoxal and 2-hydroxy-4-decenal (HDE) were detected to be produced in up to 100 times lower amounts compared to HNE.. . . . Since this and analogous hydroxy acids (LOHs) are the main biological degradation products of hydroperoxides of unsaturated acids (LOOHs) their further peroxidation seems to be a main source of toxic aldehydes.

J Clin Endocrinol Metab 2000 Dec;85(12):4515-9. Acute fructose administration decreases the glycemic response to an oral glucose tolerance test in normal adults. Moore MC, Cherrington AD, Mann SL, Davis SN. In animal models, a small (catalytic) dose of fructose administered with glucose decreases the glycemic response to the glucose load. In conclusion, low dose fructose improves the glycemic response to an oral glucose load in normal adults without significantly enhancing the insulin or triglyceride response. Fructose appears most effective in those normal individuals who have the poorest glucose tolerance.

Tumour Biol 1988;9(5):225-32. Modulation of cell-mediated immune response by steroids and free fatty acids in AIDS patients: a critical survey. Nunez EA. The overall data presented in this review show that cortisol and free fatty acids, in particular long-chain polyunsaturated fatty acids, each have immunoinhibitory properties on lymphoblastic transformation of certain T lymphocytes. This effect is enhanced when the two factors are associated. These data could explain in part the immunosuppression observed in acquired immunodeficiency syndrome (AIDS) patients where enhanced concentrations of cortisol and polyunsaturated fatty acids have been observed. These new weapons could be the administration of diets or treatments (liposomes) modifying the lipid profile of circulating cells and/or viruses and the utilization of hormonal therapy in AIDS and in some types of cancer which often present a biologic picture similar to that of AIDS.

Diabetes Care 1984 Sep-Oct;7(5):465-70. Effect of protein ingestion on the glucose and insulin response to a standardized oral glucose load. Nuttall FQ, Mooradian AD, Gannon MC, Billington C, Krezowski P. The plasma glucose area above the baseline following a glucose meal was reduced 34% when protein was given with the glucose. The insulin area following glucose was only modestly greater than with a protein meal (97 +/- 35, 83 +/- 19 microU X h/ml, respectively). When various amounts of protein were given with 50 g glucose, the insulin area response was essentially first order. Subsequently, subjects were given 50 g glucose or 50 g glucose with 50 g protein as two meals 4 h apart in random sequence. The insulin areas were not significantly different for each meal but were higher when protein + glucose was given. After the second glucose meal the plasma glucose area was 33% less than after the first meal. Following the second glucose + protein meal the plasma glucose area was markedly reduced, being only 7% as large as after the first meal. These data indicate that protein given with glucose will increase insulin secretion and reduce the plasma glucose rise in at least some type II diabetic persons. Randomized Controlled Trial

Biochem J 1985 Sep 1;230(2):329-37. Inhibitory effects of some long-chain unsaturated fatty acids on mitochondrial beta-oxidation. Effects of streptozotocin-induced diabetes on mitochondrial beta-oxidation of polyunsaturated fatty acids. Osmundsen H, Bjornstad K. Evidence showing that some unsaturated fatty acids, and in particular docosahexaenoic acid, can be powerful inhibitors of mitochondrial beta-oxidation is presented. This inhibitory property is, however, also observed with the cis- and trans-isomers of the C18:1(16) acid. Hence it is probably the position of the double bond(s), and not the degree of unsaturation, which confers the inhibitory property. It is suggested that the inhibitory effect is caused by accumulation of 2,4-di- or 2,4,7-tri-enoyl-CoA esters in the mitochondrial matrix.

Free Radic Biol Med 1999 Oct;27(7-8):901-10. Thyroid status modulates glycoxidative and lipoxidative modification of tissue Proteins. Pamplona R, Portero-Otin M, Ruiz C, Bellmunt MJ, Requena JR, Thorpe SR, Baynes JW, Romero M, Lopez-Torres M, Barja G. Steady state protein modification by carbonyl compounds is related to the rate of carbonyl adduct formation and the half-life of the protein. Thyroid hormones are physiologic modulators of both tissue oxidative stress and protein degradation. The levels of the glycation product N(epsilon)-fructoselysine (FL) and those of the oxidation products, N(epsilon)-(carboxymethyl)lysine (CML) and malondialdehyde-lysine (MDA-lys), identified by GC/MS in liver proteins, decreased significantly in hyperthyroid rats, as well as (less acutely) in hypothyroid animals. Immunoblotting of liver proteins for advanced glycation end-products (AGE) is in agreement with the results obtained by GC/MS. Cytosolic proteolytic activity against carboxymethylated foreign proteins measured in vitro was significantly increased in hypo- and hyperthyroidism. Oxidative damage to DNA, estimated as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8oxodG), did not show significant differences between groups. The results suggests that the steady state levels of these markers depend on the levels of thyroid hormones, presumably through their combined effects on the rates of protein degradation and oxidative stress, whereas DNA is more protected from oxidative damage.

Metabolism 1999 Mar;48(3):406-9. The blood vessel, linchpin of diabetic lesions. Plante GE, Alfred J, Chakir M. The morbidity and mortality associated with diabetes mellitus are essentially related to the vascular lesions that develop over time in this condition. Both the macrocirculation and microcirculation are involved, and as a consequence, vital organs such as the brain, retina, heart, and kidney and the limbs become damaged. Changes in the structure of conduit arteries, partly responsible for the alteration in compliance characteristics, could well be related to the way these arteries are fed by the vasa vasorum system. Preliminary results indicate that the size of terminal arterioles of the vasa vasorum (increased diameter) and the capillary permeability to albumin (markedly enhanced) in this specialized network are profoundly affected in the thoracic aorta obtained from diabetic animals. Albumin extravasation into the interstitial fluid compartment of the aorta is likely to lead to structural and physicochemical changes: in fact, removal of interstitial macromolecules via lymphatic drainage is poor in the blood vessel wall of large arteries.

Metabolism 2001 Dec;50(12):1472-8. Serum phospholipid fatty acid composition and insulin action in type 2 diabetic patients. Pelikanova T, Kazdova L, Chvojkova S, Base J. Increased contents of highly unsaturated n-6 family FA (P <.01), arachidonic acid in particular . . . were found in all groups of diabetics compared with HS [healthy subjects], while lower levels of linoleic acid were seen in DMN (P <.001) and DMH (P <.05). The contents of saturated FA and monounsaturated FA were comparable in HS, DMN, and DMD.

J Clin Invest 2002 Mar;109(6):805-15. Acute intensive insulin therapy exacerbates diabetic blood-retinal barrier breakdown via hypoxia-inducible factor-1alpha and VEGF. Poulaki V, Qin W, Joussen AM, Hurlbut P, Wiegand SJ, Rudge J, Yancopoulos GD, Adamis AP. Here we demonstrate that acute intensive insulin therapy markedly increases VEGF mRNA and protein levels in the retinae of diabetic rats. Blood-retinal barrier breakdown is markedly increased with acute intensive insulin therapy. . . . To our knowledge, these data are the first to identify a specific mechanism for the transient worsening of diabetic retinopathy, specifically blood-retinal barrier breakdown, that follows the institution of intensive insulin therapy.

Acta Endocrinol (Copenh) 1992 Apr;126(4):378-80. Lipid peroxidation in early experimental diabetes in rats: effects of diabetes and insulin. Rungby J, Flyvbjerg A, Andersen HB, Nyborg K. In the kidney, lipid peroxidation was increased after one week of diabetes; insulin treatment reduced the level of lipid peroxidation to levels lower than seen in controls. In the liver, diabetes caused an increased lipid peroxidation, which could be reversed by insulin; no additional effect of insulin was found. In heart and pancreas no effects of diabetes or insulin were demonstrated. The present paper provides evidence that lipid peroxidation is increased in the early stages of experimental diabetes and is reversible by insulin treatment. Hyperinsulinaemia may, in itself, counteract lipid peroxidation in kidney.

Br J Nutr 1997 Sep;78(3):459-67. Influence of dietary protein and fat on serum lipids and metabolism of essential fatty acids in rats. Ratnayake WM, Sarwar G, Laffey P. A In general, the concentrations of serum triacylglycerols and total cholesterol and liver phospholipid levels of arachidonic acid (AA) and docosahexaenoic acid (DHA) were higher in rats fed on casein diets compared with those fed on the gelatin diets. These effects were more pronounced in rats fed on the high-casein (300 g/kg)-high-fat (150 g/kg) diet. Gelatin was hypocholesterolaemic and also suppressed the liver phospholipid levels of AA and DHA (reported for the first time). The difference in the amino acid composition between casein and gelatin may be responsible for the observed effects. Casein contains higher levels of glutamic acid, methionine, phenylalanine and tyrosine, while gelatin contains higher levels of arginine, glycine and hydroxyproline.

Br Med J 1979 Jun 30;1(6180):1753-6. Improved glucose control in maturity-onset diabetes treated with high-carbohydrate-modified fat diet. Simpson RW, Mann JI, Eaton J, Moore RA, Carter R, Hockaday TD. Fourteen patients with established maturity-onset diabetes were treated as outpatients with a high-carbohydrate-(about 60% of total daily energy requirements)-modified fat diet (ratio of polyunsaturated fatty acids to other fatty acids greater than or equal to 1:1) for six weeks. The findings suggest that it is no longer justifiable to prescribe a low-carbohydrate diet for maturity-onset diabetes.

Postgrad Med J 1981 Aug;57(670):511-5. Severe hypertriglyceridaemia responding to insulin and nicotinic acid therapy. Smith SR. Treatment with insulin and restriction of dietary carbohydrate led to a 50% reduction in the triglyceride concentration, and the addition of nicotinic acid in modest doses led ultimately to a complete normalization of the patient's lipid values. A close correlation was noted between the falling triglyceride concentration and the rising serum sodium concentration during the course of successful therapy. Overall, it is felt likely that this patient's severe and reversible hypertriglyceridaemia was on the basis of excessively rapid lipolysis leading to high concentrations of very low density lipoprotein production.

Am J Clin Nutr 1993 Nov;58(5 Suppl):766S-770S. Fructose and dietary thermogenesis. Tappy L, Jequier E. Fructose ingestion induces a greater thermogenesis than does glucose. This can be explained by the hydrolysis of 3.5-4.5 mol ATP/mol fructose stored as glycogen, vs 2.5 mol ATP/mol glucose stored. Therefore the large thermogenesis of fructose corresponds essentially to an increase in obligatory thermogenesis. Obese individuals and obese patients with non-insulin-dependent diabetes mellitus commonly have a decrease in glucose-induced thermogenesis. These individuals in contrast display a normal thermogenesis after ingestion of fructose. This may be explained by the fact that the initial hepatic fructose metabolism is independent of insulin.

Diabetes 2002 Jun;51(6):1772-8. Inhibition of interleukin-1beta-induced COX-2 and EP3 gene expression by sodium salicylate enhances pancreatic islet beta-cell function. Tran PO, Gleason CE, Robertson RP.

Proc Natl Acad Sci U S A 1998 Apr 28;95(9):4882-7. Protein-bound acrolein: potential markers for oxidative stress. Uchida K, Kanematsu M, Sakai K, Matsuda T, Hattori N, Mizuno Y, Suzuki D, Miyata T, Noguchi N, Niki E, Osawa T. Acrolein (CH2==CH---CHO) is known as a ubiquitous pollutant in the environment. Here we show that this notorious aldehyde is not just a pollutant, but also a lipid peroxidation product that could be ubiquitously generated in biological systems. Upon incubation with BSA, acrolein was rapidly incorporated into the protein and generated the protein-linked carbonyl derivative, a putative marker of oxidatively modified proteins under oxidative stress. Immunohistochemical analysis of atherosclerotic lesions from a human aorta demonstrated that antigenic materials recognized by mAb5F6 indeed constituted the lesions, in which intense positivity was associated primarily with macrophage-derived foam cells and the thickening neointima of arterial walls. The observations that (i) oxidative modification of low-density lipoprotein with Cu2+ generated the acrolein-low-density lipoprotein adducts and (ii) the iron-catalyzed oxidation of arachidonate in the presence of protein resulted in the formation of antigenic materials suggested that polyunsaturated fatty acids are sources of acrolein that cause the production of protein-bound acrolein. These data suggest that the protein-bound acrolein represents potential markers of oxidative stress and long-term damage to protein in aging, atherosclerosis, and diabetes.

J Intern Med 1990 Aug;228(2):165-71. Dietary supplementation with n-3 fatty acids may impair glucose homeostasis in patients with non-insulin-dependent diabetes mellitus. Vessby B, Boberg M. The blood glucose concentration tended to increase during MaxEPA treatment, and to decrease during the placebo period, the changes under the two regimes being significantly different (P less than 0.01). In addition, the rate constant for glucose disappearance (k value) for the intravenous insulin-tolerance test, which reflected the peripheral insulin sensitivity, tended to decrease during MaxEPA treatment and increase during administration of the placebo, there being a significant difference (P less than 0.03) between the changes during the two treatments. The reason for the observed changes in blood glucose concentration and peripheral insulin sensitivity is still unclear.

Diabet Med 1992 Mar;9(2):126-33. Polyunsaturated fatty acids may impair blood glucose control in type 2 diabetic Patients. Vessby B, Karlstrom B, Boberg M, Lithell H, Berne C. Average blood glucose concentrations during the third week were significantly higher fasting (+15%, p less than 0.01), and during the day at 1100 h (+18%, p less than 0.001) and 1500 h (+17%, p = 0.002) on PUFA than on the saturated fat diet.

Drugs 1999;58 Suppl 1:31-9; discussion 75-82. The antihyperglycaemic effect of metformin: therapeutic and cellular mechanisms. Wiernsperger NF, Bailey CJ Other effects involved in the blood glucose-lowering effect of metformin include an insulin-independent suppression of fatty acid oxidation and a reduction in hypertriglyceridaemia. These effects reduce the energy supply for gluconeogenesis and serve to balance the glucose-fatty acid (Randle) cycle.

J Biol Chem 2001 Mar 30;276(13):9800-7. Polyunsaturated fatty acids suppress hepatic sterol regulatory element-binding protein-1 expression by accelerating transcript decay. Xu J, Teran-Garcia M, Park JH, Nakamura MT, Clarke SD. Our initial studies indicated that the induction of SREBP-1 expression by insulin and glucose was blocked by PUFA. Nuclear run-on assays suggested PUFA reduced SREBP-1 mRNA by post-transcriptional mechanisms. Although the mechanism by which PUFA accelerate SREBP-1 mRNA decay remains to be determined, cloning and sequencing of the 3'-untranslated region for the rat SREBP-1 transcript revealed the presence of an A-U-rich region that is characteristic of a destablizing element.

Recent Adv Stud Cardiac Struct Metab 1976 May 26-29;12:271-7. Arrhythmogenic effects of acute free fatty acid mobilization on ischemic heart. Yamazaki N, Suzuki Y, Kamikawa T, Ogawa K, Mizutani K, Kakizawa N, Yamamoto M.

Science 1978 Jul 28;201(4353):358-60. Brain edema: induction in cortical slices by polyunsaturated fatty acids. Chan PH, Fishman RA The presence of polyunsaturated and saturated fatty acids in leukocytic membranes prompted study of their possible role in the induction of brain edema. Polyunsaturated fatty acids including sodium arachidonate, sodium linoleate, sodium linolenate, and docasahexaenoic acids induced edma in slices of rat brain cortex. This cellular edema was specific, since neither saturated fatty acids nor a fatty acid containing a single double bond had such effect.

J Neurochem 1986 Oct;47(4):1181-9. Effects of arachidonic acid on glutamate and gamma-aminobutyric acid uptake in primary cultures of rat cerebral cortical astrocytes and neurons. Yu AC, Chan PH, Fishman RA. Arachidonic acid inhibited glutamate uptake in both astrocytes and neurons. The inhibitory effect was observed within 10 min of incubation with arachidonic acid and reached approximately 80% within 120 min in both types of culture. The arachidonic acid effect was not only time-dependent, but also dose-related. Arachidonic acid, at concentrations of 0.015 and 0.03 mumol/mg protein, significantly inhibited glutamate uptake in neurons, whereas 20 times higher concentrations were required for astrocytes. The effects of arachidonic acid were not as deleterious on GABA uptake as on glutamate uptake in both astrocytes and neurons. Other polyunsaturated fatty acids, such as docosahexaenoic acid, affected amino acid uptake in a manner similar to arachidonic acid in both astrocytes and neurons. However, saturated fatty acids, such as palmitic acid, exerted no such effect.

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A R T I C L E

How do you know? Students, patients, and discovery

For the real world has inexhaustible splendour, the real life is full of meaning and abundance, where we grasp it, it is full of miracles and glory. N. Hartmann

"I am myself plus my circumstances" Jose Ortega y Gasset

Knowledge should be useful and provisional.

I think comparing the doctor-patient relationship with the teacher-student relationship can be useful, and it might suggest ways that both of them could be made more productive, with implications for the nature of learning and knowing.

40 or 50 years ago, advocates of student-centered education were encouraged by the popularity of psychologist Carl Rogers' client centered therapy. Rogers was interested in what made some therapists successful, and he found that their personality and attitude, not their theories or techniques, accounted for their success. Successful therapists had three essential traits. They offered their clients acceptance or unconditional positive regard and empathic understanding, and they themselves were congruent, not presenting a facade of authority or esoteric knowledge. According to Rogers, accurate diagnosis and specific treatment didn't have anything to do with helping the client.

Some therapists thought Rogers' approach was impractical, others were sure it was foolish. Medically oriented psychiatrists saw Roger's prestige among psychologists as evidence that psychology wasn't suited for dealing with the mentally ill, who needed authoritative diagnosis and treatment--such as drugs, convulsive shock, or surgery. Scientifically, however, Rogers' ideas were supported by evidence, and medical psychiatry had no evidence to support many of its diagnostic concepts or their therapeutic usefulness.

Most university professors felt that Rogers' ideas were irrelevant to their educational work, and some clearly saw their own function as being a sort of Malthusian selection of the fittest, and deliberately designed their classes as barriers that only a few could surmount.

When I taught English composition, instructors were told that they must grade according to a standard scoring system for errors of grammar, punctuation, spelling, and diction. Our success was seen in terms of the number of freshmen who had dropped out by the end of the year, as evidence that the department had high standards. Knowing that system, most students chose to write in the style of the first grade See Spot run readers, hoping that they could handle the mechanics of writing if they reduced the complexity and content of their essays. It didn't work, and they didn't improve during the weeks when their mistakes were being brought painfully to their attention. Since I hated reading their meaningless efforts, I told them that I was going to grade them on content, rather than punctuation and spelling, and that they should try to write about something that was important to them. Only their success in communicating something would be graded. Their papers became more readable, and the interesting thing was that the mechanical things improved immediately. (The intention to communicate something is the real source of structure in language.) I had another teacher score some of their compositions, and he confirmed that they had improved according to the department's system. The attempt to steer a person can make it hard for them to move, because it inactivates their own guidance system.

A physics professor would notice that writing classes have a lot in common with psychotherapy, and would dismiss the possibility that such an approach could be used in serious education.

Professors of medicine see themselves as models of the authority that their students will need to apply in dealing with patients, and the physicians trained in the authoritarian style are likely to see their patients as recipients of their medical knowledge, rather than as occasions for listening and learning something new.

Students entering these disciplines must expect to be disciplined. This means that they learn not to ask silly questions about the fundamental assumptions of their profession. Their common sense of meaning, their original guidance system, must be inactivated to keep them from asking questions such as is that a disease or a theory? Some patients find that their physician has little patience for their questions, but most patients don't want to ask questions, because they have been taught to respect the authorities.

Our nervous systems are made up of physiology and culture.

That can be a philosophical problem, because our experience is governed by our composition. In people like Heraclitus, physiology was in the foreground, and in people like Plato, culture was in the foreground. (Heraclitus understood that things are always becoming, Plato believed that change wasn't real.) To change someone's mind, it's necessary to change the way they experience themselves and the world, and that requires changing their substance.

In the 1950s a group called Synectics was formed to study the creative process. They found that having an expert in the group could be useful, but it could also often stifle the group's ability to find a good solution to a problem. W.J.J. Gordon described their method as "trusting things that are alien, and alienating things that are trusted." They used metaphorical thinking to help them to see the complexity and potentiality of a situation, and to go beyond the existing understanding.

Professors and physicians too often present themselves as having definitive knowledge about a subject. For people who already have definitive knowledge about something, anomalous facts (if they are perceived at all) will simply remain anomalous and will be quickly forgotten. The things they produce will be extensions of what already exists. For others, things that aren't easily explained have special interest, and cause them to ask new questions. New perspectives can lead to new possibilities and new realities.

Once during a lecture, Alfred Korzybski offered his students some cookies, which they seemed to enjoy, then he showed them a label on the bag, dog cookies, and some of them felt sick. "I have just demonstrated that people don't just eat food, but also words, and that the taste of the former is often outdone by the taste of the latter." Hypnotists have often demonstrated that words can have physiological effects.

Many of our institutions use language as a system for preserving culture, that is, for preventing change. Korzybski wanted to correct the cultural habit of making abstractions seem like objects or elements, by making people aware of the degree of abstraction in their words. This can be useful, but his book has been used to promote an extreme linguistic relativism in the theory of knowledge and science, placing meaning entirely within the nervous system.

This approach evades the fact that patterns exist objectively, and that they can be perceived as they unfold through time. Although Korzybski thought he was teaching people to overcome the limitations of thinking in the style of Aristotle or Plato, he was supporting an attitude that would make it impossible to perceive in the style of Heraclitus.

If Heraclitus said it's impossible to step in the same river twice, his comment was directed to those who ignore the rich complexity of experience because of stereotyped elemental thinking. He was pointing to the abundance of the world, but elemental-concept thinkers have felt that he simply negated their objective meanings.

To perceive another person accurately requires the ability to perceive the person as a pattern unfolding coherently through time, as a potential realizing itself. Carl Rogers' insight was that one's awareness of being perceived in this way encourages the unfolding of potentials.

The refusal of institutions or individuals to perceive others in this way is an imposition of their way of understanding, and is itself a form of oppression. People who think in terms of professional training often describe learning in terms of conditioned reflexes, producing a desired response to each stimulus.

The terms conditioned reflex and conditioning were introduced into psychology by the behaviorist J. B. Watson, who mistranslated and misrepresented Pavlov's ideas, and who insisted that the ideas of consciousness, volition, and self should be eliminated from the science of psychology.

The orienting reflex, the alertness provoked by something new, was described by Sechenov in 1863, and explored by Pavlov (who also called it the what is that? reflex and the exploration reflex) who considered it to be our most basic and most powerful reflex. The fact that novelty powerfully arouses our exploratory systems means that we have a mental image of our familiar environment, and that a change in that environment requires us to investigate the properties of the new thing, to see whether it can be explained by the things we already know, or whether it requires us to change our basic ideas about our place in our surroundings. For Pavlov, the study of psychology or physiology without consciousness was simply crazy.

Pavlov said that he studied nutrition to understand consciousness and the nervous system, because eating is our closest interaction with the world. Our brain is part of our digestive system. But eating has become highly institutionalized and influenced by our cultural beliefs. If people begin to think about the meanings of eating, they are beginning a process of cultural and philosophical criticism.

Helping people with physical problems (such as obesity, headaches or joint or nerve pain, or named diseases) and helping people who want to understand something about the world beyond themselves, are structurally similar, but in the issues of health the questions and the potential answers are more clearly present and immediate.

The Synectics group began with the study of artistic creation, but they found that it was easier to evaluate their progress when they concentrated on technical invention. They found, as Pavlov had, that consciousness and meaning could best be studied in concrete situations. The process of goal-seeking was to be studied in action.

I see the therapeutic or educational or productive situation as a goal-directed biological and social interaction, and the goal can be either the creation of something new and better, or simply the preservation and application of something already existing.

Until just about a generation ago, teleology (especially in biological explanation) was considered to be metaphysical and inappropriate for science. Norbert Wiener, who coined the word cybernetics (from Greek for proficient pilot or good steersman) helped to change attitudes toward the word when he used the phrase teleological mechanism to describe cybernetic control systems.

A goal-directed system is one that senses its actions and makes adaptations so that its actions can be refined to achieve a purpose. Between 1932 and 1935, a student and colleague of Pavlov's, P.K. Anokhin, developed this idea of self-regulating systems, and originated the concept of feedback, in describing the ways organisms guide themselves and their adaptations. Building on Pavlov's work, and investigating the origins of innate reflexes, he found principles that would explain the origin of organs and their functions, and that would also apply to the interactions between individuals. The functional system on any level, in embryology, psychology, or society, is a sequence of interactions with a useful result. Movement towards a goal is adaptive, and the system is shaped by the adaptations it makes in moving toward the goal. Resources are mobilized to meet needs, changing the system as it moves towards its goal.

Since there is always novelty in the real world as contexts change, the exploratory function is causing us to continually revise our understanding. Every question forms a functional system, and our brain adapts as we find answers.

This kind of systems theory and self-regulation theory developed along with the field theories in embryology, psychology, chemistry, and some branches of physics. Pattern and analogy were central to their approach. The functional systems are processes that occupy time and space.

The field idea in biology (wholes shaping themselves) can be understood by considering its opposite, the belief that cells are guided by their genes (producing a mosaic of parts). That idea, in its extreme form, claimed that cells contained an internal map and an internal clock telling them when and where to move and how to change their form and function as they matured and aged. In reality, cells communicate with surrounding cells and with the material between cells. The existence of long-range ordering processes between atoms, molecules, and cells threatened some of the central dogmas of the sciences.

Although Norbert Wiener popularized some aspects of the teleological approach to regulatory systems in the 1950s, and saw analogies between the teleological machines and the way the brain functions in Parkinson's disease, by 1950 the digital approach to information processing, storage, and transmission was displacing analog devices in computation and engineering, and was compatible with theories of intelligence, such as neo-Kantianism, that believed that human intelligence can be defined precisely, in terms of discrete rules and operations. Field thinking in embryology, cancer theory, psychology, and other sciences effectively disappeared--or was disappeared, for ideological reasons.

Wiener's goal-directed machines, like Anokhin's functional systems, worked in space and time, and the idea of steering or guidance assumes a context of time and space in which the adjustments or adaptations are made. Analog computers and control systems in various ways involved formal parallels with reality. The components of the system, like reality, occupied space and time.

Digital computers, with their different history and functions, for example their use for creating or breaking military codes, didn't intrinsically model reality in any way. Information had to be encoded and processed by systems of definitions. A sequence of binary digits has meaning only in terms of someone's arbitrary definitions.

Parallel with the development of electronic digital computing machines, binary digital theories of brain function were being developed, by people who subscribed to views of knowledge very different from those of Anokhin and Wiener. (Anokhin argued against the idea that nerves use a simple binary code.) These computer models of intelligence justify educational practices based on authoritative knowledge and conditioned (arbitrary) reflexes. Neo-Kantianism has been the dominant academic philosophy in the U.S., turning philosophy into epistemology to exclude ontology. "Operationism" and logical positivism share with neo-Kantianism its elimination of ontology (concern with being itself).

In the 1960s, Ludwig von Bertalanffy developed a theory of systems, defining a system as an arrayed multitude of inter-linked elements. Although it was intended as a description of biological systems, it reduced the teleological factors, needs and goals, to a kind of mechanical inner program, such as regulatory genes. Following old modes of thought, some called this orderliness of life 'purposiveness' and sought for the 'purpose' of an organ or function. However, in the concept of a 'purpose' a desiring or intending of the goal always appeared to be involved--the type of idea to which the natural scientist is justly unsympathetic (von Bertalanffy).

His system theory was highly compatible with programmed digital computers, that could define the interactions of elements, but unlike Anokhin's definition of functional systems, it lacked a pattern-forming mechanism. In Anokhin's view, the system is formed by seeking its goal, and perceiving its progress toward the goal.

Carl Rogers' approach to person-centered processes recognized that the interacting therapist and client or teacher and student were a formative system, rather than just an occasion for one to inform the other.

In the Synectics group, they learned to identify the types of deeply involved interaction that would lead to the best inventions. As in Anokhin's functional systems, resources are mobilized or generated as they are needed. Like Anokhin, they showed that the process of creating something new can be understood and controlled.

Every meaningful interaction involves formative systems.

Stimulation of sensory nerves can cause cells to move into the stimulated area, causing the organ to grow. Environmental enrichment causes brains to become larger, and to metabolize at a higher rate. All of these processes, from the level of energy production to the birth of new cells and the creation of new patterns in the brain, are called up in the formation of a functional system.

The studies of organismic coherence by Mae-Wan Ho and Fritz Popp appear to support the idea that even the alignment of molecules in cells is responsive to the state of the entire organism.

The reason this seems implausible to most biologists is that cells are commonly still seen as analogous to little test-tubes in which chemical processes occur as the result of random collisions between molecules floating in water. But Sidney Bernhard's study of glycolysis showed that the reactive sugar molecules are passed individually from one enzyme to the next, in an orderly manner.

In this system, the flow of energy, a series of oxidations and reductions changing glucose into other substances, effectively pulls the molecules through the system, contributing to order on a molecular level. Function creates structure, which supports function.

Self-regulating systems are self-ordering systems. When a person is allowed to function freely as a goal-directed, questioning system, the formation of patterns in the brain will be spontaneous and appropriate, and orderly. Knowing is the ability to hold patterns in awareness. Knowledge, rather than being stored like money in the bank, is something that is regenerated, or generated, as we need it.

When our own steering system is commandeered by the authorities, our patterns of knowledge will be compartmented, and arranged in a fixed pattern. This kind of knowledge either deteriorates, or it seeks more of its own kind.

While self-regulation and the generation of knowledge are pleasurable, having knowledge imposed isn't.

Korzybski was right in warning about the dangers of letting names become elements. This perception led Paolo Freire to emphasize the educational importance of critically giving things their appropriate names, rather than just banking the names given by an authority. To exist, humanly, is to name the world, to change it. Once named, the world in its turn reappears to the namers as a problem and requires of them a new naming. Human beings are not built in silence, but in word, in work, in action-reflection. . . . to speak a true word is to transform the world. 'Problem-posing' education, responding to the essence of consciousness--intentionality--rejects communiques and embodies communication (Freire, 1993).

Having the power to assign names is a source of power and wealth. The pharmaceutical industry has been accused of inventing new diseases to sell new drugs for treating them. Old definitions of cancer are hard to change, when the medical profession has invested so much in treatments--radiation and cytotoxic chemotherapy--which conflict with newer biological understanding of cancer.

The person who is learning is critically interacting with both nature and culture, with practical issues and theories.

Applying this to practical problems of health and nutrition, a first step is to begin to think about which things are theories or deductions from theories, which are habits, and which things are felt needs or appetites, and to get in the habit of watching processes or things--such as signs and symptoms--develop through time.

With practice, people can begin to see themselves as functional systems in their main activities, such as eating, and to watch how their needs influence their actions, and what effects different ways of eating have on their other functions, such as sleeping and working. Do appetites govern the timing of meals and the choice of foods? How does the time of day or time of month affect appetites? People often watch for effects of foods, but usually only for a few minutes or hours after eating. Some foods can produce symptoms days after they were eaten, and the activation of the digestive system by a recent meal can cause a reaction to something eaten previously.

Our traditional cultures, and advertising and schools give us definitions and expectations relating to foods and symptoms and physiology, and they teach us to think of our bodies in terms of an immune system, endocrine system, digestive system, nervous system, and circulatory system, which are mainly anatomical concepts that are more useful to the drug companies than to the consumer of culture. Both conventional and alternative approaches to medicine and health are likely to let those arbitrary ideas of systems cause them to overlook real, but unnamed, processes.

When the organism is seen as a mosaic of parts, rather than as a system of developing fields, medical treatments for one part, such as the circulatory system, are likely to cause problems in other systems, because the parts being treated don't exist as such in the real organism, with the result that the treatments are seldom biologically reasonable.

Besides learning to perceive one's own physiology and becoming aware of the processes of perceiving and knowing so that they can be improved, it's important to seek information to expand the interpretive framework, and to look for new contexts and implications.

Reading with a critical imagination is as important for science as it is for literature or advertising. Good literature often opens expansive new ways of seeing the world, and good science writing can do that too, but too often scientific publications have ulterior motives, and should be read the way advertising propaganda is read.

Some publications now require authors to state their conflicts of interest (such as receiving money from a drug company while testing a drug), but editors and publishers, who choose which studies will be published, seldom reveal their conflicts of interest. As Marcia Angell showed, editorial choices can turn statistical randomness into statistical significance. Private ownership of science journals permits control of their content.

Besides being aware of the conflicts of interest and the frequent insignificance of statistical significance, it's possible to recognize some features of the style of argument which is often used in science propaganda. A deductive style, rather than a descriptive and inductive style is extremely common in technical writing, and it should always lead the reader to question the principle from which deductions are made.

Membranes are made from Essential Fatty Acids, therefore those fatty acids are nutritionally essential. But cells can multiply in a culture medium that provides no fats. In biology, the most popular principles are simply dogmatic beliefs about genes and membranes.

In physics, where testable inferences can be drawn from arbitrary assumptions or doctrines, predictions that may be made based on different assumptions are often ignored for ideological reasons. This ideological quality of physics can permeate the other sciences when they use reductionist explanations.

Korzybski felt he was helping humanity to escape word magic and to advance to a mathematical view of the world. But the same processes that caused people to confuse words with things can cause people to confuse mathematical descriptions with reality.

Chaos theory, which was a faddish excitement about the ability to generate unpredictable output from a simple rule (which could be endlessly repeated by a computer), has been suggested to explain many things in biology, including heart rate variability. It doesn't. Instead, it has probably had a slightly harmful effect, by distracting attention from real biological pattern- forming processes.

Real substance can sometimes be modeled by descriptions of randomness, but substances at all levels have intrinsic pattern-forming tendencies, and context-dependent histories. Water, for example, has structure and structural memory that can affect even simple chemical reactions, and even gases have internal complexities that are often ignored. Real observations shouldn't be displaced by theories. The ideal and identical atoms of the reductionists are a crude fantasy, invented, more or less consciously, to serve their ideological purposes. One purpose has been to justify their abstract models of reality. A particularly noxious way of modeling reality has been based on the assumption of randomness, justifying a statistical view of all things.

The neo-Kantian philosophy that has dominated US universities for more than a century argues that our senses (even when extended instrumentally) are limited, so our knowledge must be limited--we can only speak of theories or interpretations, not of being. The world we see is, according to them, only an artifact of our senses. A popular example is that the flower a bee sees is different from the flower a human sees, because the bee's eye is sensitive to ultraviolet light. (The triviality of the example is shown by the fact that when a person's lens is removed because of a cataract, ultraviolet light becomes visible, because it is no longer blocked by the tissue that is many times thicker than a bee's lens.) There is a straw-man quality to their arguments against philosophical realism and empirical science: No one claims that our senses deliver complete knowledge all at once. What the realists claim is that interacting with the world is an endless source of valid knowledge.

When reading science articles, or listening to lectures, and even while privately thinking about experiences, it can be useful to watch for the improper use of assumptions. Our understanding has been shaped by the assumptions of our culture, and these assumptions present an attitude toward the nature of the world, in some cases even about the ontology that our philosophers have said is beyond our reach. Evolution is shaped by random mutations, nuclear decay is random, the universe is expanding, entropy only increases, DNA controls inheritance, membrane pumps keep cells alive, and all of the negative assumptions that have for so long denied the systematic generation of order.

Every communicative interaction is an opportunity for the discovery of new meanings and potentials.

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Aristotelian motto: If the knower and the known form a functional system they are substantially the same.

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REFERENCES

P.K. Anokhin: 1975, The essays on physiology of functional systems.

1978, Philosophical aspects of the theory of functional systems.

1998, Cybernetics of functional systems: Selected works, Moscow, Medicine, 400 p., (in Russian).

Pedagogy of the Oppressed, by Paulo Freire. New York: Continuum Books, 1993.

Synectics, W.J.J. Gordon, Harper & Row, 1961.

Crystals, Fabrics, and Fields : Metaphors of Organicism in Twentieth-Century Developmental Biology, Donna Jeanne Haraway, 1976.

We Make the Road by Walking: Conversations on Education and Social Change, Myles Horton, Paolo Freire, 1990.

Science and Sanity, Alfred Korzybski, 1933.

Alfred Korzybski, "The Role of Language in the Perceptual Processes," in Perception: An Approach to Personality, edited by Robert R. Blake and Glenn V. Ramsey. 1951, The Ronald Press Company, New York.

Marshall McLuhan: ...the devil is in the media, quoted by Derrick DeKerkhove, Director of the McLuhan Program in Culture and Technology at the University of Toronto.

Biochemistry and Morphogenesis, by Joseph Needham. Cambridge University Press, 1942.

Cybernetics--or Control and Communication in the Animal and the Machine, Norbert Wiener 1948

The Human Use of Human Beings, The Riverside Press (Houghton Mifflin Co.), 1950.

...the rules of the war game never catch up with the facts of the real situation. The future offers very little hope for those who expect that our new mechanical slaves will offer us a world in which we may rest from thinking. Help us they may, but at the cost of supreme demands upon our honesty and our intelligence. Norbert Weiner, God and Golem, Inc., 1964.

Digital thinking sees the organism as a mosaic of parts, making rigid and specific naming essential; analog thinking sees the organism as fields in development, making flexibility in naming essential.

PS: When defense lawyers collaborate (collude) with prosecutors, it's considered a crime. What if physicians, instead of covering up for each other, used the adversary system that is supposed to produce the best knowledge in law and science, to evaluate their patient's diagnoses and treatments?

J Intern Med. 1999 Jan;245(1):57-61. Decreased heart rate variability in patients with type 1 diabetes mellitus is related to arterial wall stiffness. Jensen-Urstad K, Reichard P, Jensen-Urstad M.

Eur J Appl Physiol. 2010 Apr 23. Heart period sensitivity to forced oscillations in ventilatory pressure. Quint SR, Vaughn BV.

Copyright 2007. Raymond Peat, P.O. Box 5764, Eugene OR 97405. All Rights Reserved. www.RayPeat.com
Not for republication without written permission.

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A R T I C L E

Intelligence and metabolism

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Appropriate stimulation is an essential part of the developmental process. Inappropriate stimulation is a stress that deforms the process of growth. Mediators of stress, such as serotonin, can cause persistent distortions of physiology and behavior.

Education can either activate or suppress mental energy. If it is mainly obedience training, it suppresses energy. If it creates social dislocations, it disturbs mental and emotional energy.

Stress early in life can impair learning, cause aggressive or compulsive behavior, learned helplessness, shyness, alcoholism, and other problems.

Serotonin activates the glucocorticoid system, which can produce brain atrophy. Antiserotonin agents protect against brain atrophy and many other effects of stress. The brain-protecting neurosteroids, including pregnenolone and progesterone, which are increased by some kinds of stimulation, are decreased by isolation stress, and in their absence, serotonin and the glucocorticoids are relatively unopposed.

Since excess serotonin can cause thrombosis and vasospasms, and the excess cortisol resulting from hyperserotonemia can weaken blood vessels and the immune system, a person's longevity is likely to be shortened if something doesn't intervene to alter the patterns induced by stress early in life.

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Baroness Blatch: My Lords, the levels of achievement are well above the national average of our own state schools.

This is a school which attained 75 per cent A to C passes in 1998, and 63.9 per cent in 1999. Those figures are well above national averages. There is no truancy; and there is the highest possible level of parental satisfaction with the school. When those parents are paying their money and know what they are paying for, who are we to take a different view about the philosophy of education in a private school?

Comment during debate in House of Lords, June 30, 1999, on Chief Inspector of Schools Woodhead's threat to close Summerhill, a democratic school which had been started in 1921.

In 1927, the government inspectors had recommended that 'all educationalists' should come to Summerhill to see its 'invaluable' research, which demonstrated that students' development is better when they regulate themselves and are not required to attend lessons.

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Having written about animal intelligence, and the ways in which it is similar to human intelligence, now I want those ideas to serve as a context for thinking about human intelligence without many of the usual preconceptions.

Intelligence is an interface between physiology and the environment, so it's necessary to think about each aspect in relation to the other. Things, both biochemical and social, that enhance intelligence enhance life itself, and vice versa.

Psychologists have tried to give their own definitions to words like idiot, imbecile, moron, and genius, but they have just been refining the clichés of the culture, in which dummy is one of the first words that kids in the U.S. learn. Many psychologists have tried to create culture-free tests of intelligence, making it clear that they believe in something like innate animal intelligence, though they usually call it genetic intelligence. Other psychometrists have transcended not only biology but even rationality, and have catalogued the preferences of people that they define as intelligent, and designed I.Q. tests based on the selection of things that were preferred by intelligent people. This behavior is remarkably similar to the psychometry of the general culture, in which smart people are those who do things the right way.

About thirty years ago, someone found that the speed with which the iris contracts in response to a flash of light corresponds very closely to the I.Q. measured by a psychologist using a standard intelligence test. The devices used to measure reaction time in drivers' education courses also give a good indication of a person's intelligence, but so does measuring their heart rate, or taking their temperature. Colleges would probably be embarrassed to admit students on the basis of their temperature (though they commonly award scholarships on the basis of the ability to throw a ball). Colleges, to the extent that they are serious about the business of education, are interested in the student's ability to master the culture.

The way a person has learned during childhood can shape that person's manner of grasping the culture. To simply accelerate the learning of a standard curriculum will increase that person's I.Q. on a conventional test, but the important issue is whether it is really intelligent to learn and to value the things taught in those curricula. Some educators say that their purpose is to socialize and indoctrinate the students into their discipline, others believe their purpose is to help their students to develop their minds. Both of these approaches may operate within the idea that the culture is something like a museum, and that students should become curators of the collection, or of some part of it. If we see the culture metaphorically as a mixture of madhouse, prison, factory, and theater, the idea of developing the student's mind will suggest very different methods and different attitudes toward the curriculum

Even sophisticated people can fall into stereotyped thinking when they write about issues of intelligence. For example, no one considers it a sign of genius when a slum kid is fluent in both Spanish and English, but when some of history's brightest people are discussed, the fact that they learned classical Greek at an early age is always mentioned. No one mentions whether they were competent in idiomatic Spanish.

One of the old cultural stereotypes is that child prodigies always burn out, as if they were consuming a fixed amount of mental energy at an accelerated rate. (This idea of burn-out is isomorphic with the other cultural stereotypes relating aging to the rate of living, for example that people with slow heart beats will live longer.) Some of the men who have been considered as the world's brightest have, in fact, gone through a crisis of depression, and Terman's long-term study of bright people found that maladjustment did increase with I.Q., especially among women. But the facts don't support the concept of burn-out at all. I think the facts reveal instead a deep flaw in our ideas of education and professional knowledge.

In a world run by corporation executives, university presidents (football is central to the university's mission), congressmen, bankers, oilmen, and agency bureaucrats, people with the intelligence of an ant (a warm ant) might seem outlandishly intelligent. This is because the benighted self-interest of the self-appointed ruling class recognizes that objective reality is always a threat to their interests. If people, for example, realized that estrogen therapy and serotonin-active drugs and x-rays and nuclear power and atomic bomb tests were beneficial only to those whose wealth and power derive from them, the whole system would lose stability. Feigned stupidity becomes real stupidity.

But apart from ideologically institutionalized stupidity, there are real variations in the ability to learn, to remember and to apply knowledge, and to solve problems. These variations are generally metabolic differences, and so will change according to circumstances that affect metabolism. Everyday social experiences affect metabolism, stimulating and supporting some kinds of brain activity, suppressing and punishing others. All of the activities in the child's environment are educational, in one way or another.

Some of the famous prodigies of history illustrate the importance of ideology in the development of intellect. Family ideology, passing on the philosophical orientations of parents and their friends, shapes the way the children are educated.

Some of these family traditions can be traced by considering who the child's godfather was. Jeremy Bentham was John Stuart Mill's godfather, Mill was Bertrand Russell's; Ralph Waldo Emerson was William James' godfather, James was W. J. Sidis's. Willy Sidis was educated by his parents to demonstrate their theory of education, which grew out of the philosophies of Emerson and James. His father, Boris Sidis, was a pioneer in the study of hypnosis, and he believed that suggestion could mobilize the mind's reserve energy. Willy learned several languages and advanced mathematics at an early age. After he graduated from Harvard at the age of 16, he tried teaching math at Rice Institute, but he was displeased by the attitudes of his students and of the newspaper and magazine writers who made a profession of mocking him. He attended law school at Harvard, and would have been imprisoned as a conscientious objector if the war hadn't ended.

Antisemitism probably played a role in his sense of isolation when he was at Harvard and Rice. In 1912 Henry Goddard, a pioneer in intelligence testing (and author of The Kallikak Family: A Study in the Heredity of Feeble- Mindedness), administered intelligence tests to immigrants and determined that 83 percent of Jews and 87 percent of Russians were feeble-minded. By the standards of the time, it was highly inappropriate for the child of extremely poor Jewish immigrants from eastern Europe to be so bright.

Sidis hid from the press, and worked as a bookkeeper and clerk, while he studied and wrote. During his years of obscurity, he wrote books on philosophy and American history. Eventually, the journalists discovered him again, and after prolonged lawsuits against the magazines for invasion of privacy and slander, he died of a stroke at the age of 46.

Sidis is probably the culture's favorite example of the child prodigy who burns out, but people (Robert Persig, Buckminster Fuller) who have read his books have said favorable things about them. The journalists' emphasis on the fact that Sidis never held a prestigious job nicely illustrates their cliché mentality: If you're so smart, why aren't you rich? But throughout history, intelligent nonconformists have supported themselves as craft-workers or technicians--Socrates as a stone mason, Spinoza as a lens grinder, Blake as an engraver, Einstein as a patent examiner, for example.

In conventional schools (as in conventional society) 10,000 questions go unanswered, not only because a teacher with many students has no time to answer them, but also because most teachers wouldn't know most of the answers.

The parents of W. J. Sidis and J. S. Mill were remarkably well educated people who, because they dissented from society's ideology, chose to spend much of their time educating their children. Whenever a question about Euclidean geometry or Greek grammar occurred to the child, it could be answered immediately. It was only natural that progress would be fast, but there were more important differences.

When questions are answered, curiosity is rewarded, and the person is enlivened. In school, when following instructions and conforming to a routine is the main business, many questions must go unanswered, and curiosity is punished by the dulling emptiness of the routine.

Some schools are worse than others. For example, slum children were given I.Q. tests when they started school, and each subsequent year, and their I.Q.s dropped with each year of school. In a stimulating environment, the reverse can happen, the I.Q. can rise each year. Since the tests aren't culture free, their scores reflected the material that they were being taught, but they undoubtedly also reflected the increasing boredom and despair of the children in a bad school, or the increasing liveliness of the children in the stimulating environment.

I have spoken with people in recent years who still held the idea of a fixed genetic mental potential, who believe that poor children fall behind because they are reaching their genetic limit. For them, the I.Q. represents an index of intrinsic quality, and is as important as distinguishing between caviar and frogs' eggs. The rat research of Marion Diamond and others at the University of California, however, showed that the structure, weight, and biochemistry of a rat's brain changes, according to the amount of environmental stimulation and opportunity for exploration. This improvement of brain structure and function is passed on to the next generation, giving it a head-start. It isn't likely that rats are more disposed than humans to benefit from mental activity, and in the years since Diamond's research there have been many discoveries showing that brains of all sorts complexify structurally and functionally in response to stimulation.

Rats isolated in little boxes, generation after generation--the normal laboratory rats--were the standard, but now it's known that isolation is a stress that alters brain chemistry and function.

Willy Sidis and John Stuart Mill were being stimulated and allowed to develop in one direction, but they were being isolated from interaction with their peers. When Mill was twenty he went into a depression, and later he wrote that it was because he discovered that he was unable to feel. He had developed only part of his personality.

Bertrand Russell (1872-1970), orphaned at the age of four, went to live with his grandmother, who chose not to send him to school, but provided tutors. He didn't experience a sense of academic pressure, and was able to read whatever he wanted in his late grandfather's library. He didn't realize that he was unusually bright until he went to Cambridge. The unusual freedom of his childhood must have contributed to his willingness to hold unpopular opinions. In 1916 he was fined, and in 1918 imprisoned for 6 months, for opposing the war.

In 1927, Russell and his wife, Dora Black, started a school. He later wrote that, although the average student at the school was very bright, an exceptionally bright student was likely to be ostracized by the less bright students. He commented on the harm done to the brightest students by their social isolation, probably thinking about his own education in relative isolation. A psychologist (Leta Hollingworth, 1942) has made similar observations about the isolation that can be produced by a large difference of I.Q. She did a series of studies of very bright children, beginning in 1916, including working with some of them in a program she designed in a New York public school. Her empathy allowed her to discover things that weren't apparent to her contemporaries.

During this time Lewis Terman was studying bright children, and wanted to disprove some of the popular stereotypes about intelligent people, and to support his ideology of white racial superiority. In 1922 he got a large grant, and sorted out about 1500 of the brightest children from a group of 250,000 in California. He and his associates then monitored them for the rest of their lives (described in Genetic Studies of Genius). His work contradicted the stereotype of bright people as being sickly or frail, but, contrary to his expectation, there was an association between maladjustment and higher I.Q.; the incidence of neurotic fatigue, anxiety, and depression increased along with the I.Q. The least bright of his group were more successful in many ways than the most bright. He didn't really confront the implications of this, though it seriously challenged his belief in a simple genetic racial superiority of physique, intellect, and character.

I.Q. testing originated in a historical setting in which its purpose was often to establish a claim of racial superiority, or to justify sterilization or euthanasia, or to exclude immigrants. More recently, the tests have been used to assign students to certain career paths. Because of their use by people in power to control others, the I.Q. tests have helped to create misunderstanding of the nature of intelligence. A person's I.Q. now has very strong associations with the ideology of schooling as a road to financial success, rather than to enrichment of a shared mental life.

If a bad school resembles, on the intellectual level, a confining rat box, the educational isolation of Mill, Russell, and Sidis was emotionally limiting, almost like solitary confinement. Once when Willy Sidis was arrested for marching in a May Day parade, his father was able to keep him from going to prison, but Willy apparently would have preferred the real prison to life with his parents.

None of these three famous intellects was known for youthful playfulness, though playfulness is a quality that's closely associated with intelligence in mammals and birds. (Russell, however, in middle age developed many new interests, such as writing short stories, and had many new loves even in old age.) Stress early in life, such as isolation, reduces the playfulness of experimental animals. Playfulness is contagious, but so is the inability to play.

In schools like Summerhill, which was founded in 1921 by A. S. Neill, students aren't required to attend classes when they would rather do something else, but at graduation they usually do better on their standardized national examinations than students who have dutifully attended classes for years. For students, as for rats, freedom and variety are good for the brain, and tedious conformity is harmful. When a school is very good, it can spread a contagion of playfulness along with an interest in learning.

An environment that fosters optimal intelligence will necessarily promote the development of emotional health, and will almost certainly foster good physical health and longevity, because no part of the physiological system can thrive at the expense of another part. And within the boundaries of life-enriching environments, there are infinite possibilities for variety.

There is a common belief in the rigidity of the adult nervous system, in analogy with feral cats or dogs, that supposedly can't be tamed if they have grown up without knowing humans. But people who have had the inclination to understand wild animals have found that, even when the animals have been captured as adults, they can become as sociable as if they had grown up in domestication. The horse whisperer demonstrated this sort of empathetic approach to animals. Sometimes, these people have a similar ability to communicate with people who are retarded, or autistic, or demented, but the professionalization of society has made it increasingly unlikely that people with the need for intuitive help will encounter someone who is able to give it. The closest psychology has come to professionally recognizing the importance of empathy was in Carl Rogers' work, e.g., Client-Centered Therapy.

Rogers showed that a sense of solidarity must exist between therapist and client for the therapy to be helpful. A similar solidarity has to exist between teacher and student, for education to be successful. If ordinary family and social contacts could occur within such an atmosphere of mutual respect, psychopathology (including learning difficulties) would be much less common.

Although three individuals don't prove an argument, I think the lives and situations of Sidis, Mill, and Russell are usefully symbolic. Sidis, who grew up under intense pressure and social isolation and in extreme poverty, died at the age of 46. Mill, who was educated mainly by his father, in secure financial circumstances, experienced social isolation and moderate pressure, and lived about 20 years longer than Sidis did. Russell, who grew up in the highest circles of the ruling class, experienced no pressure, and only the mild kind of social isolation that wasn't exceptional for his class. He lived to be 97.

The psychopathology of social isolation has been studied in a variety of animals, and many features are similar across species, including humans. Aggression, helplessness, and reduced ability to learn are typically produced in animals by social isolation, and it's clear that certain kinds of family environment produce the same conditions in children. Schools seldom help, and often hinder, recovery from such early experiences.

Vital exhaustion, decreased slow wave sleep, and anger, which are associated with the type A personality and with circulatory and heart disease, appear to have their origin in childhood experiences. Low income and financial insecurity are strongly associated with anger, sleep disturbances, and circulatory disease. In animals stressed by social isolation, similar features emerge, under the influence of decreased neurosteroids, and increased serotonin and activity of the glucocorticoid system.

The smart drug culture has generally been thinking pharmaceutically rather than biologically. Behind that pharmaceutical orientation there is sometimes the idea that the individual just isn't trying hard enough, or doesn't have quite the right genes to excel mentally.

Many stimulants--amphetamine and estrogen, for example--can increase alertness temporarily, but at the expense of long range damage. The first principle of stimulation should be to avoid a harmful activation of the catabolic stress hormones. Light, play, environmental variety and exploratory conversations stimulate the whole organism in an integral way, stimulating repair processes and developmental processes.

Any chemical support for intelligence should take into account the mind-damaging stresses that our culture can impose, and provide defense against those. In darkness and isolation, for example, the stress hormones increase, and the brain-protective steroids decrease. The memory improvement that results from taking pregnenolone or thyroid (which is needed for synthesizing pregnenolone from cholesterol) is the result of turning off the dulling and brain-dissolving stress hormones, allowing normal responsiveness to be restored.

If we know that rats nurtured in freedom, in an interesting environment, grow more intelligent, then it would seem obvious that we should experiment with similar approaches for children--if we are really interested in fostering intelligence. And since violence and mental dullness are created by the same social stresses, even the desire to reduce school violence might force the society to make some improvements that will, as a side effect, foster intelligence.

REFERENCES

B. Russell: If you wish to know what men will do, you must know not only or principally their material circumstances, but rather the whole system of their desires with their relative strengths.

John Holt, from an interview in Mother Earth News, July/August, 1980: I suggested that we simply provide young people with schools where there are a lot of interesting things to look at and work with . . . but that we let the chidlren learn in their own wqys. If they have questions, answer the questions. If they want to know where to look for something, show them where to look.

John Holt, from the introduction to his book, Teach Your Own, (New York: Dell, 1981): The children in the classroom, despite their rich backgrounds and high I.Q.'s, were with few exceptions frightened, timid, evasive, and self-protecting. The infants at home were bold adventurers.

It soon became clear to me that children are by nature and from birth very curious about the world around them, and very energetic, resourceful, and competent in exploring it, finding out about it, and mastering. In short, much more eager to learn, and much better at learning, than most adults. Babies are not blobs, but true scientists. Why not then make schools into places in which children would be allowed, encouraged, and (if and when they asked) helped to explore and make sense of the world around them (in time and space) in ways that most interested them?

Psychosom Med 1984 Nov-Dec;46(6):546-8. Rapid communication: whole blood serotonin and the type A behavior pattern. Madsen D, McGuire MT. In 72 young males, whole blood serotonin is shown to have a pronounced relationship with the Type A behavior pattern. The relationship is explored with multivariate statistical techniques.

J Neurochem. 2000 Aug;75(2):732-40. Serra M, Pisu MG, Littera M, Papi G, Sanna E, Tuveri F, Usala L, Purdy RH, Biggio G. Social isolation-induced decreases in both the abundance of neuroactive steroids and GABA(A) receptor function in rat brain.

Ann Med 2000 Apr;32(3):210-21. Role of serotonin in memory impairment. Buhot MC, Martin S, Segu L.

Ivan Illich and Etienne Verne, Imprisoned in the global classroom. London, Writers and Readers Publishing Cooperative, 1976.

Ivan Illich, Deschooling society. Harmondsworth: Penguin, 1976 (1971).

----Tools for Conviviality (1973).

----Toward a history of needs. New York, Pantheon Books, c1978.

----Limits to medicine. medical nemesis : the expropriation of health. Harmondsworth New York, Penguin, 1977.

----Celebration of awareness: a call for institutional revolution. Harmondsworth, Penguin Education, 1976. Pelican books Originally published: Garden City [N.Y.]: Doubleday, 1970; London: Calder and Boyars, 1971.

----Disabling professions. London, Boyars, 1977, Ideas in progress series.

Eur J Pharmacol 1992 Feb 25;212(1):73-8. 5-HT3 receptor antagonists reverse helpless behaviour in rats. Martin P, Gozlan H, Puech AJ Departement de Pharmacologie, Faculte de Medecine Pitie-Salpetriere, Paris, France. The effects of the 5-HT3 receptor antagonists, zacopride, ondansetron and ICS 205-930, were investigated in an animal model of depression, the learned helplessness test. Rats previously subjected to a session of 60 inescapable foot-shocks exhibited a deficit of escape performance in three subsequent shuttle-box sessions. The 5-HT3 receptor antagonists administered i.p. twice daily on a chronic schedule (zacopride 0.03-2 mg/kg per day; ondansetron and ICS 205-930: 0.125-2 mg/kg per day) reduced the number of escape failures at low to moderate daily doses. This effect was not observed with the highest dose(s) of zacopride, ondansetron and ICS 205-930 tested.. These results indicate that 5-HT3 antagonists may have effects like those of conventional antidepressants in rats.

Neuropharmacology 1992 Apr;31(4):323-30. Presynaptic serotonin mechanisms in rats subjected to inescapable shock. Edwards E, Kornrich W, Houtten PV, Henn FA. After exposure to uncontrollable shock training, two distinct groups of rats can be defined in terms of their performance in learning to escape from a controllable stress. Learned helpless rats do not learn to terminate the controllable stress, whereas non-learned helpless rats learn this response as readily as naive control rats do. These results implicate presynaptic serotonin mechanisms in the behavioral deficit caused by uncontrollable shock. In addition, a limbic-hypothalamic pathway may serve as a control center for the behavioral response to stress.

Neurochem Int 1992 Jul;21(1):29-35. In vitro neurotransmitter release in an animal model of depression. Edwards E, Kornrich W, van Houtten P, Henn FA. Sprague-Dawley rats exposed to uncontrollable shock can be separated by a subsequent shock escape test into two groups: a "helpless" (LH) group which demonstrates a deficit in escape behavior, and a "nonlearned helpless" (NLH) group which shows no escape deficit and acquires the escape response as readily as naive control rats (NC) do. The major finding concerned a significant increase in endogenous and K(+)-stimulated serotonin (5-HT) release in the hippocampal slices of LH rats. There were no apparent differences in acetylcholine, dopamine and noradrenaline release in the hippocampus of LH rats as compared to NLH and NC rats. These results add further support to previous studies in our laboratory which implicate presynaptic 5-HT mechanisms in the behavioral deficit caused by uncontrollable shock.

Psychiatry Res 1994 Jun;52(3):285-93. In vivo serotonin release and learned helplessness. Petty F, Kramer G, Wilson L, Jordan S Mental Health Clinic, Dallas Veterans Affairs Medical Center, TX. Learned helplessness, a behavioral depression caused by exposure to inescapable stress, is considered to be an animal model of human depressive disorder. Like human depression, learned helplessness has been associated with a defect in serotonergic function, but the nature of this relationship is not entirely clear. We have used in vivo microdialysis brain perfusion to measure serotonin (5-hydroxytryptamine, 5HT) in extracellular space of medial frontal cortex in conscious, freely moving rats. Basal 5HT levels in rats perfused before exposure to tail-shock stress did not themselves correlate with subsequent learned helplessness behavior. However, 5HT release after stress showed a significant increase with helpless behavior. These data support the hypothesis that a cortical serotonergic excess is causally related to the development of learned helplessness.

Pharmacol Biochem Behav 1994 Jul;48(3):671-6. Does learned helplessness induction by haloperidol involve serotonin mediation? Petty F, Kramer G, Moeller M Veterans Affairs Medical Center, Dallas 75216. Learned helplessness (LH) is a behavioral depression following inescapable stress. Helpless behavior was induced in naive rats by the dopamine D2 receptor blocker haloperidol (HDL) in a dose-dependent manner, with the greatest effects seen at 20 mg/kg (IP). Rats were tested 24 h after injection. Haloperidol (IP) increased release of serotonin (5-HT) in medial prefrontal cortex (MPC) as measured by in vivo microdialysis. Perfusion of HDL through the probe in MPC caused increased cortical 5-HT release, as did perfusion of both dopamine and the dopamine agonist apomorphine. Our previous work found that increased 5-HT release in MPC correlates with the development of LH. The present work suggests that increased DA release in MPC, known to occur with both inescapable stress and with HDL, may play a necessary but not sufficient role in the development of LH. Also, this suggests that increased DA activity in MPC leads to increased 5-HT release in MPC and to subsequent behavioral depression.

Arzneimittelforschung 1975 Nov; 25(11):1737-44. [Central action of WA-335-BS, a substance with peripheral antiserotonin and antihistaminic activity]. Kahling J, Ziegler H, Ballhause H. In rats and mice the serotonin and histamine antagonistic drug . . . (WA 335-BS) caused stronger central sedative effects than did cyproheptadine. WA 335-BS also displayed stronger activity against reserpine- and central tremorine-induced effects than did cyproheptadine and it slightly enhanced d-amphetamine-induced effects: therefore it may have antidepressant properties. WA 335-BS proved to be very effective against isolation-induced aggression in male mice. The comparatively small anxiolytic effects may have been caused in part by the central antiserotonin properties. The results of our animal studies suggest WA 335-BS to be an antidepressant with sedative properties.

Neuroscience 2000;100(4):749-68. Behavioral, neurochemical and endocrinological characterization of the early social isolation syndrome. Heidbreder CA, Weiss IC, Domeney AM, Pryce C, Homberg J, Hedou G, Feldon J, Moran MC, Nelson P. Rearing rats in isolation has been shown to be a relevant paradigm for studying early life stress and understanding the genesis of depression and related affective disorders. Recent studies from our laboratory point to the relevance of studying the social isolation syndrome as a function of home caging conditions.

Stroke 1991 Nov;22(11):1448-51. Platelet secretory products may contribute to neuronal injury. Joseph R, Tsering C, Grunfeld S, Welch KM. BACKGROUND: We do not fully understand the mechanisms for neuronal damage following cerebral arterial occlusion by a thrombus that consists mainly of platelets. The view that certain endogenous substances, such as glutamate, may also contribute to neuronal injury is now reasonably well established. Blood platelets are known to contain and secrete a number of substances that have been associated with neuronal dysfunction. Therefore, we hypothesize that a high concentration (approximately several thousand-fold higher than in plasma, in our estimation) of locally released platelet secretory products derived from the causative thrombus may contribute to neuronal injury and promote reactive gliosis. SUMMARY OF COMMENT: We have recently been able to report some direct support for this concept. When organotypic spinal cord cultures were exposed to platelet and platelet products, a significant reduction in the number and the size of the surviving neurons occurred in comparison with those in controls. We further observed that serotonin, a major platelet product, has neurotoxic properties. There may be other platelet components with similar effect. CONCLUSIONS: The hypothesis of platelet-mediated neurotoxicity gains some support from these recent in vitro findings. The concept could provide a new area of research in stroke, both at the clinical and basic levels.

Am J Psychiatry 1981 Aug;138(8):1082-5. Tryptophan metabolism in children with attentional deficit disorder. Irwin M, Belendiuk K, McCloskey K, Freedman DX The authors present the first report, to their knowledge, of hyperserotonemia in children with attentional deficit disorder who had normal intelligence. Hyperserotonemic children had significantly lower levels of plasma total and protein-bound tryptophan and a higher percentage of free tryptophan than those with normal serotonin levels. Plasma kynurenine did not differ, suggesting that the hyperserotonemia is not due to a blockade of the kynurenine pathway but may reflect on increase in tissue tryptophan uptake and use.

J Neuropsychiatry Clin Neurosci 1990 Summer;2(3):268-74. Autistic children and their first-degree relatives: relationships between serotonin and norepinephrine levels and intelligence. Cook EH, Leventhal BL, Heller W, Metz J, Wainwright M, Freedman DX Whole-blood serotonin (5-HT) and plasma norepinephrine (NE) were studied in 16 autistic children, 21 siblings of autistic children, and 53 parents of autistic children. Both plasma NE and whole-blood 5-HT were negatively correlated with vocabulary performance. Eighteen subjects were hyperserotonemic (whole-blood 5-HT greater than 270 ng/ml). For these subjects, plasma NE was significantly higher than for subjects without hyperserotonemia.

Biol Psychiatry 1998 Dec 15;44(12):1321-8. Cerebrospinal fluid monoamines in Prader-Willi syndrome. Akefeldt A, Ekman R, Gillberg C, Mansson JE The behavioral phenotype of Prader-Willi syndrome (PWS) suggests hypothalamic dysfunction and altered neurotransmitter regulation. The purpose of this study was to examine whether there was any difference in the concentrations of monoamine metabolites in the cerebrospinal fluid (CSF) in PWS and non-PWS comparison cases. The concentrations of dopamine and particularly serotonin metabolites were increased in the PWS group. The differences were most prominent for 5-hydroxyindoleacetic acid. The increased concentrations were found in all PWS cases independently of age, body mass index, and level of mental retardation. The findings implicate dysfunction of the serotonergic system and possibly also of the dopamine system in PWS individuals . . . .

Pharmacol Biochem Behav 1976 Jul;5(1):55-61. The role of serotonergic pathways in isolation-induced aggression in mice. Malick JB, Barnett A Male mice that became aggressive following four weeks of social isolation were treated with seven known serotonin receptor antagonists. All of the antiserotonergic drugs selectively antagonized the fighting behavior of the isolated mice; the antiaggressive activity was selective since, at antifighting doses, none of the drugs either significantly altered spontaneous motor activity or impaired inclined-screen performance. Antagonism of 5-HTP-induced head-twitch was used as an in vivo measure of antiserotonergic activity and a statistically significant correlation existed between potency as an antiserotonergic and potency as an antiaggressive. PCPA, a serotonin depletor, also significantly antagonized isolation-induced aggression for at least 24 hr postdrug administration. The interrelationship between cholinergic and serotonergic mechanisms in the mediation of isolation aggression was investigated. The involvement of serotonergic systems in isolation-induced aggression is discussed.

Probl Endokrinol (Mosk) 1979 May-Jun;25(3):49-52 [Role of serotonin receptors of the medial-basal hypothalamus in the mechanisms of negative feedback of the hypophyseal-testicular complex]. Naumenko EV, Shishkina GT. Administration of serotonin into the lateral ventricle of the brain of male rats, against the background of complete isolation of the medial-basal hypothalamus was accompanied by the block of the compensatory elevation of the blood testosterone level following unilateral castration.

Encephale 1994 Sep-Oct;20(5):521-5. [Can a serotonin uptake agonist be an authentic antidepressant? Results of a multicenter, multinational therapeutic trial]. Kamoun A, Delalleau B, Ozun M The classical biochemical hypothesis of depression posits a functional deficit in central neurotransmitter systems particularly serotonin (5-HT) and noradrenaline. The major role suggested for 5-HT in this theory led to the development of a large number of compounds which selectively inhibit 5-HT uptake. Numerous clinical trials have demonstrated the antidepressant efficacy of such types of serotoninergic agents, supporting 5-HT deficit as the main origin of depression. Therefore, everything seemed clear: depression was caused by 5-HT deficit. Tianeptine is clearly active in classical animal models predictive of antidepressant activity, and is also active in behavioral screening tests: it antagonizes isolation induced aggression in mice and behavioral despair in rats. Biochemical studies have revealed that in contrast to classical tricyclic antidepressant, tianeptine stimulates 5-HT uptake in vivo in the rat brain. This somewhat surprising property was observed in the cortex and the hippocampus following both acute and chronic administrations. This increase in 5-HT uptake has also been confirmed in rat platelets after acute and chronic administrations. Moreover, in humans, a study in depressed patients demonstrated that tianeptine significantly increased platelet 5-HT uptake after a single administration as well as after 10 and 28 days of treatment. The antidepressant activity of tianeptine has been evaluated in controlled studies versus reference antidepressants. Another study aiming to compare the antidepressant efficacy of tianeptine versus placebo and versus imiporamine is presented. 186 depressed patients were included in this trial. They presented with either Major Depression, single episode (24.6%) or Major Depression recurrent (66.8%) or Bipolar Disorder (depressed) (8.6%).

Psychopharmacology (Berl) 1998 Oct;139(3):255-60. Ca2+ dependency of serotonin and dopamine release from CNS slices of chronically isolated rats. Jaffe EH. We have used chronic isolated housing as an animal model of depression. The following questions were addressed: first, if there is a change in the depolarization dependent release of DA and 5-HT from these CNS structures, and second, if the release is through the classical exocytotic mechanism. A significant increase in KCl stimulated release of 5-HT was observed in chronically isolated animals when compared to controls. 5-HT release was completely abolished from controls or isolated animals, when slices were incubated with Krebs containing zero Ca2+/10 mM Mg2+, the inorganic Ca2+ channel blockers, Cd2+ or Ni2+ and the calmodulin inhibitor, trifluoperazine. The basal release of DA and 5-HT was similar in control and isolated animals and was not affected by the Ca2+ channel antagonists. The results suggest that extracellular Ca2+-dependent release of 5-HT and, to a lesser degree, of DA, is increased in this chronic animal model of depression in several CNS structures.

Gen Pharmacol 1994 Oct;25(6):1257-1262. Serotonin-induced decrease in brain ATP, stimulation of brain anaerobic glycolysis and elevation of plasma hemoglobin; the protective action of calmodulin antagonists. Koren-Schwartzer N, Chen-Zion M, Ben-Porat H, Beitner R Department of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. 1. Injection of serotonin (5-hydroxytryptamine) to rats, induced a dramatic fall in brain ATP level, accompanied by an increase in P(i). Concomitant to these changes, the activity of cytosolic phosphofructokinase, the rate-limiting enzyme of glycolysis, was significantly enhanced. Stimulation of anaerobic glycolysis was also reflected by a marked increase in lactate content in brain. 2. Brain glucose 1,6-bisphosphate level was decreased, whereas fructose 2,6-bisphosphate was unaffected by serotonin. 3. All these serotonin-induced changes in brain, which are characteristic for cerebral ischemia, were prevented by treatment with the calmodulin (CaM) antagonists, trifluoperazine or thioridazine. 4.. Injection of serotonin also induced a marked elevation of plasma hemoglobin, reflecting lysed erythrocytes, which was also prevented by treatment with the CaM antagonists. 5. The present results suggest that CaM antagonists may be effective drugs in treatment of many pathological conditions and diseases in which plasma serotonin levels are known to increase.

Gen Pharmacol 1994 Oct;25(6):1257-1262. Serotonin-induced decrease in brain ATP, stimulation of brain anaerobic glycolysis and elevation of plasma hemoglobin; the protective action of calmodulin antagonists. Koren-Schwartzer N, Chen-Zion M, Ben-Porat H, Beitner R Department of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. 1. Injection of serotonin (5-hydroxytryptamine) to rats, induced a dramatic fall in brain ATP level, accompanied by an increase in P(i). Concomitant to these changes, the activity of cytosolic phosphofructokinase, the rate-limiting enzyme of glycolysis, was significantly enhanced. Stimulation of anaerobic glycolysis was also reflected by a marked increase in lactate content in brain. 2. Brain glucose 1,6-bisphosphate level was decreased, whereas fructose 2,6-bisphosphate was unaffected by serotonin. 3. All these serotonin-induced changes in brain, which are characteristic for cerebral ischemia, were prevented by treatment with the calmodulin (CaM) antagonists, trifluoperazine or thioridazine. 4. Injection of serotonin also induced a marked elevation of plasma hemoglobin, reflecting lysed erythrocytes, which was also prevented by treatment with the CaM antagonists. 5. The present results suggest that CaM antagonists may be effective drugs in treatment of many pathological conditions and diseases in which plasma serotonin levels are known to increase.

J Neural Transm 1998;105(8-9):975-86. Role of tryptophan in the elevated serotonin-turnover in hepatic encephalopathy. Herneth AM, Steindl P, Ferenci P, Roth E, Hortnagl H. The increase of the brain levels of 5-hydroxyindoleacetic acid (5-HIAA) in hepatic encephalopathy (HE) suggests an increased turnover of serotonin (5-HT). These results provide further evidence for the role of tryptophan in the elevation of brain 5-HT metabolism and for a potential role of BCAA in the treatment of HE.

Tugai VA; Kurs'kii MD; Fedoriv OM. [Effect of serotonin on Ca2+ transport in mitochondria conjugated with the respiratory chain]. Ukrainskii Biokhimicheskii Zhurnal, 1973 Jul-Aug, 45(4):408-12.

Kurskii MD; Tugai VA; Fedoriv AN. [Effect of serotonin and calcium on separate components of respiratory chain of mitochondria in some rabbit tissues]. Ukrainskii Biokhimicheskii Zhurnal, 1970, 42(5):584-8.

Watanabe Y; Shibata S; Kobayashi B. Serotonin-induced swelling of rat liver mitochondria. Endocrinologia Japonica, 1969 Feb, 16(1):133-47.

Mahler DJ; Humoller FL. The influence of serotonin on oxidative metabolism of brain mitochondria. Proceedings of the Society for Experimental Biology and Medicine, 1968 Apr, 127(4):1074-9.

Eur J Pharmacol 1994 Aug 11;261(1-2):25-32. The effect of alpha 2-adrenoceptor antagonists in isolated globally ischemic rat hearts. Sargent CA, Dzwonczyk S, Grover G.J. The alpha 2-adrenoceptor antagonist, yohimbine, has been reported to protect hypoxic myocardium. Yohimbine has several other activities, including 5-HT receptor antagonism, at the concentrations at which protection was found. Pretreatment with yohimbine (1-10 microM) caused a concentration-dependent increase in reperfusion left ventricular developed pressure and a reduction in end diastolic pressure and lactate dehydrogenase release. The structurally similar compound rauwolscine (10 microM) also protected the ischemic myocardium. In contrast, idozoxan (0.3-10 microM) or tolazoline (10 microM) had no protective effects. The cardioprotective effects of yohimbine were partially reversed by 30 microM 5-HT. These results indicate that the mechanism for the cardioprotective activity of yohimbine may involve 5-HT receptor antagonistic activity.

Zubovskaia AM. [Effect of serotonin on some pathways of oxidative metabolism in the mitochondria of rabbit heart muscle]. Voprosy Meditsinskoi Khimii, 1968 Mar-Apr, 14(2):152-7.

Warashina Y. [On the effect of serotonin on phosphorylation of rat liver mitochondria]. Hoppe-Seylers Zeitschrift fur Physiologische Chemie, 1967 Feb, 348(2):139-48.

Eur Neuropsychopharmacol 1997 Oct;7 Suppl 3:S323-S328. Prevention of stress-induced morphological and cognitive consequences.. McEwen BS, Conrad CD, Kuroda Y, Frankfurt M, Magarinos AM, McKittrick C. Atrophy and dysfunction of the human hippocampus is a feature of aging in some individuals, and this dysfunction predicts later dementia. There is reason to believe that adrenal glucocorticoids may contribute to these changes, since the elevations of glucocorticoids in Cushing's syndrome and during normal aging are associated with atrophy of the entire hippocampal formation in humans and are linked to deficits in short-term verbal memory. We have developed a model of stress-induced atrophy of the hippocampus of rats at the cellular level, and we have been investigating underlying mechanisms in search of agents that will block the atrophy. Repeated restraint stress in rats for 3 weeks causes changes in the hippocampal formation that include suppression of 5-HT1A receptor binding and atrophy of dendrites of CA3 pyramidal neurons, as well as impairment of initial learning of a radial arm maze task. Because serotonin is released by stressors and may play a role in the actions of stress on nerve cells, we investigated the actions of agents that facilitate or inhibit serotonin reuptake. Tianeptine is known to enhance serotonin uptake, and we compared it with fluoxetine, an inhibitor of 5-HT reuptake, as well as with desipramine. Tianeptine treatment (10 mg/kg/day) prevented the stress-induced atrophy of dendrites of CA3 pycamidal neurons, whereas neither fluoxetine (10 mg/kg/day) nor desipramine (10 mg/kg/day) had any effect. Tianeptine treatment also prevented the stress-induced impairment of radial maze learning. Because corticosterone- and stress-induced atrophy of CA3 dendrites is also blocked by phenytoin, an inhibitor of excitatory amino acid release and actions, these results suggest that serotonin released by stress or corticosterone may interact pre- or post-synaptically with glutamate released by stress or corticosterone, and that the final common path may involve interactive effects between serotonin and glutamate receptors on the dendrites of CA3 neurons innervated by mossy fibers from the dentate gyrus. We discuss the implications of these findings for treating cognitive impairments and the risk for dementia in the elderly.

© Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com

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A R T I C L E

Intuitive knowledge and its development

Understanding consciousness is necessary for understanding life. Variations of consciousness, such as dementia, depression, delusion, or insight, originality, curiosity have to be understood biologically.

To understand our ability to know and discover, I think it's valuable to consider foolishness along with wisdom, since "knowledge" consists of both. Scientists have been notorious for opposing new discoveries, but the mental rigidity of old age is so general, and well known, that many people have believed that it was caused by the death of brain cells. Individual cells do tend to become less adaptive with aging, and metabolism generally slows down with aging, but even relatively young and mentally quick people are susceptible to losing their ability to understand new ideas.

I think our use of language is both the means by which understanding can be preserved, encapsulated, and disseminated, and a great impediment to understanding. At first, words are continuous with the intuitive framework in which they are learned, but they gradually become relatively independent and abstract. Things can be learned without directly experiencing them. Even though words gradually change through use, the simple fact that they have a degree of dependability allows them to function even when there is no active thought. Uncritical listening is possible, and if a person can say something, it seems to be easy to believe that it's true. By the age of 25, our language has usually given us many assumptions about the nature of the world.

Verbal formulations of one sort are given up for new verbal formulations, in the process called education. Sometimes graduate students seem to have lost all common sense. It's as if their hard-drive had been reformatted to allow their professors to download onto it. But common sense, usually, is just what Einstein called it, an accumulation of prejudices.

Children learn language so easily that many people have seriously believed that a certain language was inherited by people of each ethnic group. Bilingual people were thought to be intellectually inferior (though it turned out that bilingualism actually increases a person's mental abilities--possibly because of the brain development known to be produced by learning1.) Eventually, people learned that the children of immigrants were as capable of learning the language of the new country as the native children were.

Then, explaining the mystery of language learning took a new form, that didn't seem foolish to most professional anthropologists and linguists. The first and most important step in the new theory was to declare that simple learning theory was inadequate to explain the development of language. Language developed, just as the silly racial theory had thought, out of our genetic endowment, except that what we inherited was now said to be a Universal Language, with its Universal Rules embedded in our chromosomes. Then, the speed with which children learn language was to be explained as the "innateness" of all of the complex stuff of language, with only a few things needing to be actually learned--those minor details that distinguish English from Eskimo or Zapotec.

Although the phrase "genetic epistemology" was coined by Jean Piaget, a major philosophical and scientific theme of the 20th century has been the idea that the "forms" of knowledge, for perceiving space, or logical relations, or language patterns, are derived from our genes, and that they are somehow built into the arrangement of our brain cells so that we spontaneously think in certain ways, and don't have the capacity to transcend the nature of our inherited brain. In that view, children have their own pre-logical way of thinking, and their thought (and language development) must proceed through certain stages, each governed by some "structural" process in the nervous system. The only thing wrong with the idea of innate knowledge is that people use it to tell us what we can't know, in other words, to rationalize stupidity. Of course, they wouldn't like to phrase it that way, because they consider their "genetic epistemology of symbolic forms" to be the essence and the totality of intelligence, and that people who allow their thoughts to be structured entirely by experience are just confused.

Years ago, I had been criticizing Noam Chomsky's theory of language so much, that I thought I might have misjudged or inappropriately depreciated his general attitude toward consciousness, so I asked him some questions about the intelligence of animals. His response confirmed my view that he subscribed to the most extreme form of "genetic epistemology":

"I don't know whether there is a common animal ability to manipulate images and generalize. In fact, I doubt it very much. Thus the kind of "generalization" that leads to knowledge of lanugage from sensory experience seems to me to involve principles such as those of universal grammar as an innate property, for reasons I have explained elsewhere, and I see no reason to believe that these principles underlie generalization in other animals. Nor do I think that the kinds of generalization that lead a bird to gain knowledge of how to build a nest, or to sing its song, or to orient itself spatially, are necessarily part of the human ability to generalize."

All of the textbooks that I have seen that discuss the issue of animal intelligence have taken a position like that of Chomsky--that any knowledge animals have is either rigidly instinctual, or else is just a set of movements that have been mechanically learned. In other words, there isn't anything intelligent about the complex things that animals may do. Konrad Lorenz and the ethologists explained animal behavior in terms of chains of reflexes that are "triggered" by certain sensations or perceptions. This claim that animals' behavior just consists of mechanical chains of reflexes strictly follows Descartes' doctrine, and Chomsky has consistently acknowledged that his theory is Cartesian. The claim that children have their own non-logical way of understanding things is very similar to the doctrine about animals, in the way it limits real rational understanding to adult human beings.

The awareness of young animals is particularly impressive to me, because we know the short time they have had in which to learn about the world. Any instance in which a young animal understands a completely novel situation, in a way that is fully adequate and workable, demonstrates that it is capable of intellectual generalization.

Beyond that, I think animal inventiveness can teach us about our own capacity for inventiveness, which both the genetic and the behaviorist theories of knowledge totally fail to explain.

Spiders that build architecturally beautiful webs have been favorite subjects for theorizing about the instinctive mechanisms of behavior. When spiders were sent up on an orbiting satellite, they were in a situation that spiders had never experienced before. Spiders have always taken advantage of gravity for building their webs, and at first, the orbiting spiders made strange little muddled arrangements of filaments, but after just a few attempts, they were able to build exactly the same sort of elegant structures that spiders normally build. (My interpretation of that was that spiders may be more intelligent than most neurobiologists.)

Nesting birds often swoop at people or animals who get too close to their nest. Early last summer, I had noticed some blue jays that seemed to be acting defensive whenever I went into one part of the yard. On a very hot day at the end of summer, a couple of plump jays were squawking and apparently trying to get my attention while I was watering the front yard, and I idly wondered why they would be acting that way so late in the year. I had gone around the house to water things in the back yard, and the birds came over the house, and were still squawking, and trying to get my attention. I realized that their excitement didn't have anything to do with their nest, and looking more carefully, I saw that they were young birds. As it dawned on me that they were interested in the water squirting out of the hose, I aimed the stream up towards them, and they got as close to it as they could. Since the force of the stream might have hurt them, I put on a nozzle that made a finer spray, and the birds immediately came down to the lowest tip of the branch, where they could get the full force of the mist, holding out their wings, and leaning into the spray so that it ruffled their breast feathers. Their persistence had finally paid off when they got me to understand what they wanted, and they were enjoying the cool water. As new young birds, I don't know how they understood hoses and squirting water, but it was clear that they recognized me as a potentially intelligent being with whom they could communicate.

For a person, that wouldn't have seemed like a tremendously inventive response to the hot weather, but for young birds that hadn't been out of the nest for long, it made it clear to me that there is more inventive intelligence in the world than is apparent to most academic psychologists and ethologists.

Early porpoise researchers were surprised when a porpoise understood a sequence in which one tone was followed by two, and then by three, and answered by producing a series of four tones. The porpoise had discovered that people knew how to count.

Experiments with bees show the same sort of understanding of numbers and intentions. An experimenter set out dishes of honey in a sequence, doubling the distance each time. After the first three dishes had been found by scouts, the bees showed up at the fourth location before the honey arrived, extrapolating from the experimenter's previous behavior and inferring his intentions.

Once I noticed that an ant seemed to be dozing at the base of every maple leaf, and that there were several aphids on each leaf. I was getting very close, trying to understand why the ant was sitting so quietly. Apparently my odor gave the ant a start, and he leaped into activity, racing up the leaf, and giving each aphid a tap as he passed. When he had reached the end of the leaf and had touched every aphid, his agitation suddenly disappeared, and he returned to his spot at the base of the leaf. Although I knew that ants could count very well, as demonstrated by experiments in which an ant had to describe a complex route to a dish of honey, it was the apparent emotion that interested me. It reminded me of the hostess who counted her dishes before the guests left.

When the brains of such different kinds of animal work in such similar ways, in situations that contain many new components, I don't think it's possible to conclude anything except that intelligence is a common property of animals, and that it comprises "generalization" and much more. It's obvious that they grasp the situation in a realistic way. The situation has structured their awareness. Some people might say that they have "modeled the situation in their mind," but it's enough to say that they understand what's going on. With that understanding, motivations and intentions form part of the perception, since the situation is a developing process. Ordinarily, we say that we "infer" motivations and intentions and "deduce" probable outcomes, but that implies that the situation is static, rather than continuous with its origin and outcome. In reality, these understandings and expectations are part of the direct perception. It isn't a matter of "intelligence" operating upon "sensations," but of intelligence inhering in the grasping of the situation. (In Latin, intelligo meant "I perceive." I suspect that a Roman might have perceived the word intelligens as being derived from roots such as tele--from Greek, or tela, web, warp thread--and ligo or lego, connoting the binding in or gathering of what is distant or extended.)

This view of a generalized animal intelligence wouldn't seem strange, except that the history of official western philosophy, the doctrine of genetic determinism in biology, and the habits that form with the rigid uses of language, have offered another way of looking at it. The simple intelligence of an animal would disrupt all of that important stuff, so it has become mandatory to dismiss all examples of intelligent behavior by animals as "mere anthropomorphizing." Sadly, this has also meant that most intelligent behavior by humans has also been dismissed.

The cellular development of an organism used to be described as a process in which everything is predetermined by the genes, but the interactions between an embryo and its environment are now known to be crucial in shaping the process of maturation, so that the real organism (the phenotype) doesn't necessarily reflect its genetic make-up (genotype); the term "phenocopy" acknowledges this process.

London taxi drivers were recently found to have an enlargement of part of the hippocampus, compared to the brains of other people, and the difference was greater, in proportion to the time they had been driving taxis. Their brains have been shaped by their activities.

If the brain's cellular anatomy is so radically affected by activity even in adulthood, then the concept of awareness as a process in which consciousness takes its form from the situation shouldn't be problematic. If a bee and a porpoise can draw similar conclusions from similar experiences, then the world is being grasped by both in an objective way.

The environment shapes the organism's response, and the momentary response contributes to the development of the supporting processes and apparatuses. So the ability to respond is the basic question. If the richly grasped situation contains its own implications, there is no need for explaining the ability to perceive those implications in terms of some prearranged neurological code, except for the ability to respond complexly and appropriately. Any specific interpretation or behavior which is predetermined is going to function as an impediment to understanding. Verbal formulations often have the function of creating a stereotyped and inappropriate response.

The "genetic epistemologists" confuse their own verbal interpretations with the real ways that understanding develops, and when a child doesn't yet know all of the connotations of a specific word, the psychologist ascribes a pre-logical brain function to the child.3 The similar failure to perceive and to communicate accounts for the foolish things ethologists have said about animal intelligence.

The process in which an organism responds to a situation is continuous with the process of communication. The organism understands that in certain situations a response can be elicited, and so it acts accordingly.

Communication is a response that is directed toward eliciting a response from another. The idea that an animal might have an intention, or a desire to communicate or respond, has been obsessively denied by most official western philosophers, who see that as a uniquely human quality, but some philosophers have even denied that quality to humans. For them, consciousness is a passive receptacle for units of meaning and logic, like a mail bin at the post-office, where letters are received, sorted, and distributed. Maybe computers work that way, but there is nothing in living substance that works like that.

Consciousness is participation, in the sense that there is a response of an organism to events. Even dreams and hallucinations have their implied reference to something real.

If a violin has been soaked in water, it will sound very odd when it's played. Its various parts won't resonate properly. Similarly, the living substance has to be in a particular state to resonate properly with its environment.

People have proposed that visual experience involves the luminescence of nerves in the optical system. Presumably, similar analogs of events could occur in various tissues when we are conscious of sounds, tastes, smells, etc. But whether or not our auditory nerves are singing when we experience music, no one questions the existence of some sort of responsive activity when we are being conscious of something. Activating certain brain areas will make us conscious of certain things, and that activation can be a response to sensory nerve impulses, or to brain chemicals produced in dreaming or drug-induced hallucinations, or to electrical stimulation, or to the act of remembering.

The history of the prefrontal leukotomy or lobotomy, in which undesirable behaviors were surgically removed, was closely associated with the development of surgical treatments for epilepsy.

Natalya Bekhtereva was exploring alternative treatments for epilepsy, implanting fine wire electrodes into the abnormal parts of the brain, and surrounding areas, to discover the nature of the electrical events that were associated with the seizures. In the process, she discovered that meanings and intentions corresponded to particular electrical patterns. She found that giving certain kinds of stimulation to healthy parts of the brain could stimulate the development of ways of functioning that by-passed the seizure-prone parts of the brain. Extending this, seeing that creating new patterns of nervous activity could overcome sickness, she proposed that creativity, the activation of the brain in new ways, would itself be therapeutic. Some people, such as Stanislav Grof, advocated the therapeutic use of LSD with a rationale that seems similar, for example to overcome chronic pain by changing its meaning, putting it into a different relation to the rest of experience. "In general, psychedelic therapy seems to be most effective in the treatment of alcoholics, narcotic-drug addicts, depressed patients, and individuals dying of cancer." 2 Since LSD shifts the balance away from serotonin dominance toward dopamine dominance, its effect can be to erase the habits of learned helplessness. Stress and pain also leave their residue in the endorphin system, and the anti-opiates such as naloxone can relieve depression, improve memory, and restore disturbed pituitary functions, for example leading to the restoration of menstrual rhythms interrupted by stress or aging. The amazing speed with which young animals can solve problems is undoubtedly a reflection of their metabolic vigor, and it is probably partly because they haven't yet experienced the paralysis that can result from repeated or prolonged and inescapable stress. Many of the factors responsible for the metabolic intensity of youth can be used therapeutically, even after dullness has developed. The right balance of amino acids and carbohydrates, and the avoidance of the antimetabolic unsaturated fatty acids, can make a great difference in mental functioning, even though we still don't know what the ideal formulas are.

While chemical -- nutritional -- hormonal approaches can help to restore creativity, the work of people like Bekhtereva shows that the exercise of creativity can help to restore biochemical and physiological systems to more normal functioning. Learning new general principles or new languages can be creatively restorative.

NOTES AND REFERENCES

1. Proc Natl Acad Sci U S A 2000 Apr 11;97(8):4398-403. Navigation-related structural change in the hippocampi of taxi drivers. Maguire EA, Gadian DG, Johnsrude IS, Good CD, Ashburner J, Frackowiak RS, Frith CD. Structural MRIs of the brains of humans with extensive navigation experience, licensed London taxi drivers, were analyzed and compared with those of control subjects who did not drive taxis. The posterior hippocampi of taxi drivers were significantly larger relative to those of control subjects. A more anterior hippocampal region was larger in control subjects than in taxi drivers. Hippocampal volume correlated with the amount of time spent as a taxi driver (positively in the posterior and negatively in the anterior hippocampus). These data are in accordance with the idea that the posterior hippocampus stores a spatial representation of the environment and can expand regionally to accommodate elaboration of this representation in people with a high dependence on navigational skills. It seems that there is a capacity for local plastic change in the structure of the healthy adult human brain in response to environmental demands.

2. ("History of LSD Therapy," Stanislav Grof, M.D. Chapter 1 of LSD Psychotherapy, ©1980, 1994 by Stanislav Grof. Hunter House Publishers, Alameda, California, ISBN 0-89793-158-0).

3. There is an example of this argument about the nature of reasoning in New Scientist magazine, December 9, 2000. P. Johnson-Laird found that more than 99% of Princeton University students were unable to solve a logical puzzle correctly. Ira Noveck of the Claude Bernard University in Lyon believes this may result simply from people's difficulty interpreting the language of the puzzles.

Fiziol Cheloveka 2000 Mar-Apr;26(2):5-9 [The cerebral organization of creativity. I. The development of a psychological test]. Starchenko MG, Vorob'ev VA, Kliucharev VA, Bekhtereva NP, Medevedev SV.

Fiziol Cheloveka 1998 Jul-Aug;24(4):55-63 [Brain processing of visually presented verbal stimuli at different levels of their integration. II. The orthographic and syntactic aspects]. Vorob'ev VA, Korotkov AD, Pakhomov SV, Rozhdestvenskii DG, Rudas MS, Bekhtereva NP, Medvedev SV.

Neurosci Behav Physiol 1986 Jul-Aug; 16(4):333-9 The systemic approach to the stability and plasticity of neurophysiological processes during adaptive brain activity. Vasilevskii VN The problem of the stability and adaptability of regulatory processes is considered, taking as a point of departure N. P. Bekhtereva's theory regarding stable pathological states, and inflexible and adaptable links in control systems. The need to introduce a probabilistic approach is emphasized. Generalizations are made on materials relating to the connectability of the separate components of the biorhythms of functional systems, and to the stability of their amplitude-frequency characteristics. The corpus of facts permitted the successful development in clinical practice of functional biocontrol and feedback.

Neurosci Behav Physiol 1986 Jul-Aug; 16(4):322-33. A study of the connectedness among distant neuronal populations in the human brain during mental activity. Bekhtereva NP, Medvedev SV, Krol EM In this article, we present the results of a study of connectedness among distant neuronal populations in human deep-brain structures. The time characteristics involved and the stability of the connections between different neuronal populations during monotonous mental activity are discussed. We show that a stable connectedness does correlate with mental activity; however, the connections themselves do not correlate with one another. We also show that the individual connections, the elements of the system which make mental activity possible, can function with various degrees of rigidity or flexibility.

Dokl Akad Nauk SSSR 1986;289(5):1276-80 [Physiologic role of changes in the human neuron discharge rate during a single mental act]. Bekhtereva NP, Gogolitsyn IuL, Pakhomov SV.

Dokl Akad Nauk SSSR 1985;285(5):1233-5 [Neurons-detectors of errors in subcortical structures of human brain]. Bekhtereva NP, Kropotov IuD, Ponomarev VA.

Neurosci Behav Physiol 1985 Jan-Feb;15(1):27-32 Bioelectrical correlates of protective mechanisms of the brain. Bekhtereva NP.

Fiziol Zh SSSR Im I M Sechenova 1984 Aug;70(8):1092-9 [Neurochemical aspects of therapeutic electric stimulation]. Bekhtereva NP, Dambinova SA, Gurchin FA, Smirnov VM, Korol'kov AV. Comparative analysis of the CSF and blood protein-peptide composition in Parkinsonian patients performed with the aid of indwelled electrodes prior to and after therapeutic electrical stimulation (TES) of the brain subcortical structures, revealed a therapeutic effect in the form of reduced muscular rigidity and a mental activation with a positive emotional response. After the TES the protein content in the biological fluids tended to become normalized and the the range of low-molecular protein-peptide fractions changed. A high-performance liquid chromatography, bidimensional electrophoresis and thin-layer chromatography revealed about 5-6 factors of peptide nature with the molecular mass less than 5000 daltons in the CSF and blood after the TES. These factors were shown to exert a biological effect upon muscle preparation of the leech.

Fiziol Zh SSSR Im I M Sechenova 1984 Jul;70(7):892-903 [Relationships of distantly located neuronal populations in the human brain in the realization of the thinking process]. Bekhtereva NP, Medvedev SV, Krol' EM The time characteristics of the interneuronal connections as well as interrelationships among distant neuronal populations of the human brain deep structures were studied during monotonous mental activity. It was shown that stable interrelationships could be considered as a correlate of mental activity though the connections themselves were not of the correlative nature. These connections, being the elements of the activity--maintaining system, could be of various degree of rigidity.

Fiziol Zh SSSR Im I M Sechenova 1984 Jul;70(7):881-91 [Reflection of the semantic characteristics of the thinking process in the impulse activity of neurons]. Bekhtereva NP The paper deals with the progress in research into the problem of reflection of semantic characteristics of psychological tests in impulse activity of neurons and neuronal assemblies. The high dynamicity of brain correlates of thinking in most brain zones is stressed. Advantages and limits of different technical approaches as well as the most urgent tasks to be solved are discussed.

Fiziol Zh SSSR Im I M Sechenova 1984 Jul;70(7):1071-5 [Natal'ia Petrovna Bekhtereva]. Iliukhina VA Biography

Hum Physiol 1982 Sep-Oct;8(5):303-16 Cerebral organization of emotional reactions and states. Bekhtereva NP, Kambarova DK, Ivanov GG

Zh Nevropatol Psikhiatr Im S S Korsakova 1980;80(8):1127-33 [Bioelectric correlates of the brain's protective mechanisms]. Bekhtereva NP The author substantiates the necessity of searching for new means producing a therapeutic effect on the brain of epileptic patients that would be similar, in principle, to the brain's own protective mechanisms. This can be done, in the author's opinion, on the basis of studying the most probable bioelectric equivalents of the protective mechanisms. The author suggests a new method for suppressing the epileptogenic focus. This suppression, close to the physiological one, is effected by applying a weak sinusoidal current to the focus via intracerebrally implanted electrodes. Data on the suppression of the epileptiform activity within the zone of the current application, as well as data confirming the local character of the current action are presented. The place of the new method in the system of complex therapy, particularly of epilepsy, is determined with consideration of the role of the stable pathological state. Probable neurophysiological mechanisms of the sinusoidal current action on the epileptogenic focus are discussed.

Vestn Akad Med Nauk SSSR 1979;(7):30-7 [Potentials of neurophysiology in the study of a resistant pathological state]. Bekhtereva NP

Act Nerv Super (Praha) 1976;18(3):157-67 The neurophysiological code of simplest mental processes in man. Bekhtereva NP

Vestn Akad Med Nauk SSSR 1975;(8):8-19 [Cerebral organization of human emotions]. Bekhtereva NP, Smirnov VM

Fiziol Zh SSSR Im I M Sechenova 1973 Dec;59(12):1785-802 [Principles of the organization of the structure of the space-time code of short-term verbal memory]. Bekhtereva NP, Bundzen PV, Kaidel VD, David EE.

Vopr Neirokhir 1972 Jan-Feb;36(1):7-12 [Therapeutic electric stimulation of deep brain structures]. Bekhtereva NP, Bondarchuk AN, Smirnov VM, Meliucheva LA

Vestn Akad Med Nauk SSSR 1972;27(9):43-9 [Principles of functional organization of the human brain]. [Article in Russian] Bekhtereva NP.

Fiziol Zh SSSR Im I M Sechenova 1971 Dec;57(12):1745-61 [Functional reorganization of the activity of human brain neuron populations during short-term verbal memory]. Bekhtereva NP, Bundzen PV, Matveev IuK, Kaplunovskii AS

From a biography by the Archives Jean Piaget: "His researches in developmental psychology and genetic epistemology had one unique goal: how does knowledge grow? His answer is that the growth of knowledge is a progressive construction of logically embedded structures superseding one another by a process of inclusion of lower less powerful logical means into higher and more powerful ones up to adulthood. Therefore, children's logic and modes of thinking are initially entirely different from those of adults."

© Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com

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A R T I C L E

Lactate vs. CO2 in wounds, sickness, and aging; the other approach to cancer

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GLOSSARY

Aerobic glycolysis, the conversion of glucose to lactic acid even in the presence of oxygen. The presence of oxygen normally restrains glycolysis so that glucose is converted to carbon dioxide instead of lactic acid.

Anaerobic glycolysis, the increased conversion of glucose to lactic acid when the supply of oxygen isn't sufficient, which is a normal event during intense muscle action.

"Warburg Effect" refers to Otto Warburg's observation that cancer cells produce lactic acid even in the presence of adequate oxygen. Cancer cells don't "live on glucose," since they are highly adapted to survive on protein and fats.

Pasteur Effect, the normal response of cells to restrain glycolysis in the presence of adequate oxygen.

Crabtree Effect, observed originally in yeast, refers to the inhibition of respiration in the presence of glucose. This occurs in cancers (e.g., Miralpeix, et al., 1990) and in rapidly proliferating normal cells (e.g., Guppy, et al., 1993).

"Cancer metabolism" or stress metabolism typically involves an excess of the adaptive hormones, resulting from an imbalance of the demands made on the organism and the resources available to the organism. Excessive stimulation depletes glucose and produces lactic acid, and causes cortisol to increase, causing a shift to the consumption of fat and protein rather than glucose. Increased cortisol activates the Randle effect (the inhibition of glucose oxidation by free fatty acids), accelerates the breakdown of protein into amino acids, and activates the enzyme fatty acid synthase, which produces fatty acids from amino acids and pyruvate, to be oxidized in a "futile cycle," producing heat, and increasing the liberation of ammonia from the amino acids. Ammonia suppresses respiratory, and stimulates glycolytic, activity.

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The presence of lactic acid in our tissues is very meaningful, but it is normally treated as only an indicator, rather than as a cause, of biological problems. Its presence in rosacea, arthritis, heart disease, diabetes, neurological diseases and cancer has been recognized, and recently it is being recognized that suppressing it can be curative, after fifty years of denial.

The influence of politics on science is so profound that neither historians nor scientists often care to consider it honestly and in depth.

From the 19th century until the second quarter of the 20th century, cancer was investigated mainly as a metabolic problem. This work, understanding the basic chemistry of metabolism, was culminating in the 1920s in the work of Otto Warburg and Albert Szent-Gyorgyi on respiration. Warburg demonstrated as early as 1920 that a respiratory defect, causing aerobic glycolysis, i.e., the production of lactic acid even in the presence of oxygen, was an essential feature of cancer. (The formation of lactic acid is normal and adaptive when the supply of oxygen isn't adequate to meet energy demands, for example when running.)

Many people recognized that this was likely to be the key to the "cancer problem." But in the US, several factors came together to block this line of investigation.

The world wars contributed to the isolation of German scientists, and Warburg, of the famous Jewish banking family, continued his work in Germany with the support of the government, despite his open opposition to Nazism. In the years after the war, nothing positive could be said in the US about his work on cancer.

The metabolic interpretation of disease that had been making progress for several decades was suddenly submerged when government research financing began concentrating on genetic and viral interpretations of disease.

If an apparently non-infectious disease couldn't be explained on the basis of an inherited tendency---insanity, epilepsy, diabetes, toxemia of pregnancy, and cancer, for example---then genetic changes occurring in the individual, as a result of chance or a virus, were invoked. Nutrition and other conditions of life were until fairly recently said to have no influence on health if the person consumed sufficient calories and a minimum amount of the essential vitamins, minerals, and protein. The cult of genetic determinism was so powerful that it wasn't affected by the facts.

In 1932, a pediatrician, Alexis Hartmann (with M. Senn) in St. Louis, injected intravenously a solution of sodium lactate into patients with metabolic acidosis, and several of them survived---despite the fact that some of them were already suffering from an excess of lactate. The subsequent widespread use of lactate solutions in hospitals has contributed to the general denial of its toxicity.

Hartmann and Senn used racemic lactate, that is, a mixture of D-lactate and L-lactate. Our own tissues produce mostly L-lactate, but they can produce small amounts of D-lactate; larger amounts are produced by diabetics. Intestinal bacteria can produce large amounts of it, and it has many toxic effects. Methylglyoxal can be formed from either form of lactate, and it is an important factor in the glycation of proteins. It can also be formed from MDA, a product of lipid peroxidation. Protein glycation is an important factor in diabetes and aging, but glucose, rather than lactate and polyunsaturated fats, is commonly said to be the cause.

About 50 years ago, lactate was known to induce the formation of new blood vessels, and for a much longer time it has been known to cause vasodilation and edema. In 1968, it was shown to stimulate collagen synthesis.

Normally, collagen synthesis and neovascularization are caused by lack of oxygen, but lactate can cause them to occur even in the presence of oxygen. Maintenance of a normal extracellular matrix is essential for normal functioning and cellular differentiation. Abnormally stimulated collagen synthesis probably accelerates tumor growth (Rajkumar, et al., 2006).

Nervous and hormonal factors can cause lactate to accumulate, even without prior damage to the mitochondria (e.g., B. Levy, et al., 2003). Psychological, as well as physical, stress and overactivation of glutamate receptors can cause harmful accumulation of lactate in the brain (Uehara, et al., 2005). Rather than just being "associated with" tissue damage, lactate directly contributes to the damage, for example in the brain, causing nerve cell loss by increasing the release of excitotoxic glutamate (Xiang, et al, 2004). When a panic reaction is produced by sodium lactate, the reduction of protective neurosteroids appears to contribute to the excitatory state (Eser, et al. 2006); this would make the brain more susceptible to damage.

Lactate increases blood viscosity, mimics stress, causes inflammation, and contributes to shock. Lactated Ringer's solution contributes to the tissue damage caused by shock, when it's used to resuscitate shock victims (Deree, et al., 2007, 2008): it contributes to the inflammatory processes associated with shock, unlike the use of hypertonic saline and other solutions. Lactate contributes to diabetes, inhibiting the ability to oxidize glucose. It promotes endothelial cell migration and leakiness, with increased vascular permeability factor (VPF or vascular endothelial growth factor, VEGF) (Nagy, et al. 1985): this can lead to breakdown of the "blood-brain barrier."

In the brain, lactate can cause nerve damage, increasing intracellular fat accumulation, chromatin clumping, and mitochondrial swelling (Norenberg, et al., 1987).

The lactate in peritoneal dialysis solution impairs differentiation and maturation of (immune, monocyte derived) dendritic cells; according to the authors of the study, "These findings have important implications for the initiation of immune responses under high lactate conditions, such as those occurring within tumor tissues or after macrophage activation" (Puig-Kröger, et al., 2003).

Lactate also causes macrophages and synovial fibroblasts to release PGE2, which can contribute to inflammation and bone resorption (Dawes and Rushton, 1994). This is the prostaglandin known to activate the formation of estrogen (Haffty, et al., 2008).

Hartmann's lactated solution has been widely used in hospitals for resuscitation and for patients after heart surgery and other stressful procedures, but until recently only a few people have objected to its use, and most of the objection has been to the use of racemic lactate, rather than to lactate itself. In recent years several studies have compared hypertonic saline (lacking the minerals considered essential since Sydney Ringer formulated his solution around 1885), and have found it in some cases superior to the "balanced" lactate solution. Even hypertonic glucose, without minerals, has produced good results in some studies.

A solution containing a large amount of lactate has been used for peritoneal dialysis when there is kidney failure, but several studies have compared solutions using bicarbonate instead of lactate, and found that they don't cause the severe damage that always happened with the traditional solution.

While Warburg was investigating the roles of glycolysis and respiration in cancer, a physician with a background in chemistry, W.F. Koch, in Detroit, was showing that the ability to use oxygen made the difference between health and sickness, and that the cancer metabolism could be corrected by restoring the efficient use of oxygen. He argued that a respiratory defect was responsible for immunodeficiency, allergy, and defective function of muscles, nerves, and secretory cells, as well as cancer. Koch's idea of cancer's metabolic cause and its curability directly challenged the doctrine of the genetic irreversibility of cancer that was central to governmental and commercial medical commitments.

Albert Szent-Gyorgyi respected Koch's work, and spent years investigating the involvement of the lactate metabolites, methylgyoxal and glyoxal, in cell physiology, but since the government's campaign against Koch was still active when Szent-Gyorgyi came to the U.S., he worked out many of the implications of Koch's work relating to cellular oxidation without mentioning his name.

Lactate formation from glucose is increased when anything interferes with respiratory energy production, but lactate, through a variety of mechanisms, can itself suppress cellular respiration. (This has been called the Crabtree effect.) Lactate can also inhibit its own formation, slowing glycolysis. In the healthy cell, the mitochondrion keeps glycolysis working by consuming pyruvate and electrons (or "hydrogens") from NADH, keeping the cell highly oxidized, with a ratio of NAD+/NADH of about 200. When the mitochondrion's ability to consume pyruvate and NADH is limited, the pyruvate itself accepts the hydrogen from NADH, forming lactic acid and NAD+ in the process. As long as lactate leaves the cell as fast as it forms, glycolysis will provide ATP to allow the cell to survive. Oxygen and pyruvate are normally "electron sinks," regenerating the NAD+ needed to produce energy from glucose.

But if too much lactate is present, slowing glycolytic production of ATP, the cell with defective respiration will die unless an alternative electron sink is available. The synthesis of fatty acids is such a sink, if electrons (hydrogens) can be transferred from NADH to NADP+, forming NADPH, which is the reducing substance required for turning carbohydrates and pyruvate and amino acids into fats.

This transfer can be activated by the transhydrogenase enzymes in the mitochondria, and also by interactions of some dehydrogenase enzymes.

The enzyme, fatty acid synthase (FAS), normally active in the liver and fat cells and in the estrogen-stimulated uterus, is highly active in cancers, and its activity is an inverse indicator of prognosis. Inhibiting it can cause cancer cells to die, so the pharmaceutical industry is looking for drugs that can safely inhibit it. This enzyme is closely associated with the rate of cell proliferation, and its activity is increased by both cortisol and estrogen.

The first biochemical event when a cell responds to estrogen is the synthesis of fat. Estrogen can activate transhydrogenases, and early studies of estrogen's biological effects provided considerable evidence that its actions were the result of the steroid molecule's direct participation in hydrogen transfers, oxidations and reductions. E.V. Jensen's claim that estrogen acts only through a "receptor protein" which activated gene transcription was based on his experimental evidence indicating that estrogen doesn't participate in oxidation and reduction processes in the uterus, but subsequently his claim has turned out to be false.

Glycolysis is very inefficient for producing usable energy compared to the respiratory metabolism of the mitochondria, and when lactate is carried to the liver, its conversion to glucose adds to the energy drain on the organism.

The hypoglycemia and related events resulting from accelerated glycolysis provide a stimulus for increased activity of the adaptive hormones, including cortisol. Cortisol helps to maintain blood sugar by increasing the conversion of protein to amino acids, and mobilizing free fatty acids from fat stores. The free fatty acids inhibit the use of glucose, so the stress metabolism relies largely on the consumption of amino acids. This increases the formation of ammonia, yet the combination of glycolysis and fat oxidation provides less carbon dioxide, which is needed for the conversion of ammonia to urea. Ammonia stimulates the formation of lactate, while carbon dioxide inhibits it.

Starving an animal with a tumor increases the stress hormones, providing free fatty acids and amino acids, and accelerates the tumor's growth (Sauer and Dauchy, 1987); it's impossible to "starve a tumor," by the methods often used. Preventing the excessive breakdown of protein and reducing the release of fatty acids from fat cells would probably cause many cancer cells to die, despite the availability of glucose, because of lactate's toxic effects, combined with the energy deficit caused by the respiratory defect that causes their aerobic glycolysis. Recently, the intrinsically high rate of cell death in tumors has been recognized. The tumor is maintained and enlarged by the recruitment of "stem cells." These cells normally would repair or regenerate the tissue, but under the existing metabolic conditions, they fail to differentiate properly.

The extracellular matrix in the tumor is abnormal, as well as the metabolites and signal substances being produced there, and the new cells fail to receive the instructions needed to restore the normal functions to the damaged tissue. These abnormal conditions can cause abnormal differentiation, and this cellular state is likely to involve chemical modification of proteins, including remodeling of the chromosomes through acetylation of the histones (Alam, et al., 2008; Suuronen, et al., 2006). The protein-protective effects of carbon dioxide are replaced by the protein-damaging effects of lactate and its metabolites.

The ability of lactic acid to displace carbon dioxide is probably involved in its effects on the blood clotting system. It contributes to disseminated intravascular coagulation and consumption coagulopathy, and increases the tendency of red cells to aggregate, forming "blood sludge," and makes red cells more rigid, increasing the viscosity of blood and impairing circulation in the small vessels. (Schmid-Schönbein, 1981; Kobayashi, et al., 2001; Martin, et al., 2002; Yamazaki, et al., 2006.)

The features of the stress metabolism include increases of stress hormones, lactate, ammonia, free fatty acids, and fat synthesis, and a decrease in carbon dioxide. Factors that lower the stress hormones, increase carbon dioxide, and help to lower the circulating free fatty acids, lactate, and ammonia, include vitamin B1 (to increase CO2 and reduce lactate), niacinamide (to reduce free fatty acids), sugar (to reduce cortisol, adrenaline, and free fatty acids), salt (to lower adrenaline), thyroid hormone (to increase CO2). Vitamins D, K, B6 and biotin are also closely involved with carbon dioxide metabolism. Biotin deficiency can cause aerobic glycolysis with increased fat synthesis (Marshall, et al., 1976).

A protein deficiency, possibly by increasing cortisol, is likely to contribute to increased FAS and fat synthesis (Bannister, et al., 1983), but the dietary protein shouldn't provide an excess of tryptophan, because of tryptophan's role as serotonin precursor--serotonin increases inflammation and glycolysis (Koren-Schwartzer, et al., 1994).

Incidental stresses, such as strenuous exercise combined with fasting (e.g., running or working before eating breakfast) not only directly trigger the production of lactate and ammonia, they also are likely to increase the absorption of bacterial endotoxin from the intestine. Endotoxin is a ubiquitous and chronic stressor. It increases lactate and nitric oxide, poisoning mitochondrial respiration, precipitating the secretion of the adaptive stress hormones, which don't always fully repair the cellular damage.

Aspirin protects cells in many ways, interrupting excitotoxic processes by blocking nitric oxide and prostaglandins, and consequently it inhibits cell proliferation, and in some cases inhibits glycolysis, but the fact that it can inhibit FAS (Beynen, et al., 1982) is very important in understanding its role in cancer.

There are several specific signals produced by lactate that can promote growth and other features of cancer, and it happens that aspirin antagonizes those: HIF, NF-kappaB, the kinase cascades, cyclin D1, and heme oxygenase.

Lactate and inflammation promote each other in a vicious cycle (Kawauchi, et al., 2008).

The toxic mechanism of bacterial endotoxin (lipopolysaccharide) involves inappropriate stimulation (Wang and White, 1999) of cells, followed by inflammation and mitochondrial inhibition. The stimulation seems to be a direct "biophysical" action on cells, causing them to take up water (Minutoli, et al., 2008), which is especially interesting, since estrogen's immediate excitatory effect causes cells to take up water.

Hypoosmolarity itself is excitatory and anabolic. It stimulates lipolysis and fat oxidation (Keller, et al. 2003), and osmotic swelling stimulates glycolysis and inhibits mitochondrial respiration (Levko, et al., 2000). Endotoxin causes hyponatremia (Tyler, et al., 1994), and a hypertonic salt solution is protective, lactate solutions are harmful. Other stresses and inflammations also cause hyponatremia.

One of the effects of endotoxin that leads to prolonged cellular excitation is its inhibition of the glucuronidation system (Bánhegyi, et al., 1995), since this inhibition allows excitatory estrogen to accumulate.

In women and rats, antibiotics were found to cause blood levels of estrogen and cortisol to decrease, while progesterone increased. This effect apparently resulted from the liver's increased ability to inactivate estrogen and to maintain blood sugar when the endotoxin stress was decreased.

Now that hog farmers' use of antibiotics to stimulate growth has been discouraged, they have sought vegetables that have a natural antibiotic effect, reducing the formation and absorption of the intestinal toxins. The human diet can be similarly adjusted, to minimize the production and absorption of the bacterial toxins.

In 2007, two Canadian researchers announced that they were investigating the drug dichloroacetate, which blocks glycolysis, stopping the production of lactic acid, as a cancer treatment, with success. The drug (dichloroacetate) has toxic side effects, but it is useful in several other conditions involving over-production of lactic acid. Other drugs that inhibit glycolysis have also shown anticancer effects in animals, but are in themselves very toxic. On the theoretical level, it would be better to inhibit only aerobic glycolysis, rather than inhibiting enzymes that are essential for all glycolysis.

Since endotoxemia can produce aerobic glycolysis in an otherwise healthy person (Bundgaard, et al., 2003), a minimally "Warburgian" approach--i.e,, a merely reasonable approach--would involve minimizing the absorption of endotoxin. Inhibiting bacterial growth, while optimizing intestinal resistance, would have no harmful side effects. Preventing excessive sympathetic nervous activity and maintaining the intestine's energy production can be achieved by optimizing hormones and nutrition. Something as simple as a grated carrot with salt and vinegar can produce major changes in bowel health, reducing endotoxin absorption, and restoring constructive hormonal functions.

Medical tradition and inertia make it unlikely that the connection between cancer and bowel toxins will be recognized by the mainstream of medicine and governemt. In another article I will describe some of the recent history relating to this issue.

It's nice that some cancer researchers are now remembering Warburg, but unfortunately they are usually just fitting the fact of cancer's aerobic glycolysis into the genetic mutant cell paradigm, thinking of the respiratory defect as just another opportunity for killing the evil deviant cancer cell, rather than looking for the causes of the respiratory defect. Warburg, Koch, and Szent-Gyorgyi had a comprehensive view of biology, in which the aerobic production of lactate, resulting from a respiratory defect, itself was functonally related to the nature of cancer.

A focus on correcting the respiratory defect would be relevant for all of the diseases and conditions (including heart disease, diabetes, dementia) involving inflammation and inappropriate excitation, not just for cancer.

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A R T I C L E

Milk in context: allergies, ecology, and some myths

Food allergies are becoming much more common in recent decades, especially in industrialized countries. Most attention has been given to theories about changes in people, such as the reduction in infectious diseases and parasites, or vitamin D deficiency, or harmful effects from vaccinations, and little attention has been given to degradation of the food supply.

Our food cultures, like linguistic and moral cultures, give us some assumptions or theories about the way the world should be, and if these beliefs aren't questioned and tested, they can permeate the culture of science, turning the research process into a rationalization of accepted opinions.

In general, those who pay for research are those with an investment in or commitment to the preservation and expansion of the existing systems of production and distribution. Cheap mass production, durability and long shelf-life are more important than the effects of foods on health. The biggest industries are usually able to keep public attention away from the harm they do.

The historical economic importance of cereals and beans is reflected in the nutritional and biochemical research literature, which has paid relatively little attention to basic questions about human adaptation to the ecosystems. From the early petrochemical Green Revolution to the contemporary imposition of genetically altered seeds, the accumulated economic power of the food industry has taken control of the food culture.

In evaluating each research publication relating to nutrition and health, we should ask what alternative possibilities are being neglected, for practical reasons, cultural preferences, and business interests.

Some people with an ecological concern have argued that grains and beans can most economically provide the proteins and calories that people need, but good nutrition involves much more than the essential nutrients.

Efficient industrial agriculture has been concerned with cheaply producing those important nutrients, and their critics have focussed on their use of toxic chemicals, on the social damage they produce, the degradation of the soil, the toxic effects of genetic modification, their unsustainable use of petroleum, and occasionally on the lower nutritional value of chemically stimulated crops.

I think far too little attention is being given to the effects of abnormal and stressful growth conditions on the plants' natural defense systems. Plants normally synthesize some toxins and inhibitors of digestive enzymes to discourage attacks by bacteria, fungi, insects, and other predators. When a plant is injured or otherwise stressed, it produces more of the defensive substances, and very often they communicate their stress to other plants, and the resulting physiological changes can cause changes in seeds that affect the resistance of the progeny. (Agrawal, 2001)

One of many substances produced by plants in response to injury is chitinase, an enzyme that breaks down chitin, a polysaccharide that is a structural component of fungi and insects. Chitinase, which is produced by bacteria and humans, as well as by plants and other organisms, is involved in developmental processes as well as in the innate immune system. In plants, the enzyme is induced by ethylene and salicylate, in animals by estrogen, light damage, and infections, and can be demonstrated in polyps and cancers.

The two main classes of plant allergens are the stress-induced chitinases, and seed storage proteins, such as gluten. The chitinase allergens are responsible for reactions to latex (which is secreted by rubber trees in reaction to a wound), bananas, avocados, many other fruits and vegetables, and some types of wood and other plant materials. Intensive agricultural methods are increasing the formation of the defensive chemicals, and the industrialized crops are responsible for the great majority of the new allergies that have appeared in the last 30 years.

The presence of the chitinase family of proteins in humans was first discovered in the inflamed asthmatic lung. It was then found at high levels in the uterine endometrium at the time of implantation of the embryo (an inflammation-like situation) and in the uterus during premature labor. Since estrogen treatment is known to increase the incidence of asthma and other inflammations, the appearance of chitinase also in the uterus in estrogen dominated conditions is interesting, especially when the role of estrogen in celiac disease (in effect an allergy to gluten) is considered. Celiac disease is more prevalent among females, and it involves the immunological cross-reaction to an antigen in the estrogen-regulated transglutaminase enzyme and the gluten protein. The (calcium-regulated) transglutaminase enzyme is involved in the cross-linking of proteins in keratinized cells, in fibrotic processes in the liver, and in cancer. (People with celiac disease often suffer from osteoporosis and urinary stone deposition, showing a general problem with calcium regulation.)

This means that estrogen and stress cause the appearance of antigens in the human or animal tissues that are essentially the same as the stress-induced and defensive proteins in plant tissues. A crocodile might experience the same sort of allergic reaction when eating estrogen-treated women and when eating commercial bananas.

The various states of the innate immune system have been neglected by immunologists, for example in relation to organ transplantation. The major histocompatibility antigens are matched, but organ transplants still sometimes fail. A study found that the livers from young men had a high survival rate when transplanted into either men or women, but the livers of older women donors were rejected at a high rate when transplanted into either men or women. Exposure to estrogen increases intracellular calcium and the unsaturation of fatty acids in tissue lipids, and the expression of enzymes such as chitinase and transglutaminase, and the various enzymes in the structure-sensitive estrogen-controlled metabolic pathways.

Estrogen's actions are closely and pervasively involved with the regulation of calcium, and these changes affect the basic tissue structures and processes that constitute the innate immune system. Estrogen's effect in increasing susceptibility to autoimmune diseases hasn't yet been recognized by mainstream medicine.

The chemist Norman Pirie argued convincingly that leaf protein had much higher nutritional value than grain and bean proteins, and that it had the potential to be much more efficient economically, if it could be separated from the less desirable components of leaves.

The amino acid composition and nutritional value of leaf protein is similar to milk protein, which is understandable since cows produce milk from the amino acids produced in their rumens by bacteria digesting the leaves the cows have eaten. The bacteria perform the refining processes that Pirie believed could be done technologically, and they also degrade or detoxify the major toxins and allergens.

The nutrients produced in the cow's rumen are selectively absorbed into the cow's bloodstream, where the liver can further filter out any toxins before the amino acids and other nutrients are absorbed by the udder to be synthesized into milk. If cows are fed extremely bad diets, for example with a very large amount of grain, the filtering process is less perfect, and some allergens can reach the milk, but since sick cows are less profitable than healthy cows, dairies usually feed their cows fairly well.

In a recent study of 69,796 hospitalized newborns, a diagnosis of cow's milk allergy was made in 0.21% of them. Among those whose birthweight had been less than a kilogram, 0.35% of them were diagnosed with the milk allergy. Gastrointestinal symptoms were the main reason for the diagnosis, but a challenge test to confirm the diagnosis was used in only 15% of the participating hospitals, and a lymphocyte stimulation test was used in only 5.5% of them (Miyazawa, et al., 2009). There are many publications about milk allergies, but they generally involve a small group of patients, and the tests they use are rarely evaluated on healthy control subjects.

Several surveys have found that of children who have a diagnosed milk allergy, about 2/3 of them grow out of the allergy.

People who have told me that they have had digestive problems with milk have sometimes found that a different brand of milk doesn't cause any problem.

Milk with reduced fat content is required by US law to have vitamins D and A added. The vehicle used in the vitamin preparation, and the industrial contaminants in the pure vitamins themselves, are possible sources of allergens in commercial milk, so whole milk is the most likely to be free of allergens.

A thickening agent commonly used in milk products, carrageenan, is a powerful allergen that can cause a pseudo-latex allergy (Tarlo, et al., 1995). It is a sulfated polysaccharide, structurally similar to heparin. There are good reasons to think that its toxic effects are the result of disturbance of calcium metabolism (see for example Abdullahi, et al., 1975; Halici, et al., 2008; Janaswamy and Chandrasekaran, 2008).

Besides the idea of milk allergy, the most common reason for avoiding milk is the belief that the genes of some ethnic groups cause them to lack the enzyme, lactase, needed to digest milk sugar, lactose, and that this causes lactose intolerance, resulting in gas or diarrhea when milk is consumed. Tests have been reported in which a glass of milk will cause the lactase deficient people to have abdominal pain. However, when intolerant people have been tested, using milk without lactose for comparison, there were no differences between those receiving milk with lactose or without it. The intolerant people consistently tolerate having a glass with each meal.

When a group of lactase deficient people have been given some milk every day for a few weeks, they have adapted, for example with tests showing that much less hydrogen gas was produced from lactose by intestinal bacteria after they had adapted (Pribila, et al., 2000).

Bacterial overgrowth in the small intestine can be caused by hypothyroidism (Lauritano, et al., 2007), and the substances produced by these bacteria can damage the lining of the small intestine, causing the loss of lactase enzymes (Walshe, et al., 1990).

Another hormonal condition that probably contributes to lactase deficiency is progesterone deficiency, since a synthetic progestin has been found to increase the enzyme (Nagpaul, et al., 1990). The particular progestin they used lacks many of progesterone's effects, but it does protect against some kinds of stress, including high estrogen and cortisol. This suggests that stress, with its increased ratio of estrogen and cortisol to progesterone, might commonly cause the enzyme to decrease.

Two other ideas that sometimes cause people to avoid drinking milk and eating cheese are that they are fattening foods, and that the high calcium content could contribute to hardening of the arteries.

When I traveled around Europe in 1968, I noticed that milk and cheese were hard to find in the Slavic countries, and that many people were fat. When I crossed from Russia into Finland, I noticed there were many stores selling a variety of cheeses, and the people were generally slender. When I lived in Mexico in the 1960s, good milk was hard to find in the cities and towns, and most women had fat hips and short legs. Twenty years later, when good milk was available in all the cites, there were many more slender women, and the young people on average had much longer legs. The changes I noticed there reminded me of the differences I had seen between Moscow and Helsinki, and I suspect that the differences in calcium intake were partly responsible for the changes of physique.

In recent years there have been studies showing that regular milk drinkers are less fat than people who don't drink it. Although the high quality protein and saturated fat undoubtedly contribute to milk's anti-obesity effect, the high calcium content is probably the main factor.

The parathyroid hormone (PTH) is an important regulator of calcium metabolism. If dietary calcium isn't sufficient, causing blood calcium to decrease, the PTH increases, and removes calcium from bones to maintain a normal amount in the blood. PTH has many other effects, contributing to inflammation, calcification of soft tissues, and decreased respiratory energy production.

When there is adequate calcium, vitamin D, and magnesium in the diet, PTH is kept to a minimum. When PTH is kept low, cells increase their formation of the uncoupling proteins, that cause mitochondria to use energy at a higher rate, and this is associated with decreased activity of the fatty acid synthase enzymes.

These changes are clearly related to the anti-obesity effect of calcium, but those enzymes are important for many other problems.

The metabolic syndrome, that involves diabetes, hypertension, and obesity, is associated with high PTH (Ahlström, et al., 2009; Hjelmesaeth, et al., 2009).

Alzheimer's disease involves decreased mitochondrial activity and low levels of the uncoupling proteins. There is evidence that milk drinkers are protected against dementia (Yamada, et al., 2003). Cancer involves increased activity of the fatty acid synthase enzymes. Increased calcium consumption beneficially affects both sets of enzymes, uncoupling proteins and fatty acid synthase.

Multiple sclerosis relapses consistently occur at times of high PTH, and remissions consistently occur at times of low PTH (Soilu-Hänninen, et al., 3008). PTH increases the activity of nitric oxide synthase, and nitric oxide is a factor in the vascular leakiness that is so important in MS.

There are components of milk that might protect against tooth decay by inhibiting the binding of bacteria to teeth (Danielsson, et al., 2009).

David McCarron has published a large amount of evidence showing how calcium deficiency contributes to high blood pressure. The chronic elevation of PTH caused by calcium deficiency causes the heart and blood vessels to retain calcium, making them unable to relax fully.

Intravenous infusion of calcium can relax blood vessels and improve heart function. The suppression of PTH is probably the main mechanism.

PTH (like estrogen) causes mast cells to release promoters of inflammation, including histamine and serotonin. Serotonin and nitric oxide contribute to increasing PTH secretion.

Removal of the parathyroid gland has reduced heart problems and mortality (Costa-Hong, et al., 2007) and insomnia (Esposito, et al., 2008; Sabbatini, et al., 2002) in people with kidney disease and excess PTH.

Increased carbon dioxide, for example when adapted to high altitude, can greatly decrease PTH. Frequent, but smaller, meals can reduce PTH.

Cancer cells often secrete PTH and related proteins with similar effects on calcium, and the PTH stimulates the growth and invasiveness of prostate cancer (DaSilva, et al., 2009) cells, and seems to be as closely involved with breast cancer. The PTH-related protein is associated with calcification in breast cancer (Kanbara, et al., 1994). Microscopic calcium crystals themselve produce inflammation (Denko and Whitehouse, 1976).

Besides being an ecologically favorable source of calcium, protein, sugar, and fat, the composition of milk causes it to be digested efficiently, supporting the growth of bacteria that are relatively safe for the intestine and liver, and reducing the absorption of endotoxin.

Dividing any food into smaller meals can lower the PTH, and milk is a convenient food to use in small amounts and frequently.

Some amino acids directly stimulate insulin secretion, decreasing blood sugar and leading to the secretion of cortisol in reaction to the depression of blood glucose. The presence of lactose in milk, and of fat, to slow absorption of the amino acids, helps to minimize the secretion of cortisol. The main protein of milk, casein, seems to have some direct antistress effects (Biswas, et al., 2003).

Since milk's primary biological function is to support the growth of a young animal, some of its features make it inappropriate as a sole food for an adult. To support cell division and growth, the methionine and tryptophan content of milk is higher than would be optimal for an adult animal, and the phosphate might be slightly more than needed, in relation to the calcium. Since the fetus stores a large amount of iron during gestation, the iron content of milk is low, and when a young animal has used the stored iron, its continuing growth requires more iron than milk provides. However, for an adult, the low iron content of milk and cheese makes these foods useful for preventing the iron overload that often contributes to the degenerative diseases.

Combining milk and cheese with fruits adds to the antistress effect. The additional sugar and potassium and other minerals allow the milk protein to be used more efficiently, by moderating the secretion of cortisol, and helping to inhibit the secretion of PTH.

Substances such as PTH, nitric oxide, serotonin, cortisol, aldosterone, estrogen, thyroid stimulating hormone, and prolactin have regulatory and adaptive functions that are essential, but that ideally should act only intermittently, producing changes that are needed momentarily. When the environment is too stressful, or when nutrition isn't adequate, the organism may be unable to mobilize the opposing and complementary substances to stop their actions. In those situations, it can be therapeutic to use some of the nutrients as supplements. Calcium carbonate (eggshell or oyster shell, for example) and vitamins D and K, can sometimes produce quick antistress effects, alleviating insomnia, hypertension, edema, inflammations and allergies, etc., but the regular use of milk and cheese can prevent many chronic stress-related diseases.

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Caries Res. 2009;43(3):171-8. Human milk compounds inhibiting adhesion of mutans streptococci to host ligand-coated hydroxyapatite in vitro. Danielsson Niemi L, Hernell O, Johansson I.

Cancer Res. 2009 Sep 15;69(18):7402-11. The neuroendocrine-derived peptide parathyroid hormone-related protein promotes prostate cancer cell growth by stabilizing the androgen receptor. DaSilva J, Gioeli D, Weber MJ, Parsons SJ.

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Dig Liver Dis. 2009 Aug;41(8):541-50. Transglutaminases in inflammation and fibrosis of the gastrointestinal tract and the liver. Elli L, Bergamini CM, Bardella MT, Schuppan D.

J Nephrol. 2008 Mar-Apr;21 Suppl 13:S92-6. Parathyroidectomy improves the quality of sleep in maintenance hemodialysis patients with severe hyperparathyroidism. Esposito MG, Cesare CM, De Santo RM, Cice G, Perna AF, Violetti E, Conzo G, Bilancio G, Celsi S, Annunziata F, Iannelli S, De Santo NG, Cirillo M, Livrea A.

Endocrinology. 1997 Jul;138(7):2665-73. Parathyroid hormone-related protein is induced in the adult liver during endotoxemia and stimulates the hepatic acute phase response. Funk JL, Moser AH, Grunfeld C, Feingold KR.

Arch Pharm Res. 2008 Jul;31(7):891-9. Effects of calcium channel blockers on hyaluronidase-induced capillary vascular permeability. Halici Z, Suleyman H, Cadirci E.

J Am Diet Assoc. 2000 May;100(5):524-8. Improved lactose digestion and intolerance among African-American adolescent girls fed a dairy-rich diet. Pribila BA, Hertzler SR, Martin BR, Weaver CM, Savaiano DA.

Dig Dis Sci. 1998 Jan;43(1):39-40. Fecal hydrogen production and consumption measurements. Response to daily lactose ingestion by lactose maldigesters. Hertzler SR, Savaiano DA, Levitt MD.

J Am Coll Nutr. 2009 Apr;28(2):142-9. Effects of dairy products on intracellular calcium and blood pressure in adults with essential hypertension. Hilpert KF, West SG, Bagshaw DM, Fishell V, Barnhart L, Lefevre M, Most MM, Zemel MB, Chow M, Hinderliter AL, Kris-Etherton PM. Consumption of dairy foods beneficially affects (Ca)(i), resulting in improved BP in a subgroup defined by (Ca)(i) response.

Cardiovasc Diabetol. 2009 Feb 3;8:7. Parathyroid hormone, but not vitamin D, is associated with the metabolic syndrome in morbidly obese women and men: a cross-sectional study. Hjelmesaeth J, Hofsø D, Aasheim ET, Jenssen T, Moan J, Hager H, Røislien J, Bollerslev J.

Eur J Epidemiol. 2003;18(7):677-84. The Swedish coeliac disease epidemic with a prevailing twofold higher risk in girls compared to boys may reflect gender specific risk factors. Ivarsson A, Persson LA, Nyström L, Hernell O.

Carbohydr Res. 2008 Feb 4;343(2):364-73. Epub 2007 Oct 30. Heterogeneity in iota-carrageenan molecular structure: insights for polymorph II-->III transition in the presence of calcium ions. Janaswamy S, Chandrasekaran R.

Metabolism. 2002 Oct;51(10):1230-4. A calcium-deficient diet caused decreased bone mineral density and secondary elevation of estrogen in aged male rats-effect of menatetrenone and elcatonin. Kato S, Mano T, Kobayashi T, Yamazaki N, Himeno Y, Yamamoto K, Itoh M, Harada N, Nagasaka A.

Nippon Geka Gakkai Zasshi. 1993 Apr;94(4):394-9. [Immunohistological evaluation of parathyroid hormone-related protein in breast cancer with and without calcification on mammography] Kanbara Y, Kono N, Nakaya M, Ishikawa Y, Fujiwara O, Kitazawa R, Kitazawa S.

J Pak Med Assoc. 1996 Jun;46(6):128-31. Changes in plasma electrolytes during acclimatization at high altitude. Khan DA, Aslam M, Khan ZU.

J Am Coll Nutr. 2009 Feb;28 Suppl 1:103S-19S. Milk products, dietary patterns and blood pressure management. Kris-Etherton PM, Grieger JA, Hilpert KF, West SG.

Br J Cancer. 1996 Jul;74(2):200-7. A new human breast cancer cell line, KPL-3C, secretes parathyroid hormone-related protein and produces tumours associated with microcalcifications in nude mice. Kurebayashi J, Kurosumi M, Sonoo H.

J Clin Endocrinol Metab. 2007 Nov;92(11):4180-4. Association between hypothyroidism and small intestinal bacterial overgrowth. Lauritano EC, Bilotta AL, Gabrielli M, Scarpellini E, Lupascu A, Laginestra A, Novi M, Sottili S, Serricchio M, Cammarota G, Gasbarrini G, Pontecorvi A, Gasbarrini A.

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Hypertension 1980 Mar-Apr;2(2):162-8. Enhanced parathyroid function in essential hypertension: a homeostatic response to a urinary calcium leak. McCarron DA, Pingree PA, Rubin RJ, Gaucher SM, Molitch M, Krutzik S. Recent reports . . . suggest that increased parathyroid gland function may be one of the more common endocrine disturbances associated with hypertension. Compared to a second age- and sex-matched normotensive population, the hypertensives demonstrated a significant (p less than 0.005) relative hypercalciuria. For any level of urinary sodium, hypertensives excreted more calcium. These preliminary data suggest that parathyroid gland function may be enhanced in essential hypertension.

Am J Med 1987 Jan 26;82(1B):27-33. The calcium paradox of essential hypertension. McCarron DA, Morris CD, Bukoski R. This evidence, and the paradoxical therapeutic efficacy of both calcium channel blockers and supplemental dietary calcium, can be integrated into a single theoretic construct.

Nephrol Dial Transplant. 2002 Oct;17(10):1854. Insomnia in maintenance haemodialysis patients. Sabbatini M, Minale B, Crispo A, Pisani A, Ragosta A, Esposito R, Cesaro A, Cianciaruso B, Andreucci VE.

J Neurol Neurosurg Psychiatry. 2008 Feb;79(2):152-7. A longitudinal study of serum 25-hydroxyvitamin D and intact parathyroid hormone levels indicate the importance of vitamin D and calcium homeostasis regulation in multiple sclerosis. Soilu-Hänninen M, Laaksonen M, Laitinen I, Erälinna JP, Lilius EM, Mononen I.

J Nutr. 2006 Apr;136(4):1107-13. Lactose intolerance symptoms assessed by meta-analysis: a grain of truth that leads to exaggeration. Savaiano DA, Boushey CJ, McCabe GP.

J Allergy Clin Immunol. 1995 May; 95(5 Pt 1): 933-6. Anaphylaxis to carrageenan: a pseudo-latex allergy. Tarlo, S M Dolovich, J Listgarten, C

Gut. 1990 Jul;31(7):770-6. Effects of an enteric anaerobic bacterial culture supernatant and deoxycholate on intestinal calcium absorption and disaccharidase activity. Walshe K, Healy MJ, Speekenbrink AB, Keane CT, Weir DG, O'Moore RR.

Metabolism. 2003 Aug;52(8):1072-7. Dietary sodium restriction exacerbates age-related changes in rat adipose tissue and liver lipogenesis. Xavier AR, Garofalo MA, Migliorini RH, Kettelhut IC.

Hypertension 1994 Apr;23(4):513-30. Dietary calcium and blood pressure in experimental models of hypertension. A review. Hatton DC, McCarron DA.

Nippon Geka Gakkai Zasshi. 1993 Apr;94(4):394-9. [Immunohistological evaluation of parathyroid hormone-related protein in breast cancer with and without calcification on mammography] [Article in Japanese] Kanbara Y, Kono N, Nakaya M, Ishikawa Y, Fujiwara O, Kitazawa R, Kitazawa S. It is suspected that PTHrP is also one of the main factors of calcification in breast cancer.

Kokuritsu Iyakuhin Shokuhin Eisei Kenkyusho Hokoku. 1998;(116):46-62. [Plant defense-related proteins as latex allergens] [Article in Japanese] Yagami T.

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Am J Hypertens 1995 Oct;8(10 Pt 1):957-64. Regulation of parathyroid hormone and vitamin D in essential hypertension. Young EW, Morris CD, Holcomb S, McMillan G, McCarron DA. The maximal stimulated PTH level was significantly higher in hypertensive than normotensive subjects in the absence of measured differences in serum ionized calcium concentration, serum 1,25(OH)2-vitamin D concentration, and creatinine clearance.

Mol Immunol. 2007 Mar;44(8):1977-85. Estradiol activates mast cells via a non-genomic estrogen receptor-alpha and calcium influx. Zaitsu M, Narita S, Lambert KC, Grady JJ, Estes DM, Curran EM, Brooks EG, Watson CS, Goldblum RM, Midoro-Horiuti T.

Copyright 2011. Raymond Peat, P.O. Box 5764, Eugene OR 97405. All Rights Reserved. www.RayPeat.com
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A R T I C L E

Membranes, plasma membranes, and surfaces

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The "essential fatty acids":

Suppress metabolism and promote obesity; are immunosuppressive; cause inflammation and shock; are required for alcoholic liver cirrhosis; sensitize to radiation damage; accelerate formation of aging pigment, cataracts, retinal degeneration; promote free radical damage and excitoxicity; cause cancer and accelerate its growth; are toxic to the heart muscle and promote atherosclerosis; can cause brain edema, diabetes, excessive vascular permeability, precocious puberty, progesterone deficiency....

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Twice, editors have printed my articles on unsaturated fats, with adjoining "rebuttals," but I was disappointed that all of my points were ignored, as if you could rebut an argument by just saying that you emphatically disagree with it. I think it is evident that those people don't know what would be involved in refuting an argument. They are annoyed that I have bothered them with some evidence, but not sufficiently annoyed to cause them to try to marshal some evidence against my arguments.

Marketing and medical claims are intertwined with a view of life that permeates our culture. I am aware that my criticism of the doctrine of the essentiality of linoleic acid threatens the large profits of many people, and threatens the prestige of the most popular "theory of cell structure," but I think it is important to point out that nutritional and medical advice depend on the truth of the theory of cell structure and function which supports that advice, and so it is reasonable to see how sound that theory is.

As I understand it, the doctrine of the "essential fatty acids" goes this way:

1. They are essential because they are required for making cell membranes and prostaglandins.

2. Rats deprived of the unsaturated fatty acids develop a skin disease, and "lose water" through the skin.

3. Human skin diseases (etc.) can be cured with polyunsaturated fats.

In fact, rats may get a skin disease when fed a fat-free diet, but the observation that vitamin B6 cures it should have laid to rest the issue of the dietary essentiality of the polyunsaturated oils more than 50 years ago. Scientifically, it did, but forces greater than science have revivified the monster. Experiments that confirm the disproof are done periodically--animals living generation after generation without unsaturated oils in their diet or any evidence of harm, human cells growing in culture-dishes without polyunsaturated fats, for example--without noticeable effect on the doctrine, which is perpetuated in many effective, nonscientific ways--textbooks, advertisements, college courses, for example.

Now, instead of demonstrating harm from a dietary lack of the "essential" fats, the presence of the Mead acid or omega-9 fatty acids is taken as evidence of a deficiency. Our cells (and animal cells) produce these unsaturated fats when their special desaturase enzymes are not suppressed by the presence of exogenous linoleic or linolenic acids. Normally, the inactivation of an enzyme system and the suppression of a natural biological process might be taken as evidence of toxicity of the vegetable oils, but here, the occurrence of the natural process is taken as evidence of a deficiency. To me, this seems very much like the "disease" of having tonsils, an appendix, or a foreskin--if it is there, you have a problem, according to the aggressive surgical mentality. But what is the "problem" in the case of the natural Mead or omega-9 acids? (I think the "problem" is simply that they allow us to live at a higher energy level, with greater resistance to stress, better immunity, and quicker healing.)

There have been arguments based on "membranes" and on prostaglandins. The absence of "good" prostaglandins would seem to be an obvious problem, except that the "good" prostaglandins always turn out to have some seriously bad effects when examined in other contexts. Animals that lack dietary unsaturated fats appear to escape most of the problems that are associated with prostaglandins, and I think this means that many of the toxic effects of the unsaturated vegetable oils result from the quantity and type of "eicosanoid"/lipoxygenase products made from them.

One type of membrane argument had to do with the fragility of red blood cells, reasoning, apparently, that the cells are "held together" by a lipid bilayer membrane. (Just what is the tensile strength of a lipid bilayer? Why do fatty acids or saponins weaken blood cells, instead of reinforcing them? If the "tensile strength" of a lipid layer exists, and is positive rather than negative, it is negligible in relation to the tensile strength of the cytoplasm.) Another type of :"membrane" argument was that the mitochondria are abnormal when animals don't get the essential fatty acids in their diet, because the mitochondria are supposed to be essentially membranous structures containing the essential fatty acids. (Actually, the deficient mitochondria produce more ATP than do mitochondria from animals fed the vegetable oils.) Another argument is that "membrane fluidity" is a good thing, and that unsaturated essential fatty acids make the membranes more fluid and thus better--by analogy with their lower bulk-phase melting temperature. (But the measure of fluidity is a very limited thing on the molecular level, and this fluidity may be associated with decreased cellular function, instead of the postulated increase.)

The most addled sort of argument about "membranes" is that animals on the diet lacking polyunsaturated oils have skin that is unable to retain water because of "defective cell membranes." The skin's actual barrier function is the result of mulptile layers of keratinized ("cornified," horny) cells, which have become specialized by their massive production of the protein keratin--very much as red blood cells become specialized by producing the protein, hemoglobin. Since these cells lose most of their water as they become horny, the issue of whether they still have a "plasma membrane" seems to have little interest to researchers; the same can be said regarding the cells of hair and nails. After the epidermal cells have become keratinized and inert, the sebaceous glands in the skin secrete oils, which are absorbed by the dense, proteinaceous cells, causing increased resistance to water absorption. The ideas of a plasma membrane on the cell, and of the water-barrier function of the skin, are two distinct things, that have been blurred together in a thoughtless way. It has been suggested that vitamin B6 cures the characteristic skin disorder of a vitamin B6 deficiency by altering fat metabolism, but the vitamin is involved in cell division and many other processes that affect the skin.

Given the fact that the "essential" oils aren't essential for the growth of cells, they can't be essential for making plasma membranes (if cells must have plasma membranes), or mitochondrial membranes, or any kind of membrane, but as long as there is the idea that fats mainly have the function of building membranes, someone is going to argue that membranes containing vegetable oils are more fluid, or more youthful, or more sensitive, or better in some way than those containing Mead acids, palmitic acid, oleic acid, stearic acid, etc.

For over a century, people have suggested that cells are enclosed in an oily membrane, because there are higher or lower concentrations of many water-soluble substances inside cells, than in the blood, lymph, and other extracellular fluids, and the idea of a membrane was invoked (W. Pfeffer, 1877; E. Overton, 1895, 1902) to explain how that difference can persist. (By 1904, the idea of a membrane largely made of lecithin was made ludicrous by A. Nathansohn's observation that water-soaked lecithin loses its oily property, and becomes very hydrophilic; the membrane was supposed to exclude water-soluble molecules while admitting oil-soluble molecules.)

Inside the cell membrane, the cell substance was seen as a watery solution. Biochemistry, as a profession, was strongly based on the assumption that, when a tissue is ground up in water, the dilute extract closely reflects the conditions that existed in the living cell. Around 1970, when I tried to talk to biochemists about ways to study the chemistry of cells that would more closely reflected the living state, a typical response was that the idea was ridiculous, because it questioned the existence of biochemistry itself as a meaningful science.. But since then, there has been a progressive recognition that organization is more important in the life of a cell than had been recognized by traditional biochemistry. Still, many biochemists thoughtlessly identify the chemistry of the living cell with their study of the water-soluble enzymes, and relegate the insoluble residue of the cell to "membrane-associated proteins" or, less traditionally, to "structural proteins." It has been several decades since the structural/contractile protein of muscle was found to be an enzyme, an ATPase, but the idea that the cell itself is a sort of watery solution, in which the water-soluble enzymes float, randomly mingling with dissolved salts, sugars, etc., persists, and makes the idea of a semipermeable membrane seem necessary, to separate a "watery internal phase" from the watery external phase. Physical chemists have no trouble with the fact that a moist protein can absorb oil as well as water, and the concept that even water-soluble enzymes have oil-loving interiors is well established. If that physical-chemical information had existed in Overton's time, there would have been no urge to postulate an oily membrane around cells, to allow substances to pass into them, in proportion to their solubility in oil.

Because biochemists like to study their enzymes in watery test-tube solutions, they find it easy to think of the cell-substance as a watery solution. With that belief, it is natural that they prefer to think of the primeval ocean as where life originated. Their definitions of chemical reactions and equilibria in the water-phase (and by extension in cells) ignore the alternative reactions and equilibria that would occur in an environment in which ordinary water was not the dominant medium. By this failure to consider the alternatives, they have created some problems that are hard to explain. For example, the polymerization of amino acids into protein is energetically expensive in water, but it is spontaneous in a relatively dry environment, and this spontaneous reaction creates non-random structures with the capacity for building larger structures, with stainable bilayer "membranes," and with catalytic action. (Sidney Fox, 1965, 1973.) Similarly, the problem of ATP synthesis essentially disappears when it is considered in an environment that controls water. The scientific basis for the origin of life in a "primeval soup" never really existed, and more people are now expressing their scepticism. However, biochemists have their commitments:

"In the course of biological evolution, one of the first developments must have been an oily membrane that enclosed the water-soluble molecules of the primitive cell, segregating them and allowing them to accumulate to relatively high concentrations. The molecules and ions contained within a living organism differ in kind and in concentration from those in the organism's surrounding." (Principles of Biochemistry, supposedly by Lehninger, Nelson, and Cox, though Lehninger is dead and I think his name is attached to it to exploit his fame.# Worth Publishers, 1993.)

Hair is composed of thoroughly dead cells, but if it is washed until it contains no sodium or potassium, and then dipped in serum, or a solution of sodium and potassium, it takes up much more potassium than sodium, in the way a living cell does, concentrating potassium "against the gradient." That is the sort of behavior that led to the postulation of a plasma membrane, to maintain the organization that was created by expending energy. "Membrane pumps" use energy, supposedly, to establish the concentration difference, and the barrier membrane keeps the solutes from diffusing away. The lipid bilayer membrane was an early guess, and the pumps were added later, as needed. Gilbert Ling reviewed the published studies on the various "membrane pumps," and found that the energy needed to operate them was 15 times greater than all the energy the cell could possibly produce.

Water softeners contain an ion-exchange resin, that uses the same principle hair does to concentrate ions, which is simply a selectivity based on the acidity of the resin, and the size of the ion. The resin binds calcium more strongly than it binds sodium, and so the water gives up its calcium in exchange for sodium.* Gilbert Ling devised many experiments that demonstrated the passivity of ion-accumulation by living cells.

Usually, cells are surrounded by and imbedded in materials that they have secreted, and their surfaces are often covered with materials that, while remaining anchored to the cell, have a considerable affinity for water. Physically, many of the molecules attached to cells are "surfactants," making the cell wettable, though it isn't customary to describe them as such. The glycoproteins that give cells their characteristic immunological properties are among these materials. At a certain point, there is a transition between the "outside" of the cell, which is relatively passive and water-friendly, and the cell itself, in which water is subordinated to the special conditions of the cell. (The postulated lipid bilayer membrane, in contrast, has two phase discontinuities, one where it meets the cytoplasm, another where it meets the outside world.) At this phase boundary, between two different substances, it is normal to find an electrical potential difference. When two electrically different substances are in contact, it isn't surprising to find an electrical double-layer at the surface. This is a passive process, which doesn't take any energy to maintain, but it can account for specific arrangements of molecules in the region of the phase boundary, since they are exposed to the electrical force of the electrical double-layer. That is to say that in a completely inert and homogeneous substance, a "surface structure" will be generated, as a result of the electrical difference between that substance and the adjoining substance. (This surface structure, if it is to be described as a membrane, must be called a "wet membrane," while the lipid bilayer would be a "dry membrane," since exclusion of water is its reason for existing.) Too many biologists still talk about "electrogenic membrane pumps," indicating that they haven't assimilated the results of Gilbert Ling's research.

To say it another way, there are several kinds of physical process that will govern the behavior of fats, and fats of different types will interact in different ways with their environments. They interact complexly with their environment, serving in many cases as regulatory signal-substances. To describe their role as "membranes" is worse than useless.

Cells can be treated with solvents to remove practically all fats, yet the cells can still show their characteristic membranes: Plasma membrane, mitochondrial membranes, even the myelin figures. The proteins that remain after the extraction of the fats appear to govern the structure of the cell.

A small drop of water can float for a moment on the surface of water; this is explained in terms of the organization of the water molecules near the surface. No membrane is needed to explain this reluctance to coalesce, even though water has a very high affinity for water.

People believed in the "lipid bilayer membrane" for decades before the electron microscope was able to produce an image that could be said to correspond to that theoretical structure. Osmic acid, which is believed to stain fats, does produce a double layer at the surface of cells. However, the arrangement of fat molecules in the lipid bilayer is such that the fatty tails of the two layers are touching each other, while their acidic heads are pointed away from each other. A lipid bilayer, in other words, contains a single zone of fat, bounded by two layers of acid. The "fat-staining" property of osmic acid, then, argues against the lipid bilayer structure.

Osmic acid is very easily reduced electrically, forming a black product. Proteins with their sulfur molecules in a reduced state, for example, would cause an osmium compound to be deposited, and the appearance of two layers of osmium at the cell's phase boundary would be compatible with the idea of an electrical double-layer, induced in proteins.

Electrically charged proteins, which are able to interact with glutathione to increase or decrease their degree of reduction/electrical charge, distributed throughout the cytoplasm, would explain another feature of osmic acid staining, which is incompatible with the "fat-staining" concept. Asphyxia increases the stainability of cells with osmic acid, and this change seems to represent the availability of electrons, rather than the distribution of fats, since the change can appear within 3 minutes. (C. Peracchia and J. D. Robertson, "Increase in osmiophilia of axonal membranes of crayfish as a result of electrical stimulation, asphyxia, or treatment with reducing agents," J. Cell Biol. 51, 223, 1971; N. N. Bogolepov, Ultrastructure of the Brain in Hypoxia, Mir, Moscow, 1983) The amino groups of proteins might also be stained by osmic acid, though asphyxia would more directly affect the disulfide groups. The increased staining with silver in asphyxia similarly suggests an increase in sulfhydryls.

Freezing cells, and then fracturing them and coating the fragments with metal or carbon is often used to "demonstrate the lipid bilayer," so it is interesting that the osmium compound that "reveals" the lipid bilayer for the electron microscope destroys the apparent membrane in the freezing technique. (R. James and D. Branton, "The correlation between the saturation of membrane fatty acids and the presence of membrane fracture faces after osmium fixation," Biochim. Biophys. Acta 233, 504-512, 1971; M. V. Nermut and B. J. Ward, "Effect of fixatives on fracture plane in red blood cells," J. Microsc. 102, 29-39, 1974.)

So, when someone says "we need the essential fatty acids to make cell membranes," my response is likely to be "no, we don't, and life probably originated on hot lava and has never needed lipid membranes."

On the third argument, that vegetable oils can be used therapeutically, I am likely to say yes, they do have some drug-like actions, for example, linseed oil has been used as a purgative, but as with any drug you should make sure that the side effects are going to be acceptable to you. Currently, it is popular to recommend polyunsaturated oils to treat eczema and psoriasis. These oils are immunosuppressive, so it is reasonable to think that there might be some pleasant consequences if a certain immunological process is suppressed, but they are also intimately involved with inflammation, sensitivity to ultraviolet light, and many other undesirable things. The traditional use of coal tar and ultraviolet light was helpful in suppressing eczema and psoriasis, but its tendency to cause cancer has led many people to forego its benefits to protect their health.

If you want to use a polyunsaturated oil as a drug, it is worthwhile to remember that the "essential fatty acids" suppress metabolism and promote obesity; are immunosuppressive; cause inflammation and shock; are required for alcoholic liver cirrhosis; sensitize to radiation damage; accelerate formation of aging pigment, cataracts, retinal degeneration; promote free radical damage and excitoxicity; cause cancer and accelerate its growth; are toxic to the heart muscle and promote atherosclerosis; can cause brain edema, diabetes, excessive vascular permeability, precocious puberty, progesterone deficiency, skin wrinkling and other signs of aging.

Whether any of the claimed pharmaceutical uses of the polyunsaturated oils, besides purgation, turn out to be scientifically valid remains to be seen. The theoretical bases often used to back up the claimed benefits are confused or false, or both.

People who are willing to question the validity of an "orthodox method," such as the glass microelectrode, are in a position to make observations that were "forbidden" by the method and its surrounding ideology. (See Davis, et al., 1970.) Their perception is freed in ways that could lead to new understanding and practical solutions to old problems.

But sometimes experiments seem to be designed as advertising, rather than science. Recent studies of the effects of fish oils on night vision or development of the retina, for example, seem to forget that fish oil contains vitamin A, and that vitamin A has the effects that are being ascribed to the unsaturated fatty acids.

With the financial cutbacks in university libraries, there is a risk that the giant seed-oil organizations will succeed in using governmental power to regulate the alternative communication of scientific information, allowing them to control both public and "scientific" opinion more completely than they do now.

ADDITIONAL REFERENCES

Gilbert N. Ling, A Revolution in the Physiology of the Living Cell, Krieger Publ., Melbourne, Florida, 1993.

G. N. Ling, "A new model for the living cell: A summary of the theory and experimental evidence for its support," Int. Rev. Cytol. 26, 1, 1969.

G. N. Ling, A Physical Theory of the Living State, Blaisdell, New York, 1960.

S. W. Fox, Nature 205, 328, 1965; Naturwissenschaften 60, 359, 1973.

S. W. Fox and K. Dose, Molecular Evolution and the Origin of Life, Marcel Dekker, New York, 1977.

S. Fleischer, B. Fleischer, and W. Stoeckenius, J. Cell Ciol. 32, 193, 1967.

H. J. Morowitz and T. M. Terry, Biochem. Biophys. Acta 183, 276, 1969.

L. Napolitano, F. Le Baron, and J. Scaletti, J. Cell Biol. 34, 817, 1967.

F. W. Cope and R. Damadian, "Biological ion exchanger resins: IV. Evidence for potassium association with fixed charges in muscle and brain by pulsed NMR of 39K," Physiol. Chem. Phys. 6, 17, 1974.

R. Damadian, "Biological ion exchanger resins. III. Molecular interpretations of cellular ion exchange," Biophys. J. 11, 773, 1971.

R. Damadian, "Biological ion exchanger resins," Ann. NY Acad. Sci. 204, 211, 1973.

B. V. Deryaguin, "Recent research into the ptroperties of water in thin films and in microcapillaries," pages 55-60, in The State and Movement of Water in Living Organisms, XIXth Symposium of Soc. Exp. Biol., Cambridge Univ. Press, 1964.

J. S. Clegg and W. Drost-Hansen, "On the density of intracellular water," J. Biol. Phys. 10, 75-84, 1982.

J. S. Clegg, "Properties and metabolism of the aqueous cytoplasm and its boundaries," Am. J. Physiol. 26, R133-R151, 1984.

J. S. Clegg, "Intracellular water and the cytomatrix: some methods of study and current views," J. Cell Biol. 99, 167S-171S, 1984.

W. Drost-Hansen, "Structure and properties of water at biological interfaces," in Chemistry of the Cell Interface, vol. 2, pages 1-184, H. D. Brown, editor, Academic Press, 1971.

W. Drost-Hansen and J. Clegg, editors, Cell-Associated Water, Academic Press, 1979.

C. F. Hazlewood, "A view of the significance and understanding of the physical properties of cell-associated water," pages 165-259 in Cell-Associated Water, Drost-Hansen and Clegg, editors, Academic Press, 1979.

P. M. Wiggins, "Water structure as a determinant of ion distribution in living tissue," J. Theor. Biol. 32, 131-144, 1971.

R. Damadian and F. W. Cope, Physiol. Chem. Phys. 5, 511, 1973.

F. W. Cope, "A review of the applications of solid state physics concepts to biological systems," J. Biol. Phys. 3, 1 1975.

D. N. Nasonov, Local Reaction of Protoplasm and Gradual Excitation, Israel Program for Scientific Translations, Jerusalem, Office of Technical Services, U.S. Dept.of Commerce, Washington, DC, 1962.

A. Nathansohn, Jahrb. Wiss. Bot. 39, 607, 1904.

A. S. Troshin, Problems of Cell Permeability, Pergamon Press, London, 1966.

A. S. Troshin, Byull. Eksp. Biol. Med. 34, 59, 1952.

I. Tasaki, Nerve Excitation: A Macromolecular Approach, Thomas, Springfield, 1968.

Albert Szent-Gyorgyi, Bioenergetics, Academic Pressn New York, 1957.

Albert Szent-Gyorgyi, The Living State and Cancer, Marcel Deker, New York, 1978.

T. L. Davis, et al., "Potentials in frog cornea and microelectrode artifact," Amer. J. Physiol. 219(1), 178-183, 1970.

NOTES:

# In their preface, Nelson and Cox say their book has retained "Lehninger's ground-breaking organization, in which a discussion of biomolecules is followed by metabolism and then information pathways," but that at every other level "this second edition is a re-creation, rather than a revision, of the original text. Every chapter has been comprehensively overhauled, not just by adding and deleting information, but by completely reorganizing its presentation and content...." This is reminiscent of the book published under the name of Max Gerson after his death, which inserted essentially fraudulent material to support an approach that is exactly what Gerson strongly advised against.

* This principle might be applicable to the removal of calcium from living cells, with a procedure that wouldn't have the dangers of chelation. Increased consumption of sodium and magnesium should facilitate the removal and excretion of abnormally retained calcium. Sodium has been found to protect tissues against oxidative damage, for example during cancer therapy with cis-platinum.

=====================

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A R T I C L E

Multiple sclerosis, protein, fats, and progesterone

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We are always subjected to antigenic burdens. The important question has to do with our ability to limit the inflammatory response to these burdens.

In MS, it is clear that the inflammatory process itself is destructive, and that estrogen is a major predisposing factor. Unsaturated fatty acids, and dietary imbalance of amino acids interact closely with hyperestrogenism and hypothyroidism to produce the autoimmune degenerative diseases.

Reduction of the mediators of inflammation is better than augmenting a single antiinflammatory agent such as cortisol. Although immunosuppressive drugs, including the "essential fatty acids," do alleviate inflammatory symptoms temporarily, they probably contribute to the underlying pathology.

People with MS have chronically increased production of cortisol. This creates a distortion of protein assimilation, resembling a nutritional protein deficiency. Excessive serotonin and estrogen cause a relatively uncontrolled production of cortisol. A vicious circle of inflammatory mediators and amino acid imbalance can result.

Depression, lupus, migraine, menopause, diabetes, and aging have several important metabolic features in common with MS.

Popular therapies are illogical, and are likely to cause disease progression.

High quality protein, thyroid, pregnenolone and progesterone tend to correct the underlying pathology. These are antiinflammatory, but they are not immunosuppressive or catabolic.

High altitude and sunny climate are associated with a low incidence of MS.

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Multiple sclerosis (MS), like other autoimmune diseases, affects women more often than men (about 2 to 1), has its onset during the reproductive years (especially after the age of 30, when estrogen is very high), is often exacerbated premenstrually, and is sometimes alleviated by pregnancy (Drew and Chavez, 2000), when progesterone is very high. Women with a high ratio of estrogen to progesterone have been found to have the most active brain lesions (Bansil, et al., 1999). Most of the mediators of inflammation that are involved in MS--mast cells, nitric oxide (NO), serotonin, prolactin, lipid peroxidation, free fatty acids, prostaglandins and isoprostanes, and the various cytokines (IL, TNF)--are closely associated with estrogen's actions, and in animals, autoimmune diseases can be brought on by treatment with estrogen (Ahmed and Talal).

The strong association of MS with estrogen has led to an illogical, but popular and well-publicized medical conclusion that estrogen is protective against MS, and some have claimed that estrogen has beneficial therapeutic effects. This strange way of thinking has its equivalent in the idea that, since women are much more likely than men to develop Alzheimer's disease, estrogen is protective against it; or that, since women have more fragile bones than men do, and their progressive bone loss occurs during the times of their greatest exposure to estrogen, estrogen prevents osteoporosis.

In this medical environment, close associations between estrogen and degenerative diseases are acknowledged, but they are given a meaning contrary to common sense by saying that the association occurs because there isn't enough estrogen. The stove burns you because it isn't hot enough.

As Dave Barry would say, I'm not making this up. Recently well publicized articles have suggested that estrogen protects the brain (even against stroke!) because it increases serotonin and NO. There is something almost esthetically pleasing when so many major errors are concentrated into a single article. Nitric oxide and serotonin are both neurotoxic (Joseph, et al., 1991; Skaper, et al., 1996; Parkinson, et al., 1997; Santiago, et al., 1998; Barger, et al., 2000), as a result of suppressing mitochondrial respiration. NO plays a major role in lipid peroxidation and demyelination. It's interesting to see serotonin and NO openly associated with estrogen, whose mitochondrial toxicity has been carefully hidden from public view.

There are several theories about the cause of MS, old theories about genes and viruses, and newer theories about bacteria, vitamin deficiencies, oil deficiencies, poisons, and reactions to vaccinations (especially for hepatitis B and influenza). The only theory that has been abandoned is the 19th century psychiatric theory about "hysterical paralysis," though occasionally someone does still talk about emotional causes of multiple sclerosis; the term "female hysteria" has evolved into "conversion disorder."

Each of the main theories has a few facts that seem to support it, but neglects to account for many other facts. Everyone agrees that the immune system is involved in MS in some way, but that's really where the problem starts, because of the idea that inflammation is an intrinsic part of immunity. If "inflammation is necessary and good," then it becomes a problem to define exactly where the boundary is between an appropriate reaction and a degenerative process. Edema, reduced cellular respiration, loss of normal functions, fibrosis in its various degrees, each component of inflammation can be seen in a good light, as part of a "defensive immune reaction." When tissue injury leads to repair, it "must" be seen as beneficial, even if it leads to the formation of a scar in place of functional tissue, because the comparison is between an imagined worst possible outcome, and an imperfect recovery, rather than comparing the inflammatory process with the possibility that a potentially noxious agent might have done no harm at all.

The simplest illustration of how inflammation relates to the organism's resources was an experiment in which blood glucose was varied, while an animal was exposed to chemicals that varied from mildly irritating to potentially deadly. When the animal had very low blood sugar, the mildest irritant could be deadly, but when its blood glucose was kept very high, even the deadly antigens were only mildly irritating. Varying the blood sodium concentration had similar, but weaker, effects.

There is a tendency to see inflammation not only as a normal part of immunity, but to see it as being proportional to the nature of the antigen, except when the immune system has been primed for it by previous contact, in which case the organism will either not react at all (because it has become immune), or it will react much more violently than it did on the first exposure, because it has become allergic. But, in reality, the mere concentration of glucose and sodium in the blood (and of thyroid, and many other substances that aren't considered to be part of the immune system) can make a tremendous difference in the degree of "immunological" reaction.

In the excessively sensitive condition produced by hypoglycemia, several things happen that contribute to the maladaptive exaggerated inflammatory response.

Adrenaline increases in hypoglycemia, and, if the adrenaline fails to convert glycogen into glucose, it will provide an alternative fuel by liberating free fatty acids from fat cells.

If the liberated fatty acids are unsaturated, they will cause serotonin to be secreted, and both serotonin and the unsaturated fatty acids will suppress mitochondrial respiration, exacerbating the hypoglycemia. They will stimulate the release of cytokines, activating a variety of immunological and inflammatory processes, and they will cause blood vessels to become leaky, creating edema and starting the first stages of fibrosis. Both adrenaline and serotonin will stimulate the release of cortisol, which mobilizes amino acids from tissues such as the large skeletal muscles. Those muscles contain a large amount of cysteine and tryptophan, which, among other effects, suppress the thyroid. The increased tryptophan, especially in the presence of free fatty acids, is likely to be converted into additional serotonin, since fatty acids release tryptophan from albumin, increasing its entry into the brain. Free fatty acids and increased serotonin reduce metabolic efficiency (leading to insulin resistance, for example) and promote an inflammatory state.

Fats in the blood-stream have easy access to the brain, and the unsaturated free fatty acids produce brain edema (Chan, et al., 1983, 1988). When brain edema is caused by vascular leakage, proteins that are normally excluded can enter. The stimulated, excited and fatigued brain exchanges glutamine for tryptophan, accelerating its uptake from the blood.

When a tissue is injured or stressed, antibodies are formed in response to the altered components of that tissue. Therefore, we could call a bruise or a sprain an autoimmune condition, but there are no commercial tests for bruised-shin antibodies. The availability of tests for specific antibodies seems to be the essential factor in classifying a condition as autoimmune, as in "autoimmune thyroiditis." Unfortunately, this way of using language is nested in a culture that is full of unrealistic ideas of causality, and thousands of people build their careers on the search for the "mutated genes that are responsible for the disease," and for the drugs that will correct the defect.

Early in the study of immunology, the focus was on antibodies. Even earlier, inflammation had been conceptualized in terms of the "humors," and other prescientific ideas. As soon as multiple sclerosis/hysterical paralysis was classified as an autoimmune disease, primitive ideas about the nature of the immune system, interacting with primitive ideas about the nature of the brain and the structure of cells, blended into the various theories of what the disease is.

Rather than seeing immunological nerve damage as the cause of all the other features of multiple sclerosis, I think it's important to look at some of the general features of the condition, as contexts in which to interpret the events in the nerves.

It has been known for a long time that the incidence of MS tends to increase with distance from the equator. Incidence is low in sunny dry climates, and at high altitudes. Two clear dietary influences have been found: eating pork, and horsemeat.

People with MS don't regulate their body temperature very well. Their nerve conduction is slow, and in normal people, conduction is faster at higher temperatures, but in people with MS the conduction is slower at the normal temperature of 98.6O F than at lower temperatures. A subnormal temperature is also associated with old age, and with the hot flashes of menopause.

Brain metabolism of glucose is very low in multiple sclerosis, and in my own observations, the general metabolic rate is subnormal. However, some people reason that the hypometabolism is caused by the lesions, rather than vice versa.

Animals that lack the unsaturated fatty acids have a higher metabolic rate and ability to use glucose, converting it to CO2 more readily, have a greater resistance to toxins (Harris, et al., 1990; even cobra venom: Morganroth, et al., 1989), including endotoxin (Li, et al., 1990)--preventing excessive vascular leakage--and to immunological damage (Takahashi, et al., 1992), and to trauma, and their neuromuscular response is accelerated while fast twitch muscles are less easily fatigued (Ayre and Hulber, 1996).

In people with MS, the blood is more viscous, and the platelets tend to clump together more easily. Their cortisol level is higher than normal, and their pituitary adrenal-cortex-stimulating hormone is harder to suppress. This is a condition that is also seen in depression and old age. Despite the chronically elevated cortisol, people with MS typically have hypoglycemia. They are occasionally found to have low blood sodium, hyponatremia, but this is hard to determine when the blood's water content is variable. Their prolactin is likely to be high, and this can result from high estrogen, high serotonin, low sodium, or low thyroid. Drinking too much water can increase prolactin, and can damage the nerves' myelin enclosures; too much serotonin tends to cause excessive drinking. Disturbances of blood glucose, sodium, and water content can disrupt the brain's myelin structure. High estrogen disturbs the blood osmotically, making it retain too much water in relation to the solutes, and this relates to many of estrogen's effects; since simple osmotic variations can damage the myelin structures, it seems that this mechanism should be investigated thoroughly before it is assumed that the immunological events are primary.

Mast cells, which promote inflammation by releasing substances such as histamine and serotonin (and make blood vessels leaky), are more numerous in the brain in multiple sclerosis than in normal brains. Since platelet clumping releases serotonin, and also because serotonin excess is suggested by so many other features of MS, serotonin antagonists (ondansetron and ketanserin, for example) have been used therapeutically with success.

Estrogen causes mast cells to release their inflammatory mediators, and it causes platelets to aggregate, releasing their serotonin. Since estrogen dominance is closely associated with the presence of active brain lesions, antiestrogen therapy would seem obvious in MS. Progesterone counteracts estrogen's effects on both mast cells and platelets.

Aspirin protects against a variety of inflammatory processes, but it's most famous for the inhibition of prostaglandins. While aspirin is often used to relieve pain in MS, and another inhibitor of prostaglandin synthesis, indomethacin, has been used therapeutically in MS, it would seem appropriate to investigate more carefully aspirin's possible role in preventing or relieving MS.

A simple protein deficiency has many surprising effects. It lowers body temperature, and suppresses the thyroid, but it increases inflammation and the tendency of blood to clot. Since the brain and heart and lungs require a continuous supply of essential amino acids if they are to continue functioning, in the absence of dietary protein, cortisol must be produced continuously to mobilize amino acids from the expendable tissues, which are mainly the skeletal muscles. These muscles have a high concentration of tryptophan and cysteine, which suppress the thyroid. Cysteine is excitoxic, and tryptophan is the precursor for serotonin. Presumably, their presence in, and stress-induced release from, the muscles is one of the mechanisms that reduce metabolic activity during certain types of stress.

When pregnant animals are deprived of protein, the newborn animals have abnormally high levels of serotonin, and the enzymes responsible for that excess tend to maintain the serotonin excess even when they are grown and have adequate protein. This is analogous to the effect of excess estrogen early in life, which creates a tendency to develop breast or prostate cancer in adulthood. It would be interesting to study the gestational experience, e.g., length of gestation and birth weight, of the people who later develop MS.

Although people in the northern countries aren't normally protein-starved, they do tend to get a large part of their protein from the muscle meats. In traditional cultures, all parts of the food animals were eaten--chicken feet, heads, and necks, animals' ears and eyeballs, etc.--and so the amino acid balance was favorable for maintaining a high metabolic rate and preventing stress.

The observation that multiple sclerosis is associated with the consumption of pork and horsemeat, but not beef, lamb, or goat, is very interesting, since the fat of those animals is essentially like the fats of the plant materials that they eat, meaning that it is extremely high in linoleic and linolenic acids. The rumen of cows, sheep, and goats contains bacteria that convert the polyunsaturated fats into more saturated fats. Unsaturated fats inhibit the enzymes that digest protein, and MS patients have been reported to have poor digestion of meat (Gupta, et al., 1977).

The polyunsaturated fats are in themselves toxic to mitochondria, and suppress glucose oxidation, and inhibit the thyroid function, with the same suppressive effect on the ability to oxidize glucose, but they are also turned, enzymically, into the prostaglandins, and non-enzymically, by spontaneous lipid peroxidation, into the toxic isoprostanes. The isoprostanes, and some of the prostaglandins, are elevated in the brain and other tissues of people with MS.

Lipid peroxidation is very high in multiple sclerosis. Nitric oxide (whose synthesis is promoted by estrogen in most parts of the brain) is a free radical that activates peroxidation.

Lipid peroxidation selectively destroys, naturally, the unstable polyunsaturated fats. In atherosclerosis, the blood vessel plaques contain very little unsaturated fat. This is because they are peroxidized so rapidly, but their high ratio of saturated to unsaturated fats has been used to argue that the polyunsaturated oils are "heart protective." Similar arguments are often made in MS, though some studies don't support the idea that there is a lack of any of the unsaturated fats. Since lipid peroxidation is very high, it would be reasonable to assume that there was an abundance of polyunsaturated fats being peroxidized through reactions with catalysts such as iron (S.M. LeVine, 1997) and nitric oxide and peroxynitrile.

I believe that an important aspect of the intolerance for heat so often reported in people with MS could be the tendency of relative hyperthermia to release increased amounts of free fatty acids into the blood stream. Women, because of estrogen's effects, usually have much higher levels of free fatty acids in the blood than men do. Estrogen increases the release of free fatty acids from stored fat, and the unsaturated fats synergize with both estrogen and prolactin, increasing their effects.

Temperature regulation apparently involves some nerve cells that sense temperature very accurately, and change their activity accordingly. Water has a remarkably high heat capacity, meaning that it takes a relatively large amount of heat to change its temperature. The "disappearing heat" is being consumed by structural changes in the water. Proteins have the same sort of structural complexity as water, and together they can make effective temperature transducers, "thermometers." (Other substances tend to undergo major structural changes only as they melt or vaporize. The famous "liquid crystals" have a few distinct structural phases, but cytoplasm is like a very subtle liquid crystal.) The "thermostat cells" are actually responding to a degree of internal structure, not to the temperature in the abstract. So things that change their internal structure will modify their temperature "set-point."

Increased estrogen causes an animal to lower its temperature, and it probably does this by increasing the "structural temperature" of the thermostat cells, "melting" their internal structure. Progesterone causes the animal to increase its temperature, and it apparently does this by increasing the structure/decreasing the structural temperature of the thermostat cells. If you put ice in the thermostat, the room gets hot.

A cell's internal structure is equivalent to its readiness to work. Fatigue represents a slightly "melted" state of the cell, in which structure appears to have been consumed along with the chemical energy reserves. Experiments that demonstrated this effect were very clear, but they were ignored because they didn't fit people's stereotyped idea of the cell. With a very sensitive thermometer, it's possible to measure the heat produced by a nerve when it is stimulated. That's not surprising. But it's surprising that, when the nerve is recovering from the stimulation, it absorbs heat from its environment, lowering the temperature locally. That even violated some people's conception of "entropy," but it can easily be demonstrated that changing the form of some materials changes their heat capacity, as when a rubber band is stretched (it gets hot), or contracts (it gets cooler).

The excitants, estrogen and cortisol, slow the conduction of nerves, because they cause its internal structure to be dissipated. They create a "pre-fatigued" state in the cell.

In experiments with rabbit hearts, Szent-Gyorgyi showed that estrogen decreased the heart's readiness to work, and that progesterone increased its readiness to work, and he said it did this by "building structure." He pointed out that, for a given drug or other stimulus, cells have a characteristic response, becoming either more activated or more inhibited, but he showed that, outside the normal concentration or intensity range of the stimulus, a cell's response is often reversed.

If this is the situation in the nerves in MS, it explains the strange behavior, in which warming the nerve reduces its function. The implication is that internal structure (and energy) must be restored to the nerves. In experiments that I have described in previous newsletters, increasing sodium, ATP, carbon dioxide, and progesterone, and increasing the ratio of magnesium to calcium, have been found to increase cellular energy and structure. The thyroid hormone is ultimately responsible for maintaining cells' energy and structure, and responsiveness, but if it is increased suddenly without allowing all the other factors to adjust, it will raise the temperature too suddenly. It needn't take a long time, but all the factors have to be present at the same time.

Serotonin, melatonin, estrogen, and polyunsaturated fats all tend to lower body temperature. Since estrogen and the unsaturated fats are cellular excitants, the actual decrease in body temperature helps to offset their excitatory effects.

Both bright light and high altitude tend to reduce serotonin's effects. The tissue carbon dioxide retained at high altitude reduces the incidence of many diseases, and multiple sclerosis might be affected as heart disease and cancer are. It is known that carbon dioxide is involved in myelin's regulation of its own water content. Hyperventilation, by causing a loss of carbon dioxide, releases both histamine and serotonin, making blood more viscous, while making blood vessels more permeable, and causing them to constrict.

If people with MS have developed it through the interactions of excessive estrogen, serotonin, unsaturated fats, iron, and water, and deficient thyroid, and deficient pregnenolone produced in the myelin-forming cells (oligodendrocytes), there are many things that can be done to stop its progress, and possibly to reverse it.

Since a sudden increase in temperature will release increased amounts of the pro-inflammatory fats, things should be changed gradually. Increased salt is thermogenic, but increased magnesium is protective against hyperthermia, so increased magnesium (epsom salts baths, for example, coffee, fruits, some vegetables and meats) would be helpful. Magnesium is rapidly lost from cells in hypothyroidism. Sugar, when accompanied by fats and minerals, as in milk, is needed to lower cortisol, and to maintain thyroid activity. Balanced proteins, such as cheese, potatoes, eggs, and beef- or lamb-broth (for the gelatin and mineral content in particular) will prevent the tryptophan excess that suppresses the thyroid and is potentially a nerve toxin. Saturated fats, used regularly, reduce the immediate toxic antimetabolic effects of the stored unsaturated fats, but it takes a long time to change the balance of stored fats.

Since aspirin lowers temperature, is antiinflammatory, in some situations antiestrogenic, and is a powerful antioxidant, it is likely that it would alleviate symptoms and prevent progression of MS, as it does in other degenerative diseases. Since platelet aggregation is likely to be involved in the focuses of inflammation, aspirin might help to prevent the formation of new areas of damage.

While the glucocorticoids are useful for their antiinflammatory actions, cortisol is known to promote the killing of brain cells by excitotoxicity. Since estrogen decreases GABA, and both estrogen and serotonin activate the excitatory amino acid transmitters, the addition of synthetic glucocorticoids to the pre-existing cortisol excess is likely to damage parts of the brain in addition to the inflamed areas.

The excess cortisol of depression, old age, and hyperestrogenism often comes down with use of a thyroid supplement, but pregnenolone has a very direct action (in opposition to serotonin) that can quiet the pituitary, reducing ACTH and cortisol. Progesterone has some similar effects, and is protective against excess cortisol, and is a major factor in nerve and brain restoration. Thyroid, progesterone, and pregnenolone are all involved in the formation of new myelin, and in the prevention of the edema that damages it.

Since thyroid and progesterone decrease the formation of estrogen in inflamed tissue, while cortisol stimulates its formation, it would seem wise to use thyroid and progesterone for their immediate antiinflammatory effects, which include the inhibition of NO formation (Drew and Chavez, 2000), and their lack of the excitotoxic, estrogen-stimulating effects of the glucocorticoids. While the glucocorticoids are catabolic and liberate cysteine and tryptophan from muscles, thyroid and progesterone are not catabolic, and protect against the toxic consequences of those amino acids.

REFERENCES

J Neurol Neurosurg Psychiatry 1988 Feb;51(2):260-5. Perivascular iron deposition and other vascular damage in multiple sclerosis. Adams CW. "The multiple sclerosis cases showed venous intramural fibrinoid deposition (7%), recent haemorrhages (17%), old haemorrhages revealed by haemosiderin deposition (30%), thrombosis (6%) and thickened veins (19%). In all, 41% of all multiple sclerosis cases showed some evidence of vein damage." "Haemosiderin deposition was common in the substantia nigra and other pigmented nuclei in all cases. It is concluded that the cerebral vein wall in multiple sclerosis is subject to chronic inflammatory damage, which promotes haemorrhage and increased permeability, and constitutes a form of vasculitis."

Am J Pathol 1985 Dec;121(3):531-51. Sex hormones, immune responses, and autoimmune diseases. Mechanisms of sex hormone action. Ansar Ahmed S, Penhale WJ, Talal N. "Immune reactivity is greater in females than in males. In both experimental animals and in man there is a greater preponderance of autoimmune diseases in females, compared with males. Studies in many experimental models have established that the underlying basis for this sex-related susceptibility is the marked effects of sex hormones. Sex hormones influence the onset and severity of immune-mediated pathologic conditions by modulating lymphocytes at all stages of life, prenatal, prepubertal, and postpubertal."

J Appl Physiol 1996 Feb;80(2):464-71. Effects of changes in dietary fatty acids on isolated skeletal muscle functions in rats. Ayre KJ, Hulbert AJ The effects of manipulating dietary levels of essential polyunsaturated fatty acids on the function of isolated skeletal muscles in male Wistar rats were examined. Three isoenergetic diets were used: an essential fatty acid-deficient diet (EFAD), a diet high in essential (n-6) fatty acids [High (n-6)], and a diet enriched with essential (n-3) fatty acids [High (n-3)]. After 9 wk, groups of rats on each test diet were fed a stock diet of laboratory chow for a further 6 wk. Muscle function was examined by using a battery of five tests for soleus (slow twitch) and extensor digitorum longus (EDL; fast twitch). Tests included single muscle twitches, sustained tetanic contractions, posttetanic potentiation, sustained high-frequency stimulation, and intermittent low-frequency stimulation. Results for muscles from the High (n-6) and High (n-3) groups were very similar. However, the EFAD diet resulted in significantly lower muscular tensions and reduced response times compared with the High (n-6) and High (n-3) diets. Peak twitch tension in soleus muscles was 16-21% less in the EFAD group than in the High (n-6) and High (n-3) groups, respectively [analysis of variance (ANOVA), P < 0.01). During high-frequency stimulation, EDL muscles from the EFAD rats fatigued 32% more quickly (ANOVA, P < 0.01)]. Also, twitch contraction and half-relaxation times were significantly 5-7% reduced in the EFAD group (ANOVA, P < 0.01). During intermittent low-frequency stimulation, soleus muscles from the EFAD group generated 25-28% less tension than did the other groups (ANOVA, P < 0.01), but in EDL muscles from the EFAD group, endurance was 20% greater than in the High (n-6) group (ANOVA, P < 0.05). After 6 wk on the stock diet, there were no longer any differences between the dietary groups. Manipulation of dietary fatty acids results in significant, but reversible, effects in muscles of rats fed an EFAD diet.

Endocr Res 1999 May;25(2):207-14. Prolactin secretion is increased in patients with multiple sclerosis. Azar ST, Yamout B

Acta Neurol Scand 1999 Feb;99(2):91-4. Correlation between sex hormones and magnetic resonance imaging lesions in multiple sclerosis. Bansil S, Lee HJ, Jindal S, Holtz CR, Cook SD "Patients with high estradiol and low progesterone levels had a significantly greater number of Gd enhancing lesions than those with low levels of both these hormones. Patients with a high estrogen to progesterone ratio had a significantly greater number of active MRI lesions than those with a low ratio."

J Neuroimmunol 1996 Mar;65(1):75-81. Circulating antibodies directed against conjugated fatty acids in sera of patients with multiple sclerosis. Boullerne A, Petry KG, Geffard M "These results suggest that in MS and RA, autoepitopes on cell membranes that are normally hidden from the immune system become immunogenic. This may arise because of previous membrane disruption by oxidative processes."

J Neurosci Res 2000 Nov 15;62(4):503-9. Dehydroepiandrosterone inhibits microglial nitric oxide production in a stimulus-specific manner. Barger SW, Chavis JA, Drew PD.

J Exp Med 1984 Nov 1;160(5):1532-43. Inhibition of autoimmune neuropathological process by treatment with an iron-chelating agent. Bowern N, Ramshaw IA, Clark IA, Doherty PC "Iron is believed to influence both the migration and function of immune effector cells. It can also act as a catalyst in the formation of free radicals, which are highly toxic agents causing tissue damage in sites of inflammation."

J Neurol Neurosurg Psychiatry 1981 Apr;44(4):340-3. Rheological and fibrinolytic findings in multiple sclerosis. Brunetti A, Ricchieri GL, Patrassi GM, Girolami A, Tavolato B. "The whole blood viscosity was found to be increased in multiple sclerosis."

J Neurochem 1988 Apr;50(4):1185-93. Induction of intracellular superoxide radical formation by arachidonic acid and by polyunsaturated fatty acids in primary astrocytic cultures. Chan PH, Chen SF, Yu AC "Other PUFAs, including linoleic acid, linolenic acid, and docosahexaenoic acid, were also effective in stimulating NBF formation in astrocytes, whereas saturated palmitic acid and monounsaturated oleic acid were ineffective. Similar effects of these PUFAs were observed in malondialdehyde formation in cells and lactic acid accumulation in incubation medium. These data indicate that both membrane integrity and cellular metabolism were perturbed by arachidonic acid and by other PUFAs."

Ann Neurol 1983 Jun;13(6):625-32. Induction of brain edema following intracerebral injection of arachidonic acid. Chan PH, Fishman RA, Caronna J, Schmidley JW, Prioleau G, Lee J "Intracerebral injection of polyunsaturated fatty acids (PUFAs), including linolenic acid (18:3) and arachidonic acid (20:4), caused significant increases in cerebral water and sodium content concomitant with decreases in potassium content and Na+- and K+- dependent adenosine triphosphatase activity. There was gross and microscopic evidence of edema. Saturated fatty acids and monounsaturated fatty acid were not effective in inducing brain edema. The [125I]-bovine serum albumin spaces increased twofold and threefold at 24 hours with 18:3 and 20:4, respectively, indicating vasogenic edema with increased permeability of brain endothelial cells" "These data indicate that arachidonic acid and other PUFAs have the ability to induce vasogenic and cellular brain edema and further support the hypothesis that the degradation of phospholipids and accumulation of PUFAs, particularly arachidonic acid, initiate the development of brain edema in various disease states."

Med Sci Sports Exerc 1997 Jan;29(1):58-62. Effects of acute physical exercise on central serotonergic systems. Chaouloff F "Works from the 1980's have established that acute running increases brain serotonin (5-hydroxytryptamine: 5-HT) synthesis in two ways. Lipolysis-elicited release of free fatty acids in the blood compartment displaces the binding of the essential amino acid tryptophan to albumin, thereby increasing the concentration of the so-called "free tryptophan" portion, and because exercise increases the ratio of circulating free tryptophan to the sum of the concentrations of the amino acids that compete with tryptophan for uptake at the blood-brain barrier level, tryptophan enters markedly in the brain compartment." "Indirect indices of 5-HT functions open the possibility that acute exercise-induced increases in 5-HT biosynthesis are associated with (or lead to) increases in 5-HT release."

Med Hypotheses 1995 Nov;45(5):455-8. Melanin, melatonin, melanocyte-stimulating hormone, and the susceptibility to autoimmune demyelination: a rationale for light therapy in multiple sclerosis. Constantinescu CS "The hypothesis formulated here is based on the observation that resistance to multiple sclerosis and experimental autoimmune encephalomyelitis is associated with dark skin pigmentation. While this may signify a protective role for melanin against environmental factors producing oxidative damage, the mechanism postulated here is that susceptibility to autoimmune demyelination is influenced by hormonal factors, i.e. the neurohormones melatonin and melanocyte stimulating hormone, which have opposing effects on immune functions and, the same time, are important determinants of the individual's production of melanin."

Neurosci Lett 1989 Nov 6;105(3):246-50. Presence of Schwann cells in neurodegenerative lesions of the central nervous system. Dusart I, Isacson O, Nothias F, Gumpel M, Peschanski M Ultrastructural analysis of neurodegenerative CNS lesions produced by an excitotoxic substance revealed that the majority of cells ensheathing axons were not oligodendrocytes. By their morphology and the presence of both a basal lamina and collagen fibers they were identified as Schwann cells. The presence of Schwann cells, whose growth-promoting role in the peripheral nervous system has been largely documented, may account for the development of regenerating growth cones which have been observed in the excitotoxically lesioned central nervous system. Further support for this hypothesis came from the analysis of fetal neural transplants implanted into the lesioned area. Schwann cells ensheathing axons were indeed numerous in the neuron-depleted area surrounding the transplants, where neurite outgrowth of graft origin occurred.

J Neuroimmunol 2000 Nov 1;111(1-2):77-85. Female sex steroids: effects upon microglial cell activation. Drew PD, Chavis JA.

Neurology 1999 Nov 10;53(8):1876-9 Cerebrospinal fluid isoprostane shows oxidative stress in patients with multiple sclerosis. Greco A, Minghetti L, Sette G, Fieschi C, Levi G "The CSF level of the isoprostane 8-epi-prostaglandin (PG)-F2alpha (a reliable marker of oxidative stress in vivo) was three times higher in subjects with definite MS than in a benchmark group of subjects with other neurologic diseases."

J Intern Med 1989 Oct;226(4):241-4. Serum sex hormone and gonadotropin concentrations in premenopausal women with multiple sclerosis. Grinsted L, Heltberg A, Hagen C, Djursing H.

Am J Gastroenterol 1977 Dec;68(6):560-5. Multiple sclerosis and malabsorption. Gupta JK, Ingegno AP, Cook AW, Pertschuk LP.

Free Radic Res 1997 Apr;26(4):351-62. Toxicity of polyunsaturated fatty acid esters for human monocyte-macrophages: the anomalous behaviour of cholesteryl linolenate. Hardwick SJ, Carpenter KL, Law NS, Van Der Veen C, Marchant CE, Hird R, Mitchinson MJ. "The triglycerides showed a direct relationship between toxicity and increasing unsaturation, which in turn correlated with increasing susceptibility to oxidation." "Triarachidonin (20:4; omega-6), trieicosapentaenoin (20:5; omega-3) and tridocosahexaenoin (22:6; omega-3) were profoundly and rapidly toxic. There was a similar relationship between toxicity and increasing unsaturation for most of the cholesterol esters, but cholesteryl linolenate was apparently anomalous, being non-toxic in spite of possessing three double bonds and being extensively oxidised." "The toxicity of triglycerides suggests that polyunsaturated fatty acid peroxidation products are also toxic."

J Clin Invest 1990 Oct;86(4):1115-23. Essential fatty acid deficiency ameliorates acute renal dysfunction in the rat after the administration of the aminonucleoside of puromycin. Harris KP, Lefkowith JB, Klahr S, Schreiner GF.

Mikrobiyol Bul 1989 Oct;23(4):342-7. [Leukotrienes and neurological diseases]. [Article in Turkish] Irkec C, Ercan S, Irkec M "LTC4 levels were found to be elevated in MS and Behcet patient in comparison with controls. Augmentation of LTC4 levels underlines the fact that leukotrienes may be held responsible the pathogenesis of these disorders."

Lancet 1982 Feb 13;1(8268):380-6. Evidence for subacute fat embolism as the cause of multiple sclerosis. James PB "The neurological features of decompression sickness, which is thought to be due to gas embolism, are similar to those of multiple sclerosis (MS). This similarity suggested the re-examination of a concept, first proposed in 1882, that the demyelination in MS is due to venous thrombosis. Unfortunately, although the plaques of MS are often perivenular, thromboses are not always present. Nevertheless, vascular theories can explain the topography of the lesions in MS." "There is also evidence in man that fat may lodge in the microcirculation of the nervous system and cause distal perivenous oedema with the loss of myelin from axons."

J Clin Pathol 1979 Oct;32(10):1025-9. Antithrombin activities in childhood malnutrition. Jimenez RA, Jimenez E, Ingram GI, Mora LA, Atmetlla F, Carrillo JM, Vargas W.

Arch Latinoam Nutr 1980 Dec;30(4):580-9. [Prethrombosis in child malnutrition]. Jimenez R, Jimenez E, Mora LA, Vargas W, Atmetlla F, Carrillo JM

Stroke 1991 Nov;22(11):1448-51. Platelet secretory products may contribute to neuronal injury. Joseph R, Tsering C, Grunfeld S, Welch KM "The view that certain endogenous substances, such as glutamate, may also contribute to neuronal injury is now reasonably well established. Blood platelets are known to contain and secrete a number of substances that have been associated with neuronal dysfunction. Therefore, we hypothesize that a high concentration (approximately several thousand-fold higher than in plasma, in our estimation) of locally released platelet secretory products derived from the causative thrombus may contribute to neuronal injury and promote reactive gliosis." "We further observed that serotonin, a major platelet product, has neurotoxic properties."

Zh Nevropatol Psikhiatr Im S S Korsakova 1985;85(2):198-206. [Role of disorders of the hemostatic system in the pathogenesis of multiple sclerosis and ways of correcting them]. [Article in Russian] Karlov VA, Makarov VA, Savina EB, Seleznev AN, Savin AA The changes in the hemostatic system were studied in 77 patients with different patterns of disseminated sclerosis (DS). The studies demonstrated activation of both vasculothrombocytic and coagulation components of hemostasis as well as of fibrinolytic blood properties. The latent course of the disseminated intravascular coagulation was revealed in 20.7% of cases. The role of hemostatic disorders in the pathogenetic mechanisms of DS is discussed. The patients with DS received pathogenetic treatment including drugs eliminating hemostatic disorders, which was beneficial for most patients.

Zh Nevropatol Psikhiatr Im S S Korsakova 1990;90(11):47-50. [Changes in rheological properties of blood in multiple sclerosis and their correction]. [Article in Russian] Karlov VA, Savin AA, Smertina LP, Redchits EG, Seleznev AN, Svetailo LI, Margosiuk NV, Stulin ID As many as 45 patients with multiple sclerosis were examined for rheological blood properties. As compared to controls, the group under examination manifested the rise of plasma viscosity, acceleration of red blood cell aggregation. 26.2% of patients demonstrated an appreciable increase of blood viscosity. It is assumed that these changes contribute to the deterioration of microcirculation and aggravate the demyelinating process. Correction of the rheological properties of the blood by plasmapheresis coupled with other methods of pathogenetic therapy turned out effective.

Brain Res 1997 Jun 20;760(1-2):298-303 Iron deposits in multiple sclerosis and Alzheimer's disease brains. LeVine SM "In summary, the localization of iron deposition in MS and AD brains indicates potential sites where iron could promote oxidative damage in these disease states."

Circ Shock 1990 Jun;31(2):159-70. Resistance of essential fatty acid-deficient rats to endotoxin-induced increases in vascular permeability. Li EJ, Cook JA, Spicer KM, Wise WC, Rokach J, Halushka PV.

FEBS Lett 1978 Nov 1;95(1):181-4. Selective inactivation of the NADH-ubiquinone segment of the respiratory chain of submitochondrial particles by endogenous free fatty acids during hyperthermia. Ludwig P, Bartels M, Schewe T, Rapoport S.

J Pain Symptom Manage 2000 Nov;20(5):388-91. Ondansetron in multiple sclerosis. Macleod AD. "Two young women with chronic nausea and vertigo caused by multiple sclerosis responded to the introduction and maintenance of the 5HT3 receptor antagonist, ondansetron."

Am J Phys Med Rehabil 1994 Jul-Aug;73(4):283-5. Intracranial venous thrombosis in a patient with multiple sclerosis. A case report and review of contraceptive alternatives in patients with disabilities. Malanga GA, Gangemi E.

Folia Biol (Praha) 1999;45(4):133-41. Essential fatty acids and related molecular and cellular mechanisms in multiple sclerosis: new looks at old concepts. Mayer M.

J Clin Endocrinol Metab 1994 Sep;79(3):848-53. Multiple sclerosis is associated with alterations in hypothalamic-pituitary-adrenal axis function. Michelson D, Stone L, Galliven E, Magiakou MA, Chrousos GP, Sternberg EM, Gold PW "Compared to matched controls, patients with MS had significantly higher plasma cortisol levels at baseline. Despite this hypercortisolism and in contrast to patients with depression who had similar elevations in plasma cortisol levels, patients with MS showed normal, rather than blunted, plasma ACTH responses to ovine CRH, suggesting that the pathophysiology of hypercortisolism in MS is different from that in depression." "Taken together, these findings are compatible with data from studies of experimental animals exposed to chronic inflammatory stress, which showed mild increased activation of the HPA axis with increased relative activity of AVP in the regulation of the pituitary-adrenal axis."

Exp Neurol 1977 Oct;57(1):142-57. Tryptophan availability: relation to elevated brain serotonin in developmentally protein-malnourished rats. Miller M, Leahy JP, Stern WC, Morgane PJ, Resnick O.

Am J Physiol 1989 Oct;257(4 Pt 2):H1192-9. Lung injury caused by cobra venom factor is reduced in rats raised on an essential fatty acid-deficient diet. Morganroth ML, Schoeneich SO, Till GO, Pickett W, Ward PA.

Eur J Haematol 2000 Jul;65(1):82-3. More on the relationship between cystic fibrosis and venous thrombosis. Mori PG, Acquila M, Bicocchi MP, Bottini F, Romano L. Letter

Acta Neurol Scand 1982 Oct;66(4):497-504, Platelet aggregation and multiple sclerosis. Neu IS, Prosiegel M, Pfaffenrath V Measurements of blood platelet aggregation were carried out in 30 patients suffering from multiple sclerosis (MS) and in 15 healthy individuals. Compared with the control group, the MS patients showed an increase in both spontaneous and induced (ADP and serotonin) platelet aggregation. The possible pathogenetic significance of these results is discussed.

Neurology 1975 Aug;25(8):713-6. Schwann cells and regenerated peripheral myelin in multiple sclerosis: an ultrastructural study. Ogata J, Feigin I Tissue of a multiple sclerosis plaque in the brachium conjunctivum of the pons known to contain peripheral myelin by light microscopic studies were removed from the paraffin block and processed for electron microscopic studies. The cells related to the peripheral myelin possessed the ultrastructural characteristics of Schwann cells, with basement membranes and associated collagen fibers. No continuity was seen with the peripheral within the central nervous tissues by selective maturation of multipotential primitive reticular cells, a phenomenon consistent with the view that Schwann cells are mesenchymal in character.

Tohoku J Exp Med 1999 Dec;189(4):259-65. Elevated plasma level of plasminogen activator inhibitor-1 (PAI-1) in patients with relapsing-remitting multiple sclerosis. Onodera H, Nakashima I, Fujihara K, Nagata T, Itoyama Y "Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system and one of the earliest changes in inflammatory focus involves the activation of vascular endothelial cells." "The level of plasma PAI-1 was significantly higher in active MS cases when compared to stable MS and controls." "These results suggested that PAI-1 plasma levels are associated with MS disease activity and is a good marker for MS relapse."

J Mol Med 1997 Mar;75(3):174-86. The role of nitric oxide in multiple sclerosis. Parkinson JF, Mitrovic B, Merrill JE "Elevated nitric oxide bio-synthesis has been associated with nonspecific immune-mediated cellular cytotoxicity and the pathogenesis of chronic, inflammatory autoimmune diseases including rheumatoid arthritis, insulin-dependent diabetes, inflammatory bowel disease, and multiple sclerosis."

Fed Proc 1987 Jan;46(1):91-6. Role of the clotting system in the pathogenesis of neuroimmunologic disease. Paterson PY, Koh CS, Kwaan HC "Our studies of the clotting system and ensuing fibrinolysis implicate coagulation and cleavage of fibrin within or on the luminal surface of the cerebrovasculature as events initiating the inflammation characterizing EAE." "We postulate that the critical event precipitating EAE is binding of circulating MBP-reactive immune effector cells to MBP immunodeterminants on the surface of cerebrovascular endothelial cells. Coagulation and ensuing fibrinolysis occur at sites of binding of effector cells to cerebrovascular endothelium. Release of biologically active peptides cleaved from fibrin open the BBB, thereby setting the stage for the cascade of inflammatory events culminating in clinical manifestations of EAE."

Neurotoxicology 1998 Aug-Oct;19 (4-5):599-603. In vitro effect of the cysteine metabolites homocysteic acid, homocysteine and cysteic acid upon human neuronal cell lines. Parsons RB, Waring RH, Ramsden DB, Williams AC "Cysteine (CYS) is a non-essential amino acid which elicits excitotoxic properties via the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor.. CYS levels are known to be elevated in association with neurological disease such as Alzheimers Disease (AD) and Parkinsons Disease (PD)." "These results show that toxic responses are cell-type specific for CYS and its metabolites and this may be reflected in the patterns of neurodegeneration observed in such diseases as AD and PD."

WMJ 1983 Mar-Apr;55(2):146-50. [Effect of tryptophan excess in a diet on amino acid composition of skin collagen and on an initial stage of protein biosynthesis in rat liver]. Pechenova TN, Sushkova VV, Solodova EV, Gulyi MF Protein deficiency and tryptophane load against its background lead to the acid-soluble collagen synthesis in the rat skin. The amino acid composition of the collagen differs from the norm. This is accompanied by changes in the free amino acid pool of blood serum and liver, under tryptophane load the free amino acids pool of the liver increasing twice as high. At the same time protein deficiency increases and tryptophane load decreases the level of tRNA amino acylation with tryptophane in the animal liver. Thus, protein deficiency and tryptophane load against its background cause deep changes in the protein biosynthesis.

Fed Proc 1987 Jan;46(1):91-6. Role of the clotting system in the pathogenesis of neuroimmunologic disease. Paterson PY, Koh CS, Kwaan HC "Our studies of the clotting system and ensuing fibrinolysis implicate coagulation and cleavage of fibrin within or on the luminal surface of the cerebrovasculature as events initiating the inflammation characterizing EAE." "We postulate that the critical event precipitating EAE is binding of circulating MBP-reactive immune effector cells to MBP immunodeterminants on the surface of cerebrovascular endothelial cells. Coagulation and ensuing fibrinolysis occur at sites of binding of effector cells to cerebrovascular endothelium. Release of biologically active peptides cleaved from fibrin open the BBB, thereby setting the stage for the cascade of inflammatory events culminating in clinical manifestations of EAE."

Rev Esp Fisiol 1983 Mar;39(1):39-44. Intralipid and free plasmatic tryptophan in vitro. Pena JM, Aulesa C, Vinas O, Bosch J, Farriol M, Schwartz S "In an attempt to investigate the role of the lipidic emulsion Intralipid in the development of metabolic encephalopathy in a patient showing high free tryptophan levels, the relationship between lipidic emulsion and free tryptophan was examined in in vitro experiments. The addition of intralipid to normal serum produces an immediate increase in non-esterified fatty acids and a parallel rise in free tryptophan. Moreover, when serum with intralipid is incubated at 37 degrees C, the lipases release new non-esterified fatty acids and the free tryptophan increases proportionally." "It is concluded that intralipid causes an increase in free tryptophan levels. It is known that in vivo free tryptophan modulates 5-hydroxytryptamine synthesis and thus may be considered a possible causal agent for encephalopathy."

Med Hypotheses 1980 May;6(5):545-557. Fatty acids, fibrinogen and blood flow: a general mechanism for hyperfibrinogenemia and its pathologic consequences. Pickart LR, Thaler MM Plasma fibrinogen is elevated in various stressful states and conditions in which active mobilization of free fatty acids (FFA) occurs. Reduction of plasma FFA by an assortment of hypolipidemic drugs is consistently followed by a decrease in the accompanying hyperfibrinogenemia. A direct link between FFA and fibrinogen has been demonstrated in animals, and in experiments employing incubated liver slices. Based on these clinical and experimental observations, we postulate that hepatic fibrinogen synthesis is stimulated by FFA. Since fibrinogen is a major determinant of whole blood viscosity, erythrocyte aggregation, and sludging of red cells in terminal and pre-terminal blood vessels, we propose that microcirculatory blood flow may be impaired in the presence of chronically elevated plasma FFA levls. Consequently, hypolipidemic drugs may be effective in prevention of circulatory complications associated with FFA-induced hyperfibrinogenemia.

Neurologia 1996 Aug-Sep;11(7):272. [Exacerbation of spasticity induced by serotonin reuptake inhibitors. Letter]. del Real MA, Hernandez A, Vaamonde J, Gudin M

J Neurol Neurosurg Psychiatry 1997 Mar;62(3):282-4. Ondansetron, a 5-HT3 antagonist, improves cerebellar tremor. Rice GP, Lesaux J, Vandervoort P, Macewan L, Ebers GC. "It has been previously shown that ondansetron, a 5-HT3 antagonist, can ameliorate vertigo in patients with acute brainstem disorders. A coincidental benefit was the improvement of cerebellar tremor in some patients with both vertigo and tremor. To further evaluate this effect, a placebo controlled, double blind, crossover study was conducted of a single dose of intravenous ondansetron in 20 patients with cerebellar tremor caused by multiple sclerosis, cerebellar degeneration, or drug toxicity." "Thirteen of 19 patients were deemed to have improved spiral copying after treatment with ondansetron when compared with baseline performance."

Neurologia 1993 Oct;8(8):252-5. [Retinal periphlebitis in multiple sclerosis. A prospective study]. Rio J, Colin A, Salvador F, Tintore M, Viguera ML, Montalban J, Codina A "In three cases (12.5%) retinal periphlebitis was observed." "Given the absence of myelin in the retina, the presence of retinal periphlebitis suggests the existence of a vascular mechanism in the pathogenesis of multiple sclerosis."

Int J Neurosci 1995 Dec;83(3-4):187-98. Premenstrual exacerbation of symptoms in multiple sclerosis is attenuated by treatment with weak electromagnetic fields. Sandyk R. "The present report concerns two women with chronic progressive stage MS who experienced, coincident with increasing functional disability, regular worsening of their symptoms beginning about a week before menstruation and abating with the onset of menstruation. These symptoms resolved two months after the initiation of treatment with EMFs."

J Physiol Biochem 1998 Dec;54(4):229-37. The role of nitric oxide in the pathogenesis of multiple sclerosis. Santiago E, Perez-Mediavilla LA, Lopez-Moratalla N "The inducible NOS (iNOS) is associated with the development of a number of autoimmune diseases." "Induction of the enzyme is effected by proinflammatory cytokines, immunomodulating peptides, and even beta-endorphin through a mechanism involving an increase in cAMP. An excessive production of NO has been implicated in the severe lesions observed in multiple sclerosis (MS)."

J Neurol 1980 Jan;222(3):177-82. Cerebrospinal fluid lipids in demyelinating disease. II. Linoleic acid as an index of impaired blood-CSF barrier. Seidel D, Heipertz R, Weisner B "The linoleic acid content of control CSF (1.6 +/- 0.8 nMol/ml) is considerably lower than the corresponding serum value (2.5--4.1 muMol/ml). Although CSF from MS patients contains a significantly higher linoleic acid concentration than controls the close correlation between CSF linoleic acid and CSF albumin is maintained. The high CSF concentration of cholesterol esters rich in linoleic acid, which are abundant in serum but represent only traces in CNS lipids, points towards an impaired BBB function as the cause of CSF linoleic increase. We are able to show that both albumin and linoleic acid are suitable as "serum markers...."

J Neurol Sci 1987 Feb;77(2-3):147-52. Chronic periphlebitis retinae in multiple sclerosis. A histopathological study. Shaw PJ, Smith NM, Ince PG, Bates D Retinal periphlebitis in multiple sclerosis is of particular interest in relation to our understanding of the pathogenesis of the demyelinating central nervous system plaques. Previous studies have largely been clinical, and there is little detailed histopathological information relating to this condition. We present the first detailed report in the neurological literature on the histological findings in chronic periphlebitis retinae associated with multiple sclerosis. The most significant abnormalities of the affected retinal veins were the presence of thick laminated collagen in the wall, associated with a scanty infiltration of plasma cells.

Am Heart J 2000 Aug;140(2):212-8. Low intracellular magnesium levels promote platelet-dependent thrombosis in patients with coronary artery disease. Shechter M, Merz CN, Rude RK, Paul Labrador MJ, Meisel SR, Shah PK, Kaul S.

J Neurochem 1996 Mar;66(3):1157-66. Mast cell activation causes delayed neurodegeneration in mixed hippocampal cultures via the nitric oxide pathway. Skaper SD, Facci L, Romanello S, Leon A. "Neurotoxicity required a prolonged period (12 h) of mast cell incubation, and appeared to depend largely on elaboration of the free radical nitric oxide by astrocytes." "Myelin basic protein and 17 beta-estradiol had a synergistic action on the induction of mast cell-associated neuronal injury." "Further, palmitoylethanolamide, which has been reported to reduce mast cell activation by a local autacoid mechanism, decreased neuron loss resulting from mast cell stimulation in the mixed cultures but not that caused by direct cytokine induction of astrocytic nitric oxide synthase." "These results support the notion that brain mast cells could participate in the pathophysiology of chronic neurodegenerative and inflammatory diseases of the nervous system, and suggest that down-modulation of mast cell activation in such conditions could be of therapeutic benefit."

International Journal of Microcirculation--Clinical and Experimental, 1996, Vol 16, Iss 5, pp 266-270. Hyperventilation enhances transcapillary diffusion of sodium fluorescein. J Steurer, D Schiesser, C Stey, W Vetter, MV Elzi, JP Barras, UK Franzeck. "Voluntary hyperventilation (HV) provokes hemoconcentration due to a loss of fluid from the intravascular space." "The exact, mechanism of enhanced transcapillary diffusion of Na fluorescein is not known, The distinct increase in FLI without a significant change in microvascular skin flux suggests an HV-induced increase in capillary pressure or an enhancement in capillary permeability for water and small solutes."

Kidney Int 1992 May;41(5):1245-53. Essential fatty acid deficiency normalizes function and histology in rat nephrotoxic nephritis. Takahashi K, Kato T, Schreiner GF, Ebert J, Badr KF.

Arthritis Rheum 1981 Aug;24 (8):1054-6. Sex steroid hormones and systemic lupus erythematosus. Talal N.

Clin Rheum Dis 1982 Apr;8(1):23-8. Sex hormones and modulation of immune response in SLE. Talal N.

Ann N Y Acad Sci 1986;475:320-8. Hormonal approaches to immunotherapy of autoimmune disease. Talal N, Ahmed SA, Dauphinee M.

Ann Nucl Med 1998 Apr;12(2):89-94. Clinical significance of reduced cerebral metabolism in multiple sclerosis: a combined PET and MRI study. Sun X, Tanaka M, Kondo S, Okamoto K, Hirai S "The severity of cerebral hypometabolism was also related to the number of relapses." "Our results suggest that measurement of cerebral metabolism in MS has the potential to be an objective marker for monitoring disease activity and to provide prognostic information."

Fed Proc 1987 Jan;46(1):118-26. Pathway to carrageenan-induced inflammation in the hind limb of the rat. Vinegar R, Truax JF, Selph JL, Johnston PR, Venable AL, McKenzie KK "Antiserotonin agents inhibited the hypoalgesia and part of the edema. These findings and histological observations suggested that dermal mast cells were injured by C. The hyperalgesia and part of the edema were sensitive to arachidonate cyclooxygenase inhibitors (AACOIs). It is speculated that injured mast cells metabolize arachidonic acid and reactive intermediates, not prostaglandins, mediate the NPIR hyperalgesia and part of the edema." "Arachidonic acid metabolism by neutrophils is speculated to produce the mediators of phagocytic inflammatory (PI) edema and hyperalgesia."

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<span class="koboSpan" id="kobo.1.1">Progesterone Summaries - Progesterone Supplementation - Dosage of Progesterone</span> A R T I C L E

Progesterone Summaries

Progesterone Information | Progesterone Supplementation
Dosage of Progesterone

PROGESTERONE INFORMATION

Sixty years ago, progesterone was found to be the main hormone produced by the ovaries. Since it was necessary for fertility and for maintaining a healthy pregnancy, it was called the pro-gestational hormone, and its name sometimes leads people to think that it isn't needed when you don't want to get pregnant. In fact, it is the most protective hormone the body produces, and the large amounts that are produced during pregnancy result from the developing baby's need for protection from the stressful environment. Normally, the brain contains a very high concentration of progesterone, reflecting its protective function for that most important organ. The thymus gland, the key organ of our immune system, is also profoundly dependent of progesterone.

In experiments, progesterone was found to be the basic hormone of adaptation and of resistance to stress. The adrenal glands use it to produce their antistress hormones, and when there is enough progesterone, they don't have to produce the potentially harmful cortisol. In a progesterone deficiency, we produce too much cortisol, and excessive cortisol causes osteoporosis, aging of the skin, damage to brain cells, and the accumulation of fat, especially on the back and abdomen.

Experiments have shown that progesterone relieves anxiety, improves memory, protects brain cells, and even prevents epileptic seizures. It promotes respiration, and has been used to correct emphysema. In the circulatory system, it prevents bulging veins by increasing the tone of blood vessels, and improves the efficiency of the heart. It reverses many of the signs of aging in the skin, and promotes healthy bone growth. It can relieve many types of arthritis, and helps a variety of immunological problems.

If progesterone is taken dissolved in vitamin E, it is absorbed very efficiently, and distributed quickly to all of the tissues. If a woman has ovaries, progesterone helps them to regulate themselves and their hormone production. It helps to restore normal functioning of the thyroid and other glands. If her ovaries have been removed, progesterone should be taken consistently to replace the lost supply. A progesterone deficiency has often been associated with increased susceptibility to cancer, and progesterone has been used to treat some types of cancer.

It is important to emphasize that progesterone is not just the hormone of pregnancy. To use it only to protect the uterus would be like telling a man he doesn't need testosterone if he doesn't plan to father children, except that progesterone is of far greater and more basic physiological significance than testosterone. While men do naturally produce progesterone, and can sometimes benefit from using it, it is not a male hormone. Some people get that impression, because some physicians recommend combining estrogen with either testosterone or progesterone, to protect against some of estrogen's side effects, but progesterone is the body's natural complement to estrogen. Used alone, progesterone often makes it unnecessary to use estrogen for hot flashes or insomnia, or other symptoms of menopause.

When dissolved in vitamin E, progesterone begins entering the blood stream almost as soon as it contacts any membrane, such as the lips, tongue, gums, or palate, but when it is swallowed, it continues to be absorbed as part of the digestive process. When taken with food, its absorption occurs at the same rate as the digestion and absorption of the food.

PROGESTERONE SUPPLEMENTATION

SYMPTOMATIC: For tendonitis, bursitis, arthritis, sunburn, etc., progesterone in vitamin E can be applied locally after a little olive oil has been put on the skin to make it easier to spread the progesterone solution. For migraines, it has been taken orally just as the symptoms begin.

FOR PMS: The normal pattern of progesterone secretion during the month is for the ovaries to produce a large amount in the 2nd two weeks of the menstrual cycle, (i.e., day 14 through day 28) beginning at ovulation and ending around the beginning of menstruation, and then to produce little for the following two weeks. An average person produces about 30 milligrams daily during the 2nd two weeks. The solution I have used contains approximately 3 or 4 milligrams of progesterone per small drop. Three to four drops, or about 10 to 15 milligrams of progesterone, is often enough to bring the progesterone level up to normal. That amount can be taken days 14 through 28 of the menstrual cycle; this amount may be repeated once or twice during the day as needed to alleviate symptoms. Since an essential mechanism of progesterone's action involves its opposition to estrogen, smaller amounts are effective when estrogen production is low, and if estrogen is extremely high, even large supplements of progesterone will have no clear effect; in that case, it is essential to regulate estrogen metabolism, by improving the diet, correcting a thyroid deficiency, etc. (Unsaturated fat is antithyroid and synergizes with estrogen.)

PERIMENOPAUSAL: The symptoms and body changes leading up to menopause are associated with decreasing production of progesterone, at a time when estrogen may be at a lifetime high. The cyclic use of progesterone, two weeks on, two weeks off, will often keep the normal menstrual cycle going. Three to our drops, providing ten or twelve milligrams of progesterone, is typical for a day, but some women prefer to repeat that amount. Progesterone is always more effective when the diet contains adequate protein, and when thee isn't an excessive amount of unsaturated fat in the diet..

POSTMENOPAUSAL: Some women continue the cyclic use of progesterone ater menopause, because the pituitary gland and brain may continue to cycle long after menstruation has stopped, and progesterone is an important regulator of pituitary and brain function. The cycling pituitary affects the adrenal glands and other organs, and progesterone tends to protect against the unopposed actions of prolactin, cortisol, and adrenal androgenic hormones. Progesterone's effects on the pituitary apparently contribute to its protective effect against osteoporosis, hypertension, hirsutism, etc. But some women prefer to use progesterone without interruption after the menopause, for its protective antistress effects. Slender people usually find that two or three drops are enough, but this amount may be repeated once or twice as needed to relieve symptoms. Adequate protein in the diet and good thyroid function help the body to produce its own progesterone; even if the ovaries have been removed, the adrenal glands and brain continue to produce progesterone.

DOSAGE OF PROGESTERONE

Since progesterone has none of the harmful side effects of other hormones (except for alteration of the menstrual cycle if it is taken at the wrong time of month), the basic procedure should be to use it in sufficient quantity to make the symptoms disappear, and to time its use so that menstrual cycles are not disrupted. This normally means using it only between ovulation and menstruation unless symptoms are sufficiently serious that a missed period is not important. The basic idea of giving enough to stop the symptoms can be refined by some information on a few of the factors that condition the need for progesterone.

If a person has an enlarged thyroid gland, progesterone promotes secretion and unloading of the stored colloid, and can bring on a temporary hyperthyroid state. This is a corrective process, and in itself isn't harmful. A thyroid supplement should be used to shrink the goiter before progesterone is given. Normal amounts of progesterone facilitate thyroid secretion, while a deficiency, with unopposed estrogen, causes the thyroid to enlarge. The production of euphoria has been mentioned as a side effect, but I think euphoria is simply an indication of a good physiological state. (The history of official medical attitudes toward euphoria is a subject that deserves more attention.) Very large doses that are given in vitamin E solution, allowing complete absorption, can reach the level that is sometimes achieved late in pregnancy, producing both euphoria and a degree of anesthesis. To avoid unexpected anesthesia, the correct dose should be determined by taking about 10 mg. at a time allowing it to spread into the membranes of the mouth, and repeating the dose after 10 minutes until the symptoms are controlled.

An excessive estrogen/progesterone ratio is more generally involved in producing or aggravating symptoms than either a simple excess of estrogen or a deficiency of progesterone, but even this ratio is conditioned by other factors, including age, diet, other steroids, thyroid, and other hormones. The relative estrogen excess seems to act by producing tissue hypoxia (as reported in my dissertation, University of Oregon, 1972), and this is the result of changes induced by estrogen in alveolar diffusion, peripheral vascular changes, and intracellular oxygen wastage.

Hypoxia in turn produces edema (as can be observed in the cornea when it is deprived of oxygen, as by a contact lens) and hypoglycemia (e.g., diminished ATP acts like insulin), because glycolysis must increase greatly for even a small deficiency of oxygen. Elevated blood lactic acid is one sign of tissue hypoxia. Edema, hypoglycemia, and lactic academia can also be produced by other respiratory defects, including hypothyroidism, in which the tissue does not use enough oxygen. In hypoxia, the skin will be bluer (in thin places, such as around the eyes), than when low oxygen consumption is the main problem. Low thyroid is one cause of excess estrogen, and when high estrogen is combined with low thyroid, the skin looks relatively bloodless.

Symptoms in cycling women are most common around ovulation and in the premenstrual week, when the estrogen/progesterone ratio is normally highest. At puberty, in the early twenties and in the late thirties and menopause are the ages when the ratio is most often disturbed--and these are also the ages when thyroid disorders are commonest in women.

The individual who suffers from one aspect of the progesterone (and/or thyroid) deficiency will tend to develop other problems at different times. With cyclic depressions or migraine headaches at age 22, there will possibly be breast disease later, and often there will be problems with pregnancy. These people with a history of sever symptoms are the ones most likely to have severe problems around menopause. Prenatal exposure to poorly balanced hormones seems to predispose the child to later hormone problems.

Excess stress (which can block progesterone synthesis and elevate estrogen) may bring on symptoms in someone who never had them. Spending a summer in Alaska, with an unusually long day, may relieve the symptoms of a chronic sufferer. Dark cloudy winters in England or the Pacific Northwest are powerful stressors, and cause lower production of progesterone in women, and testosterone in men. Toxins can produce similar symptoms, as can nutritional deficiencies. A very common cause of an estrogen excess is a dietary protein deficiency--the liver simply cannot detoxify estrogen when it is under-nourished.

With a diet high in protein (e.g., at least 70-100 grams per day, including eggs) and vitamin A (not carotene), I have found that the dose of progesterone can be reduced each month. Using thyroid will usually reduce the amount of progesterone needed. Occasionally, a woman won't feel any effect even from 100 mg. of progesterone; I think this indicates that they need to use thyroid and diet, to normalize their estrogen, prolactin, and cortisol.

Progesterone stimulates the ovaries and adrenals to produce progesterone, and it also activates the thyroid, so one dose can sometimes have prolonged effects. It shouldn't be necessary to keep using progesterone indefinitely, unless the ovaries have been removed. In slender post-menopausal women, 10 mg. per day is usually enough to prevent progesterone deficiency symptoms.

In a 10% solution of progesterone in vitamin E, one drop contains about three milligrams of progesterone. Normally, the body produces 10 to 20 milligrams per day. A dose of 3 or 4 drops usually brings the blood levels up to the normal range, but this dose can be repeated several times during the day if it is needed to control symptoms.

For general purposes, it is most economical and effective to take progesterone dissolved in vitamin E orally, for example taking a few drops on the lips and tongue, or rubbing it into the gums. (It is good for the general health of the gums.) These membranes are very thin, and the progesterone quickly enters the blood. When it is swallowed, the vitamin E allows it to be absorbed through the walls of the stomach and intestine, and it can be assimilated along with food, in the chylomicrons, permitting it to circulate in the blood to all of the organs before being processed by the liver. These droplets are smaller than red blood cells, and some physicians seem to forget that red blood cells pass freely through the liver.

For the topical treatment of sun damaged skin, or acne, wrinkles, etc. the oil can be applied directly to the affected area.

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<span class="koboSpan" id="kobo.1.1">Progesterone Summaries - Progesterone Supplementation - Dosage of Progesterone</span> A R T I C L E

The Progesterone Deceptions

In the 1930s, it was demonstrated that estrogen, even in small doses, produced abortions, and that when it is given early enough, even a very small dose will prevent implantation of the fertilized embryo. Progesterone was known, by the early 1940s, to protect against the many toxic effects of estrogen, including abortion, but it was also known as nature's contraceptive, since it can prevent pregnancy without harmful side-effects, by different mechanisms, including prevention of sperm entry into the uterus. That is, progesterone prevents the miscarriages which result from excess estrogen (1,2), but if used before intercourse, it prevents conception, and thus is a true contraceptive, while estrogen is an abortifacient, not a contraceptive.

In the 1950s, there was a search for chemicals which would prevent ovulation. According to Carl Djerassi (), drug companies were extremely reluctant to risk a religious backlash against their other products, and so hesitated to market contraceptives. Obviously, the induction of monthly abortions would have been even harder to sell.

According to Djerassi (3), Until the middle 1940s ti was assumed that progesterone's biological activity was extremely specific and that almost any alteration of the molecule would diminish or abolish its activity. This would obviously discourage interest from the drug companies, who could patent a substance which they had chemically modified, but could not patent a simple natural substance. However, many substances--even non-steroidal chemicals--were known to have estrogenic action. (4)

By 1942, Hans Selye had demonstrated that natural steroids retain their activity when administered orally. But every drug company with a steroid patent had an obvious interest in having the public believe that there is a reason that the natural steroids cannot be conveniently used. The doctrine that natural steroids are destroyed by stomach acid appeared, was promoted, and was accepted--without any supporting evidence. In the manufacture of progesterone, the precursor steroid is boiled in hydrochloric acid to free it from its glucose residue. No one seriously believed that stomach acid hurts progesterone, except the public--and the doctors, who had seen the claim in their medical journals, and had heard it from drug salesmen.

The myth stopped the use of the cheap tablets of progesterone, as tablets of the synthetic progestins came on the market, at a much higher price. Doctors who insisted on using real progesterone were forced to buy it in an injectable form. As a result, solubility became an issue. Progesterone is extremely insoluble in water, and, though it is vastly more soluble in vegetable oil than in water, it does not stay in solution at room temperature even at the low concentration of 1 part in 1000 parts of a typical vegetable oil.

When people speak of an allergy to progesterone (or even to penicillin) they generally are not aware of the presence of a very toxic solvent.(5) For a time, progesterone was often sold dissolved in benzyl benzoate. The Physician's Desk Reference warned of possible allergic reactions to progesterone. Now, it is supposedly sold dissolved in vegetable oil, with about 10% benzyl alcohol as--supposedly--a bacteriostatic agent.

Bacteriostatic water contains 0.9% to 1.9% benzyl alcohol, and can irreversibly harm nerves. (6,7) Its use in hospitals killed thousands of babies. Awareness of benzyl alcohol's toxicity goes back to 1918 at least; it was proposed as an effective insecticide, and was found to be toxic to many animal systems. The safe systemic dose (7) is exceeded with an injection of 150 mg. of progesterone, yet the local concentration is far higher. It can cause a severe reaction even when used at a lower concentration, in bacteriostatic water. (5)

Other alcohols, including ethanol, have been used as solvents, but since they (ethanol even more than benzyl alcohol) have an affinity for water, the solution decomposes in contact with tissue water.

In spite of the toxicity of the vehicle, several beneficial effects can be obtained with injected progesterone, in serious conditions such as epilepsy or caner of the breast or uterus. Many researchers have commented on the very obvious difficulty of giving very large amounts of progesterone. (8) My comparisons of oral progesterone in tocopherol with other forms and methods of administration show a roughly similar efficiency for oral and inject progesterone, and about 1/20 the effect for suppositories. Crystals of progesterone are visible in the suppositories I have examined, and this material is obviously wasted.

An old theory of vitamin E's mechanism of action in improving fertility was that it spares progesterone.(9) It is established that some of the effects of vitamin E and progesterone are similar, for example, both prevent oxygen waste and appear to improve mitochondrial coupling of phosphorylation with respiration. I suspected that if they actually both work at the same mitochondrial site, then they must have a high mutual solubility.

Knowing the long-standing problem of administering large doses of progesterone without a toxic solvent, I applied for and was granted a patent for the composition of progesterone in tocopherol. One of my reasons for publishing in the form of patents is that I have had many years of experience in having my discoveries taken up by others without acknowledgment, if they are compatible with conventional prejudices. Typically, an editor rejects a paper, and then a few months later publishes a very similar paper by someone else. My dissertation research, which established that an estrogen excess kills the embryo by suffocation, and that progesterone protects the embryo by promoting the delivery of both oxygen and glucose, didn't strike a responsive chord in the journals which are heavily influenced by funds from the drug industry.

According to a consultant for a major medical journal, the idea of dissolving progesterone, a fat soluble steroid hormone, in vitamin E which is then incorporated into chylomicrons absorbed via the lymphatics, and thus avoids the liver on the so called first pass is so simple it is amazing that the pharmaceutical companies have not jumped on it. (A more sophisticated writer might have said stomped on it.)

In the powder form, direct and intimate contact with a mucous membrane allows lipid phase to lipid phase transfer of progesterone molecules. Instead of by-passing the liver, much of the progesterone is picked up in the portal circulation, where a major part of it is glucuronidated, and made water soluble for prompt excretion.

Since this glucuronide form cross-reacts to some extent with the ordinary progesterone in the assay process, and since 50% of the ordinary free progesterone is carried inside the red blood cells (10,11), and 50% is associated with proteins in the plasma, while the glucuronide hardly enters the red blood cells at all, it is better to judge by clinical efficacy when comparing different oral forms. My comparisons show several times higher potency in the tocopherol composition than in powder form.

Since progesterone's use as a drug antedates the 1938 law requiring special federal approval, its legal status is similar to that of thyroid hormone. Unfortunately, for both thyroid and progesterone, there is a tendency to cut corners for the sake of a bigger profit margin.

For example, steroid acetates are generally a little cheaper than the simple natural steroid. Some people assume that an acetate or butyrate can be substituted for the steroid itself. This can cause dangerous reactions.

Medroxyprogesterone acetate is considered a progestin (though it is not supportive of gestation), because it modifies the uterus in approximately the wasy progesterone does, but it is luteolytic, and lowers the ovaries' production of progesterone while progesterone itself has a positive effect on the corpus luteum, stimulating progesterone synthesis. Defining progestin in a narrow way allows many synthetics to be sold as progestogens, though some of them are strongly estrogenic, allowing them to function as contraceptives--it is odd that contraceptives and agents which suppress progesterone synthesis should be officially called supported of pregnancy. It is probably partly the acetate group in the medroxyprogesterone acetate molecule which makes it bind firmly to receptors, yet causes it to block the enzymes which would normally be involved in progesterone metabolism. (I think testosterone, even, might be a safer progestin than medroxyprogesterone acetate.) Pregnenolone acetate similarly blocks the enzymes which normally metabolize pregnenolone. (12) In aspirin, it has been found that it is the acetyl group which (by a free radical action) blocks an enzyme involved in prostaglandin synthesis.

If the category called progestogens or progestins is to be defined on the basis of a single tissue reaction, then it is possible to classify progesterone with the toxic synthetic substances, but then it becomes highly deceptive to imply that progesterone is just a progestin, or that it has any of the other properties of the toxic synthetics, but this continues to be done. The warnings about progestins causing birth defects, for example, cause epileptic women t use conventional anti-seizure drugs (all of which cause birth defects) during pregnancy, and to avoid natural progesterone, which generally could control their seizures. Thus, a false message attached to progesterone creates precisely the harm it claims to want to prevent. In my communications with the regulatory agencies, I have concluded that their attempts to deceive are too blatant to ascribe to incompetence. Whether it's the Forest Service the FDA, the principle is the same: The regulatory agencies have been captured by the regulated industries.

Another place to cut costs is in the tocopherol. Tocopherol acetate does have vitamin E activity, but sine it is only about half as efficiently absorbed as the simple tocopherol (13), it is a mistake to save a few dollars an ounce, at the expense of losing half of the therapeutic effect. People who have compared natural progesterone in natural tocopherols with other compositions have insisted that the other compositions must not contain progesterone.

The taste of natural vitamin E is stronger than that of the synthetic forms, but since the mixture is absorbed by any tissue it contacts, including various parts of the bowel, it can be taken in a capsule. If a small amount of olive oil is used with it, absorption through the skin is very rapid. Many women use it vaginally, spread onto a diaphragm, to hold it in contact with the membranes. The efficiency of absorption by all routes is so high that patients should be warned against its anesthetic effect, until their dosage requirement is known approximately. Some physicians prefer concentrations higher than 10%, but the risk of accidental drunkenness or anesthesia is higher with the stronger solutions.

It is an indication of the tocopherol solution's high availability that medical researchers such as Roy Hertz (8), who thought they were administering maximal doses by combining injections with suppositories, never mentioned the problem of an anesthetic effect from an overdose. Similarly, it si evidence of the extremely poor availability of the micropulverized progesterone that the researchers have administered hundreds of milligrams per day, without mentioning the symptoms of an overdose. Because of the difficulties involved in scientifically studying the clinical effectiveness of various formulations, I think the most practical way of evaluating the effectiveness of different progesterone formulations is to measure the amount extractable from the red blood cells, a few hours after the peak serum level has been reached. This will reasonably reflect the amounts reaching brain cells, adrenal glands, and the various other cells on which progesterone has its therapeutic action.

REFERENCES

1. A A. Gidley-Baird, et aI., Failure of implantation in human in vitro fertilization and embryo transfer patients: the effects of altered progesterone/estrogen ratios in humans and mice, Fertility and Sterility 45(1): 69-74, 1986.

2. J. L. Yovich, et aI., Early luteal serum progesterone concentrations are higher in pregnancy cycles, Fertility and Sterility 44 (1): 185-189, 1985.

3. C. Djerassi, The making of the pill, Science 84: 127-129, 1984.

4. R. Kehl, Les Glandes Endocrines, Presses Universitaires de France, Paris, 1952.

5. J. A. Grant, et aI., New England Journal of Medicine 306(2): 108, 1982, Unsuspected benzyl alcohol hypersensitivity.

6. T. E. Feasby, et aI., Neurotoxicity of bacteriostatic water, New England Journal of Medicine 308(6): 966-7, 1983.

7. E. T. Kimura, et aI., Parenteral toxicity studies with benzyl a1cohol,Toxicol Appl Pharmacol18: 60-68, 1971.

8. A. White, editor, Symposium on Steroids in Experimental and Clinical Practice, The Blakiston Co., N.Y., 1951, p. 401.

9. A. Fraschini, II Metodo Biologico di Rinvigorimento, Edizioni Minerva Medica, Milan, 1954.

10. E. Mulder, et aI., Metabolism of free and conjugated steroids by intact and haemolysed mammalian erythrocytes, Biochim. Biophys. Acta 263: 290-297, 1972.

11. M. Holzbauer, The association of steroids with blood cells in vivo, J. of Steroid Biochemistry 3: 579-592, 1972.

12. S. Lieberman, et aI., A heuristic proposal for understanding steroidogenic processes, Endocrine Reviews 5(1): 128-148, 1984.

13. L. J. Machlin and E. Gabriel, Kinetics of tissue alpha-tocopherol uptake and depletion, following administration of high levels of

vitamin E, p. 48 in annals of the N.Y. Academy of Science 393,B. Lubin and I. J. Machlin, editors, New York, 1982.

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<span class="koboSpan" id="kobo.1.1">Preventing and treating cancer with progesterone.</span> A R T I C L E

Preventing and treating cancer with progesterone.

"The energy of the mind is the essence of life." Aristotle

All through the last century, as more and more resources were devoted to solving "the cancer problem," the death rate from cancer increased every year. Something was clearly wrong with the way the problem was being approached.

If you grind up a computer and dissolve it in acid, you can find out exactly what substances it was made of, but you won't learn from that information how the computer worked. Twentieth century biologists became fond of emulsifying cells and studying the soluble parts. By the end of the century, they had identified so many parts that the government was financing projects to use supercomputers to try to understand how the parts interacted.

If some essential information was lost in studying the parts, supercomputation isn't the way to find it. Even with infinite computing capacity, a description of the electrons on carbon and hydrogen atoms on amino acids in protein molecules won't lead to the reality of how those atoms would have functioned in the living state.

The image of a cell as a watery solution contained in an elastic membrane bag is still having a radically stupefying effect on biology and medicine. The idea that a cell can be understood by using a computer to model a network of interactions between genes and gene products is nothing more than a technologizing of the primitive understanding of life that was promulgated by the Weismann-Mendel-Morganist school. It was the dogmatic insistence of that genetic determinist school that cancer originated with a genetic mutation.

By the middle of the 20th century, that dogma had excluded the most important parts of biology from the schools and the journals. Ideas of a developmental field, cellular coherence, and holistic cooperativity were denounced as unscientific vitalism. Returning to the idea of a "cancer field" is an essential first step in thinking realistically about preventing and treating cancer, but that idea has hardly progressed since the 1930s.

In the last few years, interest in cloning and stem cells and tissue regeneration has revived interest in studying the factors that contribute to the spatial and temporal ordering of cell growth.

The idea of a developmental field was a fundamental part of embryology in the first half of the 20th century. It was an empirical idea, supported most commonly by evidence that diffusing substances and secreted materials governed the differentiation of cells and tissues, but the form-generating effects of bioelectric fields were also often demonstrated, and there was some evidence that tissue radiations played a role. The extracellular matrix secreted by cells served to transmit information between cells, but its form was regulated by cells, and its structure was a factor governing the cells' differentiation.

Experiments in amphibians showed that regeneration of organs had a reciprocal relationship with the development of cancer--a tumor could be turned into a tail, for example, if it was grafted onto the stump following amputation of the tail, but factors that weakened regeneration could cause a tumor to develop. In these experiments, the normal organism's morphogenetic or epimorphic field overrode the disordered developmental field of the tumor.

In the absence of overriding external influences, the disordered system of the tumor, in which cells emitted many products of their disordered metabolism, could interfere with the normal functions of the organism. All of the products of the injured cells, including their altered extracellular matrix, constituted the cancer field.

The recent recognition of the "bystander effect" of radiation exposure, in which cells that haven't been irradiated undergo genetic changes or death when they are exposed to irradiated cells, has provided an opportunity to return to the "field" idea in cancer, because the stress-induced factors emitted by irradiated cells are the same toxic factors emitted by cells undergoing carcinogenesis from other causes, such as over-exposure to estrogen.

H. J. Muller, one of T. H. Morgan's students and colleagues, studied the mutagenic effects of x-rays, and the genetic determinists argued that the random changes produced in the genetic material by ionizing radiation provided a model of the evolutionary process. Randomly altered genes and natural selection would explain everything, including cancer. Every time cells divide, their genes supposedly become more susceptible to random changes, so increased replication of cells would increase the risk of producing genetic changes leading to cancer. This idea is so simple and so widely believed that many people focus only on the rate of proliferation, and the random mutations that supposedly occur during proliferation, when they try to explain carcinogenesis. They feel that it's reasonable to discuss cancer without bothering to understand the physiology of the cell or the organism.

The organism can only be understood in its environments, and a cell can't be understood without reference to the tissue and organism in which it lives. Although the geneticists were at first hostile to the idea that nutrition and geography could have anything to do with cancer, they soon tried to dominate those fields, insisting that mutagens and ethnicity would explain everything. But the evidence now makes it very clear that environment and nutrition affect the risk of cancer in ways that are not primarily genetic.

Every tumor, like every person, has a uniqueness, but valid and practical empirical generalizations can be made, if we understand some of their properties and the conditions that govern their development and survival.

Percival Potts' observation of scrotal cancer in chimney sweeps eventually led to the study of soot carcinogenesis, and then to the study of the properties of the polycyclic aromatic hydrocarbons in soot. The similarities of those properties to estrogen's soon became apparent.

Over the decades, many studies have confirmed that prolonged, continuous exposure to estrogen is carcinogenic, and that progesterone offsets those effects.

Following the animal studies that showed that carcinogenesis by estrogen could be prevented or reversed by progesterone, studies of the endogenous hormones in women showed that those with a natural excess of estrogen, and/or deficiency of progesterone, were the most likely to develop uterine or breast cancers.

The Morganist school of genetic determinism moved into endocrinology with a doctrine that hormones act only through hormone receptors, proteins which activate certain genes.

Many researchers -- physical chemists, biochemists, cytologists, embryologists, reproductive and developmental biologists, gerontologists, physiologists, neurologists, endocrinologists -- were investigating estrogen's properties and actions, and had made great progress by the 1950s, despite the medical frauds being perpetrated by the estrogen industry (Rothenberg, 2005).

All of this complex and subtle work was of no interest to a small group of people who wanted to impose their genetic views onto biology.

The inventor of the estrogen receptor, Elwood Jensen, has written that the results of certain of his experiments "caused the demise of the transhydrogenation hypothesis and convinced all but the most diehard enzymologists that estradiol binds to a characteristic component of target cells to exert its physiological effect without itself being chemically altered." The hypothesis he referred to was just part of a large fairly systematic international effort.

How he did away with the opposition, who were studying the complex metabolic actions of estrogen, was by synthesizing isotope-labeled estradiol and estrone, and claiming to observe that they weren't metabolically altered, as they produced their hormonal effect. Since the experiment was extremely expensive, and required the cooperation of the Atomic Energy Commission, it wasn't easily repeated. However, many experiments have subsequently demonstrated that practically every tissue in the body (and plants and bacteria) metabolize the estrogens, causing estradiol to change into estrone, and estrone, into estradiol. Jensen's decisive and historically crucial experiment was false.

But it served its purpose, and (with help from the pharmaceutical industry and government granting agencies) marginalized the work of those "enzymologists" and everyone else who persisted in studying the complex actions of estrogen.

The enzyme that converts the weaker estrone into the stronger estradiol is an important factor in determining estrogen's effects on a particular tissue. Progesterone is able to regulate the cell's metabolism, so that the oxidative pathway, forming estrone from estradiol, predominates. Estrogen-dominated tissues are likely to have a balance in the direction of reduction rather than oxidation, increasing the amount of the active estradiol.

The immediate effects of estrogen and progesterone on cells, that occur long before genes can be activated, were simply ignored or denied by the promoters of the estrogen receptor doctrine. Some of these excitatory or antiexcitatory effects are probably structural changes, that involve the mobilization of calcium inside cells, and the activation or inhibition of reactions involving phosphoric acid. Although they have been known for many years, they are always referred to as "novel" or "non-classical" effects, and are called "membrane effects," because that's the only way the reductionists are able to identify changes that happen immediately throughout the cell.

Cellular excitation involves an increase of intracellular calcium and the activation of phosphorylating enzymes in cells. Some experiments suggest (Improta-Brears, et al., 1999) that the estrogen receptor mediates estrogen's ability to mobilize calcium (leading to the activation of cell division, mitosis). Whether or not it does, the recognition that estrogen activates calcium, leading to activation of the phosphorylation system, should "cause the demise of" the "classical estrogen receptor" doctrine, because the phosphorylation system alters the expression of genes, much as the estrogen receptor was supposed to do by its direct actions. But before it alters the expression of genes, it alters the activities of enzymes. When estrogen activates calcium and phosphorylation independently of the estrogen receptor, the situation is even worse for the Jensen dogma.

Progesterone's opposition to those early excitatory effects of estrogen are so basic, that there shouldn't be any difficulty in thinking of it as an antiestrogen, that stops cell division primarily by opposing the excitatory effects of estrogen and other mitogens. Progesterone's opposition to the calcium-activating and phosphorylating effects of estrogen affects everything in the cell, according to the cell's specific nature.

But the reductionists don't like "nongenomic" explanations of anything, even when they are triggered by the estrogen receptor rather than by a membrane-event. So, to argue that progesterone's opposition to estrogen is general, it's necessary to examine each of estrogen's actions, where those actions are clearly known, and to evaluate progesterone's effects on the same events.

When a cell is stimulated or slightly stressed, homeostatic mechanisms are activated that help it to return to its normal resting state. The mobilization of calcium and the phosphorylation system is followed by increased synthesis of cholesterol and the formation of glucose from glycogen. Cholesterol itself is protective, and in some cells it is massively converted into progesterone, which is even more effective in restoring homeostasis.

In the ovary, the enzymes that synthesize cholesterol, along with the production of progesterone, are activated by the pituitary hormone, FSH, but also by estrogen. In the liver and uterus and vascular endothelium, which aren't specialized for the production of progesterone, stimulation by estrogen activates the enzymes to increase the formation of cholesterol.

When cells are injured or seriously stressed, instead of being able to directly recover their normal quiescence, they may instead mobilize their systems for growing and replicating, to replace damaged or destroyed cells.

Prolonged exposure to estrogen, that can't be offset by the homeostatic factors, such as progesterone, typically causes cells to enter a growth phase. (But so do other excitatory processes, such as ionizing radiation.)

One of the basic reactions to injury is to shift the cell away from oxidative metabolism to glycolytic metabolism, which is inefficient, but can support cell division. Chemical stains show that during cell division cells are in a reduced state, with abundant sulfhydryl groups including reduced glutathione and protein sulfhydryls. This shift in itself increases the formation of active estradiol from estrone.

In the inflamed or estrogen dominated cell, enzymes such as the cyclooxidases (COX), that convert arachidonic acid into prostaglandins, are activated. Beta-glucuronidase and sulfatases are activated, and these cause intracellular estrogen to increase, by removing the water soluble sulfate and glucuronate portions from estrogens that had been inactivated. The detoxifying enzymes that attach those molecules to estrogen are inactivated in the estrogen dominated cell. The prostaglandin formed from arachidonic acid stimulates the formation of the enzyme aromatase or estrogen synthetase, that converts androgens into estrogen.

Those processes, initiated by excitation or injury, increase the amount of estrogen in the cell, which intensifies the excitation.

Progesterone opposes all of those processes, decreasing the amount of estrogen in the cell by modifying the activities of those five types of enzyme.

Although many kinds of protein (including enzymes) bind estrogen, the protein that Jensen called "the estrogen receptor" is largely responsible for the ability of the uterus and breasts to retain high concentrations of estrogen. Various kinds of stimulation or stress (including heat and oxygen deprivation) cause its appearance, and estrogen itself increases the amount of the estrogen receptor in a cell. The estrogen receptor doesn't just "activate genes," as the Jensen dogma claimed. For example, the estrogen receptor directly binds and inactivates the "tumor suppressor" p53 protein, which otherwise would restrain the replication of damaged cells.

Progesterone causes the estrogen receptor to be eliminated. (Batra; Boling and Blandau; Resko, et al.)

Among the cell activating factors, other than estrogen, are proteins that are considered to be "oncogenes," because of their involvement in cancer. Several of these proteins are activated by estrogen, inhibited by progesterone. The term "oncogene" refers to any gene that contributes to the development of cancer, but it is so burdened by ideology that it shouldn't be used as if it had a simple clear meaning.

A variety of proteins promote cell activity and replication, under the influence of estrogen. The "composite transcription factor activating protein 1," AP-1 which integrates the effects of other transcription factors, is important in a variety of cell types, and its activity is increased by estrogen and decreased by progesterone.

When the "progesterone receptor" lacks progesterone, it has the opposite effect of progesterone, and this feature has been used propagandistically, by infecting cells with a virus carrying the progesterone receptor protein, and then suggesting that the disturbed functions of the cell reflect a potential effect of progesterone. The receptor, lacking progesterone, tells the cell that it has a progesterone deficiency, but too many molecular endocrinologists are trying to say that the receptor protein is the same as the progesterone.

The generality of the process of excitation/activation can be clearly seen in the effects of the nerve-inhibiting GABA and the nerve-exciting glutamate or NMDA. In cultured breast cancer cells, GABA inhibits growth, NMDA increases growth. As in the brain, progesterone supports the actions of GABA, and opposes those of NMDA or the excitatory amino acids, while estrogen in general promotes the effects of the excitatory amino acids, and opposes those of GABA.

Both the excitatory amino acids and a peptide that promotes inflammation, tumor necrosis factor (TNF), activate the enzyme which makes estrogen, aromatase. Estrogen, by activating NF kappaB, increases the formation of TNF, which in itself can promote the growth and metastasis of cancer. Various antiinflammatory agents, including aspirin, progesterone, testosterone, saturated fats, and glycine, can inhibit the production of NF kappaB.

An enzyme that has been thought of mainly in relation to the brain is catechol-O-methyl transferase, which is inhibited by estrogen (producing effects similar to cocaine), leading to brain excitation.The enzyme detoxifies catecholestrogen (Creveling, 2003), protecting cells from DNA damage (Lavigne, et al., 2001). When the activity of this enzyme is low, there is increased risk of breast cancer (Matsui, et al., 2000). Progesterone increases its activity (Inoue and Creveling, 1991, 1995).

Another enzyme system that affects the body's reactions to stress and modifies processes of inflammation and growth, the monoamino-oxidases, is affected oppositely by estrogen and progesterone. Estrogen's effects are partly mediated by increased formation of serotonin, progesterone's, by decreasing it. Histamine is another promoter of inflammation that is increased by estrogen, decreased by progesterone.

Estrogen's effects in the nervous system go beyond the production of cocaine-like hypomania, or chorea, or epilepsy, and include the activation of the basic stress hormones, increasing the formation in the hypothalamus of pro-opiomelanocortin (POMC), which is a precursor of ACTH to activate the adrenals, and endorphins ("endogenous opiates"), which stimulate growth processes. Both endorphins and ACTH can be found in tumors such as breast cancer. The ACTH stimulates the production of cortisol, that protects against some of the immediate causes of inflammation and growth, but that contributes to the loss of resistance, and increases estrogen synthesis.

A protein called the sigma receptor, known for its role in cocaine's action, binds progesterone, and can inhibit the growth of cancer. Some anesthetics have similar effects on tumors, acting through this protein. The sigma receptor, in association with progesterone or pregnenolone, is protective against the excitatory amino acids.

The extracellular medium changes during the development of a tumor. Irritated hypoxic cells, and estrogen-stimulated cells, increase their production of collagen, and the increase of collagen interferes with normal cell functions. Progesterone reduces the formation of collagen, and probably contributes to its removal.

Naloxone or naltrexone, which blocks the actions of the endorphins and morphine, is being used to inhibit the growth of various kinds of cancer, including breast cancer and prostate cancer. Leptin (which is promoted by estrogen) is a hormone produced by fat cells, and it, like estrogen, activates the POMC-related endorphin stress system. The endorphins activate histamine, another promoter of inflammation and cell division.

Progesterone opposes those various biochemical effects of estrogen in multiple ways, for example by inhibiting the ACTH stress response, by restraining cortisol's harmful actions, and by inhibiting leptin.

Mediators of the radiation bystander effect include NO, TNF, COX, and prostaglandins. These are produced by other things that cause inflammation and injury, including estrogen.

Cell division, when it is part of the body's continuous renewal and adaptation, isn't a source of mutations or degeneration, but when it is induced by the mediators of inflammation produced in response to injury, it leads to inherited changes, loss of differentiated function, and eventually to genetic instability.

When cell division is so disturbed that the number of chromosomes becomes abnormal, the instability of these cells decreases their ability to survive, but when the causes of the inflammation persist, they will continue to be replaced by other abnormal cells. The toxic products of dying cells can reach a point at which the debris can't be removed, adding to the injury and inflammation. The damaged bystander cells spread their influence through a cancer field, injuring more cells.

One of the "field" effects of cancer is the stimulation of new blood vessel development, angiogenesis. Lactic acid stimulates the formation of new blood vessels, the secretion of collagen, and tumor growth. Low oxygen, nitric oxide, carbon monoxide, prostaglandins and other products of tissue stress can stimulate the growth of new blood vessels, at the same time that they stimulate tumor growth and impair oxidative metabolism. Several of these agents promote each other's activity.

Therapeutic thinking has been influenced by the doctrine of the mutant cell as the initiator of cancer, leading to the idea that only things which kill the cancer cells can cure cancer. But when the body stops activating the processes of inflammation and growth, normal processes of tissue repair have an opportunity to eliminate the tumor. Even the fibroblasts which normally secrete collagen can participate in its removal (Simoes, et al., 1984). Something as simple as eliminating lactate can change their functions.

Although the angiogenic action of lactate has been known for several decades, some researchers believed that a specific anti-angiogenic peptide could be found which would stop the growth of cancer cells. The interest in angiogenesis tacitly acknowledges that there is a cancer field, but the faith that cancer could be cured only by killing the mutant cells seems to have guided the search for a single antiangiogenic substance. Such a substance would be toxic to normal tissues, since blood vessels are constantly being renewed.

The more advanced a tumor is, the more numerous the growth-promoting factors are likely to be, and the weaker the body's ability becomes to control them.

The search for toxic factors to kill the cancer cells is unlikely to lead to a generally effective treatment. Even immunological approaches that think in terms of destroying a tumor might be misconceiving the nature of the problem. For example, the protein called "tumor necrosis factor" (TNF) or cachectin was discovered as a result of Lawrence Burton's work in the 1960s. He extracted proteins from the blood that could shrink some tumors in mice with amazing speed. In the right setting, TNF is involved in the destruction of tumors, but when other factors are missing, it can make them worse. Burton was focussing on factors in the immune system that could destroy cancer, but he ignored the basic problem of tissue degeneration that produces tumors which are complex and changing.

If the cancer-productive field is taken into account, all of the factors that promote and sustain that field should be considered during therapy.

Two ubiquitous carcinogenic factors that can be manipulated without toxins are the polyunsaturated fatty acids (PUFA) and estrogen. These closely interact with each other, and there are many ways in which they can be modulated.

For example, keeping cells in a well oxygenated state with thyroid hormone and carbon dioxide will shift the balance from estradiol toward the weaker estrone. The thyroid stimulation will cause the liver to excrete estrogen more quickly, and will help to prevent the formation of aromatase in the tissues. Low temperature is one of the factors that increases the formation of estrogen. Lactic acid, serotonin, nitric oxide, prostaglandins, and the endorphins will be decreased by the shift toward efficient oxidative metabolism.

Progesterone synthesis will be increased by the higher metabolic rate, and will tend to keep the temperature higher.

Thyroid hormone, by causing a shift away from estrogen and serotonin, lowers prolactin, which is involved in the promotion of several kinds of cancer.

Vitamin D and vitamin K have some antiestrogenic effects. Vitamin D and calcium lower the inflammation-promoting parathyroid hormone (PTH).

Eliminating polyunsaturated fats from the diet is essential if the bystander effect is eventually to be restrained. Aspirin and salicylic acid can block many of the carcinogenic effects of the PUFA. Saturated fats have a variety of antiinflammatory and anticancer actions. Some of those effects are direct, others are the result of blocking the toxic effects of the PUFA. Keeping the stored unsaturated fats from circulating in the blood is helpful, since it takes years to eliminate them from the tissues after the diet has changed. Niacinamide inhibits lipolysis. Avoiding over-production of lipolytic adrenaline requires adequate thyroid hormone, and the adjustment of the diet to minimize fluctuations of blood sugar.

The endorphins are antagonistic to progesterone, and when they are minimized, progesterone tends to increase, and to be more effective. The drugs naloxone and naltrexone, which block the effects of the endorphins, have several remarkable effects that resemble progesterone's. Naltrexone has been successfully used to treat prostate and breast cancer.

Opiates are still commonly used for pain relief in cancer patients, despite the evidence that has accumulated for several decades indicating that they promote inflammation and cancer growth, while suppressing immunity and causing tissue catabolism, exacerbating the wasting that commonly occurs with cancer. Their use, rather than alternatives such as procaine, aspirin, and progesterone, is nothing but a medical fetish.

Stress and estrogen tend to produce alkalosis, while thyroid, carbon dioxide, and adequate protein in the diet help to prevent alkalosis.

Antihistamines and some of the antiserotonin drugs (including "dopaminergic" lisuride and bromocriptine) are sometimes useful in cancer treatment, but the safe way to lower serotonin is to reduce the consumption of tryptophan, and to avoid excessive cortisol production (which mobilizes tryptophan from the muscles). Pregnenolone and sucrose tend to prevent over-production of cortisol.

In the breast, COX-2 converts arachidonic acid into prostaglandins, which activate the enzyme aromatase, that forms estrogen from androgens. Until the tissues are free of PUFA, aspirin and salicylic acid can be used to stop prostaglandin synthesis.

Thyroid is needed to keep the cell in an oxidative, rather than reductive state, and progesterone (which is produced elsewhere only when cells are in a rapidly oxidizing state) activates the processes that remove estrogen from the cell, and inactivates the processes that would form new estrogen in the cell.

Thyroid, and the carbon dioxide it produces, prevent the formation of the toxic lactic acid. When there is enough carbon dioxide in the tissues, the cell is kept in an oxidative state, and the formation of toxic free radicals is suppressed. Carbon dioxide therapy is extremely safe.

In the 1930s, primates as well as rodents had been used in experiments to show the carcinogenic effects of estrogen, and the protective effects of progesterone.

By 1950, the results of animal studies of progesterone's anticancer effects were so clear that the National Cancer Institute got involved. But the estrogen industry had already been conducting its campaign against progesterone, and had convinced most doctors that it was inactive when taken orally, and so was inferior to their proprietary drugs that they called "progestins." The result was that it was usually given by injection, dissolved in vegetable oil or synthetic solvents such as benzyl benzoate or benzyl alcohol, which are very toxic and inflammation-producing.

The NCI researchers (Hertz, et al., 1951) treated 17 women with visible cancers of the uterine cervix that had been confirmed by biopsies. They were given daily intramuscular injections of 250 mg of progesterone in vegetable oil. Although they described the treatment as "massive dosage with progesterone," it didn't prevent menstruation in any of the women who had been menstruating before the treatment began. During a healthy pregnancy, a woman produces more progesterone than that.

Their article includes some photographs of cervical tumors before treatment, and after 31 days, 50 days, and 65 days of progesterone treatment. The improvement is clear. The examining physicians described softening of the tumor, and stopping of bleeding and pain.

"In eleven of the 17 treated patients visible and palpable evidence of regressive alteration of the tumor mass could be demonstrated. This consisted of (a) distinct reduction in size of the visible portion of the cancer as well as reduction of the palpable extent of the mass, (b) reduction in vascularity and friability of the visible lesion with a clearly demonstrable epithelization of previously raw surfaces and (c) markedly increased pliability of the previously rigid and infiltrated parametria."

"In 10 cases there was associated with this type of gross change a reduction in, or complete cessation of vaginal bleeding and discharge."

"Only one of the 17 patients showed active progression of the carcinomatous process while under the progesterone administration. The six patients whose lesions failed to show clearly demonstrable regressive changes showed minor alterations in size and vascularity of insufficient degree to be convincing to all clinical observers concerned. Nevertheless, none of the lesions under study appeared to be accelerated by progesterone."

Observing very similar patients under similar conditions while they were waiting for surgery, but were not receiving progesterone, they saw no such regressions of tumors.

The photographs and descriptions of the changes in the tumors were remarkable for any cancer study, but to have been produced by a treatment that didn't even alter the patients' menstrual cycle, the reader might expect the authors to discuss their plans for further studies of such a successful method.

But instead, they concluded "We do not consider the regressive changes observed to be sufficient to indicate the use of progesterone as a therapeutic agent in carcinoma of the cervix."

(Their research was supported by a grant from the American Cancer Society.)

If the researchers had bothered to test progesterone on themselves or on animals, they would have discovered that it is fully active when taken orally, dissolved in oil, and that nontoxic saturated fats could have been used. Progesterone anesthesia was very well known at that time, so it would have been reasonable to use doses that were at least equivalent to the concentrations present during pregnancy, even if they didn't want to use doses that would approach the anesthetic level. The total daily doses could have been about ten times higher, if they had been given orally as divided doses.

The solvent issue continues to impede research in the use of progesterone for treating cancer, but the main problem is the continuing belief that "the cancer cell" is the problem, rather than the cancer field. Substances are tested for their ability to kill cancer cells in vitro, because of the basic belief that mutated genes are the cause of the disease. When progesterone is tested on cancer cells in vitro, the experimenter often sees nothing but the effects of the solvent, and doesn't realize that nearly all of the progesterone has precipitated in the medium, before reaching the cancer cells.

The cancer industry began a few years ago to combine chemicals for chemotherapy, for example adding caffeine to paclitaxel or platinum (cisplatin), or histamine to doxorubicin, but they do it simply to increase the toxicity of the chemical to the tumor, or to decrease its toxicity to the patient. Doctors sometimes refer to combined chemotherapy as a "shotgun approach," meaning that it lacks the acumen of their ideal silver bullet approach. If cancers were werewolves, the cancer industry's search for more refined killing technologies might be going in the right direction. But the genetic doctrine of cancer's origin is just as mythical as werewolves and vampires.

A safe physiological approach to cancer, based on the opposition of progesterone to estrogen, would be applicable to every type of cancer promoted by estrogen, or by factors which produce the same effects as estrogen, and that would include all of the known types of cancer. Estrogen acts even on cells that have no "estrogen receptors," but estrogen receptors can be found in every organ.

As estrogen's non-feminizing actions are increasingly being recognized to include contributions to other kinds of disease, including Alzheimer's disease, heart disease, and rheumatoid arthritis, the idea of the bystander effect, and the field of cellular degeneration, will eventually clear the way for a rational use of the therapeutic tools that already exist.

There are several types of drug---carbonic anhydrase inhibitors, to increase carbon dioxide in the tissues, lysergic acid derivatives, to block serotonin and suppress prolactin, anti-opiates, antiexcitotoxic and GABAergic agents, anesthetics, antihistamines, anticholinergics, salicylic acid derivatives---that could probably be useful in a comprehensive therapy for cancer, but their combinations won't be explored as long as treatments are designed only to kill.

Preventing or correcting disturbances in the morphogenetic field should be the focus of attention.

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Int J Cancer. 2004 Nov 1;112(2):312-8. Endogenous sex hormones and subsequent breast cancer in premenopausal women. Micheli A, Muti P, Secreto G, Krogh V, Meneghini E, Venturelli E, Sieri S, Pala V, Berrino F.

J Clin Endocrinol Metab 2000 Sep;85(9):3442-52. Progesterone withdrawal up-regulates vascular endothelial growth factor receptor type 2 in the superficial zone stroma of the human and macaque endometrium: potential relevance to menstruation. Nayak NR, Critchley HO, Slayden OD, Menrad A, Chwalisz K, Baird DT, Brenner RM.

Endocrinology 1981 Dec;109(6):2273-5. Progesterone-induced estrogen receptor-regulatory factor in hamster uterine nuclei: preliminary characterization in a cell-free system. Okulicz WC, MacDonald RG, Leavitt WW In vitro studies have demonstrated a progesterone-induced activity associated with the uterine nuclear fraction which resulted in the loss of nuclear estrogen receptor.

Mol Endocrinol. 1991 May;5(5):709-17. Progestins induce down-regulation of insulin-like growth factor-I (IGF-I) receptors in human breast cancer cells: potential autocrine role of IGF-II. Papa V, Hartmann KK, Rosenthal SM, Maddux BA, Siiteri PK, Goldfine ID.

Gynecol Endocrinol. 1999 Jun;13 Suppl 4:11-9. Biological effects of progestins in breast cancer. Pasqualini JR, Ebert C.

Gynecol Endocrinol. 2001 Dec;15 Suppl 6:44-52. Biological effects of progestins in breast cancer. Pasqualini JR, Ebert C, Chetrite GS.

J Steroid Biochem Mol Biol. 2005 Feb;93(2-5):221-36. Recent insight on the control of enzymes involved in estrogen formation and transformation in human breast cancer. Pasqualini JR, Chetrite GS.

Cancer Epidemiol Biomarkers Prev. 2002 Apr;11(4):361-8. Steroid hormone levels during pregnancy and incidence of maternal breast cancer. Peck JD, Hulka BS, Poole C, Savitz DA, Baird D, Richardson BE. "When estrogen-to-progesterone ratios were evaluated, there was an indication of a modest increased incidence of breast cancer for those with high total estrogens and high estrone levels relative to progesterone."

Br J Urol. 1990 Mar;65(3):268-70. Erythrocyte stearic to oleic acid ratio in prostatic carcinoma. Persad RA, Gillatt DA, Heinemann D, Habib NA, Smith PJ.

Int J Cancer. 2006 Nov 9; Inflammation and IGF-I activate the Akt pathway in breast cancer. Prueitt RL, Boersma BJ, Howe TM, Goodman JE, Thomas DD, Ying L, Pfiester CM, Yfantis HG, Cottrell JR, Lee DH, Remaley AT, Hofseth LJ, Wink DA, Ambs S.

Biology of reproduction 15, 153-157, 1976, Sex steroids in reproductive tract tissues: Regulation of estradiol concentrations by progesterone. Resko JA, Boling JL, Brenner RM and Blandau RJ.

Carla Rothenberg, History of hormone therapy, http:leda.law.harvard.edu/leda/data/711/Rothenberg05. pdf. 2005.

J Clin Endocrinol Metab 1996 Apr;81(4):1495-501. Characterization of reproductive hormonal dynamics in the perimenopause. Santoro N, Brown JR, Adel T, Skurnick JH. Overall mean estrone conjugate excretion was greater in the perimenopausal women compared to that in the younger women [76.9 ng/mg Cr (range, 13.1-135) vs. 40.7 ng/mg Cr (range, 22.8-60.3); P = 0.023] and was similarly elevated in both follicular and luteal phases. Luteal phase pregnanediol excretion was diminished in the perimenopausal women compared to that in younger normal subjects (range for integrated pregnanediol, 1.0-8.4 vs. 1.6-12.7 microg/mg Cr/luteal phase; P = 0.015). We conclude that altered ovarian function in the perimenopause can be observed as early as age 43 yr and include hyperestrogenism, hypergonadotropism, and decreased luteal phase progesterone excretion. These hormonal alterations may well be responsible for the increased gynecological morbidity that characterizes this period of life.

Cancer Res. 1984 Feb;44(2):841-4. High testosterone and low progesterone circulating levels in premenopausal patients with hyperplasia and cancer of the breast. Secreto G, Recchione C, Fariselli G, Di Pietro S.

Gen Comp Endocrinol. 1988 Dec;72(3):443-52. Progesterone down-regulation of nuclear estrogen receptor: a fundamental mechanism in birds and mammals. Selcer KW, Leavitt WW.

Clin Exp Obstet Gynecol 2000;27(1):54-6. Hormonal reproductive status of women at menopausal transition compared to that observed in a group of midreproductive-aged women. Sengos C, Iatrakis G, Andreakos C, Xygakis A, Papapetrou P. "CONCLUSION: The reproductive hormonal patterns in perimenopausal women favor a relatively hypergonadotropic hyper-estrogenic milieu."

J Natl Cancer Inst Monogr. 1994;(16):85-90. Menstrual timing of treatment for breast cancer. Senie RT, Kinne DW.

J Neurosci. 2001 Aug 1;21(15):5723-9. Progesterone blockade of estrogen activation of mu-opioid receptors regulates reproductive behavior. Sinchak K, Micevych PE.

J Clin Pathol. 2005 Oct;58(10):1033-8. Proliferating fibroblasts at the invading tumour edge of colorectal adenocarcinomas are associated with endogenous markers of hypoxia, acidity, and oxidative stress. Sivridis E, Giatromanolaki A, Koukourakis MI.

Neuroscience. 1991;42(2):309-20. Progesterone administration attenuates excitatory amino acid responses of cerebellar Purkinje cells. Smith SS.

Cancer Causes Control. 2004 Feb;15(1):45-53. Serum levels of sex hormones and breast cancer risk in premenopausal women: a case-control study (USA). Sturgeon SR, Potischman N, Malone KE, Dorgan JF, Daling J, Schairer C, Brinton LA. "For luteal progesterone, the RR for the highest versus lowest tertile was 0.55 (0.2-1.4)."

Biomed Pharmacother 1984;38(8):371-9. Breast cancer and oral contraceptives: critique of the proposition that high potency progestogen products confer excess risk. Sturtevant FM A recent report by Pike et al. from the U. S. A. concluded on the basis of epidemiologic evidence that an increased risk of breast cancer was manifested by young women who had used combination oral contraceptives (OC) with a high "potency" of progestogen over a prolonged period. This conclusion is criticized in the present article, centering on three cardinal defects in the Pike study: (1) The assigned potencies of OC's are fiction and were derived from out-dated delay-of-menses data; (2) Well-known risk factors for breast cancer were ignored; (3) The method assumed no error of recall of OC brand, dose and duration of use occurring many years before telephone interviews. Noting that others have not been able to confirm these findings, it is concluded that there is no scientific basis for accepting the suggestion of Pike et al.

Cancer Res. 2004 Nov 1;64(21):7886-92. Reduction of human metastatic breast cancer cell aggressiveness on introduction of either form a or B of the progesterone receptor and then treatment with progestins. Sumida T, Itahana Y, Hamakawa H, Desprez PY.

Endocr Relat Cancer 1999 Jun;6(2):307-14. Aromatase overexpression and breast hyperplasia, an in vivo model--continued overexpression of aromatase is sufficient to maintain hyperplasia without circulating estrogens, and aromatase inhibitors abrogate these preneoplastic changes in mammary glands. Tekmal RR, Kirma N, Gill K, Fowler K To test directly the role of breast-tissue estrogen in initiation of breast cancer, we have developed the aromatase-transgenic mouse model and demonstrated for the first time that increased mammary estrogens resulting from the overexpression of aromatase in mammary glands lead to the induction of various preneoplastic and neoplastic changes that are similar to early breast cancer. Our current studies show aromatase overexpression is sufficient to induce and maintain early preneoplastic and neoplastic changes in female mice without circulating ovarian estrogen. Preneoplastic and neoplastic changes induced in mammary glands as a result of aromatase overexpression can be completely abrogated with the administration of the aromatase inhibitor, letrozole. Consistent with complete reduction in hyperplasia, we have also seen downregulation of estrogen receptor and a decrease in cell proliferation markers, suggesting aromatase-induced hyperplasia can be treated with aromatase inhibitors. Our studies demonstrate that aromatase overexpression alone, without circulating estrogen, is responsible for the induction of breast hyperplasia and these changes can be abrogated using aromatase inhibitors.

Ann N Y Acad Sci 1986;464:106-16. Uptake and concentration of steroid hormones in mammary tissues. Thijssen JH, van Landeghem AA, Poortman J "For estradiol the highest tissue levels were found in the malignant samples. No differences were seen in these levels between pre- and postmenopausal women despite the largely different peripheral blood levels." "Striking differences were seen between the breast and uterine tissues for the total tissue concentration of estradiol, the ratio between estradiol and estrone, and the subcellular distribution of both estrogens. At similar receptor concentrations in the tissues these differences cannot easily be explained." "Lower concentrations of DHEAS and DHEA were observed in the malignant tissues compared with the normal ones and the benign lesions."

Cancer. 1983 Jun 1;51(11):2100-4. Elevated serum acute phase protein levels as predictors of disseminated breast cancer. Thompson DK, Haddow JE, Smith DE, Ritchie RF.

Crit Care Med. 2003 Nov;31(11):2705-7. Carbon dioxide: a "waste product" with potential therapeutic utilities in critical care. Torbati D.

J Steroid Biochem Mol Biol 2000 Jun;73(3-4):141-5. Elevated steroid sulfatase expression in breast cancers. Utsumi T, Yoshimura N, Takeuchi S, Maruta M, Maeda K, Harada N. In situ estrogen synthesis makes an important contribution to the high estrogen concentration found in breast cancer tissues. Steroid sulfatase which hydrolyzes several sulfated steroids such as estrone sulfate, dehydroepiandrosterone sulfate, and cholesterol sulfate may be involved. In the present study, we therefore, assessed steroid sulfatase mRNA levels in breast malignancies and background tissues from 38 patients by reverse transcription and polymerase chain reaction. The levels in breast cancer tissues were significantly increased at 1458.4+/-2119.7 attomoles/mg RNA (mean +/- SD) as compared with 535.6+/-663.4 attomoles/mg RNA for non-malignant tissues (P<0.001). Thus, increased steroid sulfatase expression may be partly responsible for local overproduction of estrogen and provide a growth advantage for tumor cells.

Fed Proc. 1980 Jun;39(8):2533-8. Influence of endogenous opiates on anterior pituitary function. Van Vugt DA, Meites J.

Clin Endocrinol (Oxf) 1978 Jul;9(1):59-66. Sex hormone concentrations in post-menopausal women. Vermeulen A, Verdonck L. Plasma sex hormone concentrations (testosterone, (T), androstenedione (A), oestrone (E1) and oestradiol (E2) were measured in forty post-menopausal women more than 4 years post-normal menopause. Sex hormone concentrations in this group of postmenopausal women (greater than 4YPM) did not show any variation as a function of age, with the possible exception of E2 which showed a tendency to decrease in the late post-menopause."

J Steroid Biochem 1984 Nov;21(5):607-12. The endogenous concentration of estradiol and estrone in normal human postmenopausal endometrium. Vermeulen-Meiners C, Jaszmann LJ, Haspels AA, Poortman J, Thijssen JH The endogenous estrone (E1) and estradiol (E2) levels (pg/g tissue) were measured in 54 postmenopausal, atrophic endometria and compared with the E1 and E2 levels in plasma (pg/ml). The results from the tissue levels of both steroids showed large variations and there was no significant correlation with their plasma levels. The mean E2 concentration in tissue was 420 pg/g, 50 times higher than in plasma and the E1 concentration of 270 pg/g was 9 times higher. The E2/E1 ratio in tissue of 1.6, was higher than the corresponding E2/E1 ratio in plasma, being 0.3. We conclude that normal postmenopausal atrophic endometria contain relatively high concentrations of estradiol and somewhat lower estrone levels. These tissue levels do not lead to histological effects.

J Natl Cancer Inst Monogr. 2000;(27):67-73. Endogenous estrogens as carcinogens through metabolic activation. Yager JD.

Regul Pept. 2003 Jul 15;114(2-3):101-7. Inhibition of cytosolic phospholipase A2 mRNA expression: a novel mechanism for acetylsalicylic acid-mediated growth inhibition and apoptosis in colon cancer cells. Yu HG, Huang JA, Yang YN, Luo HS, Yu JP, Meier JJ, Schrader H, Bastian A, Schmidt WE, Schmitz.

Brain Res. 1999 Aug 28;839(2):313-22. Opioid growth factor and organ development in rat and human embryos. Zagon IS, Wu Y, McLaughlin PJ.

J Biol Chem. 2005 Apr 29;280(17):17480-7. Epub 2005 Feb 22. A novel antiestrogenic mechanism in progesterone receptor-transfected breast cancer cells. Zheng ZY, Bay BH, Aw SE, Lin VC.

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A R T I C L E

Protective CO2 and aging

The therapeutic effects of increasing carbon dioxide are being more widely recognized in recent years. Even Jane Brody, the NY Times writer on health topics, has favorably mentioned the use of the Buteyko method for asthma, and the idea of permissive hypercapnia during mechanical ventilation, to prevent lung damage from excess oxygen, has been discussed in medical journals. But still very few biologists recognize its role as a fundamental, universal protective factor. I think it will be helpful to consider some of the ways carbon dioxide might be controlling situations that otherwise are poorly understood.

The brain has a high rate of oxidative metabolism, and so it forms a very large proportion of the carbon dioxide produced by an organism. It also governs, to a great extent, the metabolism of other tissues, including their consumption of oxygen and production of carbon dioxide or lactic acid. Within a particular species, the rate of oxygen consumption increases in proportion to brain size, rather than body weight. Between very different species, the role of the brain in metabolism is even more obvious, since the resting metabolic rate corresponds to the size of the brain. For example, a cat's brain is about the size of a crocodile's, and their oxygen consumption at rest is similar, despite their tremendous difference in body size.

Stress has to be understood as a process that develops in time, and the brain (especially the neocortex and the frontal lobes) organizes the adaptive and developmental processes in both the spatial and temporal dimensions. The meaning of a situation influences the way the organism responds. For example, the stress of being restrained for a long time can cause major gastrointestinal bleeding and ulcerization, but if the animal has the opportunity to bite something during the stress (signifying its ability to fight back, and the possibility of escape) it can avoid the stress ulcers.

The patterning of the nervous activity throughout the body governs the local ability to produce carbon dioxide. When the cortex of the brain is damaged or removed, an animal becomes rigid, so the cortex is considered to have a tonic inhibitory action on the body. But when the nerves are removed from a muscle (for example, by disease or accident), the muscle goes into a state of constant activity, and its ability to oxidize glucose and produce carbon dioxide is reduced, while its oxidation of fatty acids persists, increasing the production of toxic oxidative fragments of the fatty acids, which contributes to the muscle's atrophy.

The organism's intentions, expectations, or plans, are represented in the nervous system as a greater readiness for action, and in the organs and tissues controlled by the nerves, as an increase or decrease of oxidative efficiency, analogous to the differences between innervated and denervated muscles. This pattern in the nervous system has been called the acceptor of action, because it is continually being compared with the actual situation, and being refined as the situation is evaluated. The state of the organism, under the influence of a particular acceptor of action, is called a functional system, including all the components of the organism that participate most directly in realizing the intended adaptive action.

The actions of nerves can be considered anabolic, because during a stressful situation in which the catabolic hormones of adaption, e.g., cortisol, increase, the tissues of the functional system are protected, and while idle tissues may undergo autophagy or other form of involution, the needs of the active tissues are supplied with nutrients from their breakdown, allowing them to change and, when necessary, grow in size or complexity.

The brain's role in protecting against injury by stress, when it sees a course of action, has a parallel in the differences between concentric (positive, muscle shortening) and eccentric (negative, lengthening under tension) exercise, and also with the differences between innervated and denervated muscles. In eccentric exercise and denervation, less oxygen is used and less carbon dioxide is produced, while lactic acid increases, displacing carbon dioxide, and more fat is oxidized. Prolonged stress similarly decreases carbon dioxide and increases lactate, while increasing the use of fat.

Darkness is stressful and catabolic. For example, in aging people, the morning urine contains nearly all of the calcium lost during the 24 hour period, and mitochondria are especially sensitive to the destructive effects of darkness. Sleep reduces the destructive catabolic effects of darkness. During the rapid-eye-movement (dreaming) phase of sleep, breathing is inhibited, and the level of carbon dioxide in the tissues accumulates. In restful sleep, the oxygen tension is frequently low enough, and the carbon dioxide tension high enough, to trigger the multiplication of stem cells and mitochondria.

Dreams represent the acceptor of action operating independently of the sensory information that it normally interacts with. During dreams, the brain (using a system called the Ascending Reticular Activating System) disconnects itself from the sensory systems. I think this is the nervous equivalent of concentric/positive muscle activity, in the sense that the brain is in control of its actions. The active, dreaming phase of sleep occurs more frequently in the later part of the night, as morning approaches. This is the more stressful part of the night, with cortisol and some other stress hormones reaching a peak at dawn, so it would be reasonable for the brain's defensive processes to be most active at that time. The dreaming process in the brain is associated with deep muscle relaxation, which is probably associated with the trophic (restorative) actions of the nerves.

In ancient China the Taoists were concerned with longevity, and according to Joseph Needham (Science and Civilization in China) their methods included the use of herbs, minerals, and steroids extracted from the urine of children. Some of those who claimed extreme longevity practiced controlled breathing and tai chi (involving imagery, movement, and breating), typically in the early morning hours, when stress reduction is most important. As far as I know, there are no studies of carbon dioxide levels in practitioners of tai chi, but the sensation of warmth they typically report suggests that it involves hypoventilation.

In the 1960s, a Russian researcher examined hospital records of measurements of newborn babies, and found that for several decades the size of their heads had been increasing. He suggested that it might be the result of increasing atmospheric carbon dioxide.

The experiences and nutrition of a pregnant animal are known to affect the expression of genes in the offspring, affecting such things as allergies, metabolic rate, brain size, and intelligence. Miles Storfer (1999) has reviewed the evidence for epigenetic environmental control of brain size and intelligence. The main mechanisms of epigenetic effects or imprinting are now known to involve methylation and acetylation of the chromosomes (DNA and histones).

Certain kinds of behavior, as well as nutrition and other environmental factors, increase the production and retention of carbon dioxide. The normal intrauterine level of carbon dioxide is high, and it can be increased or decreased by changes in the mother's physiology. The effects of carbon dioxide on many biological processes involving methylation and acetylation of the genetic material suggest that the concentration of carbon dioxide during gestation might regulate the degree to which parental imprinting will persist in the developing fetus. There is some evidence of increased demethylation associated with the low level of oxygen in the uterus (Wellman, et al., 2008). A high metabolic rate and production of carbon dioxide would increase the adaptability of the new organism, by decreasing the limiting genetic imprints.

A quick reduction of carbon dioxide caused by hyperventilation can provoke an epileptic seizure, and can increase muscle spasms and vascular leakiness, and (by releasing serotonin and histamine) contribute to inflammation and clotting disorders. On a slightly longer time scale, a reduction of carbon dioxide can increase the production of lactic acid, which is a promoter of inflammation and fibrosis. A prolonged decrease in carbon dioxide can increase the susceptibility of proteins to glycation (the addition of aldehydes, from polyunsaturated fat peroxidation or methylglyoxal from lactate metabolism, to amino groups), and a similar process is likely to contribute to the methylation of histones, a process that increases with aging. Histones regulate genetic activity.

With aging, DNA methylation is increased (Bork, et al., 2009). I suggest that methylation stabilizes and protects cells when growth and regeneration aren't possible (and that it's likely to increase when CO2 isn't available). Hibernation (Morin and Storey, 2009) and sporulation (Ruiz-Herrera, 1994; Clancy, et al., 2002) appear to use methylation protectively.

Parental stress, prenatal stress, early life stress, and even stress in adulthood contribute to imprinting of the genes, partly through methylation of DNA and the histones.

Methionine and choline are the main dietary sources of methyl donors. Restriction of methionine has many protective effects, including increased average (42%) and maximum (44%) longevity in rats (Richie, et al., 1994). Restriction of methyl donors causes demethylation of DNA (Epner, 2001). The age accelerating effect of methionine might be related to disturbing the methylation balance, inappropriately suppressing cellular activity. Besides its effect on the methyl pool, methionine inhibits thyroid function and damages mitochondria.

The local concentration of carbon dioxide in specific tissues and organs can be adjusted by nervous and hormonal activation or inhibition of the carbonic anhydrase enzymes, that accelerate the oonversion of CO2 to carbonic acid, H2CO3. The activity of carbonic anhydrase can determine the density and strength of the skeleton, the excitability of nerves, the accumulation of water, and can regulate the structure and function of the tissues and organs.

Ordinarily, carbon dioxide and bicarbonate are thought of only in relation to the regulation of pH, and only in a very general way. Because of the importance of keeping the pH of the blood within a narrow range, carbon dioxide is commonly thought of as a toxin, because an excess can cause unconsciousness and acidosis. But increasing carbon dioxide doesn't necessarily cause acidosis, and acidosis caused by carbon dioxide isn't as harmful as lactic acidosis.

Frogs and toads, being amphibians, are especially dependent on water, and in deserts or areas with a dry season they can survive a prolonged dry period by burrowing into mud or sand. Since they may be buried 10 or 11 inches below the surface, they are rarely found, and so haven't been extensively studied. In species that live in the California desert, they have been known to survive 5 years of burial without rainfall, despite a moderately warm average temperature of their surroundings. One of their known adaptations is to produce a high level of urea, allowing them to osmotically absorb and retain water. (Very old people sometimes have extremely high urea and osmotic tension.)

Some laboratory studies show that as a toad burrows into mud, the amount of carbon dioxide in its tissues increases. Their skin normally functions like a lung, exchanging oxygen for carbon dioxide. If the toad's nostrils are at the surface of the mud, as dormancy begins its breathing will gradually slow, increasing the carbon dioxide even more. Despite the increasing carbon dioxide, the pH is kept stable by an increase of bicarbonate (Boutilier, et al., 1979). A similar increase of bicarbonate has been observed in hibernating hamsters and doormice.

Thinking about the long dormancy of frogs reminded me of a newspaper story I read in the 1950s. Workers breaking up an old concrete structure found a dormant toad enclosed in the concrete, and it revived soon after being released. The concrete had been poured decades earlier.

Although systematic study of frogs or toads during their natural buried estivation has been very limited, there have been many reports of accidental discoveries that suggest that the dormant state might be extended indefinitely if conditions are favorable. Carbon dioxide has antioxidant effects, and many other stabilizing actions, including protection against hypoxia and the excitatory effects of intracellular calcium and inflammation (Baev, et al., 1978, 1995; Bari, et al., 1996; Brzecka, 2007; Kogan, et al., 1994; Malyshev, et al., 1995).

When mitochondria are uncoupled, they produce more carbon dioxide than normal, and the mitochondria produce fewer free radicals. Animals with uncoupled mitochondria live longer than animals with the ordinary, more efficient mitochondria, that produce more reactive oxidative fragments. One effect of the high rate of oxidation of the uncoupled mitochondria is that they can eliminate polyunsatured fatty acids that might otherwise be integrated into tissue structures, or function as inappropriate regulatory signals.

Birds have a higher metabolic rate than mammals of the same size, and live longer. Their tissues contain fewer of the highly unsaturated fatty acids. Queen bees, which live many times longer than worker bees, have mainly monounsaturated fats in their tissues, while the tissues of the short-lived worker bees, receiving a different diet, within a couple of weeks of hatching will contain highly unsaturated fats.

Bats have a very high metabolic rate, and an extremely long lifespan for an animal of their size. While most animals of their small size live only a few years, many bats live a few decades. Bat caves usually have slightly more carbon dioxide than the outside atmosphere, but they usually contain a large amount of ammonia, and bats maintain a high serum level of carbon dioxide, which protects them from the otherwise toxic effects of the ammonia.

The naked mole rat, another small animal with an extremely long lifespan (in captivity they have lived up to 30 years, 9 or 10 times longer than mice of the same size) has a low basal metabolic rate, but I think measurements made in laboratories might not represent their metabolic rate in their natural habitat. They live in burrows that are kept closed, so the percentage of oxygen is lower than in the outside air, and the percentage of carbon dioxide ranges from 0.2% to 5% (atmospheric CO2 is about 0.038). The temperature and humidity in their burrows can be extremely high, and to be very meaningful their metabolic rate would have to be measured when their body temperature is raised by the heat in the burrow.

When they have been studied in Europe and the US, there has been no investigation of the effect of altitude on their metabolism, and these animals are native to the high plains of Kenya and Ethiopia, where the low atmospheric pressure would be likely to increase the level of carbon dioxide in their tissues. Consequently, I doubt that the longevity seen in laboratory situations accurately reflects the longevity of the animals in their normal habitat.

Besides living in a closed space with a high carbon dioxide content, mole rats have another similarity to bees. In each colony, there is only one female that reproduces, the queen, and, like a queen bee, she is the largest individual in the colony. In beehives, the workers carefully regulate the carbon dioxide concentration, which varies from about 0.2% to 6%, similar to that of the mole rat colony. A high carbon dioxide content activates the ovaries of a queen bee, increasing her fertility.

Since queen bees and mole rats live in the dark, I think their high carbon dioxide compensates for the lack of light. (Both light and CO2 help to maintain oxidative metabolism and inhibit lactic acid formation.) Mole rats are believed to sleep very little. During the night, normal people tolerate more CO2, and so breathe less, especially near morning, with increased active dreaming sleep.

A mole rat has never been known to develop cancer. Their serum C-reactive protein is extremely low, indicating that they are resistant to inflammation. In humans and other animals that are susceptible to cancer, one of the genes that is likely to be silenced by stress, aging, and methylation is p53, a tumor-suppressor gene.

If the intrauterine experience, with low oxygen and high carbon dioxide, serves to reprogram cells to remove the accumulated effects of age and stress, and so to maximize the developmental potential of the new organism, a life that's lived with nearly those levels of oxygen and carbon dioxide might be able to avoid the progressive silencing of genes and loss of function that cause aging and degenerative diseases.

Several diseases and syndromes are now thought to involve abnormal methylation of genes. Prader-Willi sydrome, Angelman's syndrome, and various autistic spectrum disorders, as well as post-traumatic stress disorder and several kinds of cancer seem to involve excess methylation.

Moderate methionine restriction (for example, using gelatin regularly in the diet) might be practical, but if increased carbon dioxide can activate the demethylase enzymes in a controlled way, it might be a useful treatment for the degenerative diseases and for aging itself.

The low carbon dioxide production of hypothyroidism (e.g., Lee and Levine, 1999), and the respiratory alkalosis of estrogen excess, are often overlooked. An adequate supply of calcium, and sometimes supplementation of salt and baking soda, can increase the tissue content of CO2.

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Endocr Pract. 2009 Jun 2:1-13. Fibrotic Appearance of Lungs in Severe Hypothyroidism is Reversible with Thyroxine Replacement. George JT, Thow JC, Rodger KA, Mannion R, Jayagopal V.

J Bioenerg Biomembr. 2009 Jun;41(3):309-21. Epub 2009 Jul 25. Effect of methionine dietary supplementation on mitochondrial oxygen radical generation and oxidative DNA damage in rat liver and heart. Gomez J, Caro P, Sanchez I, Naudi A, Jove M, Portero-Otin M, Lopez-Torres M, Pamplona R, Barja G.

Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7612-7. Increased tricarboxylic acid cycle flux in rat brain during forepaw stimulation detected with 1H[13C]NMR. Hyder F, Chase JR, Behar KL, Mason GF, Siddeek M, Rothman DL, Shulman RG.

Can J Neurol Sci. 1979 May;6(2):105-12. The effects of partial chronic denervation on forearm metabolism. Karpati G, Klassen G, Tanser P.

Biull Eksp Biol Med. 1994 Oct;118(10):395-8. [CO2--a natural inhibitor of active oxygen form generation by phagocytes] Kogan AKh, Manuilov BM, Grachev SV, Bolevich S, Tsypin AB, Daniliak IG.

Izv Akad Nauk Ser Biol. 1997 Mar-Apr;(2):204-17. [Carbon dioxide--a universal inhibitor of the generation of active oxygen forms by cells (deciphering one enigma of evolution)] Kogan AKh, Grachev SV, Eliseeva SV, Bolevich S.

Vopr Med Khim. 1996 Jul-Sep;42(3):193-202. [Ability of carbon dioxide to inhibit generation of superoxide anion radical in cells and its biomedical role] Kogan AKh, Grachev SV, Eliseeva SV, Bolevich S.

Dokl Akad Nauk. 1996 May;348(3):413-6. [New evidence for the inhibitory action of CO2 on generation of superoxide anion radicals by phagocytes in various tissues. (Mechanism of bio- and eco-effects of CO2)] Kogan AKh, Grachev SV, Bolevich S, Eliseeva SV.

Biull Eksp Biol Med. 1996 Apr;121(4):407-10. [Carbon dioxide gas inhibition of active forms of oxygen generation by cells in the internal organs and its biological significance] Kogan AKh, Grachev SV, Eliseeva SV.

Fiziol Cheloveka. 1995 Jul-Aug;21(4):128-36. [CO2--a natural inhibitor of the generation of active species of oxygen in phagocytes] Kogan AKh, Manuilov BM, Grachev SV, Bolevich S, Tsypin AB, Daniliak IG.

Patol Fiziol Eksp Ter. 1995 Jul-Sep;(3):34-40. [Comparative study of the effect of carbon dioxide on the generation of active forms of oxygen by leukocytes in health and in bronchial asthma] Kogan AKh, Bolevich S, Daniliak IG.

Can J Anaesth. 1999 Feb;46(2):185-9. Acute respiratory alkalosis associated with low minute ventilation in a patient with severe hypothyroidism. Lee HT, Levine M. Tl128@columbia.edu PURPOSE: Patients with severe hypothyroidism present unique challenges to anesthesiologists and demonstrate much increased perioperative risks. Overall, they display increased sensitivity to anesthetics, higher incidence of perioperative cardiovascular morbidity, increased risks for postoperative ventilatory failure and other physiological derangements. The previously described physiological basis for the increased incidence of postoperative ventilatory failure in hypothyroid patients includes decreased central and peripheral ventilatory responses to hypercarbia and hypoxia, muscle weakness, depressed central respiratory drive, and resultant alveolar hypoventilation. These ventilatory failures are associated most frequently with severe hypoxia and carbon dioxide (CO2) retention. The purpose of this clinical report is to discuss an interesting and unique anesthetic presentation of a patient with severe hypothyroidism. CLINICAL FEATURES: We describe an unique presentation of ventilatory failure in a 58 yr old man with severe hypothyroidism. He had exceedingly low perioperative respiratory rate (3-4 bpm) and minute ventilation volume, and at the same time developed primary acute respiratory alkalosis and associated hypocarbia (P(ET)CO2 approximately 320-22 mmHg). CONCLUSION: Our patient's ventilatory failure was based on unacceptably low minute ventilation and respiratory rate that was unable to sustain adequate oxygenation. His profoundly lowered basal metabolic rate and decreased CO2 production, resulting probably from severe hypothyroidism, may have resulted in development of acute respiratory alkalosis in spite of concurrently diminished minute ventilation.

Anal Bioanal Chem. 2008 Jan;390(2):679-88. Epub 2007 Oct 27. The structural modification of DNA nucleosides by nonenzymatic glycation: an in vitro study based on the reactions of glyoxal and methylglyoxal with 2'-deoxyguanosine. Li Y, Cohenford MA, Dutta U, Dain JA.

Biull Eksp Biol Med. 1995 Jun;119(6):590-3. [Adaptation to high altitude hypoxia facilitates a limitation of lipid peroxidation activation in inflammation and stress] [Article in Russian] Malyshev VV, Vasil'eva LS, Belogorov SB, Nefedova TV.

Am J Physiol Regul Integr Comp Physiol. 2007 Sep;293(3):R1159-68. Epub 2007 Jun 20. Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS production. Muller FL, Song W, Jang YC, Liu Y, Sabia M, Richardson A, Van Remmen H.

Radiobiologiia. 1984 Jan-Feb;24(1):29-34. [Enzyme activity of glutamic acid metabolism and the Krebs cycle in the brain of rats laser-irradiated against a background of altered adrenoreceptor function] [Article in Russian] Pikulev AT, Dzhugurian NA, Zyrianova TN, Lavrova VM, Mostovnikov VA.

Rejuvenation Res.2007 Dec12; :18072884, Exploring Overlooked Natural Mitochondria-Rejuvenative Intervention: The Puzzle of Bowhead Whales and Naked Mole Rats. Prokopov A.F.

Proceedings of the Japan Academy. Ser. B: Physical and Biological Sciences Vol.78, No.10(2002)pp.293-298. DNA methylation and Lamarckian inheritance, Sano H.

Biol Chem. 2009 Nov;390(11):1145-53. The epigenetic bottleneck of neurodegenerative and psychiatric diseases. Sananbenesi F, Fischer A. The orchestrated expression of genes is essential for the development and survival of every organism. In addition to the role of transcription factors, the availability of genes for transcription is controlled by a series of proteins that regulate epigenetic chromatin remodeling. The two most studied epigenetic phenomena are DNA methylation and histone-tail modifications. Although a large body of literature implicates the deregulation of histone acetylation and DNA methylation with the pathogenesis of cancer, recently epigenetic mechanisms have also gained much attention in the neuroscientific community. In fact, a new field of research is rapidly emerging and there is now accumulating evidence that the molecular machinery that regulates histone acetylation and DNA methylation is intimately involved in synaptic plasticity and is essential for learning and memory. Importantly, dysfunction of epigenetic gene expression in the brain might be involved in neurodegenerative and psychiatric diseases. In particular, it was found that inhibition of histone deacetylases attenuates synaptic and neuronal loss in animal models for various neurodegenerative diseases and improves cognitive function. In this article, we will summarize recent data in the novel field of neuroepigenetics and discuss the question why epigenetic strategies are suitable therapeutic approaches for the treatment of brain diseases.

Ukr Biokhim Zh 1994 Jan-Feb;66(1):109-12. [Protective effect of sodium bicarbonate in nitrite ion poisoning]. Shugalei IV, L'vov SN, Baev VI, Tselinskii IV

Am J Respir Crit Care Med. 2000 Mar;161(3 Pt 1):891-8. Modulation of release of reactive oxygen species by the contracting diaphragm. Stofan DA, Callahan LA, DiMarco AF, Nethery DE, Supinski GS.

Ecology: Vol. 50, No. 3, pp. 492-494. Carbon Dioxide Retention: A Mechanism of Ammonia Tolerance in Mammals. Studier EM and Fresquez AA.

Sci Signal. 2009 Mar 31;2(64): pe17. Reversing DNA methylation: new insights from neuronal activity-induced Gadd45b in adult neurogenesis. Wu H, Sun YE. Neurogenesis in the adult mammalian brain involves activity-dependent expression of genes critical for the proliferation of progenitors and for neuronal maturation. A recent study suggests that the stress response gene Gadd45b (growth arrest and DNA-damage-inducible protein 45 beta) can be transiently induced by neuronal activity and may promote adult neurogenesis through dynamic DNA demethylation of specific gene promoters in adult hippocampus. These results provide evidence supporting the provocative ideas that active DNA demethylation may occur in postmitotic neurons and that DNA methylation-mediated dynamic epigenetic regulation is involved in regulating long-lasting changes in neural plasticity in mammalian brains.

Patol Fiziol Eksp Ter. 2005 Apr-Jun;(2):13-5. [The effect of the NMDA-receptor blocker MK-801 on sensitivity of the respiratory system to carbon dioxide] Tarakanov IA, Dymetska A, Tarasova NN.

Life Sci. 1997;61(5):523-35. Effect of acidotic challenges on local depolarizations evoked by N-methyl-D-aspartate in the rat striatum. Urenjak J, Zilkha E, Gotoh M, Obrenovitch TP. Hypercapnia reduced NMDA-evoked responses in a concentration-dependent manner, with 7.5 and 15 % CO2 in the breathing mixture reducing the depolarization amplitude to 74 % and 64 % of that of the initial stimuli, respectively. Application of 50 mM NH4+ progressively reduced dialysate pH, and a further acidification was observed when NH4+ was discontinued. Perfusion of NMDA after NH4+ application evoked smaller depolarizations (56 % of the corresponding control, 5 min after NH4+ removal), and this effect persisted for over 1 h. Together, these results demonstrate that extracellular acidosis, such as that associated with excessive neuronal activation or ischemia, inhibits NMDA-evoked responses in vivo.

Arch Int Physiol Biochim. 1977 Apr;85(2):295-304. Glutamate and glutamine in the brain of the neonatal rat during hypercapnia. Van Leuven F, Weyne J, Leusen I.

Pediatrics 1995 Jun;95(6):868-874. Carbon dioxide protects the perinatal brain from hypoxic-ischemic damage: an experimental study in the immature rat. Vannucci RC, Towfighi J, Heitjan DF, Brucklacher RM

Pediatr Res 1997 Jul;42(1):24-29. Effect of carbon dioxide on cerebral metabolism during hypoxia-ischemia in the immature rat. Vannucci RC, Brucklacher RM, Vannucci SJ

Sci. Signal., 31 March 2009 Vol. 2, Issue 64, p. pe17, Reversing DNA Methylation: New Insights from Neuronal Activity-Induced Gadd45b in Adult Neurogenesis Wu H, Sun YI

Copyright 2011. Raymond Peat, P.O. Box 5764, Eugene OR 97405. All Rights Reserved. www.RayPeat.com
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<span class="koboSpan" id="kobo.1.1">RU486, cancer, estrogen, and progesterone.</span> A R T I C L E

RU486, Cancer, Estrogen, and Progesterone.

Recently many people have been disturbed by reading claims that progesterone can cause cancer, or diabetes, or autoimmune diseases, or heart disease, or Alzheimer's disease. A flurry of press conferences, and a few groups of "molecular biologists" working on "progesterone receptors," and the results of studies in which Prempro (containing a synthetic "progestin") increased breast cancer, have created great confusion and concern, at least in the English speaking countries.

Wyeth, the manufacturer of Prempro, has been highly motivated to recover their sales and profits that declined about 70% in the first two years after the Women's Health Initiative announced its results. When billions of dollars in profits are involved, clever public relations can achieve marvelous things.

Women and other mammals that are deficient in progesterone, and/or that have an excess of estrogen, have a higher than average incidence of cancer. Animal experiments have shown that administering progesterone could prevent cancer. Cells in the most cancer-susceptible tissues proliferate in proportion to the ratio of estrogen to progesterone. When the estrogen dominance persists for a long time without interruption, there are progressive distortions in the structure of the responsive organs--the uterus, breast, pituitary, lung, liver, kidney, brain, and other organs--and those structural distortions tend to progress gradually from fibroses to cancer.

As a result of the early studies in both humans and animals, progesterone was used by many physicians to treat the types of cancer that were clearly caused by estrogen, especially uterine, breast, and kidney cancers. But by the 1950s, the drug industry had created the myth that their patented synthetic analogs of progesterone were medically more effective than progesterone itself, and the result has been that medroxyprogesterone acetate and other synthetics have been widely used to treat women's cancers, including breast cancer.

Unfortunately, those synthetic compounds have a variety of functions unlike progesterone, including some estrogenic and/or androgenic and/or glucocorticoid and/or antiprogesterone functions, besides other special, idiosyncratic side effects. The rationale for their use was that they were "like progesterone, only better." The unpleasant and unwanted truth is that, as a group, they are seriously carcinogenic, besides being toxic in a variety of other ways. Thousands of researchers have drawn conclusions about the effects of progesterone on the basis of their experiments with a synthetic progestin.

The earliest studies of estrogen and progesterone in the 1930s had the great advantage of a scientific culture that was relatively unpolluted by the pharmaceutical industry. As described by Carla Rothenberg, the massive manipulation of the medical, regulatory, and scientific culture by the estrogen industry began in 1941. After that, the role of metaphysics, word magic, and epicycle-like models increasingly replaced empirical science in endocrinology and cell physiology.

As the estrogen industry began losing billions of dollars a year following the 2002 report from the Women's Health Initiative regarding estrogen's toxicity, and as it was noticed that progesterone sales had increased more than 100-fold, it was clear what had to be done--the toxic effects of estrogen had to be transferred to progesterone. For more than 50 years, progesterone was recognized to be antimitotic and anti-inflammatory and anticarcinogenic, but suddenly it has become a mitogenic pro-inflammatory carcinogen.

Science used to involve confirmation or refutation of published results and conclusions. A different experimenter, using the technique described in a publication, would often get a different result, and a dialog or disputation would develop, sometimes continuing for years, before consensus was achieved, though many times there would be no clear conclusion or consensus.

In that traditional scientific environment, it was customary to recognize that a certain position remained hypothetical and controversial until some new technique or insight settled the question with some degree of clarity and decisiveness. People who cherry-picked studies to support their position, while ignoring contradictory evidence, were violating the basic scientific principles of tentativeness and reasonableness. Contradictory, as well as confirmatory, data have to be considered.

But when a single experiment involves several people working for a year or more, at a cost of a million or more dollars, who is going to finance an experiment that "would merely confirm" those results? The newly developed techniques for identifying specific molecules are often very elaborate and expensive, and as a result only a few kinds of molecule are usually investigated in each experiment. The results are open to various interpretations, and most of those interpretations depend on results from other studies, whose techniques, results, and conclusions have never been challenged, either. There is no significant source of funding to challenge the programs of the pharmaceutical industry.

The result is that the pronouncements of the principal investigator, and the repetitions of those conclusions in the mass media, create a culture of opinion, without the foundation of multiple confirmations that used to be part of the scientific process. The process has taken on many of the features of a cult, in which received opinions are repeatedly reinforced by the investment of money and authority. Newspaper reporters know that the team of investigators spent two years on their project, and the lead investigator wears a white lab coat during the interview, so the reporters don't notice that the investigators' conclusion is a non sequitur, supported by chains of non sequiturs.

The public gets most of its information about science from the mass media, and the increasingly concentrated ownership of the media contributes to the use of scientific news as an adjunct to their main business, advertising and product promotion. The pharmaceutical industry spends billions of dollars annually on direct-to-consumer advertising, so the big scientific news, for the media, is likely to be anything that will increase their advertising revenue.

Social-economic cults often simplify the thought processes required by the participants, by inventing a scapegoat. The estrogen cult has decided that progesterone will be its scapegoat.

Hans Selye argued that steroid hormones should be named by their origin, or by their chemical structural names, rather than their effects, because each hormone has innumerable effects. To name a substance according to its effects is to predict and to foreordain the discoveries that will be made regarding its effects.

The common system of hormonal names according to their putative effects has allowed ideology and metaphysical ideas to dominate endocrinology. The worst example of metaphysical medicine was the use, for more than 50 years, of "estrogen, the female hormone" to treat prostate cancer, in the belief that "male hormones" cause the cancer, and that the female hormone would negate it. This word magic led to a vast psychotic medical endeavor, that has only recently been reconsidered.

Within the scheme of hormones understood according to their names, "hormone receptors" were proposed to be the mechanism by which hormones produced their effects. Each hormone had a receptor. If another substance bound more strongly than the hormone to its receptor, without producing the effects of the hormone, it was called an antihormone.

The industry of synthetic hormones used the ideology of unitary hormonal action to identify new substances as pharmaceutical hormones, that were always in some way said to be better than the natural hormones--for example by being "orally active," unlike natural hormones, supposedly. Physicians docilely went along with whatever the drug salesmen told them. If a drug was classified as a "progestin" by a single reaction in one animal tissue, then it had a metaphysical identity with the natural hormone, except that it was better, and patentable.

The natural hormones eventually were assigned any of the toxic properties that were observed for the pharmaceutical products "in their class." If synthetic progestins caused heart disease, birth defects, and cancer, then the "natural progestin" was assumed to do that, too. It's important to realize the impact of logical fallacies on the medical culture.

Like the hormones themselves, which metaphysically supposedly acted upon one receptor, to activate one gene (or set of genes), the antihormones came to be stereotyped. If a particular hormonal action was blocked by a chemical, then that substance became an antagonistic antihormone, and when its administration produced an effect, that effect was taken to be the result of blocking the hormone for which it was "the antagonist."

The "antiprogesterone" molecule, RU486, besides having some progesterone-like and antiestrogenic properties, also has (according to Hackenberg, et al., 1996). some androgenic, antiandrogenic, and antiglucocorticoid properties. Experiments in which it is used might have pharmaceutical meaning, but they so far have very little clear biological meaning.

Adding to the conceptual sloppiness of the "molecular biology" wing of endocrinology, the culture in which pharmaceutical products had come to dominate medical ideas about hormones allowed the conventional pharmaceutical vehicles to be disregarded in most experiments, both in vitro and in vivo. If progesterone was injected into patients mixed with sesame oil and benzyl alcohol, then it often didn't occur to animal experimenters to give control injections of the solvent. For in vitro studies, in a watery medium, oil wouldn't do, so they would use an alcohol solvent, and again often forgot to do a solvent control experiment.

The importance of the solvent was seen by an experimenter studying the effect of vitamin E on age pigment in nerves. It occurred to that experimenter to test the ethyl alcohol alone, and he found that it produced almost the same effect as that produced by the solution of alcohol and vitamin E. Workers with hormones often just assume that a little alcohol wouldn't affect their system. But when the effects of alcohol by itself have been studied, many of the effects produced by very low concentrations happen to be the same effects that have been ascribed to hormones, such as progesterone.

In some cases, the solvent allows the hormone to crystallize, especially if the solvent is water-miscible, and fails to distribute it evenly through the medium and cells as the experimenter assumed would happen, and so the experimenter reports that the hormone is not effective in that kind of cell, even though the hormone didn't reach the cells in the amount intended.

These are four of the common sources of error about progesterone: (1) Saying that progesterone has produced an effect which was produced by a different substance. (2) Saying that progesterone is the cause of a certain effect, if an "anti-progesterone" chemical prevents that effect. (3) Saying that progesterone caused something, when in fact the solvent caused it. And (4) saying that progesterone fails to do something, when progesterone hasn't been delivered to the system being studied.

Many years ago, experimenters who wanted to minimize the problems involved in administering progesterone in toxic solvents found that, with careful effort, progesterone could be transferred to a protein, such as albumin, and that the albumin-progesterone complex could be washed to remove the solvent. In this form, the progesterone can be delivered to cells in a form that isn't radically different from the form in which it naturally circulates in the body. Apparently, the labor involved discourages the widespread use of this technique.

Although the industry's early generalizations about estrogen and progesterone, defining them as "the female hormone" and "the pregnancy hormone," were radically mistaken, some useful generalizations about their effects were gradually being built up during the first few decades in which their chemical and physiological properties were studied.

Estrogen's name, derived from the gadfly, accurately suggests its role as an excitant, getting things started. Progesterone's name, relating to pregnancy, is compatible with thinking of it as an agent of calming and fulfillment. But these properties show up in every aspect of physiology, and the special cases of female estrus and pregnancy can be properly understood only in the larger context, in which, for example, progesterone is a brain hormone in both sexes and at all ages, and estrogen is an essential male hormone involved in the sperm cell's function and male libido.

Progesterone can, without estrogen, create the uterine conditions for implantation of an embryo (Piccini, 2005, progesterone induces LIF; Sherwin, et al., 2004, LIF can substitute for estrogen), and it has many other features that can be considered apart from estrogen, such as its regulation of salts, energy metabolism, protein metabolism, immunity, stress, and inflammation, but without understanding its opposition to estrogen, there will be no coherent understanding of progesterone's biological meaning.

Both estrogen and progesterone are hydrophobic molecules (progesterone much more so than estrogen) which bind with some affinity to many components of cells. Certain proteins that strongly bind the hormones are called their receptors.

Cells respond to stimulation by estrogen by producing a variety of molecules, including the "progesterone receptor" protein. When progesterone enters the cell, binding to these proteins, the estrogenic stimulation is halted, by a series of reactions in which the estrogen receptors disintegrate, and in which estrogen is made water soluble by the activation of enzymes that attach sulfate or a sugar acid, causing it leave the cell and move into the bloodstream, and by reactions that prevent its reentry into the cell by inactivating another type of enzyme, and that suppress its de novo formation in the cell, and that oxidize it into a less active form. Progesterone terminates estrogen's cellular functions with extreme thoroughness.

A recent publication in Science ("Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist," Poole, et al., Dec. 1, 2006), with associated press conferences, reported an experiment in which a special kind of mouse was prepared, which lacked two tumor-suppressing genes called BRCA and p53.

One of the functions of the BRCA gene product is to repair genetic damage, and another function is to (like progesterone) suppress the estrogen receptor and its functions. Estrogen, and some environmental carcinogens, can suppress the BRCA gene product. Estrogen can also turn off the tumor suppressor protein, p53. So it is interesting that a group of experimenters chose to produce a mouse that lacked both the normal BRCA and p53 genes. They had a mouse that was designed to unleash estrogen's effects, and that modeled some of the features of estrogen toxicity and progesterone deficiency.

This mouse, lacking an essential gene that would allow progesterone to function normally, probably affecting progesterone's ability to eliminate the estrogen receptor, also lacked the tumor suppressor gene p53, which is required for luteinization (Cherian-Shaw 2004); in its absence, progesterone synthesis is decreased, estrogen synthesis is increased.

(Chen, Y, et al., 1999: BRCA represses the actions of estrogen and its receptor, and, like progesterone, activates the p21 promoter, which inhibits cell proliferation. Aspirin and vitamin D also act through p21.)

The mutant BRCA gene prevents the cell, even in the presence of progesterone, from turning off estrogen's effects the way it should. The antiestrogenic RU486 (some articles below), which has some of progesterone's effects (including therapeutic actions against endometrial and breast cancer), appears to overcome some of the effects of that mutation.

It might have been proper to describe the engineered mouse that lacked both the BRCA and the p53 genes as a mouse in which the effects of estrogen excess and progesterone deficiency would be especially pronounced and deadly. To speak of progesterone as contributing to the development of cancer in that specially designed mouse goes far beyond bad science. However, that study makes sense if it is seen as preparation for the promotion of a new drug similar in effect to RU486, to prevent breast cancer.

The study's lead author, Eva Lee, quoted by a university publicist, said "We found that progesterone plays a role in the development of breast cancer by encouraging the proliferation of mammary cells that carry a breast cancer gene." But they didn't measure the amount of progesterone present in the animals. They didn't "find" anything at all about progesterone. The "anti-progesterone" drug they used has been used for many years to treat uterine, ovarian, and breast cancers, in some cases with progesterone, to intensify its effects, and its protective effects are very likely the result of its antiestrogenic and anti-cortisol effects, both of which are well established, and relevant. In some cases, it acts like progesterone, only more strongly.

"Other more specific progesterone blockers are under development," Lee notes. And the article in Science magazine looks like nothing more than the first advertisement for one that her husband, Wen-Hwa Lee, has designed.

According to publicists at the University of California, Irvine, "Lee plans to focus his research on developing new compounds that will disrupt end-stage cancer cells. The goal is a small molecule that, when injected into the blood stream, will act as something of a biological cruise missile to target, shock and awe the cancerous cells." "In this research, he will make valuable use of a breast cancer model developed by his wife." "She developed the model, and I will develop the molecule," Lee says. "We can use this model to test a new drug and how it works in combination with old drugs."

"Previously we blamed everything," Lee says of his eye cancer discovery. "We blamed electricity, we blamed too much sausage - but in this case it's clear: It's the gene's fault."

The things that these people know, demonstrated by previous publications, but that they don't say in the Science article, are very revealing. The retinoblastoma gene (and its protein product), a specialty of Wen-Hwa Lee, is widely known to be a factor in breast cancer, and to be responsive to progesterone, RU486, and p21. Its links to ubiquitin, the hormone receptors, proteasomes, and the BRCA gene are well known, but previously they were seen as linking estrogen to cell proliferation, and progesterone to the inhibition of cellular proliferation.

By organizing their claims around the idea that RU486 is acting as an antiprogesterone, rather than as a progesterone synergist in opposing estrogen, Eva Lee's team has misused words to argue that it is progesterone, rather than estrogen, that causes breast cancer. Of the many relevant issues that their publication ignores, the absence of measurements of the actual estrogen and progesterone in the animals' serum most strongly suggests that the project was not designed for proper scientific purposes.

They chose to use techniques that are perfectly inappropriate for showing what they claim to show.

In the second paragraph of their article, Poole, et al., say "Hormone replacement therapy with progesterone and estrogen, but not estrogen alone, has been associated with an elevation risk in postmenopausal women." Aside from the gross inaccuracy of saying "progesterone," rather than synthetic progestin, they phrase their comment about "estrogen alone" in a way that suggests an identity of purpose with the estrogen industry apologists, who have been manipulating the data from the WHI estrogen-only study, clearly to lay the blame on progesterone. (Women who took estrogen had many more surgeries to remove mammographically abnormal breast tissue. This would easily account for fewer minor cancer diagnoses; despite this, there were more advanced cancers in the estrogen group.)

While the Poole, et al., group are operating within a context of new views regarding estrogen, progesterone, and cancer, they are ignoring the greater part of contemporary thinking about cancer, a consensus that has been growing for over 70 years: All of the factors that produce cancer, including breast cancer, produce inflammation and cellular excitation.

Progesterone is antiinflammatory, and reduces cellular excitation.

Even within their small world of molecular endocrinology, thinking in ways that have been fostered by computer technology, about gene networks, interacting nodes, and crosstalk between pathways, their model and their arguments don't work. They have left out the complexity that could give their argument some weight.

The medical mainstream has recognized for 30 years that progesterone protects the uterus against cancer; that was the reason for adding Provera to the standard menopausal hormonal treatment. The new claim that natural progesterone causes breast cancer should oblige them to explain why the hormone would have opposite effects in different organs, but the mechanisms of action of estrogen and progesterone are remarkably similar in both organs, even when examined at the molecular level. If "molecular endocrinologists" are going to have interpretations diametrically opposed to classical endocrinology (if black is to be white, if apples are to fall up), they will have to produce some very interesting evidence.

Cancer is a malignant (destructive, invasive) tumor that kills the organism. The main dogma regarding its nature and origin is that it differs genetically from the host, as a result of mutations. Estrogen causes mutations and other forms of genetic instability, as well as cancer itself. Progesterone doesn't harm genes or cause genetic instability.

The speculative anti-progesterone school has put great emphasis on the issue of cellular proliferation, with the reasoning that proliferating cells are more likely to undergo genetic changes. And synthetic progestins often do imitate estrogen and increase cellular proliferation. People like the Lees are asserting as an established fact that progesterone increases cellular proliferation.

A paper by Soderqvist has been cited as proof that progesterone increases the proliferation of breast cells. He saw more mitoses in the breasts during the luteal phase of the menstrual cycle, and said the slightly increased mitotic rate was "associated with" progesterone. Of course, estrogen increased at the same time, and estrogen causes sustained proliferation of breast cells, while progesterone stimulation causes only two cell divisions, ending with the differentiation of the cell. (Groshong, et al., 1997, Owen, et al., 1998)

One of the ways that progesterone stops proliferation and promotes differentiation is by keeping the retinoblastoma protein in its unphosphorylated, active protective state (Gizard, et al., 2006) The effects of estrogen and progesterone on that protein are reciprocal (Chen, et al., 2005). It's hard for me to imagine that the Lees don't know about these hormonal effects on Wen-Hwa's retinoblastoma gene product.

The inactivation of that protein by hyperphosphorylation is part of a general biological process, in which activation of a cell (by injury or nervous or hormonal or other stimulation, including radiation) leads to the activation of a large group of about 500 enzymes, phosphorylases, which amplify the stimulation, and cause the cell to respond by becoming active in many ways, for example, by stopping the synthesis of glycogen, and beginning its conversion to glucose to provide energy for the adaptive responses, that include the activation of genes and the synthesis or destruction of proteins. Another set of enzymes, the phosphatases, remove the activating phosphate groups, and allow the cell to return to its resting state.

The "molecular" endocrinologists and geneticists are committed to a reductionist view of life, the view that DNA is the essence, the secret, of life, and that it controls cells through its interactions with smaller molecules, such as the hormone receptors.

The idea of hormone receptors can be traced directly to the work of Elwood Jensen, who started his career working in chemical warfare, at the University of Chicago. Jensen claims that an experiment he did in the 1950s "caused the demise" of the enzymic-redox theory of estrogen's action, by showing that uterine tissue can't oxidize estradiol, and that its only action is on the genes, by way of "the estrogen receptor." But the uterus and other tissues do oxidize estradiol, and its cyclic oxidation and reduction is clearly involved in some of estrogen's toxic and excitatory effects.

For some reason, the military is still interested in hormone receptors. Lawrence National Weapons Laboratory (with its giant "predictive science" computer) is now the site of some of the anti-progesterone research.

Molecular biologists have outlined a chain of reactions, starting at the cell surface, and cascading through a series of phosphorylations, until the genes are activated. The cell surface is important, because cells are always in contact with something, and their functions and structure must be appropriate for their location. But the reductionist view of a network of phosphorylating enzymes ignores some facts.

Glycogen phosphorylase was the first enzyme whose activity was shown to be regulated by structural changes, allosterism. The active form is stabilized by phosphorylation, but this process takes seconds or minutes to develop, and the enzyme becomes active immediately when the cell is stimulated, for example in muscle contraction, within milliseconds. This kind of allosteric activation (or inactivation) can be seen in a variety of other enzymes, the cold-labile enzymes. A coherent change of the cell causes coordinated changes in its parts. These processes of enzymic regulation are fast, and can occur throughout a cell, practically simultaneously. Strict reductionists don't like to talk about them. "Network analysis" becomes irrelevant.

While a cell in general is activated by a wave of phosphorylation, certain processes (including glycogen synthesis) are blocked. When BRCA1 or retinoblastoma protein is hyperphosphorylated, its anti-estrogenic, anti-proliferative functions are stopped. The communication between cells is another function that's stopped by injury-induced phosphorylation.

Estrogen generally activates phosphorylases, and inactivates phosphatases. Progesterone generally opposes those effects.

Phosphorylation is just one of the regulatory systems that are relevant to the development of cancer, and that are acted on oppositely by estrogen and progesterone. To reduce the explanation for cancer to a gene or two or three may be an attractive idea for molecular endocrinologists, but the idea's simplicity is delusive.

Each component of the cell contributes complexly to the cell's regulatory stability. Likewise, a drug such as RU486 complexly modifies the cell's stability, changing thresholds in many ways, some of which synergize with progesterone (e.g., supporting the GABA system), others of which antagonize progesterone's effects (e.g., increasing exposure to prostaglandins).

There are other proteins in cells, besides the "hormone receptors," that bind progesterone, and that regulate cell functions globally. The sigma receptor, for example, that interacts with cocaine to excite the cell, interacts with progesterone to quiet the cell. The sigma receptor is closely related functionally to the histones, that regulate the activity of chromosomes and DNA, and progesterone regulates many processes that control the histones.

The GABA receptor system, and the systems that respond to glutamic acid (e.g., the "NMDA receptors") are involved in the inhibitory and excitatory processes that restrain or accelerate the growth of cancer cells, and progesterone acts through those systems to quiet cells, and restrain growth.

The inhibitor of differentiation, Id-1, is inhibited by progesterone, activated by estrogen (Lin, et al., 2000). Proteins acting in the opposite direction, PTEN and p21, for example, are activated by progesterone, and inhibited by estrogen.

The inflammatory cytokines, acting through the NFkappaB protein to activate genes, are generally oppositely regulated by estrogen and progesterone.

Prostaglandins, platelet activating factor, nitric oxide, peroxidase, lipases, histamine, serotonin, lactate, insulin, intracellular calcium, carbon dioxide, osmolarity, pH, and the redox environment are all relevant to cancer, and are affected systemically and locally by estrogen and progesterone in generally opposing ways.

About ten years ago, Geron corporation announced that it was developing products to control aging and cancer, by regulating telomerase, the enzyme that lengthens a piece of DNA at the end of the chromosomes. Their argument was that telomeres get shorter each time a cell divides, and that after about 50 divisions, cells reach the limit identified by Leonard Hayflick, and die, and that this accounts for the aging of the organism. Cancer cells are immortal, they said, because they maintain active telomerase, so the company proposed to cure cancer, by selling molecules to inhibit the enzyme, and to cure aging, by providing new enzymes for old people. However, Hayflick's limit was mainly the effect of bad culture methods, and the theory that the shortening of telomeres causes aging was contradicted by the finding of longer telomeres in some old people than in some young people, and different telomere lengths in different organs of the same person.

But it's true that cancer cells have active telomerase, and that most healthy cells don't. It happens that telomerase is activated by cellular injury, such as radiation, that activates phosphorylases, and that it is inactivated by phosphatases. Estrogen activates telomerase, and progesterone inhibits it.

Molecular endocrinology is very important to the pharmaceutical industry, because it lends itself so well to television commercials and corporate stock offerings. Monsanto and the Pentagon believe they can use reductionist molecular biology to predict, manipulate, and control life processes, but so far it is only their ability to damage organisms that has been demonstrated.

Besides the early animal studies that showed experimentally that progesterone can prevent or cure a wide variety of tumors, the newer evidence showing that progesterone is a major protective factor against even breast cancer, would suggest that dishonest efforts to protect estrogen sales by preventing women from using natural progesterone will be causing more women to develop cancer.

The recent report that the incidence of breast cancer in the United States fell drastically between 2002 and 2004, following the great decline in estrogen sales, shows the magnitude of the injury and death caused by the falsifications of the estrogen industry--a matter of millions of unnecessary deaths, just in the years that I have been working on the estrogen issue. The current campaign against progesterone can be expected to cause many unnecessary cancer deaths (e.g., Plu-Bureau, et al., Mauvais-Jarvis, et al.), while distracting the public from the culpability of the estrogen industry.

REFERENCES

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J Clin Endocrinol Metab. 1985 Apr;60(4):692-7. RU486, a progestin and glucocorticoid antagonist, inhibits the growth of breast cancer cells via the progesterone receptor. Bardon S, Vignon F, Chalbos D, Rochefort H.

Mol Carcinog. 2003 Dec;38(4):160-9. Suppression of the transformed phenotype and induction of differentiation-like characteristics in cultured ovarian tumor cells by chronic treatment with progesterone. Blumenthal M, Kardosh A, Dubeau L, Borok Z, Schonthal AH.

Contraception. 1998 Jul;58(1):45-50. Screening for antiproliferative actions of mifepristone. Differential endometrial responses of primates versus rats. Burleigh DW, Williams RF, Gordon K, Hsiu JG, Hodgen GD.

Hum Reprod Update. 1998 Sep-Oct;4(5):570-83. Modulation of oestrogenic effects by progesterone antagonists in the rat uterus. Chwalisz K, Stockemann K, Fritzemeier KH, Fuhrmann U.

J Vasc Surg. 2002 Oct;36(4):833-8. Progesterone inhibits human infragenicular arterial smooth muscle cell proliferation induced by high glucose and insulin concentrations. Carmody BJ, Arora S, Wakefield MC, Weber M, Fox CJ, Sidawy AN.

J Cell Physiol. 1999 Dec;181(3):385-92. Emerging roles of BRCA1 in transcriptional regulation and DNA repair. Chen Y, Lee WH, Chew HK.

Mol Endocrinol. 2005 Aug;19(8):1978-90. Progesterone inhibits the estrogen-induced phosphoinositide 3-kinase--> AKT--> GSK-3beta--> cyclin D1--> pRB pathway to block uterine epithelial cell proliferation. Chen B, Pan H, Zhu L, Deng Y, Pollard JW.

Endocrinology. 2004 Dec;145(12):5734-44. Regulation of steroidogenesis by p53 in macaque granulosa cells and H295R human adrenocortical cells. Cherian-Shaw M, Das R, Vandevoort CA, Chaffin CL.

Breast Cancer Res Treat. 1994;32(2):153-64. Expression of insulin-like growth factor binding proteins by T-47D human breast cancer cells: regulation by progestins and antiestrogens. Coutts A, Murphy LJ, Murphy LC.

Progr. Exp. Tumor Res. 1971, vol. 14: 59, Inhibition of tumor induction in chemical carcinogenesis in the mammary gland, Dao TL.

Br J Cancer. 2004 Apr 5;90(7):1450-6. Gap junction communication dynamics and bystander effects from ultrasoft X-rays. Edwards GO, Botchway SW, Hirst G, Wharton CW, Chipman JK, Meldrum RA. "Loss of gap junction-mediated intercellular communication between irradiated cells was dose-dependent, indicating that closure of junctions is proportional to dose. Closure was associated with hyperphosphorylation of connexin43."

Breast Cancer Res Treat. 1998 May;49(2):109-17. Effect of antiprogestins and tamoxifen on growth inhibition of MCF-7 human breast cancer cells in nude mice. El Etreby MF, Liang Y.

Prostate. 2000 Apr 1;43(1):31-42. Induction of apoptosis by mifepristone and tamoxifen in human LNCaP prostate cancer cells in culture. El Etreby MF, Liang Y, Lewis RW.

Breast Cancer Res Treat. 1998 Sep;51(2):149-68. Additive effect of mifepristone and tamoxifen on apoptotic pathways in MCF-7 human breast cancer cells. El Etreby MF, Liang Y, Wrenn RW, Schoenlein PV.

Ann Clin Lab Sci. 1998 Nov-Dec;28(6):360-9. Progesterone inhibits growth and induces apoptosis in breast cancer cells: inverse effects on Bcl-2 and p53. Formby B, Wiley TS.

Mol Cell Biochem. 1999 Dec;202(1-2):53-61. Bcl-2, survivin and variant CD44 v7-v10 are downregulated and p53 is upregulated in breast cancer cells by progesterone: inhibition of cell growth and induction of apoptosis. Formby B, Wiley TS.

Mol Cell Biol. 2006 Oct;26(20):7632-44. TReP-132 is a novel progesterone receptor coactivator required for the inhibition of breast cancer cell growth and enhancement of differentiation by progesterone. Gizard F, Robillard R, Gross B, Barbier O, Revillion F, Peyrat JP, Torpier G, Hum DW, Staels B.

FEBS Lett. 2005 Oct 24;579(25):5535-41. Epub 2005 Sep 27. Progesterone inhibits human breast cancer cell growth through transcriptional upregulation of the cyclin-dependent kinase inhibitor p27Kip1 gene. Gizard F, Robillard R, Gervois P, Faucompre A, Revillion F, Peyrat JP, Hum WD, Staels B.

Mol Cell Biol. 2005 Jun;25(11):4335-48. TReP-132 controls cell proliferation by regulating the expression of the cyclin-dependent kinase inhibitors p21WAF1/Cip1 and p27Kip1. Gizard F, Robillard R, Barbier O, Quatannens B, Faucompre A, Revillion F, Peyrat JP, Staels B, Hum DW.

Mol Endocrinol. 1997 Oct;11(11):1593-607. Biphasic regulation of breast cancer cell growth by progesterone: role of the cyclin-dependent kinase inhibitors, p21 and p27(Kip1). Groshong SD, Owen GI, Grimison B, Schauer IE, Todd MC, Langan TA, Sclafani RA, Lange CA, Horwitz KB.

Eur J Cancer. 1996 Apr;32A(4):696-701. Androgen-like and anti-androgen-like effects of antiprogestins in human mammary cancer cells. Hackenberg R, Hannig K, Beck S, Schmidt-Rhode P, Scholz A, Schulz KD.

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Cancer Res. 2000 Mar 1;60(5):1332-40. A role for Id-1 in the aggressive phenotype and steroid hormone response of human breast cancer cells. Lin CQ, Singh J, Murata K, Itahana Y, Parrinello S, Liang SH, Gillett CE, Campisi J, Desprez PY. "Estrogen stimulated proliferation and induced Id-1 expression, whereas progesterone inhibited proliferation and repressed Id-1 expression. Progesterone repressed Id-1 expression, at least in part by repressing transcription."

Endocrinology. 2003 Dec;144(12):5650-7. Epub 2003 Sep 11. Distinct molecular pathways mediate progesterone-induced growth inhibition and focal adhesion. Lin VC, Woon CT, Aw SE, Guo C.

Clin Cancer Res. 1999 Feb;5(2):395-403. Progestins inhibit the growth of MDA-MB-231 cells transfected with progesterone receptor complementary DNA. Lin VC, Ng EH, Aw SE, Tan MG, Ng EH, Chan VS, Ho GH.

Differentiation. 2006 Dec;74(9-10):481-7. The multiple roles of Id-1 in cancer progression. Ling MT, Wang X, Zhang X, Wong YC.

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A R T I C L E

Salt, energy, metabolic rate, and longevity

In the 1950s, when the pharmaceutical industry was beginning to promote some new chemicals as diuretics to replace the traditional mercury compounds, Walter Kempners low-salt rice diet began to be discussed in the medical journals and other media. The diuretics were offered for treating high blood pressure, pulmonary edema, heart failure, idiopathic edema, orthostatic edema and obesity, and other forms of water retention, including pregnancy, and since they functioned by causing sodium to be excreted in the urine, their sale was accompanied by advising the patients to reduce their salt intake to make the diuretic more effective.

It was clear to some physicians (and to most veterinarians) that salt restriction, especially combined with salt-losing diuresis, was very harmful during pregnancy, but that combination became standard medical practice for many years, damaging millions of babies.

Despite numerous publications showing that diuretics could cause the edematous problems that they were supposed to remedy, they have been one of the most profitable types of drug. Dietary salt restriction has become a cultural cliché, largely as a consequence of the belief that sodium causes edema and hypertension.

Salt restriction, according to a review of about 100 studies (Alderman, 2004), lowers the blood pressure a few points. But that generally doesnt relate to better health. In one study (3000 people, 4 years), there was a clear increase in mortality in the individuals who ate less salt. An extra few grams of salt per day was associated with a 36% reduction in coronary events (Alderman, et al., 1995). Another study (more than 11,000 people, 22 years) also showed an inverse relation between salt intake and mortality (Alderman, et al., 1997).

Tom Brewer, an obstetrician who devoted his career to educating the public about the importance of prenatal nutrition, emphasizing adequate protein (especially milk), calories, and salt, was largely responsible for the gradual abandonment of the low-salt plus diuretics treatment for pregnant women. He explained that sodium, in association with serum albumin, is essential for maintaining blood volume. Without adequate sodium, the serum albumin is unable to keep water from leaving the blood and entering the tissues. The tissues swell as the volume of blood is reduced.

During pregnancy, the reduced blood volume doesnt adequately nourish and oxygenate the growing fetus, and the reduced circulation to the kidneys causes them to release a signal substance (renin) that causes the blood to circulate faster, under greater pressure. A low salt diet is just one of the things that can reduce kidney circulation and stimulate renin production. Bacterial endotoxin, and other things that cause excessive capillary permeability, edema, or shock-like symptoms, will activate renin secretion.

The blood volume problem isnt limited to the hypertension of pregnancy toxemia: Plasma volume is usually lower in patients with essential hypertension than in normal subjects (Tarazi, 1976).

Several studies of preeclampsia or toxemia of pregnancy showed that supplementing the diet with salt would lower the womens blood pressure, and prevent the other complications associated with toxemia (Shanklin and Hodin, 1979).

It has been known for many years that decreasing sodium intake causes the body to respond adaptively, increasing the renin-angiotensin-aldosterone system (RAAS). The activation of this system is recognized as a factor in hypertension, kidney disease, heart failure, fibrosis of the heart, and other problems. Sodium restriction also increases serotonin, activity of the sympathetic nervous system, and plasminogen activator inhibitor type-1 (PAI-1), which contributes to the accumulation of clots and is associated with breast and prostate cancer. The sympathetic nervous system becomes hyperactive in preeclampsia (Metsaars, et al., 2006).

Despite the general knowledge of the relation of dietary salt to the RAA system, and its application by Brewer and others to the prevention of pregnancy toxemia, it isnt common to see the information applied to other problems, such as aging and the stress-related degenerative diseases.

Many young women periodically crave salt and sugar, especially around ovulation and premenstrually, when estrogen is high. Physiologically, this is similar to the food cravings of pregnancy. Premenstrual water retention is a common problem, and physicians commonly offer the same advice to cycling women that was offered as a standard treatment for pregnant women--the avoidance of salt, sometimes with a diuretic. But when women premenstrually increase their salt intake according to their craving, the water retention can be prevented.

Blood volume changes during the normal menstrual cycle, and when the blood volume is low, it is usually because the water has moved into the tissues, causing edema. When estrogen is high, the osmolarity of the blood is low. (Courtar, et al., 2007; Stachenfeld, et al., 1999). Hypothyroidism (which increases the ratio of estrogen to progesterone) is a major cause of excessive sodium loss.

The increase of adrenalin caused by salt restriction has many harmful effects, including insomnia. Many old people have noticed that a low sodium diet disturbs their sleep, and that eating their usual amount of salt restores their ability to sleep. The activity of the sympathetic nervous system increases with aging, so salt restriction is exacerbating one of the basic problems of aging. Chronically increased activity of the sympathetic (adrenergic) nervous system contributes to capillary leakage, insulin resistance (with increased free fatty acids in the blood), and degenerative changes in the brain (Griffith and Sutin, 1996).

The flexibility of blood vessels (compliance) is decreased by a low-salt diet, and vascular stiffness caused by over-activity of the sympathetic nervous system is considered to be an important factor in hypertension, especially with aging.

Pregnancy toxemia/preeclampsia involves increased blood pressure and capillary permeability, and an excess of prolactin. Prolactin secretion is increased by serotonin, which is one of the substances increased by salt restriction, but prolactin itself can promote the loss of sodium in the urine (Ibarra, et al., 2005), and contributes to vascular leakage and hypertension.

In pregnancy, estrogen excess or progesterone deficiency is an important factor in the harmful effects of sodium restriction and protein deficiency. A deficiency of protein contributes to hypothyroidism, which is responsible for the relative estrogen excess.

Protein, salt, thyroid, and progesterone happen to be thermogenic, increasing heat production and stabilizing body temperature at a higher level. Prolactin and estrogen lower the temperature set-point.

The downward shift of temperature and energy metabolism in toxemia or salt deprivation tends to slow the use of oxygen, increasing the glycolytic use of sugar, and contributing to the formation of lactic acid, rather than carbon dioxide. In preeclampsia, serum lactate is increased, even while free fatty acids are interfering with the use of glucose.

One way of looking at those facts is to see that a lack of sodium slows metabolism, lowers carbon dioxide production, and creates inflammation, stress and degeneration. Rephrasing it, sodium stimulates energy metabolism, increases carbon dioxide production, and protects against inflammation and other maladaptive stress reactions.

In recent years, Weissmans wear-and-tear theory of aging, and Pearls rate of living theory have been clearly refuted by metabolic studies that are showing that intensified mitochondrial respiration decreases cellular damage, and supports a longer life-span.

Many dog owners are aware that small dogs eat much more food in proportion to their size than big dogs do. And small dogs have a much greater life expectancy than big dogs, in some cases about twice as long (Speakman, 2003).

Organisms as different as yeasts and rodents show a similar association of metabolic intensity and life-span. A variety of hamster with a 20% higher metabolic rate lived 15% longer than hamsters with an average metabolic rate (Oklejewicz and Daan, 2002).

Individuals within a strain of mice were found to vary considerably in their metabolic rate. The 25% of the mice with the highest rate used 30% more energy (per gram of body weight) than the 25% with the lowest metabolic rate, and lived 36% longer (Speakman, et al., 2000).

The mitochondria of these animals are uncoupled, that is, their use of oxygen isnt directly proportional to the production of ATP. This means that they are producing more carbon dioxide without necessarily producing more ATP, and that even at rest they are using a considerable amount of energy.

One important function of carbon dioxide is to regulate the movement of positively charged alkali metal ions, such as sodium and calcium. When too much calcium enters a cell it activates many enzymes, prevents muscle and nerve cells from relaxing, and ultimately kills the cell. The constant formation of acidic carbon dioxide in the cell allows the cell to remove calcium, along with the small amount of sodium which is constantly entering the cell.

When there is adequate sodium in the extracellular fluid, the continuous inward movement of sodium ions into the resting cell activates an enzyme, sodium-potassium ATPase, causing ATP to break down into ADP and phosphate, which stimulates the consumption of fuel and oxygen to maintain an adequate level of ATP. Increasing the concentration of sodium increases the energy consumption and carbon dioxide production of the cell. The sodium, by increasing carbon dioxide production, protects against the excitatory, toxic effects of the intracellular calcium.

Hypertonic solutions, containing more than the normal concentration of sodium (from about twice normal to 8 or 10 times normal) are being used to rescuscitate people and animals after injury. Rather than just increasing blood volume to restore circulation, the hypertonic sodium restores cellular energy production, increasing oxygen consumption and heat production while reducing free radical production, improves the contraction and relaxation of the heart muscle, and reduces inflammation, vascular permeability, and edema.

Seawater, which is hypertonic to our tissues, has often been used for treating wounds, and much more concentrated salt solutions have been found effective for accelerating wound healing (Mangete, et al., 1993).

There have been several publications suggesting that increasing the amount of salt in the diet might cause stomach cancer, because countries such as Japan with a high salt intake have a high incidence of stomach cancer.

Studies in which animals were fed popular Japanese foods--salted cuttlefish guts, broiled, salted, dried sardines, pickled radish, and soy sauce--besides a chemical carcinogen, showed that the Japanese foods increased the number of tumors. But another study, adding only soy sauce (with a salt content of about 18%) to the diet did not increase the incidence of cancer, in another it was protective against stomach cancer (Benjamin, et al., 1991). Several studies show that dried fish and pickled vegetables are carcinogenic, probably because of the oxidized fats, and other chemical changes, and fungal contamination, which are likely to be worse without the salt. Animals fed dried fish were found to have mutagenic urine, apparently as a result of toxic materials occurring in various preserved foods (Fong, et al., 1979).

Although preserved foods develop many peculiar toxins, even fresh fish in the diet have been found to be associated with increased cancer risk (Phukan, et al., 2006).

When small animals were given a milliliter of a saturated salt solution with the carcinogen, the number of tumors was increased with the salt. However, when the salt was given with mucin, it had no cancer promoting effect. Since the large amount of a saturated salt solution breaks down the stomachs protective mucus coating, the stomach cells were not protected from the carcinogen. Rather than showing that salt causes stomach cancer, the experiments showed that a cup or more of saturated salt solution, or several ounces of pure salt, shouldnt be ingested at the same time as a strong carcinogen.

Some studies have found pork to be associated with cancer of the esophagous (Nagai, et al., 1982), thyroid (Markaki, et al., 2003), and other organs, but an experiment with beef, chicken, or bacon diet in rats provides another perspective on the role of salt in carcinogenesis. After being given a carcinogen, rats were fed meat diets, containing either 30% or 60% of freeze-dried fried beef, chicken, or bacon. Neither beef nor chicken changed the incidence of precancerous lesions in the intestine, but the incidence was reduced by 12% in the animals on the 30% bacon diet, and by 20% in rats getting the diet with 60% bacon. Salt apparently made the difference.

Other protective effects of increased sodium are that it improves immunity (Junger, et al., 1994), reduces vascular leakiness, and alleviates inflammation (Cara, et al., 1988). All of these effects would tend to protect against the degenerative diseases, including tumors, atherosclerosis, and Alzheimers disease. The RAA system appears to be crucially involved in all kinds of sickness and degeneration, but the protective effects of sodium are more basic than just helping to prevent activation of that system.

A slight decrease in temperature can promote inflammation (Matsui, et al., 2006). The thermogenic substances--dietary protein, sodium, sucrose, thyroid and progesterone--are antiinflammatory for many reasons, but very likely the increased temperature itself is important.

A poor reaction to stress, with increased cortisol, can raise the body temperature by accelerating the breakdown and resynthesis of proteins, but adaptive resistance to stress increases the temperature by increasing the consumption of oxygen and fuel. In the presence of increased cortisol, abdominal fat increases, along with circulating fatty acids and calcium, as mitochondrial respiration is suppressed.

When mice are chilled, they spontaneously prefer slightly salty water, rather than fresh, and it increases their heat production (Dejima, et al., 1996). When rats are given 0.9 per cent sodium chloride solution with their regular food, their heat production increases, and their body fat, including abdominal fat, decreases (Bryant, et al., 1984). These responses to increased dietary sodium are immediate. Part of the effect of sodium involves regulatory processes in the brain, which are sensitive to the ratio between sodium and calcium. Decreasing sodium, or increasing calcium, causes the bodys metabolism to shift away from thermogenesis and accelerated respiration.

Regulating intracellular calcium by increasing the production of carbon dioxide is probably a basic mechanism in sodiums protection against inflammation and excitatory cell damage and degeneration.

Cortisols suppression of mitochondrial respiration is closely associated with its ability to increase intracellular calcium. Cortisol blocks the thermogenic effects of sodium, allowing intracellular calcium to damage cells. With aging, the tissues are more susceptible to these processes.

The thermogenic effects of sodium can be seen in long-term studies, as well as short. A low-sodium diet accelerates the decrease in heat production that normally occurs with aging, lowering the metabolic rate of brown fat and body temperature, and increasing the fat content of the body, as well as the activity of the fat synthesizing enzyme (Xavier, et al., 2003).

Activation of heat production and increased body temperature might account for some of the GABA-like sedative effects of increased sodium. Increasing GABA in the brain increases brown fat heat production (Horton, et al., 1988). Activation of heat production by brown fat increases slow wave sleep (Dewasmes, et al., 2003), the loss of which is characteristic of aging. (In adult humans, the skeletal muscles have heat-producing functions similar to brown fat.)

Now that inflammation is recognized as having a central role in the degenerative diseases, the fact that renin, angiotensin, and aldosterone all contribute to inflammation and are increased by a sodium deficiency, should arouse interest in exploring the therapeutic uses of sodium supplementation, and the integrated use of all of the factors that normally support respiratory energy production, especially thyroid and progesterone. Progesterones antagonism to aldosterone has been known for many years, and the synthetic antialdosterone drugs are simply poor imitations of progesterone.

But the drug industry is interested in selling new drugs to block the formation and action of each of the components of the RAAS, rather than an inexpensive method (such as nutrition) to normalize the system.

REFERENCES

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<span class="koboSpan" id="kobo.1.1">Stem cells, cell culture, and culture: Issues in regeneration</span> A R T I C L E

Stem cells, cell culture, and culture: Issues in regeneration

Cell renewal is a factor in all aspects of health and disease, not just in aging and the degenerative diseases. Many people are doing valid research relating to cell renewal and regeneration, but its usefulness is seriously limited by cultural and commercial constraints. By recovering some of our suppressed traditional culture, I think regenerative therapies can be developed quickly, by identifying and eliminating as far as possible the main factors that interfere with tissue renewal.

Science grew up in the highly authoritarian cultures of western Europe, and even as it contributed to cultural change, it kept an authoritarian mystique. Any culture functions as a system of definitions of reality and the limits of possibility, and to a great extent the "laws of nature" are decreed so that they will harmonize with the recognized laws of society.

The practical success of Newton's "laws" of motion when they were applied to ballistics and "rocket science" has led many people to value calculation, based on those laws, over evidence. In biology, the idea that an organism is "the information it contains in its DNA blueprint" is an extention of this. The organism is turned into something like a deductive expression of the law of DNA. This attitude has been disastrous.

The old feudal idea of a divine and stable social organization was applied by some people to their idea of biological organization, in which each cell (ruled by its nucleus) had its ordained place in the organism, with the brain and the "master gland," the pituitary, ruling the subordinate organs, tissues, and cells. "Anatomy" was taught from dead specimens, microscope slides, and illustrations in books. Most biologists' thoughts about cells in organisms reflect the static imagery of their instruction. ("The histological image of these tissues actually reflects an instantaneous picture of cells in a continuous flux." Zajicek, 1981.)

When a person has playful and observant interactions with natural things, both regularities and irregularities will be noticed, and in trying to understand those events, the richness of the experience will suggest an expansive range of possibilities. Perception and experimentation lead to understandings that are independent of culture and tradition.

But the mystique of science easily imposes itself, and distracts our attention from direct interactions with things. As we learn to operate lab instruments, we are taught the kinds of results that can be expected, and the concepts that will explain and predict the results of our operations. Science, as we learn about it in schools and the mass media, is mostly a set of catechisms.

Our theories about organisms inform our experiments with cells or tissues that have been isolated from those organisms. The conditions for growing cells in dishes are thought of as "physiological," in relation to the solution's "physiological osmolarity," "physiological pH," nutrients, oxygenation, temperature, pressure, etc. But these concepts of what is physiological derive from the monolithic ideology of the doctrinaire, and often fraudulent, mainstream of biological science.

The catechismic nature of science has led people to expect some "break-throughs" to occur in certain areas, and as authoritarian science has grown into "big science" managed by corporations and governments, those break-throughs are generally expected to be produced by the newest and most expensive developments of "high technology."

But looking closely at the real events and processes in the sciences in the last couple of centuries, it turns out that useful advances have been produced mainly by breaking away from authoritarian doctrines, to return to common sense and relatively simple direct observations.

Although people were cloning animals in the 1960s, it was still widely taught that it was impossible. The students of the professors who taught that it was impossible are now saying that it requires high technology and new research.

For the last 100 years the most authoritative view in biology has been that there are no stem cells in adults, that brains, hearts, pancreases and oocytes are absolutely incapable of regeneration. But now, people seem to be finding stem cells wherever they look, but there is a mystique of high technology involved in finding and using them.

Whether it's deliberate or not, the emphasis on stem cell technology has the function of directing attention away from traditional knowledge, the way allopathic medicine has de-emphasized the intrinsic ability of people to recover from disease.

This resembles the way that the Mendel-Morgan gene doctrine was used to suppress the knowledge gained from centuries of experience of plant and animal breeders, and to belittle the discoveries of Luther Burbank, Paul Kammerer, Trofim Lysenko, and Barbara McClintock. The same type of biochemical process that caused the hereditary changes those researchers studied are involved in the differentiation and dedifferentiation of stem cells that regulate healing and regeneration.

In the 1940s, even children discussed the biological discoveries of the 1920s and 1930s, the work in regeneration and adaptation, parthenogenesis, and immortalization. The ideas of J. Loeb, T. Boveri, A. Gurwitsch, J. Needham, C.M. Child, A. Carrel, et al., had become part of the general culture.

But that real biology was killed by a consortium of industry and government that began a little before the second world war. In 1940, the government was supporting research in chemical and biological warfare, and with the Manhattan Project the role of government became so large that all of the major research universities were affected. Shortly after the war, many researchers from the Manhattan Project were redeployed into "molecular genetics," where the engineering attitude was applied to organisms.

The simplistic genetic dogmas were compatible with the reductionist engineering approach to the organism. The role of the government assured that the universities would subscribe to the basic scientific agenda. The atmosphere of that time was described by Carl Lindegren as "The Cold War in Biology" (1966).

The disappearance of the field concept in developmental biology was one of the strangest events in the history of science. It didn't just fade away, it was "disappeared," in a massive undertaking of social engineering. In its absence, stem cells will seem to be a profitable technological marvel, rather than a universal life function, with a central role in everything we are and everything we do and can become.

Many people have tried to explain aging as a loss of cells, resulting from an intrinsic inability of any cell other than a germ cell to multiply more than a certain number of times. More than 40 years ago Leonard Hayflick popularized this doctrine in its most extreme form, saying that no cell can divide more than 50 times unless it is converted into a cancer cell. He and his followers claimed that they had explained why organisms must age and die. At the moment the ovum is fertilized, the clock starts ticking for the essentially mortal somatic cells.

In 1970, it was being seriously proposed that memory was produced by the death of brain cells, in a manner analogous to the holes punched in cards to enter data into computers. The cultural dogma made it impossible to consider that learning could be associated with the birth of new cells in the adult brain.

With the announcement in 1997 of the cloning of the sheep Dolly from a somatic cell taken from a 6 year old sheep, there was renewed interest in the idea made famous by Alexis Carrel that all cells are potentially immortal, and in the possibility of preserving the vitality of human cells. Within a few months, Hayflick began reminding the public that "In the early 1960's we overthrew this dogma after finding that normal cells do have a finite replicative capacity." ("During the first half of this century it was believed that because cultured normal cells were immortal, aging must be caused by extra-cellular events.") The way Hayflick "overthrew" more than 35 years of work at the Rockefeller Institute was by growing one type of cell, a lung fibroblast, in culture dishes, and finding that the cultures deteriorated quickly.

To draw global conclusions about an organism's development and aging from the degenerative processes seen in a single type of cell, grown in isolation from all normal stimuli, would have been treated as nothing but wild speculation, except that it occurred within a culture that needed it. No aspect of Hayflick's cell culture system could properly be called physiological.

Other researchers, simply by changing a single factor, caused great increases in the longevity of the cultured cells. Simply using a lower, more natural oxygen concentration, the cells were able to undergo 20 more divisions. Just by adding niacin, 30 more divisions; vitamin E, 70 more divisions. Excess oxygen is a poison requiring constant adaptation.

Hayflick also published the observation that, while the cells kept in dishes at approximately body temperature deteriorated, cells kept frozen in liquid nitrogen didn't deteriorate, and he concluded that "time" wasn't the cause of aging. When I read his comments about the frozen cells, I wondered how anyone of normal intelligence could make such stupid statements. Since then, facts that came out because of the Freedom of Information Act, cause me to believe that a financial motive guided his thoughts about his cultured fibroblasts.

Hayflick and his followers have been attacking the idea of anti-aging medicine as quackery. But he is closely involved with the Geron corporation, which proposes that genetic alterations relating to telomeres may be able to cure cancer and prevent aging. Their claims were reported by CNN as "Scientists discover cellular 'fountain of youth'."

The "wear and tear" doctrine of aging that derived from the ideology of the gene was reinforced and renewed by Hayflick's cell culture observations, and it continued to rule the universities and popular culture.

But detailed investigation of skin cell growth showed that cells in the lower layer of the skin divide at least 10,000 times in a normal lifetime, and similar processes occur in the lining of the intestine. The endometrium and other highly renewable tissues just as obviously violated Hayflick's limit. Transplantation experiments showed that pieces of mammary tissue or skin tissue could survive through ten normal lifetimes of experimental animals without suffering the effects of aging.

Even the liver and adrenal gland are now known to be continuously renewed by "cell streaming," though at a slower rate than the skin, conjunctiva, and intestine. Neurogenesis in the brain is now not only widely accepted, it is even proposed as a mechanism to explain the therapeutic effects of antidepressants (Santarelli, et al., 2003).

August Weismann's most influential doctrine said that "somatic cells are mortal, only the germline cells are immortal," but he based the doctrine on his mistaken belief that only the "germline" cells contained all the genes of the organism. In 1885, to "refute" Darwin's belief that acquired traits could be inherited, he promulgated an absolute "barrier" between "germline" and "soma," and invented facts to show that hereditary information can flow only from the germline to the somatic cells, and not the other direction. Shortly after DNA became popular in the 1950s as "the genetic material," Weismann's barrier was restated as the Central Dogma of molecular genetics, that information flows only from DNA to RNA to protein, and never the other direction.

It was only in 2003, after the reality of cloning was widely recognized, that a few experimenters began to investigate the origin of "germline" cells in the ovary, and to discover that they derive from somatic cells (Johnson, et al., 2004). With this discovery, the ancient knowledge that a twig (klon, in Greek) cut from a tree could grow into a whole tree, bearing fruit and viable seeds, was readmitted to general biology, and the Weismann barrier was seen to be an illusion.

Millions of people have "explained" female reproductive aging as the consequence of the ovary "running out of eggs." Innumerable publications purported to show the exact ways in which that process occurs, following the Weismann doctrine. But now that it is clear that adult ovaries can give birth to new oocytes, a new explanation for female reproductive aging is needed. It is likely that the same factors that cause female reproductive aging also cause aging of other systems and organs and tissues, and that those factors are extrinsic to the cells themselves, as Alexis Carrel and others demonstrated long ago. This is a way of saying that all cells are potential stem cells. The "niche" in which new cells are born in the streaming organism, and the processes by which damaged cells are removed, are physiological issues that can be illuminated by the idea of a morphogenetic field.

When the post-war genetic engineers took over biological research, the idea of a biophysical field was totally abandoned, but after about 15 years, it became necessary to think of problems beyond those existing within a single bacterium, namely, the problem of how an ovum becomes and embryo. Francis Crick, of DNA fame, who was educated as a physicist, revived (without a meaningful historical context) the idea of a diffusion gradient as a simple integrating factor that wouldn't be too offensive to the reductionists. But for events far beyond the scale of the egg's internal structure, for example to explain how a nerve axon can travel a very long distance to innervate exactly the right kind of cell, the diffusion of molecules loses its simplicity and plausibility. (Early in the history of experimental embryology, it was observed that electrical fields affect the direction of growth of nerve fibers.)

C. M. Child saw a gradient of metabolic activity as an essential component of the morphogenetic field. This kind of gradient doesn't deny the existence of diffusion gradients, or other physical components of a field. Electrical and osmotic (and electro-osmotic) events are generated by metabolism, and affect other factors, including pH, oxidation and reduction, cell motility and cell shape, ionic selectivity and other types of cellular selectivity and specificity. Gradients of DNA methylation exist, and affect the expression of inherited information.

Methylation decreases the expression of particular genes, and during the differention of cells in the development of an embryo, genes are methylated and demethylated as the cell adapts to produce the proteins that are involved in the structure and function of a particular tissue. Methylation (which increases a molecule's affinity for fats) is a widespread process in cells, and for example regulates cellular excitability. It is affected by diet and a variety of stresses.

DNA methylation patterns are normally fairly stable, and can help to account for the transgenerational transmission of acquired adaptations, and for neonatal imprinting that can last a lifetime. But with injury, stress, and aging, the methylation patterns of differentiated tissues can be changed, contributing to the development of tumors, or to the loss of cellular functions. Even learning can change the methylation of specific genes. During in vitro culture, the enzymes of gene methylation are known to be increased, relative to their normal activity (Wang, et al., 2005).

The phenomenon of "gene" methylation in response to environmental and metabolic conditions may eventually lead to the extinction of the doctrine that "cells are controlled by their genes."

During successful adaptation to stress, cells make adjustments to their metabolic systems (for example with a holistic change of the degree of phosphorylation, which increases molecules' affinity for water), and their metabolic processes can contribute to changes in their state of differentiation. Some changes may lead to successful adaptation (for example by producing biogenic stimulators that stimulate cell functioning and regeneration), others to failed adaptation. Even the decomposition of cells can release substances that contribute to the adaptation of surrounding cells, for example when sphingosines stimulate the production of stem cells.

DNA methylation is just one relatively stable event that occurs in relation to a metabolic field. Modifications of histones (regulatory proteins in chromosomes, which are acetylated as well as methylated) and structural-contractile filaments also contribute to the differentiation of cells, but the pattern of DNA methylation seems to guide the methylation of histones and the structure of the chromosomes (Nan, et al., 1998).

Steroids and phospholipids, neurotransmitters and endorphins, ATP, GTP, other phosphates, retinoids, NO and CO2--many materials and processes participate in the coherence of the living state, the living substance. Carbon dioxide, for example, by binding to lysine amino groups in the histones, will influence their methylation. Carbon dioxide is likely to affect other amino groups in the chromosomes.

The number and arrangement of mitochondria is an important factor in producing and maintaining the metabolic gradients. Things that decrease mitochondrial energy production--nitric oxide, histamine, cytokines, cortisol--increase DNA methylation. Decreased gene expression is associated with reduced respiratory energy. It seems reasonable to guess that increased gene expression would demand increased availability of energy.

As an ovum differentiates into an organism, cells become progressively more specialized, inhibiting the expression of many genes. Less energy is needed by stably functioning cells, than by actively adapting cells. A.I. Zotin described the process of maturing and differentiating as a decrease of entropy, an increase of order accompanying a decreased energy expenditure. The entropic egg develops into a less entropic embryo with a great expenditure of energy.

The partially differentiated stem cell doesn't go through all the stages of development, but it does expend energy intensely as it matures.

The restoration of energy is one requirement for the activation of regeneration. When a hormone such as noradrenaline or insulin causes a stem cell to differentiate in vitro, it causes new mitochondria to form. This is somewhat analogous to the insertion of mitochondria into the ripening oocyte, by the nurse cells that surround it. The conditionally decreased entropy of maturation is reversed, and when sufficient respiratory energy is available, the renewed and refreshed cell will be able to renew an appropriate degree of differentiation.

When simple organisms, such as bacteria, fungi, or protozoa are stressed, for example by the absence of nutrients or the presence of toxins, they slow their metabolism, and suppress the expression of genes, increasing the methylation of DNA, to form resistant and quiescent spores. Our differentiated state doesn't go to the metabolic extreme seen in sporulation, but it's useful to look at maturity and aging in this context, because it suggests that the wrong kind of stress decreases the ability of the organism to adapt, by processes resembling those in the spore-forming organisms.

Charles Vacanti, who has grown cartilage from cells taken from 100 year old human cartilage, believes our tissues contain "spore cells," very small cells with slow metabolism and extreme resistance to heat, cold, and starvation.

If the slowed metabolism of aging, like that of sporulating cells, is produced by a certain kind of stress that lowers cellular energy and functions, it might be useful to think of the other stages of the stress reaction in relation to the production of stem cells. Selye divided stress into a first stage of shock, followed by a prolonged adaptation, which could sometimes end in exhaustion. If the maturity of differentiated functioning is equivalent to the adaptation phase, and cellular decline and disintegration is the exhaustion phase, then the shock-like reaction would correspond to the birth of new stem cells.

Selye described estrogen's effects as equivalent to the shock-phase of stress. Estrogen's basic action is to make oxygen unavailable, lowering the oxygen tension of the tissues, locally and temporarily. Like nitric oxide, which is produced by estrogenic stimulation, estrogen interferes with energy production, so if its stimulation is prolonged, cells are damaged or killed, rather than being stimulated to regenerate.

Extrinsic factors elicit renewal, the way stress can elicit adaptation. While aging cells can't use the oxygen that is present, a scarcity of oxygen can serve as a stimulus to maximize the respiratory systems. Brief oxygen deprivation excites a cell, causes it to swell, and to begin to divide.

Oxygen deprivation, as in the normally hypoxic bone marrow, stimulates the formation of stem cells, as well as the biogenesis of mitochondria. As the newly formed cells, with abundant mitochondria, get adequate oxygen, they begin differentiation.

Form, based on cellular differentiation, follows function--a vein transplanted into an artery develops anatomically into an artery, a colon attached directly to the anus becomes a new rectum with its appropriate innervation, a broken bone restructures to form a normal bone. If the bladder is forced to function more than normal, by artificially keeping it filled, its thin wall of smooth muscle develops into a thick wall of striated muscle that rhythmically contracts, like the heart. If a tadpole is given a vegetarian diet, the absorptive surface of its digestive system will develop to be twice the size of those that are fed meat. Pressure, stretching, and pulsation are among the signals that guide cells' differentiation.

Very early in the study of embryology it was noticed that the presence of one tissue sometimes induced the differentiation of another kind, and also that there were factors in embryonic tissues that would stimulate cell division generally, and others that could inhibit the growth of a particular tissue type. Diffusable substances and light were among the factors identified as growth regulators.

Extracts of particular tissues were found to suppress the multiplication of cells in that type of tissue, in adult animals as well as in embryos. In the 1960s, the tissue-specific inhibitors were called chalones.

The brain's development is governed by the presence in the organism of the body part to which it corresponds, such as the eyes or legs. The number of cells in a particular part of the nervous system is governed by the quantity of nervous input, sensory or motor, that it receives. An enriched environment causes a bigger brain to grow. Sensory nerve stimulation of a particular region of the brain causes nerve cells to migrate to that area (a process called neurobiotaxis; deBeers, 1927), but nerve stimulation also causes mitochondria to accumulate in stimulated areas. Nerve activity has a trophic, sustaining influence on other organs, as well as on the brain. Nerve stimulation, like mechanical pressure or stretching, is an important signal for cellular differentiation.

When stem cells or progenitor cells are called on to replace cells in an organ, they are said to be "recruited" by that organ, or to "home" to that organ, if they are coming from elsewhere. Traditionally, the bone marrow has been considered to be the source of circulating stem cells, but it now appears that a variety of other less differentiated cells can be recruited when needed. Cells from the blood can repair the endothelium of blood vessels, and endothelial cells can become mesenchymal cells, in the heart, for example.

The standard doctrine about cancer is that a tumor derives from a single mutant cell, but it has been known for a long time that different types of cell, such as phagocytes and mast cells, usually reside in tumors, and it is now becoming clear that tumors recruit cells, including apparently normal cells, from other parts of the same organ. For example, a brain tumor of glial cells, a glioma, recruits glial cells from surrounding areas of the brain, in a process that's analogous to the embryological movement of nerve cells to a center of excitation. Each tumor, in a sense, seems to be a center of excitation, and its fate seems to depend on the nature of the cells that respond to its signals.

To accommodate some of the newer facts about tumors, the cancer establishment has begun speaking of "the cancer stem cell" as the real villain, the origin of the tumor, while the bulk of the tumor is seen to be made up of defective cells that have a short life-span. But if we recognize that tumors are recruiting cells from beyond their boundaries, this process would account for the growth and survival of a tumor even while most of its cells are inert and dying, without invoking the invisible cancer stem cell. And this view, that it is the field which is defective rather than the cell, is consistent with the evidence which has been accumulating for 35 years that tumor cells, given the right environment, can differentiate into healthy cells. (Hendrix, et al., 2007)

Simply stretching an organ (Woo, et al., 2007) is stimulus enough to cause it to recruit cells from the bloodstream, and will probably stimulate multiplication in its local resident cells, too. Every "cancer field" probably begins as a healing process, and generally the healing and regeneration are at least partially successful.

When an organ--the brain, heart, liver, or a blood vessel--is inflamed or suffering from an insufficient blood supply, stem cells introduced into the blood will migrate specifically to that organ.

Organ specific materials (chalones) are known to circulate in the blood, inhibiting cell division in cells typical to that organ, but it also seems that organ specific materials are secreted by a damaged organ, that help to prepare stem cells for their migration into that organ. When undifferentiated cells are cultured with serum from a person with liver failure, they begin to differentiate into liver cells.

It is still common to speak of each organ as having a "clonal origin" in the differentiating embryo, as a simple expansion of a certain embryonic anlage. The implication of this way of thinking is that differentiation is determination in an irreversible sense. This is another case of medical ideas being based on images of fixed histological material. Normal cells, including nerve and muscle cells, can change type, with connective tissue cells becoming nerve cells, nerve cells becoming muscle and fiber cells, fat, fiber, and muscle cells redifferentiating, for example.

Cell movements in solid tissues aren't limited to the short distances between capillaries and the tissues nourished by those capillaries, rather, cells can migrate much greater distances, without entering the bloodstream. The speed of a single cell moving by ameboid motion can be measured by watching cells on a glass slide as they move toward food, or by watching cells of the slime mold Dictyostelium when they are aggregating, or by watching the pigment cells in and around moles or melanomas, under the influence of hormones. At body temperature, a single cell can crawl about an inch per day. Waves or spots of brown pigment can be seen migrating through the skin away from a mole, preceding the disintegration of the mole under the influence of progesterone or DHEA. Under ordinary conditions, pigment cells can sometimes be seen migrating into depigmented areas of skin, during the recovery of an area affected by vitiligo. These organized movements of masses of cells happen to be easy to see, but there is evidence that other types of cell can reconstruct tissues by their ameboid movements, when circumstances are right. Tumors or tissue abnormalities can appear or disappear with a suddenness that seems impossible to people who have studied only fixed tissue preparations.

Stimulation is anabolic, building tissue, when the organism is adapting to the stimulation. Unused structures in cells and tissues are always being recycled by metabolic processes. When tissues are injured and become unable to function, some of their substances stimulate the growth of replacement cells.

Some types of injury or irritation can activate regenerative processes. A dermatology journal described the case of an old man who had been bald for many years who fell head-first into his fireplace. As his burned scalp healed, new hair grew. In the U.S., experimenters (Ito, et al., 2007) have found that injuring the skin of mice stimulates the formation of stem cells that are able to become hair follicle cells, supporting the regeneration of cells that had been absent. A brief exposure to estrogen, and other stress related signals (nitric oxide, endorphin, prostaglandins) can initiate stem cell proliferation.

In the years after the first world war, Vladimir Filatov, who developed techniques of reconstructive surgery, including corneal transplants, found that cold storage of tissues (for example, corneas from cadavers) caused them to function better than fresh tissues, and he found that these stressed tissues would often spread a healing influence out into the surrounding tissues. Extracts of stressed tissues produced similar effects.

L.V. Polezhaev began studying the regenerative capacities of mammals in the late 1940s, and his work showed that processes similar to embryonic induction are involved in the organism's responses to damaged tissues. For example, when a piece of killed muscle tissue is enclosed in a capsule ("diffusion chamber") that permits molecules, but no cells, to diffuse through it, and implanted subcutaneously, it had no inductive effect on surrounding cells. But when the pores of the capsule allowed cells to enter, skeletal muscle formed where the dead tissue had been, and tissue resembling heart muscle formed outside the capsule. Phagocytosis had been essential for the induction to occur.

Macrophages are ordinarily thought of as "antigen-presenting cells" that help to activate the specific immune responses. But apparently phagocytosis is involved in the replacement of damaged tissues, by recruiting or inducing the differentiation of replacement cells. The phagocytosis function isn't limited to the blood cells commonly called phagocytes; even nerve cells can ingest particles and fragments of damaged tissues.

Many factors regulate the process of phagocytosis. Stress and lipid peroxidation decrease phagocytosis (Izgüt-Uysal, et al., 2004), and also damage mitochondria and inhibit cell renewal.

Unsaturated fatty acids inhibit phagocytosis (Guimaraes, et al., 1991, 1992; Costa Rosa, et al., 1996; Virella, et al., 1989; Akamatsu, et al., 1990), and suppress mitochondrial function (Gomes, et al., 2006). Dietary restriction activates phagocytosis (Moriguchi, et al., 1989), suggesting that normal diets contain suppressive materials.

Subnormal temperatures cause a shift from phagocytosis to inflammation. Light, especially the red light which penetrates easily into tissues, activates the formation of new cells as well as their differentiation. It affects energy production, increasing the formation of mitochondria, and the activity of the DNA methyltransferase enzymes. Red light accelerates wound healing, and improves the quality of the scar, reducing the amount of fibrosis. The daily cycling between darkness and light is probably an important factor in regulating the birth and differentiation of cells.

Darkness suppresses mitochondrial function, and light activates it. Prolonged darkness increases cortisol, and cortisol (which makes cells more susceptible to excitotoxic death) inhibits stem cell proliferation (Li, et al., 2006; Liu, et al., 2003). Neurogenesis is suppressed by stress, and increased by spontaneous activity, and has a circadian rhythm. Aging and depression both involve a diminished ability to rhythmically lower the production of cortisol. Cell renewal requires a rhythmic decrease in the exposure to cortisol..

In the spring, with increased day length, the brains of song-birds grow, with an increased proliferation of cells in the part of the brain involved in singing. The production of progesterone increases in most animals in the spring, and it is the main hormone responsible for the birds' brain growth.

Progesterone and its metabolites protect brain cells against injury, and improve the brain's ability to recover after traumatic injury (Brinton and Wang, 2006). In the 1960s, Marion Diamond's group showed that environmental enrichment, or progesterone, caused brains to grow larger, and that these changes were passed on to descendants in a cumulative, increasing way. This suggests that the factors that promote neurogenesis also cause changes in the apparatus of reproduction and inheritance, that support the development of the brain--probably including the methylation system, which is involved in regulating genes, and also mood and behavior.

Women's monthly cycles, in which a brief estrogen dominance is followed by sustained exposure to progesterone, are probably an important factor in the renewal of the cells of the brain and other organs, as well as those of the reproductive organs. The daily rhythms of hormones and metabolism are known to be involved in the regulation of cell renewal.

Environmental enrichment, learning, high altitude, and thyroid hormone promote the formation of new mitochondria, and stimulate stem cell proliferation. At least in some laboratories, 20% oxygen, approximately the amount as in the atmosphere, suppresses the proliferation of stem cells (He, et al., 2007). This was the unphysiologically high concentration of oxygen used in Hayflick's cell cultures. At high altitudes, where tissues are exposed to less oxygen, and more carbon dioxide, there is a lower incidence of all the degenerative diseases, including cancer, heart disease, and dementia. Improved cellular energy production and more active renewal of cells would probably account for those differences.

For Crick, the idea of a diffusion gradient to explain embryonic development was simply an extension of his reductionist orientation, in which diffusing molecules induced or inhibited bacterial genes, and in which genes controlled cells. For people with that orientation, the adaptive mutations described by Carl Lindegren, and later by John Cairns, or even the stress-induced variability described by Lysenko, Strong, and McClintock, were heretical. Polezhaev's demonstration that cells could do something that molecular diffusion didn't do, threatened to take biology away from the reductionists. If the organism's adaptation to the environment involves changing its own genes, Crick's paradigm fails.

Crick's Central Dogma, derived from the ideology that produced Weismann's Barrier, has been invoked by generations of professors who wanted to deny the possibility of adaptive tissue renewal and regeneration. Without the dogma, new ideas about aging and disease will be needed. If somatic cells can adjust their genes, and if they can also differentiate into new eggs and sperms, new ideas about inheritance of acquired traits will be needed.

The replacement of injured cells means that mutations need not accumulate. Cell renewal with elimination of mutant cells has been observed in sun-damaged skin simply by stopping the damage, and mitochondria with damaged DNA can be replaced by healthy mitochondria simply by doing the right kind of exercise.

The regulation of cell renewal probably involves all of the processes of life, but there are a few simple, interacting factors that suppress renewal. The accumulation of polyunsaturated fats, interacting with a high concentration of oxygen, damages mitochondria, and causes a chronic excessive exposure to cortisol. With mitochondrial damage, cells are unable to produce the progesterone needed to oppose cortisol and to protect cells.

Choosing the right foods, the right atmosphere, the right mental and physical activities, and finding the optimal rhythms of light, darkness, and activity, can begin to alter the streaming renewal of cells in all the organs. Designing a more perfect environment is going to be much simpler than the schemes of the genetic engineers.

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Stem cells, cell culture, and culture: Issues in regeneration

Cell renewal is a factor in all aspects of health and disease, not just in aging and the degenerative diseases. Many people are doing valid research relating to cell renewal and regeneration, but its usefulness is seriously limited by cultural and commercial constraints. By recovering some of our suppressed traditional culture, I think regenerative therapies can be developed quickly, by identifying and eliminating as far as possible the main factors that interfere with tissue renewal.

Science grew up in the highly authoritarian cultures of western Europe, and even as it contributed to cultural change, it kept an authoritarian mystique. Any culture functions as a system of definitions of reality and the limits of possibility, and to a great extent the "laws of nature" are decreed so that they will harmonize with the recognized laws of society.

The practical success of Newton's "laws" of motion when they were applied to ballistics and "rocket science" has led many people to value calculation, based on those laws, over evidence. In biology, the idea that an organism is "the information it contains in its DNA blueprint" is an extention of this. The organism is turned into something like a deductive expression of the law of DNA. This attitude has been disastrous.

The old feudal idea of a divine and stable social organization was applied by some people to their idea of biological organization, in which each cell (ruled by its nucleus) had its ordained place in the organism, with the brain and the "master gland," the pituitary, ruling the subordinate organs, tissues, and cells. "Anatomy" was taught from dead specimens, microscope slides, and illustrations in books. Most biologists' thoughts about cells in organisms reflect the static imagery of their instruction. ("The histological image of these tissues actually reflects an instantaneous picture of cells in a continuous flux." Zajicek, 1981.)

When a person has playful and observant interactions with natural things, both regularities and irregularities will be noticed, and in trying to understand those events, the richness of the experience will suggest an expansive range of possibilities. Perception and experimentation lead to understandings that are independent of culture and tradition.

But the mystique of science easily imposes itself, and distracts our attention from direct interactions with things. As we learn to operate lab instruments, we are taught the kinds of results that can be expected, and the concepts that will explain and predict the results of our operations. Science, as we learn about it in schools and the mass media, is mostly a set of catechisms.

Our theories about organisms inform our experiments with cells or tissues that have been isolated from those organisms. The conditions for growing cells in dishes are thought of as "physiological," in relation to the solution's "physiological osmolarity," "physiological pH," nutrients, oxygenation, temperature, pressure, etc. But these concepts of what is physiological derive from the monolithic ideology of the doctrinaire, and often fraudulent, mainstream of biological science.

The catechismic nature of science has led people to expect some "break-throughs" to occur in certain areas, and as authoritarian science has grown into "big science" managed by corporations and governments, those break-throughs are generally expected to be produced by the newest and most expensive developments of "high technology."

But looking closely at the real events and processes in the sciences in the last couple of centuries, it turns out that useful advances have been produced mainly by breaking away from authoritarian doctrines, to return to common sense and relatively simple direct observations.

Although people were cloning animals in the 1960s, it was still widely taught that it was impossible. The students of the professors who taught that it was impossible are now saying that it requires high technology and new research.

For the last 100 years the most authoritative view in biology has been that there are no stem cells in adults, that brains, hearts, pancreases and oocytes are absolutely incapable of regeneration. But now, people seem to be finding stem cells wherever they look, but there is a mystique of high technology involved in finding and using them.

Whether it's deliberate or not, the emphasis on stem cell technology has the function of directing attention away from traditional knowledge, the way allopathic medicine has de-emphasized the intrinsic ability of people to recover from disease.

This resembles the way that the Mendel-Morgan gene doctrine was used to suppress the knowledge gained from centuries of experience of plant and animal breeders, and to belittle the discoveries of Luther Burbank, Paul Kammerer, Trofim Lysenko, and Barbara McClintock. The same type of biochemical process that caused the hereditary changes those researchers studied are involved in the differentiation and dedifferentiation of stem cells that regulate healing and regeneration.

In the 1940s, even children discussed the biological discoveries of the 1920s and 1930s, the work in regeneration and adaptation, parthenogenesis, and immortalization. The ideas of J. Loeb, T. Boveri, A. Gurwitsch, J. Needham, C.M. Child, A. Carrel, et al., had become part of the general culture.

But that real biology was killed by a consortium of industry and government that began a little before the second world war. In 1940, the government was supporting research in chemical and biological warfare, and with the Manhattan Project the role of government became so large that all of the major research universities were affected. Shortly after the war, many researchers from the Manhattan Project were redeployed into "molecular genetics," where the engineering attitude was applied to organisms.

The simplistic genetic dogmas were compatible with the reductionist engineering approach to the organism. The role of the government assured that the universities would subscribe to the basic scientific agenda. The atmosphere of that time was described by Carl Lindegren as "The Cold War in Biology" (1966).

The disappearance of the field concept in developmental biology was one of the strangest events in the history of science. It didn't just fade away, it was "disappeared," in a massive undertaking of social engineering. In its absence, stem cells will seem to be a profitable technological marvel, rather than a universal life function, with a central role in everything we are and everything we do and can become.

Many people have tried to explain aging as a loss of cells, resulting from an intrinsic inability of any cell other than a germ cell to multiply more than a certain number of times. More than 40 years ago Leonard Hayflick popularized this doctrine in its most extreme form, saying that no cell can divide more than 50 times unless it is converted into a cancer cell. He and his followers claimed that they had explained why organisms must age and die. At the moment the ovum is fertilized, the clock starts ticking for the essentially mortal somatic cells.

In 1970, it was being seriously proposed that memory was produced by the death of brain cells, in a manner analogous to the holes punched in cards to enter data into computers. The cultural dogma made it impossible to consider that learning could be associated with the birth of new cells in the adult brain.

With the announcement in 1997 of the cloning of the sheep Dolly from a somatic cell taken from a 6 year old sheep, there was renewed interest in the idea made famous by Alexis Carrel that all cells are potentially immortal, and in the possibility of preserving the vitality of human cells. Within a few months, Hayflick began reminding the public that "In the early 1960's we overthrew this dogma after finding that normal cells do have a finite replicative capacity." ("During the first half of this century it was believed that because cultured normal cells were immortal, aging must be caused by extra-cellular events.") The way Hayflick "overthrew" more than 35 years of work at the Rockefeller Institute was by growing one type of cell, a lung fibroblast, in culture dishes, and finding that the cultures deteriorated quickly.

To draw global conclusions about an organism's development and aging from the degenerative processes seen in a single type of cell, grown in isolation from all normal stimuli, would have been treated as nothing but wild speculation, except that it occurred within a culture that needed it. No aspect of Hayflick's cell culture system could properly be called physiological.

Other researchers, simply by changing a single factor, caused great increases in the longevity of the cultured cells. Simply using a lower, more natural oxygen concentration, the cells were able to undergo 20 more divisions. Just by adding niacin, 30 more divisions; vitamin E, 70 more divisions. Excess oxygen is a poison requiring constant adaptation.

Hayflick also published the observation that, while the cells kept in dishes at approximately body temperature deteriorated, cells kept frozen in liquid nitrogen didn't deteriorate, and he concluded that "time" wasn't the cause of aging. When I read his comments about the frozen cells, I wondered how anyone of normal intelligence could make such stupid statements. Since then, facts that came out because of the Freedom of Information Act, cause me to believe that a financial motive guided his thoughts about his cultured fibroblasts.

Hayflick and his followers have been attacking the idea of anti-aging medicine as quackery. But he is closely involved with the Geron corporation, which proposes that genetic alterations relating to telomeres may be able to cure cancer and prevent aging. Their claims were reported by CNN as "Scientists discover cellular 'fountain of youth'."

The "wear and tear" doctrine of aging that derived from the ideology of the gene was reinforced and renewed by Hayflick's cell culture observations, and it continued to rule the universities and popular culture.

But detailed investigation of skin cell growth showed that cells in the lower layer of the skin divide at least 10,000 times in a normal lifetime, and similar processes occur in the lining of the intestine. The endometrium and other highly renewable tissues just as obviously violated Hayflick's limit. Transplantation experiments showed that pieces of mammary tissue or skin tissue could survive through ten normal lifetimes of experimental animals without suffering the effects of aging.

Even the liver and adrenal gland are now known to be continuously renewed by "cell streaming," though at a slower rate than the skin, conjunctiva, and intestine. Neurogenesis in the brain is now not only widely accepted, it is even proposed as a mechanism to explain the therapeutic effects of antidepressants (Santarelli, et al., 2003).

August Weismann's most influential doctrine said that "somatic cells are mortal, only the germline cells are immortal," but he based the doctrine on his mistaken belief that only the "germline" cells contained all the genes of the organism. In 1885, to "refute" Darwin's belief that acquired traits could be inherited, he promulgated an absolute "barrier" between "germline" and "soma," and invented facts to show that hereditary information can flow only from the germline to the somatic cells, and not the other direction. Shortly after DNA became popular in the 1950s as "the genetic material," Weismann's barrier was restated as the Central Dogma of molecular genetics, that information flows only from DNA to RNA to protein, and never the other direction.

It was only in 2003, after the reality of cloning was widely recognized, that a few experimenters began to investigate the origin of "germline" cells in the ovary, and to discover that they derive from somatic cells (Johnson, et al., 2004). With this discovery, the ancient knowledge that a twig (klon, in Greek) cut from a tree could grow into a whole tree, bearing fruit and viable seeds, was readmitted to general biology, and the Weismann barrier was seen to be an illusion.

Millions of people have "explained" female reproductive aging as the consequence of the ovary "running out of eggs." Innumerable publications purported to show the exact ways in which that process occurs, following the Weismann doctrine. But now that it is clear that adult ovaries can give birth to new oocytes, a new explanation for female reproductive aging is needed. It is likely that the same factors that cause female reproductive aging also cause aging of other systems and organs and tissues, and that those factors are extrinsic to the cells themselves, as Alexis Carrel and others demonstrated long ago. This is a way of saying that all cells are potential stem cells. The "niche" in which new cells are born in the streaming organism, and the processes by which damaged cells are removed, are physiological issues that can be illuminated by the idea of a morphogenetic field.

When the post-war genetic engineers took over biological research, the idea of a biophysical field was totally abandoned, but after about 15 years, it became necessary to think of problems beyond those existing within a single bacterium, namely, the problem of how an ovum becomes and embryo. Francis Crick, of DNA fame, who was educated as a physicist, revived (without a meaningful historical context) the idea of a diffusion gradient as a simple integrating factor that wouldn't be too offensive to the reductionists. But for events far beyond the scale of the egg's internal structure, for example to explain how a nerve axon can travel a very long distance to innervate exactly the right kind of cell, the diffusion of molecules loses its simplicity and plausibility. (Early in the history of experimental embryology, it was observed that electrical fields affect the direction of growth of nerve fibers.)

C. M. Child saw a gradient of metabolic activity as an essential component of the morphogenetic field. This kind of gradient doesn't deny the existence of diffusion gradients, or other physical components of a field. Electrical and osmotic (and electro-osmotic) events are generated by metabolism, and affect other factors, including pH, oxidation and reduction, cell motility and cell shape, ionic selectivity and other types of cellular selectivity and specificity. Gradients of DNA methylation exist, and affect the expression of inherited information.

Methylation decreases the expression of particular genes, and during the differention of cells in the development of an embryo, genes are methylated and demethylated as the cell adapts to produce the proteins that are involved in the structure and function of a particular tissue. Methylation (which increases a molecule's affinity for fats) is a widespread process in cells, and for example regulates cellular excitability. It is affected by diet and a variety of stresses.

DNA methylation patterns are normally fairly stable, and can help to account for the transgenerational transmission of acquired adaptations, and for neonatal imprinting that can last a lifetime. But with injury, stress, and aging, the methylation patterns of differentiated tissues can be changed, contributing to the development of tumors, or to the loss of cellular functions. Even learning can change the methylation of specific genes. During in vitro culture, the enzymes of gene methylation are known to be increased, relative to their normal activity (Wang, et al., 2005).

The phenomenon of "gene" methylation in response to environmental and metabolic conditions may eventually lead to the extinction of the doctrine that "cells are controlled by their genes."

During successful adaptation to stress, cells make adjustments to their metabolic systems (for example with a holistic change of the degree of phosphorylation, which increases molecules' affinity for water), and their metabolic processes can contribute to changes in their state of differentiation. Some changes may lead to successful adaptation (for example by producing biogenic stimulators that stimulate cell functioning and regeneration), others to failed adaptation. Even the decomposition of cells can release substances that contribute to the adaptation of surrounding cells, for example when sphingosines stimulate the production of stem cells.

DNA methylation is just one relatively stable event that occurs in relation to a metabolic field. Modifications of histones (regulatory proteins in chromosomes, which are acetylated as well as methylated) and structural-contractile filaments also contribute to the differentiation of cells, but the pattern of DNA methylation seems to guide the methylation of histones and the structure of the chromosomes (Nan, et al., 1998).

Steroids and phospholipids, neurotransmitters and endorphins, ATP, GTP, other phosphates, retinoids, NO and CO2--many materials and processes participate in the coherence of the living state, the living substance. Carbon dioxide, for example, by binding to lysine amino groups in the histones, will influence their methylation. Carbon dioxide is likely to affect other amino groups in the chromosomes.

The number and arrangement of mitochondria is an important factor in producing and maintaining the metabolic gradients. Things that decrease mitochondrial energy production--nitric oxide, histamine, cytokines, cortisol--increase DNA methylation. Decreased gene expression is associated with reduced respiratory energy. It seems reasonable to guess that increased gene expression would demand increased availability of energy.

As an ovum differentiates into an organism, cells become progressively more specialized, inhibiting the expression of many genes. Less energy is needed by stably functioning cells, than by actively adapting cells. A.I. Zotin described the process of maturing and differentiating as a decrease of entropy, an increase of order accompanying a decreased energy expenditure. The entropic egg develops into a less entropic embryo with a great expenditure of energy.

The partially differentiated stem cell doesn't go through all the stages of development, but it does expend energy intensely as it matures.

The restoration of energy is one requirement for the activation of regeneration. When a hormone such as noradrenaline or insulin causes a stem cell to differentiate in vitro, it causes new mitochondria to form. This is somewhat analogous to the insertion of mitochondria into the ripening oocyte, by the nurse cells that surround it. The conditionally decreased entropy of maturation is reversed, and when sufficient respiratory energy is available, the renewed and refreshed cell will be able to renew an appropriate degree of differentiation.

When simple organisms, such as bacteria, fungi, or protozoa are stressed, for example by the absence of nutrients or the presence of toxins, they slow their metabolism, and suppress the expression of genes, increasing the methylation of DNA, to form resistant and quiescent spores. Our differentiated state doesn't go to the metabolic extreme seen in sporulation, but it's useful to look at maturity and aging in this context, because it suggests that the wrong kind of stress decreases the ability of the organism to adapt, by processes resembling those in the spore-forming organisms.

Charles Vacanti, who has grown cartilage from cells taken from 100 year old human cartilage, believes our tissues contain "spore cells," very small cells with slow metabolism and extreme resistance to heat, cold, and starvation.

If the slowed metabolism of aging, like that of sporulating cells, is produced by a certain kind of stress that lowers cellular energy and functions, it might be useful to think of the other stages of the stress reaction in relation to the production of stem cells. Selye divided stress into a first stage of shock, followed by a prolonged adaptation, which could sometimes end in exhaustion. If the maturity of differentiated functioning is equivalent to the adaptation phase, and cellular decline and disintegration is the exhaustion phase, then the shock-like reaction would correspond to the birth of new stem cells.

Selye described estrogen's effects as equivalent to the shock-phase of stress. Estrogen's basic action is to make oxygen unavailable, lowering the oxygen tension of the tissues, locally and temporarily. Like nitric oxide, which is produced by estrogenic stimulation, estrogen interferes with energy production, so if its stimulation is prolonged, cells are damaged or killed, rather than being stimulated to regenerate.

Extrinsic factors elicit renewal, the way stress can elicit adaptation. While aging cells can't use the oxygen that is present, a scarcity of oxygen can serve as a stimulus to maximize the respiratory systems. Brief oxygen deprivation excites a cell, causes it to swell, and to begin to divide.

Oxygen deprivation, as in the normally hypoxic bone marrow, stimulates the formation of stem cells, as well as the biogenesis of mitochondria. As the newly formed cells, with abundant mitochondria, get adequate oxygen, they begin differentiation.

Form, based on cellular differentiation, follows function--a vein transplanted into an artery develops anatomically into an artery, a colon attached directly to the anus becomes a new rectum with its appropriate innervation, a broken bone restructures to form a normal bone. If the bladder is forced to function more than normal, by artificially keeping it filled, its thin wall of smooth muscle develops into a thick wall of striated muscle that rhythmically contracts, like the heart. If a tadpole is given a vegetarian diet, the absorptive surface of its digestive system will develop to be twice the size of those that are fed meat. Pressure, stretching, and pulsation are among the signals that guide cells' differentiation.

Very early in the study of embryology it was noticed that the presence of one tissue sometimes induced the differentiation of another kind, and also that there were factors in embryonic tissues that would stimulate cell division generally, and others that could inhibit the growth of a particular tissue type. Diffusable substances and light were among the factors identified as growth regulators.

Extracts of particular tissues were found to suppress the multiplication of cells in that type of tissue, in adult animals as well as in embryos. In the 1960s, the tissue-specific inhibitors were called chalones.

The brain's development is governed by the presence in the organism of the body part to which it corresponds, such as the eyes or legs. The number of cells in a particular part of the nervous system is governed by the quantity of nervous input, sensory or motor, that it receives. An enriched environment causes a bigger brain to grow. Sensory nerve stimulation of a particular region of the brain causes nerve cells to migrate to that area (a process called neurobiotaxis; deBeers, 1927), but nerve stimulation also causes mitochondria to accumulate in stimulated areas. Nerve activity has a trophic, sustaining influence on other organs, as well as on the brain. Nerve stimulation, like mechanical pressure or stretching, is an important signal for cellular differentiation.

When stem cells or progenitor cells are called on to replace cells in an organ, they are said to be "recruited" by that organ, or to "home" to that organ, if they are coming from elsewhere. Traditionally, the bone marrow has been considered to be the source of circulating stem cells, but it now appears that a variety of other less differentiated cells can be recruited when needed. Cells from the blood can repair the endothelium of blood vessels, and endothelial cells can become mesenchymal cells, in the heart, for example.

The standard doctrine about cancer is that a tumor derives from a single mutant cell, but it has been known for a long time that different types of cell, such as phagocytes and mast cells, usually reside in tumors, and it is now becoming clear that tumors recruit cells, including apparently normal cells, from other parts of the same organ. For example, a brain tumor of glial cells, a glioma, recruits glial cells from surrounding areas of the brain, in a process that's analogous to the embryological movement of nerve cells to a center of excitation. Each tumor, in a sense, seems to be a center of excitation, and its fate seems to depend on the nature of the cells that respond to its signals.

To accommodate some of the newer facts about tumors, the cancer establishment has begun speaking of "the cancer stem cell" as the real villain, the origin of the tumor, while the bulk of the tumor is seen to be made up of defective cells that have a short life-span. But if we recognize that tumors are recruiting cells from beyond their boundaries, this process would account for the growth and survival of a tumor even while most of its cells are inert and dying, without invoking the invisible cancer stem cell. And this view, that it is the field which is defective rather than the cell, is consistent with the evidence which has been accumulating for 35 years that tumor cells, given the right environment, can differentiate into healthy cells. (Hendrix, et al., 2007)

Simply stretching an organ (Woo, et al., 2007) is stimulus enough to cause it to recruit cells from the bloodstream, and will probably stimulate multiplication in its local resident cells, too. Every "cancer field" probably begins as a healing process, and generally the healing and regeneration are at least partially successful.

When an organ--the brain, heart, liver, or a blood vessel--is inflamed or suffering from an insufficient blood supply, stem cells introduced into the blood will migrate specifically to that organ.

Organ specific materials (chalones) are known to circulate in the blood, inhibiting cell division in cells typical to that organ, but it also seems that organ specific materials are secreted by a damaged organ, that help to prepare stem cells for their migration into that organ. When undifferentiated cells are cultured with serum from a person with liver failure, they begin to differentiate into liver cells.

It is still common to speak of each organ as having a "clonal origin" in the differentiating embryo, as a simple expansion of a certain embryonic anlage. The implication of this way of thinking is that differentiation is determination in an irreversible sense. This is another case of medical ideas being based on images of fixed histological material. Normal cells, including nerve and muscle cells, can change type, with connective tissue cells becoming nerve cells, nerve cells becoming muscle and fiber cells, fat, fiber, and muscle cells redifferentiating, for example.

Cell movements in solid tissues aren't limited to the short distances between capillaries and the tissues nourished by those capillaries, rather, cells can migrate much greater distances, without entering the bloodstream. The speed of a single cell moving by ameboid motion can be measured by watching cells on a glass slide as they move toward food, or by watching cells of the slime mold Dictyostelium when they are aggregating, or by watching the pigment cells in and around moles or melanomas, under the influence of hormones. At body temperature, a single cell can crawl about an inch per day. Waves or spots of brown pigment can be seen migrating through the skin away from a mole, preceding the disintegration of the mole under the influence of progesterone or DHEA. Under ordinary conditions, pigment cells can sometimes be seen migrating into depigmented areas of skin, during the recovery of an area affected by vitiligo. These organized movements of masses of cells happen to be easy to see, but there is evidence that other types of cell can reconstruct tissues by their ameboid movements, when circumstances are right. Tumors or tissue abnormalities can appear or disappear with a suddenness that seems impossible to people who have studied only fixed tissue preparations.

Stimulation is anabolic, building tissue, when the organism is adapting to the stimulation. Unused structures in cells and tissues are always being recycled by metabolic processes. When tissues are injured and become unable to function, some of their substances stimulate the growth of replacement cells.

Some types of injury or irritation can activate regenerative processes. A dermatology journal described the case of an old man who had been bald for many years who fell head-first into his fireplace. As his burned scalp healed, new hair grew. In the U.S., experimenters (Ito, et al., 2007) have found that injuring the skin of mice stimulates the formation of stem cells that are able to become hair follicle cells, supporting the regeneration of cells that had been absent. A brief exposure to estrogen, and other stress related signals (nitric oxide, endorphin, prostaglandins) can initiate stem cell proliferation.

In the years after the first world war, Vladimir Filatov, who developed techniques of reconstructive surgery, including corneal transplants, found that cold storage of tissues (for example, corneas from cadavers) caused them to function better than fresh tissues, and he found that these stressed tissues would often spread a healing influence out into the surrounding tissues. Extracts of stressed tissues produced similar effects.

L.V. Polezhaev began studying the regenerative capacities of mammals in the late 1940s, and his work showed that processes similar to embryonic induction are involved in the organism's responses to damaged tissues. For example, when a piece of killed muscle tissue is enclosed in a capsule ("diffusion chamber") that permits molecules, but no cells, to diffuse through it, and implanted subcutaneously, it had no inductive effect on surrounding cells. But when the pores of the capsule allowed cells to enter, skeletal muscle formed where the dead tissue had been, and tissue resembling heart muscle formed outside the capsule. Phagocytosis had been essential for the induction to occur.

Macrophages are ordinarily thought of as "antigen-presenting cells" that help to activate the specific immune responses. But apparently phagocytosis is involved in the replacement of damaged tissues, by recruiting or inducing the differentiation of replacement cells. The phagocytosis function isn't limited to the blood cells commonly called phagocytes; even nerve cells can ingest particles and fragments of damaged tissues.

Many factors regulate the process of phagocytosis. Stress and lipid peroxidation decrease phagocytosis (Izgüt-Uysal, et al., 2004), and also damage mitochondria and inhibit cell renewal.

Unsaturated fatty acids inhibit phagocytosis (Guimaraes, et al., 1991, 1992; Costa Rosa, et al., 1996; Virella, et al., 1989; Akamatsu, et al., 1990), and suppress mitochondrial function (Gomes, et al., 2006). Dietary restriction activates phagocytosis (Moriguchi, et al., 1989), suggesting that normal diets contain suppressive materials.

Subnormal temperatures cause a shift from phagocytosis to inflammation. Light, especially the red light which penetrates easily into tissues, activates the formation of new cells as well as their differentiation. It affects energy production, increasing the formation of mitochondria, and the activity of the DNA methyltransferase enzymes. Red light accelerates wound healing, and improves the quality of the scar, reducing the amount of fibrosis. The daily cycling between darkness and light is probably an important factor in regulating the birth and differentiation of cells.

Darkness suppresses mitochondrial function, and light activates it. Prolonged darkness increases cortisol, and cortisol (which makes cells more susceptible to excitotoxic death) inhibits stem cell proliferation (Li, et al., 2006; Liu, et al., 2003). Neurogenesis is suppressed by stress, and increased by spontaneous activity, and has a circadian rhythm. Aging and depression both involve a diminished ability to rhythmically lower the production of cortisol. Cell renewal requires a rhythmic decrease in the exposure to cortisol..

In the spring, with increased day length, the brains of song-birds grow, with an increased proliferation of cells in the part of the brain involved in singing. The production of progesterone increases in most animals in the spring, and it is the main hormone responsible for the birds' brain growth.

Progesterone and its metabolites protect brain cells against injury, and improve the brain's ability to recover after traumatic injury (Brinton and Wang, 2006). In the 1960s, Marion Diamond's group showed that environmental enrichment, or progesterone, caused brains to grow larger, and that these changes were passed on to descendants in a cumulative, increasing way. This suggests that the factors that promote neurogenesis also cause changes in the apparatus of reproduction and inheritance, that support the development of the brain--probably including the methylation system, which is involved in regulating genes, and also mood and behavior.

Women's monthly cycles, in which a brief estrogen dominance is followed by sustained exposure to progesterone, are probably an important factor in the renewal of the cells of the brain and other organs, as well as those of the reproductive organs. The daily rhythms of hormones and metabolism are known to be involved in the regulation of cell renewal.

Environmental enrichment, learning, high altitude, and thyroid hormone promote the formation of new mitochondria, and stimulate stem cell proliferation. At least in some laboratories, 20% oxygen, approximately the amount as in the atmosphere, suppresses the proliferation of stem cells (He, et al., 2007). This was the unphysiologically high concentration of oxygen used in Hayflick's cell cultures. At high altitudes, where tissues are exposed to less oxygen, and more carbon dioxide, there is a lower incidence of all the degenerative diseases, including cancer, heart disease, and dementia. Improved cellular energy production and more active renewal of cells would probably account for those differences.

For Crick, the idea of a diffusion gradient to explain embryonic development was simply an extension of his reductionist orientation, in which diffusing molecules induced or inhibited bacterial genes, and in which genes controlled cells. For people with that orientation, the adaptive mutations described by Carl Lindegren, and later by John Cairns, or even the stress-induced variability described by Lysenko, Strong, and McClintock, were heretical. Polezhaev's demonstration that cells could do something that molecular diffusion didn't do, threatened to take biology away from the reductionists. If the organism's adaptation to the environment involves changing its own genes, Crick's paradigm fails.

Crick's Central Dogma, derived from the ideology that produced Weismann's Barrier, has been invoked by generations of professors who wanted to deny the possibility of adaptive tissue renewal and regeneration. Without the dogma, new ideas about aging and disease will be needed. If somatic cells can adjust their genes, and if they can also differentiate into new eggs and sperms, new ideas about inheritance of acquired traits will be needed.

The replacement of injured cells means that mutations need not accumulate. Cell renewal with elimination of mutant cells has been observed in sun-damaged skin simply by stopping the damage, and mitochondria with damaged DNA can be replaced by healthy mitochondria simply by doing the right kind of exercise.

The regulation of cell renewal probably involves all of the processes of life, but there are a few simple, interacting factors that suppress renewal. The accumulation of polyunsaturated fats, interacting with a high concentration of oxygen, damages mitochondria, and causes a chronic excessive exposure to cortisol. With mitochondrial damage, cells are unable to produce the progesterone needed to oppose cortisol and to protect cells.

Choosing the right foods, the right atmosphere, the right mental and physical activities, and finding the optimal rhythms of light, darkness, and activity, can begin to alter the streaming renewal of cells in all the organs. Designing a more perfect environment is going to be much simpler than the schemes of the genetic engineers.

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Stem cells, cell culture, and culture: Issues in regeneration

Cell renewal is a factor in all aspects of health and disease, not just in aging and the degenerative diseases. Many people are doing valid research relating to cell renewal and regeneration, but its usefulness is seriously limited by cultural and commercial constraints. By recovering some of our suppressed traditional culture, I think regenerative therapies can be developed quickly, by identifying and eliminating as far as possible the main factors that interfere with tissue renewal.

Science grew up in the highly authoritarian cultures of western Europe, and even as it contributed to cultural change, it kept an authoritarian mystique. Any culture functions as a system of definitions of reality and the limits of possibility, and to a great extent the "laws of nature" are decreed so that they will harmonize with the recognized laws of society.

The practical success of Newton's "laws" of motion when they were applied to ballistics and "rocket science" has led many people to value calculation, based on those laws, over evidence. In biology, the idea that an organism is "the information it contains in its DNA blueprint" is an extention of this. The organism is turned into something like a deductive expression of the law of DNA. This attitude has been disastrous.

The old feudal idea of a divine and stable social organization was applied by some people to their idea of biological organization, in which each cell (ruled by its nucleus) had its ordained place in the organism, with the brain and the "master gland," the pituitary, ruling the subordinate organs, tissues, and cells. "Anatomy" was taught from dead specimens, microscope slides, and illustrations in books. Most biologists' thoughts about cells in organisms reflect the static imagery of their instruction. ("The histological image of these tissues actually reflects an instantaneous picture of cells in a continuous flux." Zajicek, 1981.)

When a person has playful and observant interactions with natural things, both regularities and irregularities will be noticed, and in trying to understand those events, the richness of the experience will suggest an expansive range of possibilities. Perception and experimentation lead to understandings that are independent of culture and tradition.

But the mystique of science easily imposes itself, and distracts our attention from direct interactions with things. As we learn to operate lab instruments, we are taught the kinds of results that can be expected, and the concepts that will explain and predict the results of our operations. Science, as we learn about it in schools and the mass media, is mostly a set of catechisms.

Our theories about organisms inform our experiments with cells or tissues that have been isolated from those organisms. The conditions for growing cells in dishes are thought of as "physiological," in relation to the solution's "physiological osmolarity," "physiological pH," nutrients, oxygenation, temperature, pressure, etc. But these concepts of what is physiological derive from the monolithic ideology of the doctrinaire, and often fraudulent, mainstream of biological science.

The catechismic nature of science has led people to expect some "break-throughs" to occur in certain areas, and as authoritarian science has grown into "big science" managed by corporations and governments, those break-throughs are generally expected to be produced by the newest and most expensive developments of "high technology."

But looking closely at the real events and processes in the sciences in the last couple of centuries, it turns out that useful advances have been produced mainly by breaking away from authoritarian doctrines, to return to common sense and relatively simple direct observations.

Although people were cloning animals in the 1960s, it was still widely taught that it was impossible. The students of the professors who taught that it was impossible are now saying that it requires high technology and new research.

For the last 100 years the most authoritative view in biology has been that there are no stem cells in adults, that brains, hearts, pancreases and oocytes are absolutely incapable of regeneration. But now, people seem to be finding stem cells wherever they look, but there is a mystique of high technology involved in finding and using them.

Whether it's deliberate or not, the emphasis on stem cell technology has the function of directing attention away from traditional knowledge, the way allopathic medicine has de-emphasized the intrinsic ability of people to recover from disease.

This resembles the way that the Mendel-Morgan gene doctrine was used to suppress the knowledge gained from centuries of experience of plant and animal breeders, and to belittle the discoveries of Luther Burbank, Paul Kammerer, Trofim Lysenko, and Barbara McClintock. The same type of biochemical process that caused the hereditary changes those researchers studied are involved in the differentiation and dedifferentiation of stem cells that regulate healing and regeneration.

In the 1940s, even children discussed the biological discoveries of the 1920s and 1930s, the work in regeneration and adaptation, parthenogenesis, and immortalization. The ideas of J. Loeb, T. Boveri, A. Gurwitsch, J. Needham, C.M. Child, A. Carrel, et al., had become part of the general culture.

But that real biology was killed by a consortium of industry and government that began a little before the second world war. In 1940, the government was supporting research in chemical and biological warfare, and with the Manhattan Project the role of government became so large that all of the major research universities were affected. Shortly after the war, many researchers from the Manhattan Project were redeployed into "molecular genetics," where the engineering attitude was applied to organisms.

The simplistic genetic dogmas were compatible with the reductionist engineering approach to the organism. The role of the government assured that the universities would subscribe to the basic scientific agenda. The atmosphere of that time was described by Carl Lindegren as "The Cold War in Biology" (1966).

The disappearance of the field concept in developmental biology was one of the strangest events in the history of science. It didn't just fade away, it was "disappeared," in a massive undertaking of social engineering. In its absence, stem cells will seem to be a profitable technological marvel, rather than a universal life function, with a central role in everything we are and everything we do and can become.

Many people have tried to explain aging as a loss of cells, resulting from an intrinsic inability of any cell other than a germ cell to multiply more than a certain number of times. More than 40 years ago Leonard Hayflick popularized this doctrine in its most extreme form, saying that no cell can divide more than 50 times unless it is converted into a cancer cell. He and his followers claimed that they had explained why organisms must age and die. At the moment the ovum is fertilized, the clock starts ticking for the essentially mortal somatic cells.

In 1970, it was being seriously proposed that memory was produced by the death of brain cells, in a manner analogous to the holes punched in cards to enter data into computers. The cultural dogma made it impossible to consider that learning could be associated with the birth of new cells in the adult brain.

With the announcement in 1997 of the cloning of the sheep Dolly from a somatic cell taken from a 6 year old sheep, there was renewed interest in the idea made famous by Alexis Carrel that all cells are potentially immortal, and in the possibility of preserving the vitality of human cells. Within a few months, Hayflick began reminding the public that "In the early 1960's we overthrew this dogma after finding that normal cells do have a finite replicative capacity." ("During the first half of this century it was believed that because cultured normal cells were immortal, aging must be caused by extra-cellular events.") The way Hayflick "overthrew" more than 35 years of work at the Rockefeller Institute was by growing one type of cell, a lung fibroblast, in culture dishes, and finding that the cultures deteriorated quickly.

To draw global conclusions about an organism's development and aging from the degenerative processes seen in a single type of cell, grown in isolation from all normal stimuli, would have been treated as nothing but wild speculation, except that it occurred within a culture that needed it. No aspect of Hayflick's cell culture system could properly be called physiological.

Other researchers, simply by changing a single factor, caused great increases in the longevity of the cultured cells. Simply using a lower, more natural oxygen concentration, the cells were able to undergo 20 more divisions. Just by adding niacin, 30 more divisions; vitamin E, 70 more divisions. Excess oxygen is a poison requiring constant adaptation.

Hayflick also published the observation that, while the cells kept in dishes at approximately body temperature deteriorated, cells kept frozen in liquid nitrogen didn't deteriorate, and he concluded that "time" wasn't the cause of aging. When I read his comments about the frozen cells, I wondered how anyone of normal intelligence could make such stupid statements. Since then, facts that came out because of the Freedom of Information Act, cause me to believe that a financial motive guided his thoughts about his cultured fibroblasts.

Hayflick and his followers have been attacking the idea of anti-aging medicine as quackery. But he is closely involved with the Geron corporation, which proposes that genetic alterations relating to telomeres may be able to cure cancer and prevent aging. Their claims were reported by CNN as "Scientists discover cellular 'fountain of youth'."

The "wear and tear" doctrine of aging that derived from the ideology of the gene was reinforced and renewed by Hayflick's cell culture observations, and it continued to rule the universities and popular culture.

But detailed investigation of skin cell growth showed that cells in the lower layer of the skin divide at least 10,000 times in a normal lifetime, and similar processes occur in the lining of the intestine. The endometrium and other highly renewable tissues just as obviously violated Hayflick's limit. Transplantation experiments showed that pieces of mammary tissue or skin tissue could survive through ten normal lifetimes of experimental animals without suffering the effects of aging.

Even the liver and adrenal gland are now known to be continuously renewed by "cell streaming," though at a slower rate than the skin, conjunctiva, and intestine. Neurogenesis in the brain is now not only widely accepted, it is even proposed as a mechanism to explain the therapeutic effects of antidepressants (Santarelli, et al., 2003).

August Weismann's most influential doctrine said that "somatic cells are mortal, only the germline cells are immortal," but he based the doctrine on his mistaken belief that only the "germline" cells contained all the genes of the organism. In 1885, to "refute" Darwin's belief that acquired traits could be inherited, he promulgated an absolute "barrier" between "germline" and "soma," and invented facts to show that hereditary information can flow only from the germline to the somatic cells, and not the other direction. Shortly after DNA became popular in the 1950s as "the genetic material," Weismann's barrier was restated as the Central Dogma of molecular genetics, that information flows only from DNA to RNA to protein, and never the other direction.

It was only in 2003, after the reality of cloning was widely recognized, that a few experimenters began to investigate the origin of "germline" cells in the ovary, and to discover that they derive from somatic cells (Johnson, et al., 2004). With this discovery, the ancient knowledge that a twig (klon, in Greek) cut from a tree could grow into a whole tree, bearing fruit and viable seeds, was readmitted to general biology, and the Weismann barrier was seen to be an illusion.

Millions of people have "explained" female reproductive aging as the consequence of the ovary "running out of eggs." Innumerable publications purported to show the exact ways in which that process occurs, following the Weismann doctrine. But now that it is clear that adult ovaries can give birth to new oocytes, a new explanation for female reproductive aging is needed. It is likely that the same factors that cause female reproductive aging also cause aging of other systems and organs and tissues, and that those factors are extrinsic to the cells themselves, as Alexis Carrel and others demonstrated long ago. This is a way of saying that all cells are potential stem cells. The "niche" in which new cells are born in the streaming organism, and the processes by which damaged cells are removed, are physiological issues that can be illuminated by the idea of a morphogenetic field.

When the post-war genetic engineers took over biological research, the idea of a biophysical field was totally abandoned, but after about 15 years, it became necessary to think of problems beyond those existing within a single bacterium, namely, the problem of how an ovum becomes and embryo. Francis Crick, of DNA fame, who was educated as a physicist, revived (without a meaningful historical context) the idea of a diffusion gradient as a simple integrating factor that wouldn't be too offensive to the reductionists. But for events far beyond the scale of the egg's internal structure, for example to explain how a nerve axon can travel a very long distance to innervate exactly the right kind of cell, the diffusion of molecules loses its simplicity and plausibility. (Early in the history of experimental embryology, it was observed that electrical fields affect the direction of growth of nerve fibers.)

C. M. Child saw a gradient of metabolic activity as an essential component of the morphogenetic field. This kind of gradient doesn't deny the existence of diffusion gradients, or other physical components of a field. Electrical and osmotic (and electro-osmotic) events are generated by metabolism, and affect other factors, including pH, oxidation and reduction, cell motility and cell shape, ionic selectivity and other types of cellular selectivity and specificity. Gradients of DNA methylation exist, and affect the expression of inherited information.

Methylation decreases the expression of particular genes, and during the differention of cells in the development of an embryo, genes are methylated and demethylated as the cell adapts to produce the proteins that are involved in the structure and function of a particular tissue. Methylation (which increases a molecule's affinity for fats) is a widespread process in cells, and for example regulates cellular excitability. It is affected by diet and a variety of stresses.

DNA methylation patterns are normally fairly stable, and can help to account for the transgenerational transmission of acquired adaptations, and for neonatal imprinting that can last a lifetime. But with injury, stress, and aging, the methylation patterns of differentiated tissues can be changed, contributing to the development of tumors, or to the loss of cellular functions. Even learning can change the methylation of specific genes. During in vitro culture, the enzymes of gene methylation are known to be increased, relative to their normal activity (Wang, et al., 2005).

The phenomenon of "gene" methylation in response to environmental and metabolic conditions may eventually lead to the extinction of the doctrine that "cells are controlled by their genes."

During successful adaptation to stress, cells make adjustments to their metabolic systems (for example with a holistic change of the degree of phosphorylation, which increases molecules' affinity for water), and their metabolic processes can contribute to changes in their state of differentiation. Some changes may lead to successful adaptation (for example by producing biogenic stimulators that stimulate cell functioning and regeneration), others to failed adaptation. Even the decomposition of cells can release substances that contribute to the adaptation of surrounding cells, for example when sphingosines stimulate the production of stem cells.

DNA methylation is just one relatively stable event that occurs in relation to a metabolic field. Modifications of histones (regulatory proteins in chromosomes, which are acetylated as well as methylated) and structural-contractile filaments also contribute to the differentiation of cells, but the pattern of DNA methylation seems to guide the methylation of histones and the structure of the chromosomes (Nan, et al., 1998).

Steroids and phospholipids, neurotransmitters and endorphins, ATP, GTP, other phosphates, retinoids, NO and CO2--many materials and processes participate in the coherence of the living state, the living substance. Carbon dioxide, for example, by binding to lysine amino groups in the histones, will influence their methylation. Carbon dioxide is likely to affect other amino groups in the chromosomes.

The number and arrangement of mitochondria is an important factor in producing and maintaining the metabolic gradients. Things that decrease mitochondrial energy production--nitric oxide, histamine, cytokines, cortisol--increase DNA methylation. Decreased gene expression is associated with reduced respiratory energy. It seems reasonable to guess that increased gene expression would demand increased availability of energy.

As an ovum differentiates into an organism, cells become progressively more specialized, inhibiting the expression of many genes. Less energy is needed by stably functioning cells, than by actively adapting cells. A.I. Zotin described the process of maturing and differentiating as a decrease of entropy, an increase of order accompanying a decreased energy expenditure. The entropic egg develops into a less entropic embryo with a great expenditure of energy.

The partially differentiated stem cell doesn't go through all the stages of development, but it does expend energy intensely as it matures.

The restoration of energy is one requirement for the activation of regeneration. When a hormone such as noradrenaline or insulin causes a stem cell to differentiate in vitro, it causes new mitochondria to form. This is somewhat analogous to the insertion of mitochondria into the ripening oocyte, by the nurse cells that surround it. The conditionally decreased entropy of maturation is reversed, and when sufficient respiratory energy is available, the renewed and refreshed cell will be able to renew an appropriate degree of differentiation.

When simple organisms, such as bacteria, fungi, or protozoa are stressed, for example by the absence of nutrients or the presence of toxins, they slow their metabolism, and suppress the expression of genes, increasing the methylation of DNA, to form resistant and quiescent spores. Our differentiated state doesn't go to the metabolic extreme seen in sporulation, but it's useful to look at maturity and aging in this context, because it suggests that the wrong kind of stress decreases the ability of the organism to adapt, by processes resembling those in the spore-forming organisms.

Charles Vacanti, who has grown cartilage from cells taken from 100 year old human cartilage, believes our tissues contain "spore cells," very small cells with slow metabolism and extreme resistance to heat, cold, and starvation.

If the slowed metabolism of aging, like that of sporulating cells, is produced by a certain kind of stress that lowers cellular energy and functions, it might be useful to think of the other stages of the stress reaction in relation to the production of stem cells. Selye divided stress into a first stage of shock, followed by a prolonged adaptation, which could sometimes end in exhaustion. If the maturity of differentiated functioning is equivalent to the adaptation phase, and cellular decline and disintegration is the exhaustion phase, then the shock-like reaction would correspond to the birth of new stem cells.

Selye described estrogen's effects as equivalent to the shock-phase of stress. Estrogen's basic action is to make oxygen unavailable, lowering the oxygen tension of the tissues, locally and temporarily. Like nitric oxide, which is produced by estrogenic stimulation, estrogen interferes with energy production, so if its stimulation is prolonged, cells are damaged or killed, rather than being stimulated to regenerate.

Extrinsic factors elicit renewal, the way stress can elicit adaptation. While aging cells can't use the oxygen that is present, a scarcity of oxygen can serve as a stimulus to maximize the respiratory systems. Brief oxygen deprivation excites a cell, causes it to swell, and to begin to divide.

Oxygen deprivation, as in the normally hypoxic bone marrow, stimulates the formation of stem cells, as well as the biogenesis of mitochondria. As the newly formed cells, with abundant mitochondria, get adequate oxygen, they begin differentiation.

Form, based on cellular differentiation, follows function--a vein transplanted into an artery develops anatomically into an artery, a colon attached directly to the anus becomes a new rectum with its appropriate innervation, a broken bone restructures to form a normal bone. If the bladder is forced to function more than normal, by artificially keeping it filled, its thin wall of smooth muscle develops into a thick wall of striated muscle that rhythmically contracts, like the heart. If a tadpole is given a vegetarian diet, the absorptive surface of its digestive system will develop to be twice the size of those that are fed meat. Pressure, stretching, and pulsation are among the signals that guide cells' differentiation.

Very early in the study of embryology it was noticed that the presence of one tissue sometimes induced the differentiation of another kind, and also that there were factors in embryonic tissues that would stimulate cell division generally, and others that could inhibit the growth of a particular tissue type. Diffusable substances and light were among the factors identified as growth regulators.

Extracts of particular tissues were found to suppress the multiplication of cells in that type of tissue, in adult animals as well as in embryos. In the 1960s, the tissue-specific inhibitors were called chalones.

The brain's development is governed by the presence in the organism of the body part to which it corresponds, such as the eyes or legs. The number of cells in a particular part of the nervous system is governed by the quantity of nervous input, sensory or motor, that it receives. An enriched environment causes a bigger brain to grow. Sensory nerve stimulation of a particular region of the brain causes nerve cells to migrate to that area (a process called neurobiotaxis; deBeers, 1927), but nerve stimulation also causes mitochondria to accumulate in stimulated areas. Nerve activity has a trophic, sustaining influence on other organs, as well as on the brain. Nerve stimulation, like mechanical pressure or stretching, is an important signal for cellular differentiation.

When stem cells or progenitor cells are called on to replace cells in an organ, they are said to be "recruited" by that organ, or to "home" to that organ, if they are coming from elsewhere. Traditionally, the bone marrow has been considered to be the source of circulating stem cells, but it now appears that a variety of other less differentiated cells can be recruited when needed. Cells from the blood can repair the endothelium of blood vessels, and endothelial cells can become mesenchymal cells, in the heart, for example.

The standard doctrine about cancer is that a tumor derives from a single mutant cell, but it has been known for a long time that different types of cell, such as phagocytes and mast cells, usually reside in tumors, and it is now becoming clear that tumors recruit cells, including apparently normal cells, from other parts of the same organ. For example, a brain tumor of glial cells, a glioma, recruits glial cells from surrounding areas of the brain, in a process that's analogous to the embryological movement of nerve cells to a center of excitation. Each tumor, in a sense, seems to be a center of excitation, and its fate seems to depend on the nature of the cells that respond to its signals.

To accommodate some of the newer facts about tumors, the cancer establishment has begun speaking of "the cancer stem cell" as the real villain, the origin of the tumor, while the bulk of the tumor is seen to be made up of defective cells that have a short life-span. But if we recognize that tumors are recruiting cells from beyond their boundaries, this process would account for the growth and survival of a tumor even while most of its cells are inert and dying, without invoking the invisible cancer stem cell. And this view, that it is the field which is defective rather than the cell, is consistent with the evidence which has been accumulating for 35 years that tumor cells, given the right environment, can differentiate into healthy cells. (Hendrix, et al., 2007)

Simply stretching an organ (Woo, et al., 2007) is stimulus enough to cause it to recruit cells from the bloodstream, and will probably stimulate multiplication in its local resident cells, too. Every "cancer field" probably begins as a healing process, and generally the healing and regeneration are at least partially successful.

When an organ--the brain, heart, liver, or a blood vessel--is inflamed or suffering from an insufficient blood supply, stem cells introduced into the blood will migrate specifically to that organ.

Organ specific materials (chalones) are known to circulate in the blood, inhibiting cell division in cells typical to that organ, but it also seems that organ specific materials are secreted by a damaged organ, that help to prepare stem cells for their migration into that organ. When undifferentiated cells are cultured with serum from a person with liver failure, they begin to differentiate into liver cells.

It is still common to speak of each organ as having a "clonal origin" in the differentiating embryo, as a simple expansion of a certain embryonic anlage. The implication of this way of thinking is that differentiation is determination in an irreversible sense. This is another case of medical ideas being based on images of fixed histological material. Normal cells, including nerve and muscle cells, can change type, with connective tissue cells becoming nerve cells, nerve cells becoming muscle and fiber cells, fat, fiber, and muscle cells redifferentiating, for example.

Cell movements in solid tissues aren't limited to the short distances between capillaries and the tissues nourished by those capillaries, rather, cells can migrate much greater distances, without entering the bloodstream. The speed of a single cell moving by ameboid motion can be measured by watching cells on a glass slide as they move toward food, or by watching cells of the slime mold Dictyostelium when they are aggregating, or by watching the pigment cells in and around moles or melanomas, under the influence of hormones. At body temperature, a single cell can crawl about an inch per day. Waves or spots of brown pigment can be seen migrating through the skin away from a mole, preceding the disintegration of the mole under the influence of progesterone or DHEA. Under ordinary conditions, pigment cells can sometimes be seen migrating into depigmented areas of skin, during the recovery of an area affected by vitiligo. These organized movements of masses of cells happen to be easy to see, but there is evidence that other types of cell can reconstruct tissues by their ameboid movements, when circumstances are right. Tumors or tissue abnormalities can appear or disappear with a suddenness that seems impossible to people who have studied only fixed tissue preparations.

Stimulation is anabolic, building tissue, when the organism is adapting to the stimulation. Unused structures in cells and tissues are always being recycled by metabolic processes. When tissues are injured and become unable to function, some of their substances stimulate the growth of replacement cells.

Some types of injury or irritation can activate regenerative processes. A dermatology journal described the case of an old man who had been bald for many years who fell head-first into his fireplace. As his burned scalp healed, new hair grew. In the U.S., experimenters (Ito, et al., 2007) have found that injuring the skin of mice stimulates the formation of stem cells that are able to become hair follicle cells, supporting the regeneration of cells that had been absent. A brief exposure to estrogen, and other stress related signals (nitric oxide, endorphin, prostaglandins) can initiate stem cell proliferation.

In the years after the first world war, Vladimir Filatov, who developed techniques of reconstructive surgery, including corneal transplants, found that cold storage of tissues (for example, corneas from cadavers) caused them to function better than fresh tissues, and he found that these stressed tissues would often spread a healing influence out into the surrounding tissues. Extracts of stressed tissues produced similar effects.

L.V. Polezhaev began studying the regenerative capacities of mammals in the late 1940s, and his work showed that processes similar to embryonic induction are involved in the organism's responses to damaged tissues. For example, when a piece of killed muscle tissue is enclosed in a capsule ("diffusion chamber") that permits molecules, but no cells, to diffuse through it, and implanted subcutaneously, it had no inductive effect on surrounding cells. But when the pores of the capsule allowed cells to enter, skeletal muscle formed where the dead tissue had been, and tissue resembling heart muscle formed outside the capsule. Phagocytosis had been essential for the induction to occur.

Macrophages are ordinarily thought of as "antigen-presenting cells" that help to activate the specific immune responses. But apparently phagocytosis is involved in the replacement of damaged tissues, by recruiting or inducing the differentiation of replacement cells. The phagocytosis function isn't limited to the blood cells commonly called phagocytes; even nerve cells can ingest particles and fragments of damaged tissues.

Many factors regulate the process of phagocytosis. Stress and lipid peroxidation decrease phagocytosis (Izgüt-Uysal, et al., 2004), and also damage mitochondria and inhibit cell renewal.

Unsaturated fatty acids inhibit phagocytosis (Guimaraes, et al., 1991, 1992; Costa Rosa, et al., 1996; Virella, et al., 1989; Akamatsu, et al., 1990), and suppress mitochondrial function (Gomes, et al., 2006). Dietary restriction activates phagocytosis (Moriguchi, et al., 1989), suggesting that normal diets contain suppressive materials.

Subnormal temperatures cause a shift from phagocytosis to inflammation. Light, especially the red light which penetrates easily into tissues, activates the formation of new cells as well as their differentiation. It affects energy production, increasing the formation of mitochondria, and the activity of the DNA methyltransferase enzymes. Red light accelerates wound healing, and improves the quality of the scar, reducing the amount of fibrosis. The daily cycling between darkness and light is probably an important factor in regulating the birth and differentiation of cells..

Darkness suppresses mitochondrial function, and light activates it. Prolonged darkness increases cortisol, and cortisol (which makes cells more susceptible to excitotoxic death) inhibits stem cell proliferation (Li, et al., 2006; Liu, et al., 2003). Neurogenesis is suppressed by stress, and increased by spontaneous activity, and has a circadian rhythm. Aging and depression both involve a diminished ability to rhythmically lower the production of cortisol. Cell renewal requires a rhythmic decrease in the exposure to cortisol..

In the spring, with increased day length, the brains of song-birds grow, with an increased proliferation of cells in the part of the brain involved in singing. The production of progesterone increases in most animals in the spring, and it is the main hormone responsible for the birds' brain growth.

Progesterone and its metabolites protect brain cells against injury, and improve the brain's ability to recover after traumatic injury (Brinton and Wang, 2006). In the 1960s, Marion Diamond's group showed that environmental enrichment, or progesterone, caused brains to grow larger, and that these changes were passed on to descendants in a cumulative, increasing way. This suggests that the factors that promote neurogenesis also cause changes in the apparatus of reproduction and inheritance, that support the development of the brain--probably including the methylation system, which is involved in regulating genes, and also mood and behavior.

Women's monthly cycles, in which a brief estrogen dominance is followed by sustained exposure to progesterone, are probably an important factor in the renewal of the cells of the brain and other organs, as well as those of the reproductive organs. The daily rhythms of hormones and metabolism are known to be involved in the regulation of cell renewal.

Environmental enrichment, learning, high altitude, and thyroid hormone promote the formation of new mitochondria, and stimulate stem cell proliferation. At least in some laboratories, 20% oxygen, approximately the amount as in the atmosphere, suppresses the proliferation of stem cells (He, et al., 2007). This was the unphysiologically high concentration of oxygen used in Hayflick's cell cultures. At high altitudes, where tissues are exposed to less oxygen, and more carbon dioxide, there is a lower incidence of all the degenerative diseases, including cancer, heart disease, and dementia. Improved cellular energy production and more active renewal of cells would probably account for those differences.

For Crick, the idea of a diffusion gradient to explain embryonic development was simply an extension of his reductionist orientation, in which diffusing molecules induced or inhibited bacterial genes, and in which genes controlled cells. For people with that orientation, the adaptive mutations described by Carl Lindegren, and later by John Cairns, or even the stress-induced variability described by Lysenko, Strong, and McClintock, were heretical. Polezhaev's demonstration that cells could do something that molecular diffusion didn't do, threatened to take biology away from the reductionists. If the organism's adaptation to the environment involves changing its own genes, Crick's paradigm fails.

Crick's Central Dogma, derived from the ideology that produced Weismann's Barrier, has been invoked by generations of professors who wanted to deny the possibility of adaptive tissue renewal and regeneration. Without the dogma, new ideas about aging and disease will be needed. If somatic cells can adjust their genes, and if they can also differentiate into new eggs and sperms, new ideas about inheritance of acquired traits will be needed.

The replacement of injured cells means that mutations need not accumulate. Cell renewal with elimination of mutant cells has been observed in sun-damaged skin simply by stopping the damage, and mitochondria with damaged DNA can be replaced by healthy mitochondria simply by doing the right kind of exercise.

The regulation of cell renewal probably involves all of the processes of life, but there are a few simple, interacting factors that suppress renewal. The accumulation of polyunsaturated fats, interacting with a high concentration of oxygen, damages mitochondria, and causes a chronic excessive exposure to cortisol. With mitochondrial damage, cells are unable to produce the progesterone needed to oppose cortisol and to protect cells.

Choosing the right foods, the right atmosphere, the right mental and physical activities, and finding the optimal rhythms of light, darkness, and activity, can begin to alter the streaming renewal of cells in all the organs. Designing a more perfect environment is going to be much simpler than the schemes of the genetic engineers.

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A R T I C L E

Thyroid, insomnia, and the insanities: Commonalities in disease

SOME FACTORS IN STRESS, INSOMNIA AND THE BRAIN SYNDROMES:

Serotonin, an important mediator of stress, shock, and inflammation, is a vasoconstrictor that impairs circulation in a great variety of circumstances.

Stress impairs metabolism, and serotonin suppresses mitochondrial energy production.

Stress and shock tend to increase our absorption of bacterial endotoxin from the intestine, and endotoxin causes the release of serotonin from platelets in the blood.

Schizophrenia is one outcome of stress, both cumulative and acute. Prenatal stress commonly predisposes a person to develop schizophrenia at a later age.

Serotonins restriction of circulation to the uterus is a major factor in toxemia of pregnancy and related complications of pregnancy.

Hypothyroidism increases serotonin activity in the body, as it increases estrogen dominance.

Estrogen inhibits the enzyme monoamino oxidase (MAO), and is highly associated with increased serotonin activity. Progesterone has the opposite effect on MAO.

The frontal lobes of the brain are hypometabolic in schizophrenia. Serotonin can cause vasoconstriction in the brain.

Serotonin release causes lipid peroxidation.

Schizophrenics have high levels of lipid peroxidation.

Antioxidants, including uric acid, are deficient in schizophrenics.

Therapies which improve mitochondrial respiration alleviate the symptoms of schizophrenia.

Energy depletion leads to brain atrophy, but with normal stimulation and nutrition even adult brains can grow.

Schizophrenics and depressed people have defective sleep.

Increasing the bodys energy level and temperature improves the quality of sleep.

================

Everyone is familiar with the problem of defining insanity, in the case of people who plead innocent by reason of insanity. The official definition of insanity in criminal law is the inability to tell right from wrong. Obviously, that cant be generalized to everyday life, because any sane person realizes that certainty is impossible, and that most situations, including elections, offer you at best the choice of the lesser of two evils, or the opportunity to do the right thing, and to throw your vote away. People who persist in doing what they know is really right are eccentric, in the sense that they dont adapt to societys norms. In a society that chooses to destroy ecosystems, rather than adapting to them, the question of sanity should be an everyday political issue.

The use of medical terms tends to give authority to the people who are in charge of defining the terms, and it can give the impression of objectivity when there really isnt any scientific validity behind the terms. In their historical senses, crazy (flawed) and insane (unsound) are probably more objective terms than the medically-invented terms, dementia praecox (premature idiocy) or schizophrenia (divided mind).

Odd Speech is one of the dimensions used in the diagnosis of insanity. I am reminded of William Wordsworths dismissal of William Blake as insane after failing to understand some of Blakes poems--Wordsworth was conventional enough to become Englands Poet Laureate, and to his limited perspective, Blakes clear verses were incomprehensibly odd.

Whenever a trusted government employee decides to blow the whistle on criminal activities, his agency invariably puts out the information that this now discharged employee is psychologically unbalanced. Dissent, in other words, is easy to dispose of by psychiatric tainting.

If we are going to speak of mental impairment, then we should have objective measures of what we are talking about. Blake unquestionably could do anything better than Wordsworth, because he was neither stupid nor dishonest, and its almost a rule that ordinary employees are more competent than the administrators who evaluate their work. Objective standards of mental impairment would be more popular among patients than among diagnosticians, judges, and lawmakers.

In a famous test of the objectivity of diagnosis, a filmed interview with a patient was shown to British and U.S. psychiatrists. 69% of the Americans diagnosed the patient as schizophrenic, but only 2% of the British psychiatrists did.

The strictly medical/psychological definition of insanity is still, despite the existence of the International Classification of Diseases, and in the U.S. the Diagnostic and Statistical Manual, which enumerate a large number of mental disorders, a crazily indefinite grouping of symptoms, and hasnt made diagnosis more objective.. For example, in the last 30 years autism has been separated from childhood schizophrenia, but now the tendency is for both of them to be called developmental brain disorders. Both schizophrenia and autism are now often described in terms of a spectrum of conditions, which hardly matters, since they are not understood in terms of cause, prevention, or cure.

The problem is in the history of psychosis as a medical idea. About 100 years ago, attempts were made to classify psychoses by their symptoms, unifying a great variety of old diagnostic categories into two groups, manic-depressive mood disorders, and dementia praecox, or schizophrenia, which (as indicated by its name, premature dementia) was considered to be progressive and incurable. Several kinds of mental disorder were found to have clear causes, including vitamin deficiencies and various poisons and infections, but the idea of a certain thing called schizophrenia still persists.

The unitary concept of psychosis grew up in a culture in which endogenous insanity was a hereditary taint, that for a time was treated by imprisonment, and that more recently has been treated with sterilization or euthanasia to eliminate the insanity genes.

The idea that the disease is in the genes now serves the drug industry well, since they offer chemicals that will correct the specific chemical error.

Not all psychiatrists and psychologists subscribed to the idea of a unitary psychosis, defined by a variety of symptoms. A positive contribution of Freudian psychoanalysis (and its congeners and competitors) was that it made people think in terms of causes and the possibility of cures, instead of hopelessness, stigmatization, isolation and eradication. Although Freud expressed the thought that biological causes and cures would eventually be found, the profession he founded was not sympathetic to the idea of physiological therapies.

Looking for general physiological problems behind the various symptoms is very different from the practice of classifying the insanities according to their symptoms and the hypothetical brain chemicals that are believed to cause the symptoms. The fact that some patients hallucinate caused many psychiatrists to believe that hallucinogenic chemicals, interfering with nerve transmitter substances such as dopamine or serotonin, were going to provide insight into psychotic states. The dopamine excess (or serotonin deficiency) theories developed at a time when only a few transmitter substances were known, and when they were thought to act as very specific on/off nerve switches, rather than as links in metabolic networks. The drug industry helps to keep those ideas alive.

The idea that the brain is like a computer, and that the nerves are like wires and switches, is behind all of the theories about transmitter substances and synapses. If this metaphor about the nature of the brain and the organism is fundamentally wrong, then the theories of schizophrenia based on nerve transmitter substances can hardly be right. Another theory of schizophrenia based on the computer metaphor has to do with the idea that nerve cells wire-like and switch-like functions depend on their membranes, and, in the most popular version, that these all-important membranes are made of fish oil. The supporting evidence is supposed to be that the fish-oil-like fatty acids are depleted from the tissues of schizophrenics. Just looking at that point, the evidence is more likely to be the result of stress, which depletes unsaturated fatty acids, especially of the specified type, in producing lipid peroxides and other toxic molecules.

In one of its variations, the essential fatty acid deficiency doctrine suggests that a certain prostaglandin deficiency is the cause of schizophrenia, but experiments have shown that an excess of that prostaglandin mimics the symptoms of psychosis.

The drug industrys effect on the way the organism is commonly understood has been pervasively pathological. For example, the dogma about cell surface receptors has sometimes explicitly led people to say that the brain chemicals are active only at the surface of cells, and not inside the cells.

The consequences of this mistake have been catastrophic. For example, serotonins precursor, tryptophan, and the drugs called serotonin reuptake inhibitors, and other serotonergic drugs, and serotonin itself, are carcinogenic and/or tumor promoters. Excessive serotonin is a major factor in kidney and heart failure, liver and lung disease, stroke, pituitary abnormalities, inflammatory diseases, practically every kind of sickness, at the beginning, middle, and end of life. In the brain, serotonin regulates circulation and mitochondrial function, temperature, respiration and appetite, alertness and learning, secretion of prolactin, growth hormones and stress hormones, and participates in the most complex biochemical webs. But the pharmaceutical industrys myth has led people to believe that serotonin is the chemical of happiness, and that tryptophan is its benign nutritional precursor, and that they are going to harmlessly influence the receptors on nerve membranes.

A particular drug has many effects other than those that are commonly recognized as its mechanism of action, but when an antidepressant or a tranquilizer or a serotonin reuptake inhibitor alleviates a particular condition, some people argue that the condition must have been caused by the specific chemistry that the drug is thought to affect. Because of the computer metaphor for the brain, these effects are commonly thought to be primarily in the synapses, the membranes, and the transmitter chemicals.

The argument for a genetic cause of schizophrenia relies heavily on twin studies in which the frequency of both twins being schizophrenic is contrasted to the normal incidence of schizophrenia in the population, which is usually about 1%. There is a concordance of 30% to 40% between monozygotic (identical) twins, and a 5% to 10% concordance between fraternal twins, and both of these rates are higher than that of other siblings in the same family. That argument neglects the closer similarity of the intrauterine conditions experienced by twins, for example the sharing of the same placenta, and experiencing more concordant biochemical interactions between fetus and mother.

Defects of the brain, head, face, and even hands and fingerprints are seen more frequently in the genetically identical twin who later develops schizophrenia than the twin who doesnt develop schizophrenia. Of the twins, it is the baby with the lower birth weight and head size that is at a greater risk of developing schizophrenia.

Oliver Gillie (in his book, Who Do You Think You Are?) discussed some of the fraud that has occurred in twin studies, but no additional fraud is needed when the non-genetic explanation is simply ignored and excluded from discussion. The editors of most medical and scientific journals are so convinced of the reality of genetic determination that they wont allow their readers to see criticisms of it.

Prenatal malnutriton or hormonal stress or other stresses are known to damage the brain, and especially its most highly evolved and metabolically active frontal lobes, and to reduce its growth, relative to the rest of the body.

The standard medical explanation for the association of pregnancy toxemia and eclampsia with birth defects has been, until recently, that both mother and child were genetically inferior, and that the defective child created the pregnancy sickness. The same reasoning has been invoked to explain the association of birth complications with later disease: The defective baby was the cause of a difficult birth. That argument has recently been discredited (McNeil and Cantor-Graae, 1999).

Schizophrenics are known to have had a higher rate of obstetrical complications, including oxygen deprivation and Cesarian deliveries, than normal people. Like people with Alzheimers disease, the circumference of their heads at birth was small, in proportion to their body weight and gestational age.

Animal studies show that perinatal brain problems tend to persist, influencing the brains metabolism and function in adulthood.

Like the other major brain diseases, shizophrenia involves a low metabolic rate in crucial parts of the brain. In schizophrenics, hypofrontality, low metabolism of the frontal lobes, is characteristic, along with abnormal balance between the hemispheres, and other regional imbalances.

A very important form of prenatal stress occurs in toxemia and preeclampsia, in which estrogen is dominant, and endotoxin and serotonin create a stress reaction with hypertension and impaired blood circulation to the uterus and placenta.

The brain, just like any organ or tissue, is an energy-producing metabolic system, and its oxidative metabolism is extremely intense, and it is more dependent on oxygen for continuous normal functioning than any other organ. Without oxygen, its characteristic functioning (consciousness) stops instantly (when blood flow stops, blindness begins in about three seconds, and other responses stop after a few more seconds). The concentration of ATP, which is called the cellular energy molecule, doesnt decrease immediately. Nothing detectable happens to the neurotransmitters, synapses, or membrane structures in this short period; consciousness is a metabolic process that, in the computer metaphor, would be the flow of electrons itself, under the influence of an electromotive force, a complex but continuous sort of electromagnetic field. The computer metaphor would seem to have little to offer for understanding the brain.

In this context, I think its necessary, for the present, to ignore the diagnostic details, the endless variety of qualifications of the idea of schizophrenia, that fill the literature. Those diagnostic concepts seem to tempt people to look for the precise cause of this particular subcategory of schizophrenia, and to believe that a specific drug or combination of drugs will be found to treat it, while encouraging them to ignore the patients physiology and history.

If we use the standard medical terms at all, it should be with the recognition that they are, in their present and historical form, not scientifically meaningful.

The idea that schizophrenia is a disease in itself tends to distract attention from the things it has in common with Alzheimers disease, autism, depression, mania, the manic-depressive syndrome, the hyperactivity-attention deficit syndrome, and many other physical and mental problems. When brain abnormalities are found in schizophrenics but not in their normal siblings, it could be tempting to see the abnormalities as the cause of schizophrenia, unless we see similar abnormalities in a variety of sicknesses.

For the present, its best to think first in the most general terms possible, such as a brain stress syndrome, which will include brain aging, stroke, altitude sickness, seizures, malnutrition, poisoning, the despair brought on by inescapable stress, and insomnia, which are relatively free of culturally arbitrary definitions. Difficulty in learning, remembering, and analyzing are objective enough that it could be useful to see what they have to do with a brain stress syndrome.

Stress damages the energy producing systems of cells, especially the aerobic mitochondria, in many ways, and this damage can often be repaired. The insanities that are most often called schizophrenia tend to occur in late adolescence, or around menopause, or in old age, which are times of stress, especially hormonal stress. Post-partum psychosis often has features that resemble schizophrenia.

Although the prenatal factors that predispose a person toward the brain stress syndrome, and those that trigger specific symptoms later in life, might seem to be utterly different, the hormonal and biochemical reactions are probably closely related, involving the adaptive responses of various functional systems to the problem of insufficient adaptive ability and inadequate energy.

By considering cellular energy production, local blood flow, and the systemic support system, we can get insight into some of the biochemical events that are involved in therapies that are sometimes successful. A unified concept of health and disease will help to understand both the origins and the appropriate treatments for a great variety of brain stress syndromes.

The simple availability of oxygen, and the ability to use it, are regulated by carbon dioxide and serotonin, which act in opposite directions. Carbon dioxide inhibits the release of serotonin. Carbon dioxide and serotonin are regulated most importantly by thyroid function. Hypothyroidism is characterized by increased levels of both noradrenalin and serotonin, and of other stress-related hormones, including cortisol and estrogen. Estrogen shifts the balance of the neurotransmitters in the same direction, toward increased serotonin and adrenalin, for example by inhibiting enzymes that degrade the monoamine neurotransmitters.

When an animal such as a squirrel approaches hibernation and is producing less carbon dioxide, the decrease in carbon dioxide releases serotonin, which slows respiration, lowers temperature, suppresses appetite, and produces torpor.

But in energy-deprived humans, increases of adrenalin oppose the hibernation reaction, alter energy production and the ability to relax, and to sleep deeply and with restorative effect.

In several ways, torpor is the opposite of sleep. Rapid eye movement (REM), that occurs at intervals during sleep and in association with increased respiration, disappears when the brain of a hibernating animal falls below a certain temperature. But torpor isnt like non-REM deep sleep, and in fact seems to be like wakefulness, in the sense that a sleep-debt is incurred: Hibernating animals periodically come out of torpor so they can sleep, and in those periods, when their temperature rises sharply, they have a very high percentage of deep slow wave sleep.

Although it is common to speak of sleep and hibernation as variations on the theme of economizing on energy expenditure, I suspect that nocturnal sleep has the special function of minimizing the stress of darkness itself, and that it has subsidiary functions, including its now well confirmed role in the consolidation and organization of memory. This view of sleep is consistent with observations that disturbed sleep is associated with obesity, and that the torpor-hibernation chemical, serotonin, powerfully interferes with learning.

Babies spend most of their time sleeping, and during life the amount of time spent sleeping decreases, with nightly sleeping time decreasing by about half an hour per decade after middle age. Babies have an extremely high metabolic rate and a stable temperature. With age the metabolic rate progressively declines, and as a result the ability to maintain an adequate body temperature tends to decrease with aging.

(The simple fact that body temperature regulates all organic functions, including brain waves, is habitually overlooked. The actions of a drug on brain waves, for example, may be mediated by its effects on body temperature, but this wouldnt be very interesting to pharmacologists looking for transmitter-specific drugs.)

Torpor is the opposite of restful sleep, and with aging, depression, hypothyroidism, and a variety of brain syndromes, sleep tends toward the hypothermic torpor.

An individual cell behaves analogously to the whole person. A babys high energy resting state is paralleled by the stable condition of a cell that is abundantly charged with energy; ATP and carbon dioxide are at high levels in these cells. Progesterones effects on nerve cells include favoring the high energy resting state, and this is closely involved in progesterones thermogenic effect, in which it raises the temperature set-point.

The basal metabolic rate, which is mainly governed by thyroid, roughly corresponds to the average body temperature. However, in hypothyroidism, there is an adaptive increase in the activity of the sympathetic nervous system, producing more adrenalin, which helps to maintain body temperature by causing vasoconstriction in the skin. In aging, menopause, and various stressful conditions, the increased adrenalin (and the increased cortisol production which is produced by excess adrenalin) causes a tendency to wake more easily, and to have less restful sleep.

While the early morning body temperature will sometimes be low in hypothyroidism, I have found many exceptions to this. In protein deficiency, sodium deficiency, in menopause with flushing symptoms, and in both phases of the manic depression cycle, and in some schizophrenics, the morning temperature is high, corresponding to very high levels of adrenalin and cortisol. Taking the temperature before and after breakfast will show a reduction of temperature, the opposite of what occurs in simple hypothyroidism, because raising the blood sugar permits the adrenalin and cortisol to fall.

The characteristic sleep pattern of hypothyroidism and old age is similar to the pattern seen in schizophrenia and depression, a decrease of deep slow wave sleep. Serotonin, like torpor, produces a similar effect. In other words, a torpor-like state can be seen in all of these brain-stress states. Several studies have found that anti-serotonin drugs improve sleep, and also reduce symptoms of schizophrenia and depression. It is common for the neuroleptic drugs to raise body temperature, even pathologically as in the neuroleptic malignant syndrome.

In old people, who lose heat easily during the day, their extreme increase in the compensatory nervous and hormonal adrenalin activity causes their night-time heat regulation (vasoconstriction in the extremities) to rise to normal.

Increased body temperature improves sleep, especially the deep slow wave sleep. A hot bath, or even warming the feet, has the same effect as thyroid in improving sleep. Salty and sugary foods taken at bedtime, or during the night, help to improve the quality and duration of sleep. Both salt and sugar lower the adrenalin level, and both tend to raise the body temperature.

Hypothyroidism tends to cause the blood and other body fluids to be deficient in both sodium and glucose. Consuming salty carbohydrate foods momentarily makes up to some extent for the thyroid deficiency.

In the peiodic table of the elements, lithium is immediately above sodium, meaning that it has the chemical properties of sodium, but with a smaller atomic radius, which makes its electrical charge more intense. Its physiological effects are so close to sodiums that we can get clues to sodiums actions by watching what lithium does.

Chronic consumption of lithium blocks the release of adrenalin from the adrenal glands, and it also has extensive antiserotonin effects, inhibiting its release from some sites, and blocking its actions at others.

Lithium forms a complex with the ammonia molecule, and since the ammonia molecule mimics the effects of serotonin, especially in fatigue, this could be involved in lithiums antiserotonergic effects. Ammonia, like serotonin, impairs mitochondrial energy production (at a minimum, it uses energy in being converted to urea), so anti-ammonia, anti-serotonin agents make more energy available for adaptation. Lithium has been demonstrated to restore the energy metabolism of mitochondria (Gulidova, 1977).

Therapies that have been successful in treating schizophrenia include penicillin, sleep therapy, hyperbaric oxygen, carbon dioxide therapy, thyroid, acetazolamide, lithium and vitamins. These all make fundamental contributions to the restoration of biological energy. Antibiotics, for example, lower endotoxin formation in the intestine, protect against the induction by endotoxin of serotonin, histamine, estrogen, and cortisol. Acetazolamide causes the tissues to retain carbon dioxide, and increased carbon dioxide acidifies cells, preventing serotonin secretion.

REFERENCES

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Lik Sprava 1997 Jan-Feb;(1):61-5. [Microhemodynamics and energy metabolism in schizophrenia patients]. Kut'ko II, Frolov VM, Rachkauskas GS, Pavlenko VV, Petrunia AM. An apparent disturbance was revealed in microhaemodynamics of patients diagnosed as having schizophrenia (n = 210) which was more pronounced in continuously progredient form of the above medical condition. An increase in conjunctival indexes, polymorphic character of capillaries, decrease in numbers of capillary loops were revealed by biomicroscopy of the bulbar conjunctiva and capillaroscopy respectively. The patients showed lowering of ATP level and rise in the content of cathodic LDG4-LDG5 fractions, accumulation in blood of lactic and pyruvic acids.

Schizophr Res 1996 Oct 18;22(1):41-7. Are reduced head circumference at birth and increased obstetric complications associated only with schizophrenic psychosis? A comparison with schizo-affective and unspecified functional psychoses. McNeil TF, Cantor-Graae E, Nordstrom LG, Rosenlund T.

Schizophr Res 1993 Jun;10(1):7-14. Puberty and the onset of psychosis. Galdos PM, van Os JJ, Murray RM Department of Child and Adolescent Psychiatry, Bethlem Royal Hospital, London, UK. According to the neurodevelopmental hypothesis of schizophrenia, maturational events in the brain at puberty interact with congenital defects to produce psychotic symptoms. As girls reach puberty at a younger age than boys, we predicted that (i) females would show earlier onset of psychotic illness arising around puberty, and (ii) onset of psychosis in females would be related to menarche. Analysis of epidemiological data regarding admission to psychiatric units in (a) England over the period 1973-1986, (b) France over the period 1975`-1980, as well as examination of 97 psychotic adolescents referred to an adolescent unit over a 14 year period, supported both these propositions.

Int J Psychophysiol 1999 Dec;34(3):237-47. Timing of puberty and syndromes of schizotypy: a replication. Kaiser J, Gruzelier JH. Active syndrome findings were confined to the male subsample with late maturing males showing higher scores on the Cognitive Failures and Odd Speech subscales than early maturers. As in the previous study, there was no relationship between a global psychosis proneness scale and maturational rate. These findings support a neurodevelopmental model of psychosis-proneness and show the importance of adopting a syndromal view.

Am J Physiol 1978 Mar;234(3):H300-4. Potentiation of the cerebrovascular response to intra-arterial 5-hydroxytryptamine. Eidelman BH, Mendelow AD, McCalden TA, Bloom DS. Infusion of 5-hydroxytryptamine (5HT) into the internal carotid artery of normal baboons was not accompanied by alteration of gray matter cerebral blood flow. In animals pretreated with depot estrogen and progesterone (dosage equivalent to oral contraceptive preparations), infusion of 5HT produced a marked decrease in gray matter blood flow. A similar decrease in flow was obtained when the 5HT was infused with a concentrate of beta-lipoprotein. Steroid substances appear to enhance the cerebrovascular constrictor responses to 5HT. A further series of six experiments has shown that the monoamine oxidase inhibitor tranylcypromine similarly produced constrictor responses to 5HT. It is possible that the steroids, the beta-lipoprotein, and the tranylcypromine produced constrictor responses to 5HT by the same mechanism (inhibition of cerebrovascular monoamine oxidase).

FASEB J 1989 Apr;3(6):1753-9. Steroid regulation of monoamine oxidase activity in the adrenal medulla. Youdim MB, Banerjee DK, Kelner K, Offutt L, Pollard HB. Administration of different steroid hormones in vivo has distinct and specific effects on the MAO activity of the adrenal medulla. As in the intact animal, we found that endothelial cell MAO activity was stimulated 1.5- 2.5-fold by 10 microM progesterone, hydrocortisone, and dexamethasone, inhibited by ca. 50% by 17-alpha-estradiol, but unaffected by testosterone. . . . steroid-induced changes in total cell division ([14C]thymidine incorporation) and total protein synthesis ([14C]leucine incorporation) were seen after changes in MAO A.

J Pharmacol Exp Ther 1984 Apr;229(1):244-9 Mechanisms of specific change by estradiol in sensitivity of rat uterus to serotonin. Ichida S, Oda Y, Tokunaga H, Hayashi T, Murakami T, Kita T.

Neuroendocrinology 1983;36 (3): 235-41. Gonadal hormone regulation of MAO and other enzymes in hypothalamic areas. Luine VN, Rhodes JC. Activities of type A monoamine oxidase (MAO), acetylcholine esterase (AChE), and glucose-6-phosphate dehydrogenase (G6PDH) were differentially altered in hormone-sensitive areas of the preoptic-hypothalamic continuum after administration of estrogen and progesterone. Estrogen decreased activity of MAO in the PVE of the anterior hypothalamus, pars lateralis of the ventromedial nucleus and in the Ar-ME. Acute administration of progesterone (1 h) to estrogen-treated females did not further alter estrogen-dependent changes in AChE or G6PDH; however, MAO activity in the ventromedial nucleus and Ar-ME was rapidly increased after progesterone. Administration of the protein synthesis inhibitor anisomycin prior to progesterone did not antagonize progesterone-dependent increases in MAO. Progesterone added in vitro to homogenates from estrogen-treated but not from untreated females increased MAO activity.

J Neurochem 1981 Sep;37(3):640-8. Gonadal influences on the sexual differentiation of monoamine oxidase type A and B activities in the rat brain. Vaccari A, Caviglia A, Sparatore A, Biassoni R When masculinization was prevented by neonatal administration of estradiol (E) to males, hypothalamic MAO-A and MAO-B activities increased in both control and MAO-inhibited rats. . . . single, high doses of steroids to adult, but not to newborn rats, did acutely affect the kinetics of MAO-A. The activity of MAO-A was also decreased by high concentrations of E or TS in vitro. The imprinting for patterns of hypothalamic MAO-A and MAO-B in the two sexes results, probably, from genetic predetermination.

Gynecol Obstet Invest 2000;49(3):150-5. Transport and metabolism of serotonin in the human placenta from normal and severely pre-eclamptic pregnancies. Carrasco G, Cruz MA, Gallardo V, Miguel P, Dominguez A, Gonzalez C. These findings suggest that the higher plasma-free serotonin levels observed in severe pre-eclampsia are mainly due to a reduction in MAO-A activity and not limited by the rate of serotonin uptake into the cells.

Psychiatry Res 1989 Jun;28(3):279-88. Acetazolamide and thiamine: an ancillary therapy for chronic mental illness. Sacks W, Esser AH, Feitel B, Abbott K Cerebral Metabolism Laboratory, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962. Twenty-four chronic schizophrenic patients were treated successfully with the addition of acetazolamide and thiamine (A + T) to their unchanged existing therapies in a double-blind, placebo-controlled crossover study. Therapeutic effects were measured by the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms. Overall, 50% of the patients showed improvement on all assessment scales. No untoward effects occurred in these patients or in patients in previous studies who have been treated continuously with A + T therapy for as long as 3 years.

J Neural Transm 1998;105(8-9):975-86. Role of tryptophan in the elevated serotonin-turnover in hepatic encephalopathy. Herneth AM, Steindl P, Ferenci P, Roth E, Hortnagl H. The increase of the brain levels of 5-hydroxyindoleacetic acid (5-HIAA) in hepatic encephalopathy (HE) suggests an increased turnover of serotonin (5-HT).

J Neurosci Res 1981;6(2):225-36 A difference in the in vivo cerebral production of [1-14C] lactate from D-[3-14C] glucose in chronic mental patients. Sacks W, Schechter DC, Sacks S. Previously unpublished whole-blood lactate determinations in these experiments indicated a cerebral production of much higher specific activity of [1-14C]-lactate from the D-[3-14C] glucose by mental patients.

Ther Umsch 2000 Feb;57(2):76-80. [Antidepressive therapy by modifying sleep]. Haug HJ, Fahndrich E.

Schizophr Res 1998 Jun 22;32(1):1-8. Reduced status of plasma total antioxidant capacity in schizophrenia. Yao JK, Reddy R, McElhinny LG, van Kammen DP.

FASEB J 1998 Dec;12(15):1777-83. Increased F2-isoprostanes in Alzheimer's disease: evidence for enhanced lipid peroxidation in vivo. Pratico D, MY Lee V, Trojanowski JQ, Rokach J, Fitzgerald GA.

Dis Nerv Syst 1976 Feb;37(2):98-103. Glucose-insulin metabolism in chronic schizophrenia. Brambilla F, Guastalla A, Guerrini A, Riggi F, Rovere C, Zanoboni A, Zanoboni-Muciaccia W.

Psychiatr Clin (Basel) 1975;8(6):304-13. Blood flow and oxidative metabolism of the brain in patients with schizophrenia. Hoyer S, Oesterreich K.

Zh Nevropatol Psikhiatr Im S S Korsakova 1977;77(8):1179-86 [Effect of lithium on the energy metabolism of nervous tissue]. Gulidova GP, Khzardzhian VG, Mikhailova NM. "Lithium (0.5--4 mM) either significantly increase, either completely normalizers the intensity of the oxidative and energy metabolism of the brain mitochondria, decreased by the influence of the blood serum of patients with manic-depressive psychosis and attack like schizophrenia." "Processes of phosphorilation become normalized in a joint action on the mitochondria by lithium and antioxidants." "It is assumed that an increase in the intensity of the energy metabolism is one of the mechanisms of therapeutical and prophylactic action of lithium."

Ateneo Parmense Acta Biomed 1975 Jan-Apr;46(1-2):5-19. [Clinical significance of changes in tryptophan metabolism]. Ambanelli U, Manganelli P. "The oxidative pathway is most important of the metabolic pathway of the amino acid; the degredation of tryptophan is particularly influenced by steroid hormones and vitamins' want. The metabolic anomalies are demonstrable both in malignant tumors (mostly in bladder cancer and Hodgkin's disease), both during psychiatric diseases (such as depression and schizophrenia) and in the diseases of connective tissue in addition to congenital errors of the degradation of tryptophan (such as Hartnup's disease, tryptophanuria and 3-hydroxychinureninuria)."

Acta Neurol Scand Suppl 1977;64:534-5. Blood flow and oxidative metabolism of the brain in the course of acute schizophrenia. Hoyer S, Oesterreich K.

Med Hypotheses 1994 Dec;43(6):420-35 Schizophrenia is a diabetic brain state: an elucidation of impaired neurometabolism. Holden RJ, Mooney PA.

Neuropsychobiology 1990-91;24(1):1-7. Frontality, laterality, and cortical-subcortical gradient of cerebral blood flow in schizophrenia: relationship to symptoms and neuropsychological functions. Sagawa K, Kawakatsu S, Komatani A, Totsuka S.

Schizophr Res 1989 Nov-Dec;2(6):439-48. Effect of attention on frontal distribution of delta activity and cerebral metabolic rate in schizophrenia. Guich SM, Buchsbaum MS, Burgwald L, Wu J, Haier R, Asarnow R, Nuechterlein K, Potkin S. Analysis confirmed increased delta activity in the frontal region of patients with schizophrenia in comparison to normal controls, and a significant correlation between increased frontal delta and relative reduction in frontal lobe metabolism among patients with schizophrenia. This finding of increased delta is consistent with PET, blood flow and topographic EEG studies of schizophrenia, suggesting reduced frontal activity.

Br J Psychiatry 1990 Feb;156:216-27. Glucose metabolic rate in normals and schizophrenics during the Continuous Performance Test assessed by positron emission tomography. Buchsbaum MS, Nuechterlein KH, Haier RJ, Wu J, Sicotte N, Hazlett E, Asarnow R, Potkin S, Guich S When the group of schizophrenic patients was divided into deficit and nondeficit types, a preliminary exploratory analysis suggested thalamic, frontal, and parietal cortical hypometabolism in the deficit subgroup, with normal metabolism in the nondeficit patient group in those areas; in contrast, hippocampal and anterior cingulate cortical metabolism was reduced in both deficit and nondeficit subtypes. These results suggest that the limbic system, especially the hippocampus, is functionally involved in schizophrenic psychosis and that different manifestations of schizophrenia may involve different neuronal circuits.

Psychol Med 1994 Nov;24(4):947-55. Patterns of cortical activity in schizophrenia. Schroeder J, Buchsbaum MS, Siegel BV, Geider FJ, Haier RJ, Lohr J, Wu J, Potkin SG. Schizophrenics were significantly more hypofrontal than the controls, with higher values on the 'parietal cortex and motor strip' factor and a trend towards higher values in the temporal cortex. A canonical discriminant analysis confirmed that the 'hypofrontality' and 'parietal cortex and motor strip' factors accurately separated the schizophrenic group from the healthy controls.

Schizophr Res 1996 Mar;19(1):41-53. Cerebral metabolic activity correlates of subsyndromes in chronic schizophrenia. Schroder J, Buchsbaum MS, Siegel BV, Geider FJ, Lohr J, Tang C, Wu J, Potkin SG. The delusional cluster showed a significantly reduced hippocampal activity, while the negative symptoms cluster presented with a prominent hypofrontality and significantly increased left temporal cortex values.

Psychiatry Res 1997 Oct 31;75(3):131-44. Cerebral glucose metabolism in childhood onset schizophrenia. Jacobsen LK, Hamburger SD, Van Horn JD, Vaituzis AC, McKenna K, Frazier JA, Gordon CT, Lenane MC, Rapoport JL, Zametkin AJ. Decreased frontal cortical glucose metabolism has been demonstrated in adult schizophrenics both at rest and while engaging in tasks that normally increase frontal metabolism, such as the Continuous Performance Test (CPT).. These findings suggest that childhood onset schizophrenia may be associated with a similar, but not more severe, degree of hypofrontality relative to that seen in adult onset schizophrenia.

Pharmacol Biochem Behav 1990 Apr; 35(4):955-62. The effects of ondansetron, a 5-HT3 receptor antagonist, on cognition in rodents and primates. Barnes JM, Costall B, Coughlan J, Domeney AM, Gerrard PA, Kelly ME, Naylor RJ, Onaivi ES, Tomkins DM, Tyers MB. The selective 5-HT3 receptor antagonist, onansetron, has been assessed in three tests of cognition in the mouse, rat and marmoset. In a habituation test in the mouse, ondansetron facilitated performance in young adult and aged animals, and inhibited an impairment in habituation induced by scopolamine, electrolesions or ibotenic acid lesions of the nucleus basalis magnocellularis. In an object discrimination and reversal learning task in the marmoset, assessed using a Wisconsin General Test Apparatus, ondansetron improved performance in a reversal learning task. We conclude that ondansetron potently improves basal performance in rodent and primate tests of cognition and inhibits the impairments in performance caused by cholinergic deficits.

Pharmacol Biochem Behav 1992 May;42(1):75-83. Ondansetron and arecoline prevent scopolamine-induced cognitive deficits in the marmoset. Carey GJ, Costall B, Domeney AM, Gerrard PA, Jones DN, Naylor RJ, Tyers MB School of Pharmacy, University of Bradford, UK. The cognitive-enhancing potential of the 5-hydroxytryptamine (5-HT) selective 5-HT3 receptor antagonist, ondansetron, was investigated in a model of cognitive impairment induced by the muscarinic receptor antagonist, scopolamine.

J Comp Physiol Psychol 1977 Jun;91(3): 642-8. Tryptophan and tonic immobility in chickens: effects of dietary and systemic manipulations. Gallup GG Jr, Wallnau LB, Boren JL, Gagliardi GJ, Maser JD, Edson PH. Systemic injections of tryptophan, the dietary precursor to serotonin, led to a dose-dependent increase in immobility, with optimal effects being observed within 30 min after injection. Dietary depletion of endogenous tryptophan served to attenuate the duration of immobility, and a diet completely free of tryptophan, but supplemented with niacin, practically abolished the reaction. Dietary replacement served to reinstate the response. The data are discussed in light of evidence showing serotonergic involvement in tonic immobility.

J Neurosci Res 1995 Feb 15;40(3):407-413. Endotoxin administration stimulates cerebral catecholamine release in freely moving rats as assessed by microdialysis. Lavicky J, Dunn AJ.

J Neurosci Res 1998 Feb 15;51(4):517-525. Lipopolysaccharide regulates both serotonin- and thrombin-induced intracellular calcium mobilization in rat C6 glioma cells: possible involvement of nitric oxide synthase-mediated pathway. Tawara Y, Kagaya A, Uchitomi Y, Horiguchi J, Yamawaki S.

Infect Immun 1996 Dec;64(12):5290-5294..Biphasic, organ-specific, and strain-specific accumulation of platelets induced in mice by a lipopolysaccharide from Escherichia coli and its possible involvement in shock. Shibazaki M, Nakamura M, Endo Y. "Platelets contain a large amount of 5-hydroxytryptamine (5HT, serotonin). Intravenous injection into BALB/c mice of a Boivin's preparation of lipopolysaccharide (LPS) from Escherichia coli induced rapid 5HT accumulation in the lung (within 5 min) and slow 5HT accumulation in the liver (2 to 5 h later)." "A shock, which was manifested by crawling, convulsion, or prostration, followed shortly after the rapid accumulation of 5HT in the lung. On the other hand, the slow accumulation of 5HT in the liver could be induced by much lower doses of LPS (1 microg/kg or less), even when given by intraperitoneal injection."

Life Sci 1997;61(18):1819-1827. Serotonin 5HT2A receptor activation inhibits inducible nitric oxide synthase activity in C6 glioma cells. Miller KJ, Mariano CL, Cruz WR.

Harefuah 2000 May 15;138(10):809-12, 910. [Jet lag causing or exacerbating psychiatric disorders]. Katz G, Durst R, Zislin J, Knobler H, Knobler HY. We presume, relying on the literature and our accumulated experience, that in predisposed individuals jet lag may play a role in triggering exacerbation of, or de novo affective disorders, as well as, though less convincing, schizophreniform psychosis or even schizophrenia. An illustrative case vignette exemplifies the possible relationship between jet lag following eastbound flight and psychotic manifestations.

Life Sci 1987 May 18;40(20):2031-9. Dysfunction in a prefrontal substrate of sustained attention in schizophrenia. Cohen RM, Semple WE, Gross M, Nordahl TE, DeLisi LE, Holcomb HH, King AC, Morihisa JM, Pickar D. Regional brain metabolism was measured in normal subjects and patients with schizophrenia while they performed an auditory discrimination task designed to emphasize sustained attention. A direct relationship was found in the normal subjects between metabolic rate in the middle prefrontal cortex and accuracy of performance. The metabolic rate in the middle prefrontal cortex of patients with schizophrenia, even those who performed as well as normals, was found to be significantly lower than normal and unrelated to performance. The findings point to a role of the mid-prefrontal region in sustained attention and to dysfunction of this region in schizophrenia.

Acta Psychiatr Scand 1987 Dec;76(6):628-41. Regional brain glucose metabolism in drug free schizophrenic patients and clinical correlates. Wiesel FA, Wik G, Sjogren I, Blomqvist G, Greitz T, Stone-Elander S. Thus, the lower the metabolic rate was, the more autistic the patient. Metabolic rates were not correlated to atrophic changes of the brain. No basis for a specific alteration in frontal cortical metabolism of schizophrenics was obtained. Changes in regional metabolic rates in schizophrenia are suggested to reflect disturbances in more general mechanisms which are of importance in neuronal function.

Chung Hua Shen Ching Ching Shen Ko Tsa Chih 1991 Oct;24(5):268-71, 316-7. [Developments observation of serum thyrohormone level in schizophrenics. Wang X. The authors reported that abnormal levels of T4, FT4I in 16 cases patients relate to disease course and severe symptoms and suggested that the change of serum T4, FT4I in some cases was related to the disease in itself.

Biol Psychiatry 1991 Mar 1;29(5):457-66. Multidimensional hormonal discrimination of paranoid schizophrenic from bipolar manic patients. Mason JW, Kosten TR, Giller EL.

Zh Nevropatol Psikhiatr Im S S Korsakova 1991;91(1):122-3 [Status of the thyroid gland in patients with schizophrenia]. Turianitsa IM, Lavkai IIu, Mishanich II, Margitich VM, Razhov KF. The rise of TTH concentration represents one of the mechanisms of correction, aimed at the attainment of the physiological content of T4 at the expense of its additional output for its level in the blood serum is appreciably reduced.

Can J Psychiatry 1990 May;35(4):342-3. Increased detection of elevated TSH using immunoradiometric assay. Little KY, Kearfott KS, Castellanos X, Rinker A, Whitley R. Using a highly sensitive immunoradiometric assay, the authors detected an increased rate of elevated thyrotropin in 2,099 patients vs 1,789 patients examined with radioimmunoassay. Closer scrutiny of mood disorder patients with elevations found confirmatory evidence of thyroid dysfunction in most.

Metabolism 1990 May;39(5):538-43. Serum thyrotropin in hospitalized psychiatric patients: evidence for hyperthyrotropinemia as measured by an ultrasensitive thyrotropin assay. Chopra IJ, Solomon DH, Huang TS.

J Nerv Ment Dis 1989 Jun;177(6):351-8. Serum thyroxine levels in schizophrenic and affective disorder diagnostic subgroups. Mason JW, Kennedy JL, Kosten TR, Giller EL Jr. For TT4, 75% of the PS group showed a rise during recovery in contrast to 4% of the remaining groups; for FT4, 50% of the PS group showed a rise compared with 14% of the other groups. This study emphasizes the importance of exploring more fully the psychiatric significance of thyroxine levels within the endocrinological normal range and of doing longitudinal assessments of thyroxine and symptom changes during clinical recovery in psychiatric disorders.

Biol Psychiatry 1989 Jan;25(1):67-74. Serum thyroxine change and clinical recovery in psychiatric inpatients. Southwick S, Mason JW, Giller EL, Kosten TR. A strong correlation between the range values for BPRS [Brief Psychiatric Rating Scale] sum and for FT4 (p less than 0.005) and TT4 (p less than 0.001) levels indicated that change in overall symptom severity was linked to change in thyroxine levels during clinical recovery. These findings suggest that a "normalizing" principle underlies the relationship between clinical recovery and thyroxine levels and that both FT4 and TT4 levels within the normal range appear to have clinical significance in either reflecting or contributing to the course of a variety of psychiatric disorders and possibly having a role in pathogenesis.

J Clin Psychiatry 1980 Sep;41(9):316-8. Myxedema psychosis--insanity defense in homicide. Easson WM.

Int J Psychiatry Med 1988;18(3):263-70. The diagnostic dilemma of myxedema and madness, axis I and axis II: a longitudinal case report. Darko DF, Krull A, Dickinson M, Gillin JC, Risch SC. A patient with presumed chronic paranoid schizophrenia had chronic thyroiditis and Grade I hypothyroidism. Psychosis cleared following treatment with thyroid replacement. The differential diagnosis among hypothyroidism and primary axis I psychotic and depressive psychopathology has always been problematic.

P R Health Sci J 1993 Jun;12(2):85-7. [Alzheimer's disease: the untold story]. Pico-Santiago G. After considering the potential relationship between amyloid deposits and myxedematous infiltrations, the hypothesis is formulated that Alzheimer's disease may be due to functional hypothyroidism and may thus respond to thyroid therapy.

Psychiatry Res 1998 Jul 27;80(1):29-39. Reduced level of plasma antioxidant uric acid in schizophrenia. Yao JK, Reddy R, van Kammen DP. There is evidence of dysregulation of the antioxidant defense system in schizophrenia. The purpose of the present study was to examine whether uric acid, a potent antioxidant, is reduced in the plasma of patients with schizophrenia. Male schizophrenic patients with either a haloperidol treatment (n=47) or a drug-free condition (n=35) had significantly lower levels of plasma uric acid than the age- and sex-matched normal control subjects (n=34). In addition, the plasma levels of uric acid in patient groups were significantly and inversely correlated with psychosis. There was a trend for lower uric acid levels in relapsed patients relative to clinically stable patients. Smoking, which can modify plasma antioxidant capacity, was not found to have prominent effects on uric acid levels. The present finding of a significant decrease of a selective antioxidant provides additional support to the hypothesis that oxidative stress in schizophrenia may be due to a defect in the antioxidant defense system.

Zh Nevropatol Psikhiatr Im S S Korsakova 1989; 89(5):108-10. [Lipid peroxidation processes in patients with schizophrenia]. Kovaleva ES, Orlov ON, Tsutsu'lkovskaia MIa, Vladimirova TV, Beliaev BS.

Zh Nevropatol Psikhiatr Im S S Korsakova 1991;91(7):121-4. [Significance of disorders of the processes of lipid peroxidation in patients with persistent paranoid schizophrenia resistant to the treatment]. Govorin NV, Govorin AV, Skazhutin SA.

Patol Fiziol Eksp Ter 1999 Jul-Sep;(3):19-22. [The biogenic amine content of rat tissues in the postresuscitation period following hemorrhagic shock and the effect of the preparation semax]. Bastrikova NA, Shestakova SV, Antonova SV, Krushinskaia IaV, Goncharenko EN, Kudriashova NIu, Novoderzhkina IS, Sokolova NA, Kozhura VL. Early after resuscitation the trend was noted to higher LPO products concentration in plasma and serotonin in the brain stem. It is suggested that biogenic amines, especially serotonin system, are involved in mechanisms of postresuscitation disorders, in cerebral defects in particular, through prolongation of secondary hypoxia early after hemorrhagic shock and activation of hypothalamo-hypophyso-adrenal system late after the shock.

Prostaglandins Leukot Essent Fatty Acids 1996 Aug;55(1-2):33-43. Free radical pathology in schizophrenia: a review. Reddy RD, Yao JK.

Schizophr Res 1996 Mar;19(1):19-26. Impaired antioxidant defense at the onset of psychosis. Mukerjee S, Mahadik SP, Scheffer R, Correnti EE, Kelkar H.

Biol Psychiatry 1998 May 1;43(9):674-9. Elevated plasma lipid peroxides at the onset of nonaffective psychosis. Mahadik SP, Mukherjee S, Scheffer R, Correnti EE, Mahadik JS.

Brain Res 1999 Aug 21;839(1):74-84. Psychological stress-induced enhancement of brain lipid peroxidation via nitric oxide systems and its modulation by anxiolytic and anxiogenic drugs in mice. Matsumoto K, Yobimoto K, Huong NT, Abdel-Fattah M, Van Hien T, Watanabe H. The effects of diazepam and FG7142 were abolished by the BZD receptor antagonist flumazenil (10 mg/kg, i.p.). These results indicate that psychological stress causes oxidative damage to the brain lipid via enhancing constitutive NOS-mediated production of NO, and that drugs with a BZD or 5-HT(1A) receptor agonist profile have a protective effect on oxidative brain membrane damage induced by psychological stress.

Anesteziol Reanimatol 1998 Nov-Dec; (6):20-5. [Role of hyperbaric oxygenation in the treatment of posthypoxic encephalopathy of toxic etiology]. Ermolov AS, Epifanova NM, Romasenko MV, Luzhnikov EA, Ishmukhametov AI, Golikov PP, Khvatov VB, Kukshina AA, Davydov BV, Kuksova NS, et al. Hyperbaric oxygenation (HBO) was used in the treatment of 475 patients with toxic encephalopathy (TE) developing as a result of exo- and endotoxicosis. HBO promoted correction of all components of homeostasis, decreased endotoxicosis, reduced psychopathological and neurological disorders, and promoted social adaptation.

J Neurochem 2000 Jan; 74(1): 114-24. Metabolic impairment elicits brain cell type-selective changes in oxidative stress and cell death in culture. Park LC, Calingasan NY, Uchida K, Zhang H, Gibson GE. Abnormalities in oxidative metabolism and inflammation accompany many neurodegenerative diseases. Thiamine deficiency (TD) is an animal model in which chronic oxidative stress and inflammation lead to selective neuronal death, whereas other cell types show an inflammatory response. Among the cell types tested, only in neurons did TD induce apoptosis and cause the accumulation of 4-hydroxy-2-nonenal, a lipid peroxidation product. On the other hand, chronic lipopolysaccharide-induced inflammation significantly inhibited cellular dehydrogenase and KGDHC activities in microglia and astrocytes but not in neurons or endothelial cells. The results demonstrate that the selective cell changes during TD in vivo reflect inherent properties of the different brain cell types.

Psychol Med 1976 Aug;6(3):359-69. Possible association of schizophrenia with a disturbance in prostaglandin metabolism: a physiological hypothesis. Feldberg W. Schizophrenia may be associated with increased prostaglandin synthesis in certain parts of the brain. This hypothesis is based on the following findings: (1) Catalepsy, which is the nearest equivalent in animals to human catatonia, develops in cats when prostaglandin E1 is injected into the cerebral ventricles and when during endotoxin or lipid A fever the prostaglandin E2 level in cisternal c.s.f. rises to high levels; however, when fever and prostaglandin level are brought down by non-steroid anti-pyretics which inhibit prostaglandin synthesis, catalepsy disappears as well. (2) Febrile episodes are a genuine syndrome of schizophrenia.

Zh Nevropatol Psikhiatr Im S S Korsakova 1966;66(6):912-7. [Treatment of acute schizophrenia with antibiotics, gamma-globulin and vitamins]. Neikoya M.

Prostaglandins Med 1979 Jan;2(1):77-80. Penicillin and essential fatty acid supplementation in schizophrenia. Vaddadi KS.

Psychiatr Dev 1989 Spring;7(1):19-47. Positron emission tomography in psychiatry. Wiesel FA. Schizophrenia is the most extensively studied psychiatric disorder. Most studies have demonstrated decreased metabolic rates in wide areas of the brain. It is proposed that the metabolic changes observed in the brains of schizophrenic patients are due to a fundamental change in neuronal function. Bipolar depressed patients probably have a decreased brain metabolism. Alcohol dependent subjects with a long duration of abuse may have a decreased brain metabolism.

Arch Gen Psychiatry 1976 Nov;33(11):1377-81. Platelet monamine oxidase in chronic schizophrenia. Some enzyme characteristics relevant to reduced activity. Murphy DL, Donnelly CH, Miller L, Wyatt RJ. These findings suggest that the reduced MAO activity found in chronic schizophrenic patients is apparently not accounted for by nonspecific changes in platelets or platelet mitochondria.

Exp Neurol 1997 May;145(1):118-29. Long-term reciprocal changes in dopamine levels in prefrontal cortex versus nucleus accumbens in rats born by Caesarean section compared to vaginal birth. El-Khodor BF, Boksa P. Epidemiological evidence indicates a higher incidence of pregnancy and birth complications among individuals who later develop schizophrenia, a disorder linked to alterations in mesolimbic dopamine (DA) function. Two birth complications usually included in these epidemiological studies, and still frequently encountered in the general population, are birth by Caesarean section (C-section) and fetal asphyxia. At 2 months of age, in animals born by rapid C-section, steady state levels of DA were decreased by 53% in the prefrontal cortex and increased by 40% in both the nucleus accumbens and striatum, in comparison to the vaginally born group. DA turnover increased in the prefrontal cortex, decreased in the nucleus accumbens, and showed no significant change in the striatum, in the C-section group. Thus, birth by a Caesarean procedure produces long-term reciprocal changes in DA levels and metabolism in the nucleus accumbens and prefrontal cortex. Although appearing robust at birth on gross observation, more subtle measurements revealed that rat pups born by C-section show altered respiratory rates and activity levels and increased levels of whole brain lactate, suggestive of low grade brain hypoxia, during the first 24 h of life, in comparison to vaginally born controls. It is concluded that C-section birth is sufficient perturbation to produce long-lasting effects on DA levels and metabolism in the central nervous system of the rat.

Rehabilitation (Stuttg) 1983 May;22(2):81-5 [Physical capacity of schizophrenic patients]. Deimel H, Lohmann S. Reduced physical capacity in schizophrenic illness has been described in medical literature, but so far not been substantiated empirically. The findings of progressive bicycle ergometry confirm the assertion, with the following main results having been obtained: 1. As opposed to a matched comparison group of untrained healthy clients, the schizophrenically ill patients demonstrated significantly lower endurance levels in respect of the aerobic-anaerobic threshold. 2. Relative to the load maximum attainable highly significant differences existed between the groups. Particularly noteworthy had been early exercise termination already at submaximal loads by the schizophrenic patients. 3. The patients under study obtained values one third below standard compared to the maximum load target for untrained persons, with age and weight being taken into account.

Folia Psychiatr Neurol Jpn 1984;38(4):425-36 Antipsychotic and prophylactic effects of acetazolamide (Diamox) on atypical psychosis. Inoue H, Hazama H, Hamazoe K, Ichikawa M, Omura F, Fukuma E, Inoue K, Umezawa Y We investigated the antipsychotic and prophylactic effects of acetazolamide (Diamox) on atypical psychosis. Acetazolamide was given to 30 patients: Type I, puberal periodic psychosis, a psychosis whose onset occurs during the period of puberty and which appears repetitively with psychosis-like condition at about the same interval as the menstrual cycle (6 cases); Type II, a) presenile atypical psychosis which initially appears in patients in their 20s or 30s accompanied by manic-depressive cycles and shows acute confusional and dreamy states in the presenile period, incurable cases (7), b) atypical psychosis, in the narrow sense, cases which show acute hallucination, delusion, confusional and dreamy states accompanied by affective symptoms (8 cases); Type III, repetitively the atypical manic and depressive states, and atypical manic-depressive psychosis, and transient changes in consciousness, refractory cases (2); Type IV, atypical schizophrenia, which is considered to be schizophrenia but shows the abnormalities in electroencephalogram and emotional disorders (7 cases). Among these cases, some extent of the therapeutic effects of acetazolamide (500-1,000 mg/day) was obtained in about 70%. The high therapeutic effects were particularly observed in Types I, II and III. It was less effective against atypical schizophrenia. Acetazolamide showed the effectiveness in 10 cases out of 13 cases to which lithium carbonate and carbamazepine were ineffective. The high therapeutic effects of acetazolamide were shown in the cases whose symptoms were aggravated at the interval of the menstrual cycle. No correlation was observed between the electroencephalographic abnormalities and the therapeutic effects. In addition, the prophylactic effects of acetazolamide on the periodic crisis were observed in 9 cases. From these results, acetazolamide was considered to have the antipsychotic and prophylactic effects on atypical psychosis. Since side effects due to acetazolamide were rarely observed, the present drug was considered to have a high safety margin.

Am J Psychiatry 1999 Apr;156(4):617-23 Minor physical anomalies, dermatoglyphic asymmetries, and cortisol levels in adolescents with schizotypal personality disorder. Weinstein DD, Diforio D, Schiffman J, Walker E, Bonsall R. The schizotypal personality disorder group showed more minor physical anomalies and dermatoglyphic asymmetries than the normal comparison group and higher cortisol levels than both of the other groups.

Am J Psychiatry 1992 Jan;149(1):57-61 Congenital malformations and structural developmental anomalies in groups at high risk for psychosis. McNeil TF, Blennow G, Lundberg L. The inferred genetic risk for psychosis does not appear to be associated with greater rates of early somatic developmental anomalies, suggesting that early developmental anomalies do not represent an expression of genetic influence toward psychosis.

Schizophr Bull 1984;10(2):204-32. Psychophysiological dysfunctions in the developmental course of schizophrenic disorders. Dawson ME, Nuechterlein KH. Two electrodermal anomalies are identified in different subgroups of symptomatic patients: (1) an abnormally high sympathetic arousal and (2) an abnormal absence of skin conductance orienting responses to innocuous environmental stimuli.

Behav Brain Res 2000 Jan;107(1-2):71-83. Changes in adult brain and behavior caused by neonatal limbic damage: implications for the etiology of schizophrenia. Hanlon FM, Sutherland RJ. .This study contributes to our understanding of the pathogenesis of schizophrenia by showing that early damage to limbic structures produced behavioral, morphological, and neuropharmacological abnormalities related to pathology in adult schizophrenics.

Neurochem Res 1996 Sep; 21(9):995-1004. Mitochondrial involvement in schizophrenia and other functional psychoses. Whatley SA, Curti D, Marchbanks RM. Gene expression has been studied in post-mortem frontal cortex samples from patients who had suffered from schizophrenia and depressive illness. We conclude that changes in mitochondrial gene expression are involved in schizophrenia and probably other functional psychoses.

Eur J Pharmacol 1994 Aug 11;261(1-2):25-32. The effect of alpha 2-adrenoceptor antagonists in isolated globally ischemic rat hearts. Sargent CA, Dzwonczyk S, Grover GJ. The alpha 2-adrenoceptor antagonist, yohimbine, has been reported to protect hypoxic myocardium. Yohimbine has several other activities, including 5-HT receptor antagonism, at the concentrations at which protection was found. The cardioprotective effects of yohimbine were partially reversed by 30 microM 5-HT. These results indicate that the mechanism for the cardioprotective activity of yohimbine may involve 5-HT receptor antagonistic activity.

J Cardiovasc Pharmacol 1993 Oct;22(4):664-672. Protective effect of serotonin (5-HT2) receptor antagonists in ischemic rat hearts. Grover GJ, Sargent CA, Dzwonczyk S, Normandin DE, Antonaccio MJ.

J Appl Physiol 1994 Jul;77(1):277-284. Aerobic muscle contraction impaired by serotonin-mediated vasoconstriction. Dora KA, Rattigan S, Colquhoun EQ, Clark MG.

J Cereb Blood Flow Metab 1995 Jul;15(4):706-13. Enhanced cerebrovascular responsiveness to hypercapnia following depletion of central serotonergic terminals. Kelly PA, Ritchie IM, McBean DE, Sharkey J, Olverman HJ.

Arch Gen Psychiatry 1984 Mar;41(3): 293-300. Regional brain glucose metabolism in chronic schizophrenia. A positron emission transaxial tomographic study. Farkas T, Wolf AP, Jaeger J, Brodie JD, Christman DR, Fowler JS. . . . schizophrenics had significantly lower activity in the frontal lobes, relative to posterior regions.

Semin Nucl Med 1986 Jan;16(1):2-34. Positron emission tomography imaging of regional cerebral glucose metabolism. Alavi A, Dann R, Chawluk J, Alavi J, Kushner M, Reivich M. In patients with Alzheimer's disease . . . parietal, temporal, and to some degree, frontal glucose metabolism is significantly diminished even in the early stages of the disease. Patients with Huntington's disease and those at risk of developing this disorder have a typical pattern of diminished CMRglu in the caudate nuclei and putamen. In patients with stroke, PET images with FDG have demonstrated abnormal findings earlier than either XCT or MRI and with a wider topographic distribution. FDG scans have revealed interictal zones of decreased LCMRglu in approximately 70% of patients with partial epilepsy. The location of the area of hypometabolism corresponds to the site of the epileptic focus as determined by electroencephalography and microscopic examination of the resected tissue.

Schizophr Bull 1988; 14(2): 169-76. From syndrome to illness: delineating the pathophysiology of schizophrenia with PET. Cohen RM, Semple WE, Gross M, Nordahl TE. In normal controls, the metabolic rate in the middle prefrontal cortex, measured during the ongoing performance of auditory discrimination, is associated with their accuracy of performance. In unmedicated patients with schizophrenia, even those who performed as well as normals, the metabolic rate in the mid-prefrontal cortex was found to be significantly lower than normal. Further, this decreased metabolic rate was unrelated to performance. The mid-prefrontal cortex and its dopamine neurotransmitter pathway input are important biological determinants of sustained attention.

Biol Psychiatry 1989 Apr 1;25(7):835-51. Increased temporal lobe glucose use in chronic schizophrenic patients. DeLisi LE, Buchsbaum MS, Holcomb HH, Langston KC, King AC, Kessler R, Pickar D, Carpenter WT Jr, Morihisa JM, Margolin R, et al. Temporal lobe glucose metabolic rate was assessed in 21 off-medication patients with schizophrenia and 19 normal controls by positron emission tomography with 18F-deoxyglucose. Patients with schizophrenia had significantly greater metabolic activity in the left than the right anterior temporal lobe, and the extent of this lateralization was in proportion to the severity of psychopathology.

Am J Obstet Gynecol 1999 Dec;181(6):1479-84. Stimulated nitric oxide release and nitric oxide sensitivity in forearm arterial vasculature during normotensive and preeclamptic pregnancy. Anumba DO, Ford GA, Boys RJ, Robson SC. Alterations in serotonin receptor coupling to nitric oxide synthase, or a limitation of availability of the substrate for nitric oxide synthase (L-arginine) during pregnancy, could account for the reduction in stimulated nitric oxide release.

J Hypertens 1999 Mar;17(3):389-96. U46619-mediated vasoconstriction of the fetal placental vasculature in vitro in normal and hypertensive pregnancies. Read MA, Leitch IM, Giles WB, Bisits AM, Boura AL, Walters WA.

Am J Obstet Gynecol 1999 Feb;180(2 Pt 1):371-7. Ketanserin versus dihydralazine in the management of severe early-onset preeclampsia: maternal outcome. Bolte AC, van Eyck J, Kanhai HH, Bruinse HW, van Geijn HP, Dekker GA. Ketanserin [a selective serotonin 2 receptor blocker] is an attractive alternative in the management of severe early-onset preeclampsia.

Am J Obstet Gynecol 1996 Dec;175(6):1543-50. Novel appearance of placental nuclear monoamine oxidase: biochemical and histochemical evidence for hyperserotonomic state in preeclampsia-eclampsia. Gujrati VR, Shanker K, Vrat S, Chandravati, Parmar SS. Placental serotonin increases with severity (rsystolic 0.84, rdiastolic 0.83) and monoamine oxidase decreases (rsystolic 0.86, rdiastolic 0.79). Placental monoamine oxidase showed marked changes in preeclampsia-eclampsia. .A severity-dependent decrease was present in the nuclei of placentas with preeclampsia-eclampsia. The study delineates an impaired catabolism of placental serotonin in preeclampsia-eclampsia. The novel appearance of monoamine oxidase in nuclei in proximity to its normal site and low activity resulting in a hyperserotonomic state may lead to preeclampsia-eclampsia.

Chung Hua Fu Chan Ko Tsa Chih 1996 Nov;31(11):670-2 [Changes of plasma levels of monoamines in normal pregnancy and pregnancy-induced hypertension women and their significance]. Lin B, Zhu S, Shao B. Compared with NP [normal pregnant], the contents of DA in moderate and severe PIH [pregnancy-induced hypertension] were markedly and very markedly decreased respectively (P < 0.05 and P < 0.01), while the levels of 5-HT in PIH increased significantly (P < 0.05). The changes of monoamines may be one of the causes of small artery spasm in PIH.

Lancet 1997 Nov 1;350(9087):1267-71. Randomised controlled trial of ketanserin and aspirin in prevention of pre-eclampsia. Steyn DW, Odendaal HJ. Pre-eclampsia is associated with extensive endothelial-cell damage and platelet activation, resulting in lower production of vasodilator prostaglandins and increased release of the vasoconstrictors thromboxane A2 and serotonin. We investigated the role of ketanserin, a selective serotonin-2-receptor antagonist, in lowering the rate of pre-eclampsia among pregnant women with mild to moderate hypertension. There were significantly fewer cases of pre-eclampsia (two vs 13; relative risk 0.15 [95% CI 0.04-0.66], p = 0.006) and severe hypertension (six vs 17; p = 0.02) in the ketanserin than in the placebo group. There was also a trend towards less perinatal mortality (one vs six deaths) but this was not significant (p = 0.28). Rates of abruptio placentae and pre-eclampsia before 34 weeks' gestation were lower in the ketanserin group, and mean birthweight was significantly higher.

Osaka City Med J 1989 Jun;35(1):1-11. Serotonin and tryptamine metabolism in the acute hepatic failure model: changes in tryptophan and its metabolites in the liver, brain and kidney. Kodama C, Mizoguchi Y, Kawada N, Sakagami Y, Seki S, Kobayashi K, Morisawa S.

Br J Pharmacol 1984 Apr;81(4):645-650. Induction of hypoglycaemia and accumulation of 5-hydroxytryptamine in the liver after the injection of mitogenic substances into mice. Endo Y.

Eur J Pharmacol 1983 Aug 5;91(4):493-499. A lipopolysaccharide and concanavalin A induce variations of serotonin levels in mouse tissues. Endo Y.

Brain Res 1986 Jul 16;378(1):164-8 5-Hydroxytryptamine-2 antagonist increases human slow wave sleep. Idzikowski C, Mills FJ, Glennard R Ritanserin, a specific 5-HT2 antagonist, was given to volunteers in a double-blind placebo controlled sleep study. Slow wave sleep doubled in duration at the expense of stage 2. The finding that a serotonin antagonist changed the architecture of sleep without producing insomnia is of fundamental importance and calls for a re-examination of traditional theories of sleep control which assign a facilitatory role to serotonin.

Med Hypotheses 2000 Apr;54(4):645-7 Role of the pineal gland in hibernators: a concept proposed to clarify why hibernators have to leave torpor and sleep. Kocsard-Varo G.

Chronobiol Int 2000 Mar;17(2):103-28. The temporal organization of daily torpor and hibernation: circadian and circannual rhythms. Kortner G, Geiser F.

Neuroreport 2000 Mar 20;11(4):881-5 Slow waves in the sleep electroencephalogram after daily torpor are homeostatically regulated. Deboer T, Tobler I.

Neuroendocrinology 1982 Jun; 34(6): 438-443. Sleep organization in hypo- and hyperthyroid rats. Carpenter AC, Timiras PS. The results show an increased number of awakenings during slow wave sleep (SWS) in hypothyroid animals, whereas total sleep time, levels of SWS, paradoxical sleep, and diurnal organization were unaffected by thyroid status. Our findings indicate that adequate levels of thyroid hormone are necessary to sustain extended periods of SWS in the adult rat while hyperthyroid animals show no disruption of sleep organization. A corollary finding is that daily sleep quotas are independent of whole body metabolic rates.

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<span class="koboSpan" id="kobo.1.1"> TSH, temperature, pulse rate, and other indicators in hypothyroidism</span> A R T I C L E

TSH, temperature, pulse rate, and other indicators in hypothyroidism

Each of the indicators of thyroid function can be useful, but has to be interpreted in relation to the physiological state.

Increasingly, TSH (the pituitary thyroid stimulating hormone) has been treated as if it meant something independently; however, it can be brought down into the normal range, or lower, by substances other than the thyroid hormones.

Basal body temperature is influenced by many things besides thyroid. The resting heart rate helps to interpret the temperature. In a cool environment, the temperature of the extremities is sometimes a better indicator than the oral or eardrum temperature.

The basal metabolic rate, especially if the rate of carbon dioxide production is measured, is very useful. The amount of water and calories disposed of in a day can give a rough idea of the metabolic rate.

The T wave on the electrocardiogram, and the relaxation rate on the Achilles reflex test are useful.

Blood tests for cholesterol, albumin, glucose, sodium, lactate, total thyroxine and total T3 are useful to know, because they help to evaluate the present thyroid status, and sometimes they can suggest ways to correct the problem.

Less common blood or urine tests (adrenaline, cortisol, ammonium, free fatty acids), if they are available, can help to understand compensatory reactions to hypothyroidism.

A book such as McGavack's The Thyroid, that provides traditional medical knowledge about thyroid physiology, can help to dispel some of the current dogmas about the thyroid.

Using more physiologically relevant methods to diagnose hypothyroidism will contribute to understanding its role in many problems now considered to be unrelated to the thyroid.

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I have spoken to several people who told me that their doctors had diagnosed them as both hypothyroid and hyperthyroid. Although physicists can believe in things which are simultaneously both particles and not particles, I think biology (and medicine, as far as it is biologically based) should occupy a world in which things are not simultaneously themselves and their opposites. Those illogical, impossible diagnoses make it clear that the rules for interpreting test results have in some situations lost touch with reality.

Until the 1940s, hypothyroidism was diagnosed on the basis of signs and symptoms, and sometimes the measurement of oxygen consumption (basal metabolic rate) was used for confirmation. Besides the introduction of supposedly scientific blood tests, such as the measurement of protein-bound iodine (PBI) in the blood, there were other motives for becoming parsimonious with the diagnosis of hypothyroidism. With the introduction of synthetic thyroxine, one of the arguments for increasing its sale was that natural Armour thyroid (which was precisely standardized by biological tests) wasn't properly standardized, and that an overdose could be fatal. A few articles in prestigious journals created a myth of the danger of thyroid, and the synthetic thyroxine was (falsely) said to be precisely standardized, and to be without the dangers of the complete glandular extract.

Between 1940 and about 1950, the estimated percentage of hypothyroid Americans went from 30% or 40% to 5%, on the basis of the PBI test, and it has stayed close to that lower number (many publications claim it to be only 1% or 2%). By the time that the measurement of PBI was shown to be only vaguely related to thyroid hormonal function, it had been in use long enough for a new generation of physicians to be taught to disregard the older ideas about diagnosing and treating hypothyroidism. They were taught to inform their patients that the traditional symptoms that were identified as hypothyroidism before 1950 were the result of the patients' own behavior (sloth and gluttony, for example, which produced fatigue, obesity, and heart disease), or that the problems were imaginary (women's hormonal and neurological problems, especially), or that they were simply mysterious diseases and defects (recurring infections, arthritis, and cancer, for example).

As the newer, more direct tests became available, their meaning was defined in terms of the statistical expectation of hypothyroidism that had become an integral part of medical culture. To make the new TSH measurements fit the medical doctrine, an 8- or 10-fold variation in the hormone was defined as normal. With any other biological measurement, such as erythrocyte count, blood pressure, body weight, or serum sodium, calcium, chloride, or glucose, a variation of ten or 20 percent from the mean is considered to be meaningful. If the doctrine regarding the 5% prevalence of hypothyroidism hadn't been so firmly established, there would have been more interest in establishing the meaning of these great variations in TSH.

In recent years the normal range for TSH has been decreasing. In 2003, the American Association of Clinical Endocrinologists changed their guidelines for the normal range to 0.3 to 3.0 microIU/ml. But even though this lower range is less arbitrary than the older standards, it still isn't based on an understanding of the physiological meaning of TSH.

Over a period of several years, I never saw a person whose TSH was over 2 microIU/ml who was comfortably healthy, and I formed the impression that the normal, or healthy, quantity was probably something less than 1.0.

If a pathologically high TSH is defined as normal, its role in major diseases, such as breast cancer, mastalgia, MS, fibrotic diseases, and epilepsy, will simply be ignored. Even if the possibility is considered, the use of an irrational norm, instead of a proper comparison, such as the statistical difference between the mean TSH levels of cases and controls, leads to denial of an association between hypothyroidism and important diseases, despite evidence that indicates an association.

Some critics have said that most physicians are treating the TSH, rather than the patient. If TSH is itself pathogenic, because of its pro-inflammatory actions, then that approach isn't entirely useless, even when they treat the TSH with only thyroxine, which often isn't well converted into the active triiodothyronine, T3. But the relief of a few symptoms in a small percentage of the population is serving to blind the medical world to the real possibilities of thyroid therapy.

TSH has direct actions on many cell types other than the thyroid, and probably contributes directly to edema (Wheatley and Edwards, 1983), fibrosis, and mastocytosis. If people are concerned about the effects of a TSH deficiency, then I think they have to explain the remarkable longevity of the animals lacking pituitaries in W.D. Denckla's experiments, or of the naturally pituitary deficient dwarf mice that lack TSH, prolactin, and growth hormone, but live about a year longer than normal mice (Heiman, et al., 2003). Until there is evidence that very low TSH is somehow harmful, there is no basis for setting a lower limit to the normal range.

Some types of thyroid cancer can usually be controlled by keeping TSH completely suppressed. Since TSH produces reactions in cells as different as fibroblasts and fat cells, pigment cells in the skin, mast cells and bone marrow cells (Whetsell, et al., 1999), it won't be surprising if it turns out to have a role in the development of a variety of cancers, including melanoma.

Many things, including the liver and the senses, regulate the function of the thyroid system, and the pituitary is just one of the factors affecting the synthesis and secretion of the thyroid hormones.

A few people who had extremely low levels of pituitary hormones, and were told that they must take several hormone supplements for the rest of their life, began producing normal amounts of those hormones within a few days of eating more protein and fruit. Their endocrinologist described them as, effectively, having no pituitary gland. Extreme malnutrition in Africa has been described as creating . . . a condition resembling hypophysectomy, (Ingenbleek and Beckers, 1975) but the people I talked to in Oregon were just following what they thought were healthful nutritional policies, avoiding eggs and sugars, and eating soy products.

Occasionally, a small supplement of thyroid in addition to a good diet is needed to quickly escape from the stress-induced hypophysectomized condition.

Aging, infection, trauma, prolonged cortisol excess, somatostatin, dopamine or L-dopa, adrenaline (sometimes; Mannisto, et al., 1979), amphetamine, caffeine and fever can lower TSH, apart from the effect of feedback by the thyroid hormones, creating a situation in which TSH can appear normal or low, at the same time that there is a real hypothyroidism.

A disease or its treatment can obscure the presence of hypothyroidism. Parkinson's disease is a clear example of this. (Garcia-Moreno and Chacon, 2002: ... in the same way hypothyroidism can simulate Parkinson's disease, the latter can also conceal hypothyroidism.)

The stress-induced suppression of TSH and other pituitary hormones is reminiscent of the protective inhibition that occurs in individual nerve fibers during dangerously intense stress, and might involve such a parabiotic process in the nerves of the hypothalamus or other brain region. The relative disappearance of the pituitary hormones when the organism is in very good condition (for example, the suppression of ACTH and cortisol by sugar or pregnenolone) is parallel to the high energy quiescence of individual nerve fibers.

These associations between energy state and cellular activity can be used for evaluating the thyroid state, as in measuring nerve and muscle reaction times and relaxation rates. For example, relaxation which is retarded, because of slow restoration of the energy needed for cellular repolarization, is the basis for the traditional use of the Achilles tendon reflex relaxation test for diagnosing hypothyroidism. The speed of relaxation of the heart muscle also indicates thyroid status (Mohr-Kahaly, et al., 1996).

Stress, besides suppressing the TSH, acts in other ways to suppress the real thyroid function. Cortisol, for example, inhibits the conversion of T4 to T3, which is responsible for the respiratory production of energy and carbon dioxide. Adrenaline, besides leading to increased production of cortisol, is lipolytic, releasing the fatty acids which, if they are polyunsaturated, inhibit the production and transport of thyroid hormone, and also interfere directly with the respiratory functions of the mitochondria. Adrenaline decreases the conversion to T4 to T3, and increases the formation of the antagonistic reverse T3 (Nauman, et al., 1980, 1984).

During the night, at the time adrenaline and free fatty acids are at their highest, TSH usually reaches its peak. TSH itself can produce lipolysis, raising the level of circulating free fatty acids. This suggests that a high level of TSH could sometimes contribute to functional hypothyroidism, because of the antimetabolic effects of the unsaturated fatty acids.

These are the basic reasons for thinking that the TSH tests should be given only moderate weight in interpreting thyroid function.

The metabolic rate is very closely related to thyroid hormone function, but defining it and measuring it have to be done with awareness of its complexity.

The basal metabolic rate that was commonly used in the 1930s for diagnosing thyroid disorders was usually a measurement of the rate of oxygen consumption, made while lying quietly early in the morning without having eaten anything for several hours. When carbon dioxide production can be measured at the same time as oxygen consumption, it's possible to estimate the proportion of energy that is being derived from glucose, rather than fat or protein, since oxidation of glucose produces more carbon dioxide than oxidation of fat does. Glucose oxidation is efficient, and suggests a state of low stress.

The very high adrenaline that sometimes occurs in hypothyroidism will increase the metabolic rate in several ways, but it tends to increase the oxidation of fat. If the production of carbon dioxide is measured, the adrenaline/stress component of metabolism will be minimized in the measurement. When polyunsaturated fats are mobilized, their spontaneous peroxidation consumes some oxygen, without producing any usable energy or carbon dioxide, so this is another reason that the production of carbon dioxide is a very good indicator of thyroid hormone activity. The measurement of oxygen consumption was usually done for two minutes, and carbon dioxide production could be accurately measured in a similarly short time. Even a measurement of the percentage of carbon dioxide at the end of a single breath can give an indication of the stress-free, thyroid hormone stimulated rate of metabolism (it should approach five or six percent of the expired air).

Increasingly in the last several years, people who have many of the standard symptoms of hypothyroidism have told me that they are hyperthyroid, and that they have to decide whether to have surgery or radiation to destroy their thyroid gland. They have told me that their symptoms of hyperthyroidism, according to their physicians, were fatigue, weakness, irritability, poor memory, and insomnia.

They didn't eat very much. They didn't sweat noticeably, and they drank a moderate amount of fluids. Their pulse rates and body temperature were normal, or a little low.

Simply on the basis of some laboratory tests, they were going to have their thyroid gland destroyed. But on the basis of all of the traditional ways of judging thyroid function, they were hypothyroid.

Broda Barnes, who worked mostly in Fort Collins, Colorado, argued that the body temperature, measured before getting out of bed in the morning, was the best basis for diagnosing thyroid function.

Fort Collins, at a high altitude, has a cool climate most of the year. The altitude itself helps the thyroid to function normally. For example, one study (Savourey, et al., 1998) showed an 18% increase in T3 at a high altitude, and mitochondria become more numerous and are more efficient at preventing lactic acid production, capillary leakiness, etc.

In Eugene during a hot and humid summer, I saw several obviously hypothyroid people whose temperature seemed perfectly normal, euthyroid by Barnes' standards. But I noticed that their pulse rates were, in several cases, very low. It takes very little metabolic energy to keep the body at 98.6 degrees when the air temperature is in the nineties. In cooler weather, I began asking people whether they used electric blankets, and ignored their temperature measurements if they did.

The combination of pulse rate and temperature is much better than either one alone. I happened to see two people whose resting pulse rates were chronically extremely high, despite their hypothyroid symptoms. When they took a thyroid supplement, their pulse rates came down to normal. (Healthy and intelligent groups of people have been found to have an average resting pulse rate of 85/minute, while less healthy groups average close to 70/minute.)

The speed of the pulse is partly determined by adrenaline, and many hypothyroid people compensate with very high adrenaline production. Knowing that hypothyroid people are susceptible to hypoglycemia, and that hypoglycemia increases adrenaline, I found that many people had normal (and sometimes faster than average) pulse rates when they woke up in the morning, and when they got hungry. Salt, which helps to maintain blood sugar, also tends to lower adrenalin, and hypothyroid people often lose salt too easily in their urine and sweat. Measuring the pulse rate before and after breakfast, and in the afternoon, can give a good impression of the variations in adrenalin. (The blood pressure, too, will show the effects of adrenaline in hypothyroid people. Hypothyroidism is a major cause of hypertension.)

But hypoglycemia also tends to decrease the conversion of T4 to T3, so heat production often decreases when a person is hungry. First, their fingers, toes, and nose will get cold, because adrenalin, or adrenergic sympathetic nervous activity, will increase to keep the brain and heart at a normal temperature, by reducing circulation to the skin and extremities. Despite the temperature-regulating effect of adrenalin, the reduced heat production resulting from decreased T3 will make a person susceptible to hypothermia if the environment is cool.

Since food, especially carbohydrate and protein, will increase blood sugar and T3 production, eating is thermogenic, and the oral (or eardrum) temperature is likely to rise after eating.

Blood sugar falls at night, and the body relies on the glucose stored in the liver as glycogen for energy, and hypothyroid people store very little sugar. As a result, adrenalin and cortisol begin to rise almost as soon as a person goes to bed, and in hypothyroid people, they rise very high, with the adrenalin usually peaking around 1 or 2 A.M., and the cortisol peaking around dawn; the high cortisol raises blood sugar as morning approaches, and allows adrenalin to decline. Some people wake up during the adrenalin peak with a pounding heart, and have trouble getting back to sleep unless they eat something.

If the night-time stress is very high, the adrenalin will still be high until breakfast, increasing both temperature and pulse rate. The cortisol stimulates the breakdown of muscle tissue and its conversion to energy, so it is thermogenic, for some of the same reasons that food is thermogenic.

After eating breakfast, the cortisol (and adrenalin, if it stayed high despite the increased cortisol) will start returning to a more normal, lower level, as the blood sugar is sustained by food, instead of by the stress hormones. In some hypothyroid people, this is a good time to measure the temperature and pulse rate. In a normal person, both temperature and pulse rate rise after breakfast, but in very hypothyroid people either, or both, might fall.

Some hypothyroid people have a very slow pulse, apparently because they aren't compensating with a large production of adrenalin. When they eat, the liver's increased production of T3 is likely to increase both their temperature and their pulse rate.

By watching the temperature and pulse rate at different times of day, especially before and after meals, it's possible to separate some of the effects of stress from the thyroid-dependent, relatively basal metabolic rate. When beginning to take a thyroid supplement, it's important to keep a chart of these measurements for at least two weeks, since that's roughly the half-life of thyroxine in the body. When the body has accumulated a steady level of the hormones, and begun to function more fully, the factors such as adrenaline that have been chronically distorted to compensate for hypothyroidism will have begun to normalize, and the early effects of the supplementary thyroid will in many cases seem to disappear, with heart rate and temperature declining. The daily dose of thyroid often has to be increased several times, as the state of stress and the adrenaline and cortisol production decrease.

Counting calories achieves approximately the same thing as measuring oxygen consumption, and is something that will allow people to evaluate the various thyroid tests they may be given by their doctor. Although food intake and metabolic rate vary from day to day, an approximate calorie count for several days can often make it clear that a diagnosis of hyperthyroidism is mistaken. If a person is eating only about 1800 calories per day, and has a steady and normal body weight, any hyperthyroidism is strictly metaphysical, or as they say, clinical.

When the humidity and temperature are normal, a person evaporates about a liter of water for every 1000 calories metabolized. Eating 2000 calories per day, a normal person will take in about four liters of liquid, and form about two liters of urine. A hyperthyroid person will invisibly lose several quarts of water in a day, and a hypothyroid person may evaporate a quart or less.

When cells, because of a low metabolic rate, don't easily return to their thoroughly energized state after they have been stimulated, they tend to take up water, or, in the case of blood vessels, to become excessively permeable. Fatigued muscles swell noticeably, and chronically fatigued nerves can swell enough to cause them to be compressed by the surrounding connective tissues. The energy and hydration state of cells can be detected in various ways, including magnetic resonance, and electrical impedance, but functional tests are easy and practical.

With suitable measuring instruments, the effects of hypothyroidism can be seen as slowed conduction along nerves, and slowed recovery and readiness for new responses. Slow reaction time is associated with slowed memory, perception, and other mental processes. Some of these nervous deficits can be remedied slightly just by raising the core temperature and providing suitable nutrients, but the active thyroid hormone, T3 is mainly responsible for maintaining the temperature, the nutrients, and the intracellular respiratory energy production.

In nerves, as in other cells, the ability to rest and repair themselves increases with the proper level of thyroid hormone. In some cells, the energized stability produced by the thyroid hormones prevents inflammation or an immunological hyperactivity. In the 1950s, shortly after it was identified as a distinct substance, T3 was found to be anti-inflammatory, and both T4 and T3 have a variety of anti-inflammatory actions, besides the suppression of the pro-inflammatory TSH.

Because the actions of T3 can be inhibited by many factors, including polyunsaturated fatty acids, reverse T3, and excess thyroxine, the absolute level of T3 can't be used by itself for diagnosis. Free T3 or free T4 is a laboratory concept, and the biological activity of T3 doesn't necessarily correspond to its freedom in the test. T3 bound to its transport proteins can be demonstrated to enter cells, mitochondria, and nuclei. Transthyretin, which carries both vitamin A and thyroid hormones, is sharply decreased by stress, and should probably be regularly measured as part of the thyroid examination.

When T3 is metabolically active, lactic acid won't be produced unnecessarily, so the measurement of lactate in the blood is a useful test for interpreting thyroid function. Cholesterol is used rapidly under the influence of T3, and ever since the 1930s it has been clear that serum cholesterol rises in hypothyroidism, and is very useful diagnostically. Sodium, magnesium, calcium, potassium, creatinine, albumin, glucose, and other components of the serum are regulated by the thyroid hormones, and can be used along with the various functional tests for evaluating thyroid function.

Stereotypes are important. When a very thin person with high blood pressure visits a doctor, hypothyroidism isn't likely to be considered; even high TSH and very low T4 and T3 are likely to be ignored, because of the stereotypes. (And if those tests were in the healthy range, the person would be at risk for the hyperthyroid diagnosis.) But remembering some of the common adaptive reactions to a thyroid deficiency, the catabolic effects of high cortisol and the circulatory disturbance caused by high adrenaline should lead to doing some of the appropriate tests, instead of treating the person's hypertension and under nourished condition.

REFERENCES

Clin Chem Lab Med. 2002 Dec;40(12):1344-8. Transthyretin: its response to malnutrition and stress injury. Clinical usefulness and economic implications. Bernstein LH, Ingenbleek Y.

Endokrinologie. 1968;53(3):217-21.[Influence of hypophysectomy and pituitary hormones on dextran edema in rats] German. Boeskor A, Gabbiani G.

J Clin Endocrinol Metab. 2001 Nov;86(11):5148-51. Sudden enlargement of local recurrent thyroid tumor after recombinant human TSH administration. Braga M, Ringel MD, Cooper DS.

J Investig Med. 2002 Sep;50(5):350-4; discussion 354-5. The nocturnal serum thyrotropin surge is inhibited in patients with adrenal Incidentaloma. Coiro V, Volpi R, Capretti L, Manfredi G, Magotti MG, Bianconcini M, Cataldo S, Chiodera P.

Rev Neurol (Paris). 1992;148(5):371-3. [Hashimoto's encephalopathy: toxic or autoimmune mechanism?] [Article in French] Ghawche F, Bordet R, Destee A. Service de Clinique Neurologique A, CHU, Lille. A 36-year-old woman presented with partial complex status epilepticus. Magnetic resonance imaging with T2-weighted sequences showed a high-intensity signal in the left posterior frontal area. Hashimoto's thyroiditis was then discovered. The disappearance of the high-intensity signal after corticosteroid therapy was suggestive of an autoimmune mechanism. However, improvement could be obtained only with a hormonal treatment, which supports the hypothesis of a pathogenetic role of the Tyrosine-Releasing Hormone (TRH).

Am J Clin Nutr. 1986 Mar;43(3):406-13. Thyroid hormone and carrier protein interrelationships in children recovering rom kwashiorkor. Kalk WJ, Hofman KJ, Smit AM, van Drimmelen M, van der Walt LA, Moore RE. We have studied 15 infants with severe protein energy malnutrition (PEM) as a model of nutritional nonthyroidal illness. Changes in circulating thyroid hormones, binding proteins, and their interrelationships were assessed before and during recovery. Serum concentrations of total thyroxine and triiodothyronine and of thyroxine-binding proteins were extremely reduced, and increased progressively during 3 wk of refeeding. The T4:TBG molar ratio was initially 0.180 +/- 0.020, and increased progressively, parallel to the increases in TT4, to 0.344 +/- 0.038 after 21 days (p less than 0.025). The changes in free T4 estimates varied according to the methods used--FTI and analogue FT4 increased, dialysis FT4 fraction decreased. Serum TSH levels increased transiently during recovery. It is concluded 1) there is reduced binding of T4 and T3 to TBG in untreated PEM which takes 2-3 wk to recover; 2) there are methodological differences in evaluating free T4 levels in PEM; 3) increased TSH secretion appears to be an integral part of the recovery from PEM.

Neuroendocrinology. 1982;35(2):139-47. Neurotransmitter control of thyrotropin secretion. Krulich L. The central dopaminergic system seems to have an inhibitory influence on the secretion of thyrotropin (TSH) both in humans and rats.

Endocrinology 1972 Mar;90(3):795-801. TSH-induced release of 5-hydroxytryptamine and histamine rat thyroid mast cells. Ericson LE, Hakanson R, Melander A, Owman C, Sundler F.

Rev Neurol. 2002 Oct 16-31;35(8):741-2. [Hypothyroidism concealed by Parkinson's disease][in Spanish] Garcia-Moreno JM, Chacon J. Servicio de Neurologia, Hospital Universitario Virgen Macarena, Sevilla, Espana. Sinue@arrakis.es AIMS: Although it is commonly recognised that diseases of the thyroids can simulate extrapyramidal disorders, a review of the causes of Parkinsonism in the neurology literature shows that they are not usually mentioned or, if so, only very briefly. The development of hypothyroidism in a patient with Parkinson s disease can go undetected, since the course of both diseases can involve similar clinical features. Generally speaking there is always an insistence on the need to conduct a thyroidal hormone study in any patient with symptoms of Parkinson, but no emphasis is put on the need to continue to rule out dysthyroidism throughout the natural course of the disease, in spite of the fact that the concurrence of both pathological conditions can be high and that, in the same way hypothyroidism can simulate Parkinson s disease, the latter can also conceal hypothyroidism. CASE REPORT: We report the case of a female patient who had been suffering from Parkinson s disease for 17 years and started to present on off fluctuations that did not respond to therapy. Hypothyroidism was observed and the hormone replacement therapy used to resolve the problem allowed the Parkinsonian fluctuations to be controlled. CONCLUSIONS: We believe that it is very wise to suspect hypothyroidism in patients known to be suffering from Parkinson s disease, and especially so in cases where the clinical condition worsens and symptoms no longer respond properly to antiparkinsonian treatment. These observations stress the possible role played by thyroid hormones in dopaminergic metabolism and vice versa.

Endocrine. 2003 Feb-Mar;20(1-2):149-54. Body composition of prolactin-, growth hormone, and thyrotropin-deficient Ames dwarf mice. Heiman ML, Tinsley FC, Mattison JA, Hauck S, Bartke A. Lilly Research Labs, Corporate Center, Indianapolis, IN, USA. Ames dwarf mice have primary deficiency of prolactin (PRL), growth hormone (GH), and thyroid-stimulating hormone (TSH), and live considerably longer than normal animals from the same line.

(Lancet. 1975 Nov 1;2(7940):845-8.. Triiodothyronine and thyroid-stimulating hormone in protein-calorie malnutrition in infants. Ingenbleek Y, Beckers C.)

Am J Med Sci. 1995 Nov;310(5):202-5. Case report: thyrotropin-releasing hormone-induced myoclonus and tremor in a patient with Hashimoto's encephalopathy. Ishii K, Hayashi A, Tamaoka A, Usuki S, Mizusawa H, Shoji S.

Rev Neurol (Paris). 1985;141(1):55-8. [Hashimoto's thyroiditis and myoclonic encephalopathy. Pathogenic hypothesis] [Article in French] Latinville D, Bernardi O, Cougoule JP, Bioulac B, Henry P, Loiseau P, Mauriac L. A 49 year old caucasian female with Hashimoto thyroiditis, developed during two years a neurological disorder with tonic-clonic and myoclonic seizures and confusional states. Some attacks were followed by a transient postictal aphasia. Some parallelism was noted between the clinical state and TSH levels. Neurological events disappeared with the normalisation of thyroid functions. This association of Hashimoto thyroiditis and myoclonic encephalopathy has been rarely published. Pathogenesis could be double. Focal signs could be due to an auto-immune mechanism, perhaps through a vasculitis. A non-endocrine central action could explain diffuse signs: tonic-clonic seizures, myoclonus and confusional episodes.

J Clin Endocrinol Metab. 1992 Jun;74(6):1361-5. Fatty acid-induced increase in serum dialyzable free thyroxine after physical exercise: implication for nonthyroidal illness. Liewendahl K, Helenius T, Naveri H, Tikkanen H.

Adv Exp Med Biol. 1990;274:315-29. Role of monokines in control of anterior pituitary hormone release. McCann SM, Rettori V, Milenkovic L, Jurcovicova J, Gonzalez MC.

Acta Endocrinol (Copenh). 1979 Feb;90(2):249-58. Dual action of adrenergic system on the regulation of thyrotrophin secretion in the male rat. Mannisto, Ranta T, Tuomisto J. "....noradrenaline (NA) (1 h), and L-Dopa (1 h) were also effective in decreasing serum TSH levels...."

Endocrinology 1971 Aug;89(2):528-33. TSH-induced appearance and stimulation of amine-containing mast cells in the mouse thyroid. Melander A, Owman C, Sundler F.

Epilepsy Res. 1988 Mar-Apr;2(2):102-10. Evidence of hypothyroidism in the genetically epilepsy-prone rat. Mills SA, Savage DD. Department of Pharmacology, University of New Mexico School of Medicine, Albuquerque 87131. A number of neurochemical and behavioral similarities exist between the genetically epilepsy-prone (GEPR) rat and rats made hypothyroid at birth. These similarities include lower brain monoamine levels, audiogenic seizure susceptibility and lowered electroconvulsive shock seizure threshold. Given these similarities, thyroid hormone status was examined in GEPR rats. Serum samples were collected from GEPR-9 and non-epileptic control rats at 5, 9, 13, 16, 22, 31, 45, 60, 90, 150 and 350 days of age. Serum thyroxine (T4) levels were significantly lower in GEPR-9 rats compared to control until day 22 of age. GEPR-9 thyrotropin (TSH) levels were significantly elevated during the period of diminished serum T4. GEPR-9 triiodothyronine (T3) levels were lower than control throughout the first year of life. The data indicate that the GEPR-9 rat is hypothyroid from at least the second week of life up to 1 year of age. The critical impact of neonatal hypothyroidism on brain function coupled with the development of the audiogenic seizure susceptible trait by the GEPR-9 rat during the third week after birth suggests that neonatal hypothyroidism could be one etiological factor in the development of the seizure-prone state of GEPR-9 rats.

Przegl Lek. 1998;55(5):250-8. [Mastopathy and simple goiter--mutual relationships] [Article in Polish] Mizia-Stec K, Zych F, Widala E. Non-toxic goitre was found in 80% patients with mastopathy, and the results of palpation examination of thyroid were confirmed by thyroid ultrasonographic examination. Non-toxic goitre was significantly more often in patients with mastopathy in comparison with healthy women, and there was found significantly higher thyroid volume in these patients. Endocrinology. 1997 Apr;138(4):1434-9. Thyroxine administration prevents streptococcal cell wall-induced inflammatory responses. Rittenhouse PA, Redei E.

Eur J Appl Physiol Occup Physiol. 1998;77(1-2):37-43. Pre-adaptation, adaptation and de-adaptation to high altitude in humans: hormonal and biochemical changes at sea level. Savourey G, Garcia N, Caravel JP, Gharib C, Pouzeratte N, Martin S, Bittel J.

Endocrinol Jpn. 1992 Oct;39(5):445-53. Plasma free fatty acids, inhibitor of extrathyroidal conversion of T4 to T3 and thyroid hormone binding inhibitor in patients with various nonthyroidal illnesses. Suzuki Y, Nanno M, Gemma R, Yoshimi T.

Natl Med J India. 1998 Mar-Apr;11(2):62-5. Neuropsychological impairment and altered thyroid hormone levels in epilepsy. Thomas SV, Alexander A, Padmanabhan V, Sankara Sarma P. Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India. BACKGROUND: Neuropsychological impairment is a common problem in epilepsy which interferes with the quality of life of patients. Similarly, thyroid hormone levels have been observed to be abnormal in patients with epilepsy on various treatments. This study aimed to ascertain any possible correlation between neuropsychological performance and thyroid hormone levels among epilepsy patients. METHODS: Thyroid hormone levels, indices of neuropsychological performance and social adaptation of 43 epilepsy patients were compared with those of age- and sex-matched healthy control subjects. RESULTS: Epilepsy patients exhibited significantly (p < 0.001) lower scores on attention, memory, constructional praxis, finger tapping time, and verbal intelligence quotient (i.q.) when compared with controls. Their T3, T4 and Free T3 levels were significantly lower; and TSH and Free T4 levels were significantly higher than that of controls. There was no statistically significant correlation between the indices of neuropsychological performance and thyroid hormone levels. CONCLUSION: We did not observe any correlation between neuropsychological impairment and thyroid hormone levels among patients with epilepsy.

Crit Care Med. 1994 Nov;22(11):1747-53. Dopamine suppresses pituitary function in infants and children. Van den Berghe G, de Zegher F, Lauwers P.

Ned Tijdschr Geneeskd. 2000 Jan 1;144(1):5-8. [Epilepsy, disturbances of behavior and consciousness in presence of normal thyroxine levels: still, consider the thyroid gland] [Article in Dutch] Vrancken AF, Braun KP, de Valk HW, Rinkel GJ. Afd. Neurologie, Universitair Medisch Centrum Utrecht. Three patients, one man aged 51 years, and two women aged 49 and 52 years, had severe fluctuating and progressive neurological and psychiatric symptoms. All three had normal thyroxine levels but elevated thyroid stimulating hormone levels and positive thyroid antibodies. Based on clinical, laboratory, MRI and EEG findings they were eventually diagnosed with Hashimoto's encephalopathy, associated with Hashimoto thyroiditis. Treatment with prednisone in addition to thyroxine suppletion resulted in a remarkable remission of their neuropsychiatric symptoms. The disease is probably under-recognized.

Cell Immunol. 1999 Mar 15;192(2):159-66. Neuroendocrine-induced synthesis of bone marrow-derived cytokines with inflammatory immunomodulating properties. Whetsell M, Bagriacik EU, Seetharamaiah GS, Prabhakar BS, Klein JR.

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A R T I C L E

Water: swelling, tension, pain, fatigue, aging

I have spoken to many people who believe they should drink "8 glasses of water every day," in addition to their normal foods, even if they don't feel thirsty. Many doctors still recite this dangerous slogan, but the addition of the qualifying phrase, "or other liquids," has become common.

The amount of water a person needs is extremely variable, depending on things such as metabolic rate, activity, and the temperature and humidity of the air. Working hard in hot, dry weather, it's possible to drink more than two quarts per hour for more than eight hours, without forming any urine, because all of the water is lost by evaporation. But in very hot, humid weather, a person with a low metabolic rate can be endangered by the smallest amount of water (e.g., "Meteorological relations of eclampsia in Lagos, Nigeria," Agobe, et al., 1981).

Most foods contain a considerable amount of water, usually more than 70% of their weight, and some water is produced in cells by metabolism. The function of water in the organism has been mystified and neglected because of some deeply rooted cultural images of the nature of organisms and their cellular make-up.

One silly image that has been perpetuated by schools and textbooks is that biochemistry consists of chemical reactions that occur in substances dissolved in water, and that the water is retained by cells because they are enclosed by an oily membrane, and because of the osmotic forces produced by the dissolved substances. Most grade school kids have seen an osmometer made from an egg, in which the egg causes a column of water to rise, and have heard the explanation that this has something to do with the way cells work. Membrane pumps are invoked to explain the differences in solute concentrations and "osmotic pressure" inside and outside cells. The story is that invisible things on the surface of a cell (in its "membrane") force dissolved molecules to move in ways that they wouldn't move spontaneously by diffusion, and that water passively follows the "actively transported" solutes. But the evidence shows that both water and its solutes are regulated by the bulk phase of the cell, not its surface.

In some cultural settings, animism has a kind of charm (water sprites, and such), but in the culture of medicine and biology, the animistic conceptualization of cells and their mechanisms has been very destructive, because it gets in the way of coherent understanding of physiology. Practically every disease would be approached differently if the physiology of water and ions were allowed to advance beyond the animistic doctrines of mainstream medicine, such as the "membrane pumps." If all the substances that are said to be "actively transported" by pumps into, or out of, cells are considered, the amount of energy required to operate the pumps is at least 15 times larger than the total energy available to cells. "Specific" pumps are commonly invoked even for novel synthetic chemicals, to explain their unequal distribution, inside and outside cells. In many biological situations water is ignored, but when it becomes an issue, its distribution is usually mechanistically subordinated to the solutes that are actively "pumped."

Cells aren't osmometers, in the sense the textbooks say. They do control their water content, but no "membrane pumps" are needed. It's more accurate to think of the water of cells as being "dissolved in cells," somewhat the way water is contained in jello or boiled eggs. The cell controls its hydration by the processes that control its structure, its metabolism, and movements, because water is part of its deepest structures and essential functions. The cell's adjustments to changes of hydration and volume appear to be regulated by contractile proteins and energy metabolism (Minkoff and Damadian, 1976).

Any stress or energy deficit that disturbs cellular structure or function disturbs the interactions among water, proteins, and other components of the cell. Excitation causes a cell to take up extra water, not by osmosis resulting from an increase in the concentration of solutes in the cell, or because the membrane has become porous, but because the structural proteins of the cell have momentarily increased their affinity for water.

This increased affinity is similar to the process that causes a gel to swell in the presence of alkalinity, and it is related to the process called electroosmosis, in which water moves toward a higher negative charge. Intense excitation or stress increases the cell's electrically negative charges, and causes it to become more alkaline and to swell. Swelling and alkalinity cause the cell to begin the synthesis of DNA, in preparation for cell division. Mitogens and carcinogens, including estrogen, cause cells to become alkaline and to swell, and substances that block the cell's alkalinization (such as the diuretics acetazolamide and amiloride) inhibit cell division. Prolonged alkaline stress alone can cause malignant transformation of kidney cells (Oberleithner, et al., 1991).

The general idea of "stress" is useful, because it includes processes such as fatigue, osmotic pressure changes, disturbed pH, and the enzyme changes that follow, producing substances such as lactic acid, nitric oxide, polyamines, estrogen, serotonin, and many more specific mediators. But paying attention to the physical factors involved in a stress reaction is important, if we are to see the organism integrally, rather than as a collection of "specific biological mechanisms," involving things like the pixie-powered "membrane pumps."

When a cell shrinks under hyperosmolar conditions, its metabolism becomes catabolic, breaking down proteins and glycogen, and sometimes producing lactic acid, which results in an alkaline shift, increasing the cell's affinity for water, and causing it to return to normal size. A slight degree of hyperosmolarity increases the cell's metabolic rate.

Swelling in hypo-osmolar conditions, i.e,, with an excess of water, is anabolic, leading to cellular proliferation, and inhibiting the breakdown of protein and glycogen.

Respiring cells are always producing some water, by transferring hydrogen from fuel molecules to oxygen. Respiration also produces carbon dioxide, which in itself is a Lewis acid (meaning that it binds electrons, rather than releasing protons), that associates with cellular proteins, acidifying them in the process. A large amount of carbon dioxide can exist inside cells in the bound form. Acidified cytoplasm (like any other mostly acidic polymer-gel) releases water and sodium. (This process is physically analogous to the process of flushing a water softener with salt, or a demineralizer with acid, to reactivate it.)

Besides binding with the cytoplasm, the carbon dioxide can be changed into carbonic acid, by chemically combining with water. Carbonic acid is hydrophilic, and so it quickly leaves the cell, taking with it some of the oppositely charged ions, such as calcium and sodium. The formation of carbonic acid, which is constantly streaming out of the respiring cell, causes some water and some positively ionized metals to leave the cell, in an "active" process, that doesn't require any mysterious pumps.

As the blood passes through the lungs, carbon dioxide leaves the system, and as carbonic acid is converted to carbon dioxide, water is left behind in the blood, along with the counterions (of alkaline metals or earths), accounting for slight differences in pH and osmolarity between the bloodstream and the tissue cells. Some experiments suggest that the normal osmolarity of various tissues is 2 or 3 times higher than that of the blood, which is called "isosmolar" or isotonic.

The kidneys adjust the osmolarity of the blood by allowing water and solutes to leave the bloodstream, in proportions that usually keep the body fluids in balance with cells. The kidneys are able to compensate for many of the imbalances produced by stress and inappropriate diets, for example by forming ammonia and carbon dioxide, to compensate for imbalances in the alkalis and acids that are being delivered to the blood by other organs. Because of the kidneys' great ability to regulate the flow of solutes between the blood and the forming urine, the "membrane pumps" have great importance for medical nephrologists. But the more extreme the "active transport" is, the more obvious it becomes that processes other than "membrane pumps" are responsible.

Some lizards and sea birds have glands near their noses that are called salt glands, because of their ability to secrete salt. The salt gland is probably the most extreme case of active transport, but its physiology is very similar to the physiology of any other secretory gland or membrane, such as tear glands and sweat glands. The mechanism of salt excretion in these glands should really settle the issue of how active transport works, but most nephrologists, oculists, and medical researchers in general aren't interested in salt glands.

Carbon dioxide is the driving force in the salt gland. The constant formation of CO2, and its loss into the air, allows a high concentration of salt to be excreted. Blocking the interchange of CO2 and carbonic acid, with acetazolamide, or inhibiting the formation of CO2, prevents the excretion of salt.

Since respiratory metabolism, governed by the thyroid hormone, is our main source of carbon dioxide, it's obvious that thyroid deficiency should impair our ability to regulate water and solutes, such as salt. An organism that illustrates this function of thyroid is the young salmon, when it leaves a freshwater river to begin its life in the ocean. As it converts its physiology to tolerate the salty environment, its thyroid hormone surges. When it's mature, and returns to the fresh water to spawn, its prolactin rises sharply. In experiments with rodents, it has been found that drinking a large amount of water increases their prolactin, but the same amount of water, with added salt, doesn't.

Hypothyroidism is typically associated with increased prolactin secretion. Hypothyroid people typically retain water, while losing salt, so the hypothyroid state is analogous to the salmon that has returned to the river, and to the mice that drink too much salt-free water.

The typical hypothyroid person loses salt rapidly in the urine (and probably in the sweat, too, though that is usually diagnosed as cystic fibrosis), and retains water, diluting the urine less than normal. The reduced production of carbon dioxide, with increased susceptibility to producing lactate and ammonium, causes the cells to be more alkaline than normal, increasing their affinity for water. The rise of estrogen that usually accompanies hypothyroidism also increases intracellular pH, loss of sodium, and over-hydration of the blood.

Hypothyroid muscles typically retain excess water, and fatigue easily, taking up more water than normal during exertion. In childhood, mild hypothyroidism often causes the leg muscles to swell and ache in the evenings, with what have been called "growing pains." When the problem is more extreme, all the skeletal muscles can become very large (Hoffman syndrome), because of the anabolic effect of over-hydration. Enlargement of any muscle can result from the excessive hydration produced by thyroid deficiency, but when it happens to the muscles behind the eyes (Itabashi, et al., 1988), it often leads to a diagnosis of hyperthyroidism, rather than hypothyroidism.

The little kids with the Hoffman syndrome don't have the bloated myxedematous appearance that's often associated with hypothyroidism. They look athletic to a ridiculous degree, like miniature body-builders. But after a few weeks of treatment with thyroid, they regain the slender appearance that's normal for their age. The swollen state actually supports enlargement of the muscle, and the cellular processes are probably closely related to the muscle swelling and growth produced by exercise. The growth of the muscle cell during swelling seems to be the result of normal repair processes, in a context of reduced turnover of cellular proteins.

The people who believe in membrane pumps that maintain normal solute distributions by active transport know that the pumps would require energy (far more than the cell can produce, but they don't confront that issue), and so their view requires that they assign a great part of the cell's resources just to maintaining ionic homeostasis, and the result of that is that they tend to neglect the actual energy economy of the cell, which is primarily devoted to the adaptive renewal of the cell structure and enzyme systems, not to driving the systems that don't exist.

The "anabolic" balance of the swollen cell is the result of decreased turnover of the cell's components. The higher rate of metabolism produced by adequate thyroid function maintains a high rate of renewal of the cell's systems, keeping the cell constantly adjusted to slight changes in the organism's needs. The evidence of a high rate of bone turnover is sometimes taken as evidence that thyroid can cause osteoporosis.

Later, in a more mature person, chronically fatigued and painful muscles that at one time would have been diagnosed as rheumatism, may be diagnosed as fibromyalgia. Most doctors are reluctant to prescribe thyroid supplements for the problem, but the association of elevated prolactin with the muscle disorder is now generally recognized.

The hypo-osmolar blood of hypothyroidism, increasing the excitability of vascular endothelium and smooth muscle, is probably a mechanism contributing to the high blood pressure of hypothyroidism. The swelling produced in vascular endothelium by hypo-osmotic plasma causes these cells to take up fats, contributing to the development of atherosclerosis. The generalized leakiness affects all cells (see "Leakiness" newsletter), and can contribute to reduced blood volume, and problems such as orthostatic hypotension. The swollen endothelium is stickier, and this is suspected to support the metastasis of cancer cells. Inflammation-related proteins, including CRP, are increased by the hypothyroid hyperhydration. The heart muscle itself can swell, leading to congestive heart failure.

Some of the nerve problems associated with hypothyroidism (e.g., carpal tunnel syndrome and "foot drop") are blamed on compression of the nerves, from swelling of surrounding tissues, but the evidence is clear that hypothyroidism causes swelling in the nerve cells themselves. For example, in hypothyroidism, nerves are slow to respond to stimulation, and their conduction of the impulse is slow. These changes are the same as those produced by hyper-hydration caused by other means. Hypothyroid nerves are easily fatigued, and fatigued nerves take up a large amount of water. Swelling of the spinal cord is probably responsible for the "spinal stenosis" commonly seen in domestic animals and people; the mobility of intracellular water molecules is distinctly increased in patients with compression of the spinal cord (Tsuchiya, et al., 2003; Ries, et al., 2001).

The hyperhydration of hypothyroidism has been known to cause swelling and softening of cartilage, with deformation of joints, but somehow it has never dawned on surgeons that this process would lead to deformation of intervertebral disks.

It has been known for a long time that hyperhydration can produce seizures; at one time, neurologists would test for epilepsy by having the patient drink a pint of water. Although there are many reasons to think that the hyperhydration produced by hypothyroidism is a factor in epilepsy, physicians have been very reluctant to consider the possibility, because they generally think of thyroid hormone as a stimulant, and believe that "stimulants" are necessarily inappropriate for people with epilepsy.

While it's true that the thyroid hormone increases sensitivity to adrenaline, its most noticeable effect is in improving the ability to relax, including the ability to sleep soundly and restfully. And it happens that increasing norepinephrine (the brain's locally produced form of adrenaline) helps to prevent seizures (Giorgi, et al., 2004).

Cell swelling increases the sensitivity of nerves, and hyperosmotic shrinkage lowers their sensitivity. Increasing carbon dioxide helps to reduce the hydration of tissue (for example, the hydration and thickness of the cornea are decreased when carbon dioxide is increased), and increasing carbon dioxide is known to inhibit epileptic seizures. Another diagnostic trick of neurologists was to have the patient hyperventilate; it would often bring on a seizure. The diuretic acetazolamide, which increases the body's carbon dioxide and reduces water retention, is very effective for preventing seizures.

The sleep-inducing effect of salty food is probably related to the anti-excitatory effects of hyperosmolarity, of adequate thyroid function, and of carbon dioxide.

Degenerative diseases, especially cancer, heart disease, and brain diseases, are less prevalent in populations that live at a high altitude. When oxygen pressure is low, the lungs lose carbon dioxide more slowly, and so the amount of carbon dioxide retained in the body is greater. If the basic problem in hypothyroidism is the deficient production of carbon dioxide causing excessive loss of salt and retention of water, resulting in hypo-osmotic body fluids, then we would expect people at high altitude to have better retention of salt, more loss of water, and more hypertonic body fluids. That has been observed in many studies. The increased rate of metabolism at altitude would be consistent with the relatively active "catabolism" of the slightly hyperosmotic condition.

After the drug companies began, in the late 1950s, marketing some newly discovered (thiazide) diuretics, which cause sodium to be lost in the urine, their advertising campaigns created a cultish belief that salt caused hypertension. They convinced a whole generation of physicians that pregnant women should limit salt in their diet, take a diuretic preventively, and restrict calories to prevent "excessive" weight gain. Millions of women and their babies were harmed by that cult.

Pre-eclampsia and pregnancy toxemia have been corrected (Shanklin and Hodin, 1979) by both increased dietary protein and increased salt, which improve circulation, lower blood pressure, and prevent seizures, while reducing vascular leakiness. The effectiveness of increased salt in pre-eclampsia led me to suggest it for women with premenstrual edema, because both conditions typically involve high estrogen, hyponatremia, and a tendency toward hypo-osmolarity. Estrogen itself causes sodium loss, reduced osmolarity, and increased capillary leakiness. Combined with a high protein diet, eating a little extra salt usually helps to correct a variety of problems involving edema, poor circulation, and high blood pressure.

The danger of salt restriction in pregnancy has hardly been recognized by most physicians, and its danger in analogous physiological situations is much farther from their consideration.

One of the things that happen when there isn't enough sodium in the diet is that more aldosterone is synthesized. Aldosterone causes less sodium to be lost in the urine and sweat, but it achieves that at the expense of the increased loss of potassium, magnesium, and probably calcium. The loss of potassium leads to vasoconstriction, which contributes to heart and kidney failure and high blood pressure. The loss of magnesium contributes to vasoconstriction, inflammation, and bone loss. Magnesium deficiency is extremely common, but a little extra salt in the diet makes it easier to retain the magnesium in our foods.

Darkness and hypothyroidism both reduce the activity of cytochrome oxidase, making cells more susceptible to stress. A promoter of excitotoxicity, ouabain, or a lack of salt, can function as the equivalent of darkness, in resetting the biological rhythms (Zatz, 1989, 1991).

Bone loss occurs almost entirely during the night, and the nocturnal rise in cortisol and prolactin has strongly catabolic effects, but many other pro-inflammatory substances also rise during the night, and are probably the basic cause of the increased catabolism. Increased salt in the diet appears to improve some aspects of calcium metabolism, such as reducing parathyroid hormone and increasing ionized calcium, when the diet is deficient in calcium (Tordoff, 1997).

The kidneys can produce large amounts of carbon dioxide and ammonia, in the process of preventing the loss of electrolytes, while allowing acid to be lost in the urine. The ammonia is produced by the breakdown of protein. During stress or fasting, the loss of tissue protein can be minimized by supplementing the minerals, potassium, sodium, magnesium, and calcium. Salt restriction can cause aldosterone to increase, and excess aldosterone causes potassium loss, and increases the use of protein to form ammonia (Norby, et al., 1976; Snart and Taylor, 1978; Welbourne and Francoeur, 1977).

Aldosterone secretion increases during the night, and its rise is greater in depressed and stressed people. It inhibits energy metabolism, increases insulin resistance, and increases the formation of proinflammatory substances in fat cells (Kraus, et al., 2005). During aging, salt restriction can produce an exaggerated nocturnal rise in aldosterone.

During the night, there are many changes that suggest that the thyroid functions are being blocked, for example a surge in the thyroid stimulating hormone, with T4 and T3 being lowest between 11 PM and 3 AM (Lucke, et al., 1977), while temperature and energy production are at their lowest. This suggests that the problems of hypothyroidism will be most noticeable during the night.

Rheumatoid arthritis and asthma are two inflammatory conditions that are notoriously worse during the night. Melatonin has been reported to be higher in patients with severe asthma and rheumatoid arthritis, and to promote the secretion of a variety of other pro-inflammatory substances. The peak of melatonin secretion is followed by the peak of aldosterone, and a little later by the peak of cortisol.

The use of bright light (which suppresses melatonin) to treat depression probably helps to inhibit the production of aldosterone, which is strongly associated with depression.

Both aldosterone and melatonin can contribute to the contraction of smooth muscle in blood vessels. Constriction of blood vessels in the kidneys helps to conserve water, which is adaptive if blood volume has been reduced because of a sodium deficiency. When blood vessels are inappropriately constricted, the blood pressure rises, while organs don't receive as much blood circulation as they need. This impaired circulation seems to be what causes the kidney damage associated with high blood pressure, which can eventually lead to heart failure and multiple organ failure.

Progesterone, which helps to maintain blood volume (partly by preventing vascular leakiness, preventing excessive sodium loss and by supporting albumin synthesis) antagonizes aldosterone. Aldosterone antagonists are now being recognized as effective treatments for hypertension, water retention, congestive heart failure, arrhythmia, diabetes, kidney disease, and a great variety of inflammatory problems. (Synthetic drugs to antagonize aldosterone are most effective when they are most like natural progesterone.) Since aldosterone contributes to fibrosis of the heart and kidneys (nephrosclerosis), progesterone, the "antifibromatogenic steroid," should be helpful for those problems that have been considered irreversible. Aldosterone appears to contribute to the hyperglycemia of diabetes itself, and not just to its complications, by interfering with the interactions of insulin and cortisol (Yamashita, et al., 2004).

One of progesterone's fundamental actions is to cause estrogen "receptors" to disintegrate; hypertonicity has this effect in some situations. Estrogen's effects are largely produced by increased tissue hydration.

Aldosterone causes cells to take up sodium, while increasing their pH, i.e., raising their alkalinity (Mihailidou and Funder, 2005). Intracellular sodium has long been known to be a factor, along with swelling and alkalinity, in stimulating cell division (Cone and Tongier, 1971). A lack of salt stimulates the formation of serotonin, which in turn stimulates aldosterone synthesis--that is, a sodium restricted diet activates processes that cause cells to take up sodium inappropriately, in a situation reminiscent of the calcium deficient diet causing inappropriate calcification.

Aldosterone, like stress or hypo-osmolarity, activates the enzyme (ODC) which produces the polyamines, that promote cell division, and that can probably account for some of the harmful effects of excessive aldosterone.

Eating salty food around bedtime usually has a sleep-inducing effect, and it helps to maintain blood volume (which tends to decrease during the night), and to restrain the nocturnal rise of aldosterone, and other indicators of stress or inflammation. Eating gelatin, which lacks tryptophan, will reduce the formation of serotonin, and is likely to limit the formation of aldosterone.

Pregnenolone can sometimes very quickly allow swollen tissues to release their water. This function is probably closely related to its antifibromatogenic function, since swelling and leaking set the stage for fibrosis.

Hyperosmotic sodium chloride solutions (e.g., 7.5%) are being used more often for treating trauma and shock, because the concentrated solution increases blood volume by removing water from the extravascular spaces, unlike the "isotonic" saline (0.9% sodium chloride), which usually adds to the edema by leaking out of the blood vessels.

A 5% sodium chloride solution is effective for promoting healing of damaged corneas, and solutions of 5% to 10% sodium chloride are effective for accelerating the healing of wounds and ulcers. Other hypertonic solutions, for example glucose or urea, have been used therapeutically, but sodium chloride seems to be the most effective in a variety of situations.

Thyroid hormone, by maintaining oxidative metabolism with the production of carbon dioxide, is highly protective against excessive water retention and loss of sodium and magnesium.

Sometimes doctors recommend that constipated people should drink extra water, "to soften the stool." The colon is where water is removed from the intestinal contents, and when it is inflamed, it removes too much water. Several decades ago, it was recognized (Orr, et al., 1931) that hypertonic saline, given intravenously, would stimulate intestinal peristalsis, and could be used to treat paralytic ileus and intestinal obstruction.

When water is taken orally, it is absorbed high in the intestine, long before it reaches the colon, so the recommendation to drink water for constipation can produce a situation that's the opposite of intravenous hypertonic saline, by diluting the blood. Using a hypertonic salt solution as an enema can have the same beneficial effect on the intestine as the intravenous treatment.

Constipation physiology is probably analogous to the physiology of congestive heart failure, in which muscles are weakened and fatigued by swelling.

In recent decades, the prevalence of congestive heart failure has increased tremendously, so that it is now often called an epidemic. Hyponatremia (too little salt, or too much water) is a recognized "risk factor" for congestive heart failure. In the failing heart, the muscle cells are swollen, causing the heart wall to stiffen, weakening its ability to pump. Osmotically shrinking the cells can restore their function.

The swollen heart, like any muscle, loses the ability to quickly and completely relax, and so it doesn't fill adequately between contractions. Elastic tissues, such as arteries and lungs, stiffen when they are over-hydrated, losing their normal functions. In small blood vessels, swelling narrows the channel, increasing resistance to the flow of blood.

When people force themselves to drink a certain amount of water every day, even when they don't feel thirsty, they are activating complex adaptive processes unnecessarily. Thirst is the best guide to the amount of fluid needed.

When extra water consumption is combined with a low salt diet--as physicians have so often recommended--a healthy person can adapt easily, but for a hypothyroid person it can have disastrous effects.

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www.gilbertling.org

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<span class="koboSpan" id="kobo.1.1">Unsaturated fatty acids: Nutritionally essential, or toxic?</span> A R T I C L E

Unsaturated fatty acids: Nutritionally essential, or toxic?

In 1929 George and Mildred Burr published a paper claiming that unsaturated fats, and specifically linoleic acid, were essential to prevent a particular disease involving dandruff, dermatitis, slowed growth, sterility, and fatal kidney degeneration.

In 1929, most of the B vitamins and essential trace minerals were unknown to nutritionists. The symptoms the Burrs saw are easily produced by deficiencies of the vitamins and minerals that they didn't know about.

What really happens to animals when the "essential fatty acids" are lacking, in an otherwise adequate diet?

Their metabolic rate is very high.

Their nutritional needs are increased.

They are very resistant to many of the common causes of sickness and death.

They are resistant to the biochemical and cellular changes seen in aging, dementia, autoimmunity, and the main types of inflammation.

The amount of polyunsaturated fatty acids often said to be essential (Holman, 1981) is approximately the amount required to significantly increase the incidence of cancer, and very careful food selection is needed for a diet that provides a lower amount.

When I was studying the age pigment, lipofuscin, and its formation from polyunsaturated fatty acids, I saw the 1927 study in which a fat free diet practically eliminated the development of spontaneous cancers in rats (Bernstein and Elias). I have always wondered whether George and Mildred Burr were aware of that study in 1929, when they published their claim that polyunsaturated fats are nutritionally essential. The German study was abstracted in Biological Abstracts, and the Burrs later cited several studies from German journals, and dismissively mentioned two U.S. studies* that claimed animals could live on fat-free diets, so their neglect of such an important claim is hard to understand. (*Their bibliography cited, without further comment, Osborne and Mendel, 1920, and Drummond and Coward, 1921.)

Since 1927, others have demonstrated that the polyunsaturated fats are essential for the development of cancer (and some other degenerative diseases), but the Burrs' failed to even mention the issue at any time during their careers. How could they, studying fat-free diets, have missed an important contemporary publication, if I, 40 years later, saw it? There were very few publications on dietary fats in those years, so it was hardly possible to miss it.

When researchers at the Clayton Foundation Biochemical Institute at the University of Texas demonstrated that "Burr's disease" was actually a vitamin B6 deficiency, rather than a fatty acid deficiency, the issue was settled. Later studies failed to confirm the existence of the Burr disease caused by a deficiency of fatty acids, though many similar conditions were produced by a variety of other dietary defects. In 1938, a group in Burr's own laboratory (Brown, et al.) failed to produce dermatitis in a man during a six month experiment. Neither of the other major features of the Burr disease, male sterility and kidney degeneration, has been subsequently confirmed. The claim that polyunsaturated fatty acid deficiency caused sterility of male animals ("A new and uniform cause of sterility is shown") was quickly dropped, probably because an excess of polyunsaturated fats was discovered to be an important cause of testicular degeneration and sterility.

One of the features of the Burrs' rats on the fat-free diet was that they ate more calories and drank much more water than the rats that received polyunsaturated fatty acids in their diet. They believed that the animals were unable to synthesize fat without linoleic acid, although in another context they cited a study in which the fat of rats on a fat-free diet was similar in composition to lard: "McAmis, Anderson, and Mendel [37] fed rats a high sucrose, fat-free diet and rendered the fat of the entire animal. This fat had an iodine number of 64 to 71, a fairly normal value for lard."

The "wasteful" food consumption, and the leanness of animals that weren't fed polyunsaturated fats became fairly common knowledge by the late 1940s, but no one repeated the Burrs' claim that the absence of those fatty acids led quickly to the animals' death. Meanwhile, "crazy chick disease" caused by feeding an excess of polyunsaturated fats, and a little later, "yellow fat disease," caused by too much fish fat, were being recognized by farmers. In the 1950s, the seed oil industry created the anti-cholesterol diet culture, and a few decades later, without any new "Burr-like" publications, the omega minus 3 oils, especially fish oils, were coming to be represented as the overlooked essential fatty acids, which were capable of preventing the toxic effects of the original "essential" linoleic acid.

Although the 1929 Burr paper is still often cited as proof of the essentiality of PUFA, Burr's younger colleague (at the University of Minnesota Hormel Institute), Ralph Holman, has cited an infant (1970), and a 78 year old woman (in 1969), who developed dermatitis while receiving fat-free intravenous feedings. Dermatitis, with dandruff, similar to Burr's disease, has been produced by various nutritional deficiencies besides vitamin B6, including a trace mineral deficiency and a biotin deficiency, so there is no valid reason to associate dermatitis with a fat deficiency. The cases of "EFA deficiency" produced by intravenous feedings that have been widely cited were probably the result of a deficiency of zinc or other trace mineral, since so-called "Total Parenteral Nutrition" was in use for many years before the trace minerals were added to the "total" formula. In 1975, I learned that our local hospital was putting all premature babies on what they called total intravenous feeding, without trace minerals, for weeks, or months. There is still more emphasis on polyunsaturated fat in intravenous feeding than on the essential trace nutrients.

Holman and the Hormel Institute have been extremely influential in promoting the doctrine of the essentiality of PUFA, including fish oils and the omega -3 oils, but their best evidence, the Burr experiment, doesn't make their case. Far worse than that is the effect it has had in distracting attention from the profoundly toxic effects of the so-called essential fatty acids. Long after he should have known better, Holman was arguing that butter was a nutritionally inferior fat.

When the Burrs were doing their study, Raymond Pearl was one of the most famous biologists in the country, and his "rate of living" theory of aging was very widely known. According to that theory, an organism has an intrinsic potential to produce a certain total amount of energy during its lifetime, and if it metabolizes at a higher than normal rate, its life span will be proportionately shorter than normal.

There is general agreement that animals on a fat free diet have a very high metabolic rate, but the people who believe the "rate of living" theory will be inclined to see the increased rate of metabolism as something harmful in itself. It is clear that this is what the Burrs thought. They didn't attempt to provide a diet that provided increased amounts of all vitamins and minerals, in proportion to the increased metabolic rate.

Pearl did an experiment, sprouting cantaloupe seeds in a dish with water. The sprouts that grew rapidly died sooner than those that grew more slowly. They died as soon as the nutrients stored in the endosperm had been consumed. Naturally, when nutrients are depleted, growth and metabolism must stop. If food and air and water are rationed, then slow metabolizers are going to live longer. But when nutritional needs are met, the organisms with the highest metabolic rate generally are healthier and live longer. In a study of nurses, those who habitually consumed the most calories lived longer than those who consumed the least. Even while Pearl was promoting his theory, other famous biologists, for example John Northrup in Jacques Loeb's lab at the Rockefeller Institute, were making observations that contradicted the rate of living theory. For example, around 1916, Northrup observed that fruit flies that metabolized at the highest rate lived the longest. Northrup was doing biology, Pearl was doing propaganda, following Weismannism.

The idea of extending life span by slowing metabolism and growth was a logical implication of the "rate of living" theory of aging, and it's an idea that is still popular. Many people have supposed that eating less would slow metabolism. Caloric restriction does extend the life span of many species, but it generally preserves the high metabolic rate of youth, so that at a given age the calorie-restricted animal has a higher rate of oxygen consumption per gram of body weight than the unrestricted eaters.

Roy Walford, a gerontologist who wrote about extending the human life span to 120 years by caloric restriction, spent 30 years limiting his diet to about 1600 calories, with little animal protein, almost no saturated fat--fish once or twice per week, poultry or beef about once, and a fat free milkshake for breakfast--and after about 15 years, began developing a degenerative brain disease, ALS, one of the nerve diseases involving lipid peroxidation and excitotoxicity. When he died from the disease, he had lived a year longer than the normal life expectancy.

V. Stefannson, one of the early polar explorers, spent a winter living entirely on caribou meat, and felt that it had prevented the scurvy that had killed so many of the other explorers, who had counted on fruit and vegetables to prevent it. But he believed that meat was a metabolic stimulant that made people age prematurely, as Pearl's rate of living theory predicted. Stefannson said that Eskimo women were getting old in their twenties, and that at the age of 60 they looked as old as Europeans did at 80. He was a well informed anthropologist, and his observations were probably accurate. The Eskimos he observed ate large amounts of fish, and other unsaturated fats, and sometimes ate highly decayed fish. An accelerated rate of aging would be expected from such a diet, because of the toxic lipid peroxides.

Calorie-restricted animals (on a diet of normal composition) have a lower degree of fat unsaturation in their mitochondria as they age, preserving the relatively more saturated fats of youth.

Birds' mitochondrial fats are much less polyunsaturated than those of mammals, and birds' metabolic rates are much higher, and they live much longer than mammals of a similar size.

With aging, the highly peroxidizable fatty acids, arachidonic and docosahexaenoic acid, increase greatly in a variety of tissues, and lipid peroxidation increases with aging. Peroxidation slows mitochondrial respiration, lowering the metabolic rate. Caloric restriction slows the accumulation of the highly unsaturated fatty acids in mitochondria, and reduces peroxidation.

Over the years, it has become evident that the polyunsaturated fats are not very compatible with a high rate of metabolism, though they are necessary for organisms that live at low temperatures and metabolize slowly, such as fish and vegetables. The saturated fats solidify at low temperature; beef fat is very stiff at refrigerator temperature, and in a fat fish, such stiffness would be lethal.

Even some hibernating rodents can stay alive with their body tissues close to the freezing point, and their stored fats have to be unsaturated. When their diet doesn't allow them to store enough polyunsaturated fat, they fail to go into hibernation. This is probably a clue to some of the general biological effects of the PUFA.

A series of studies about 20 years ago showed that the functions of the thyroid hormone are all inhibited by unsaturated fats, with the inhibition increasing in proportion to the number of unsaturations (double bonds) in the fat molecule.

When the tissues are saturated with those antithyroid fats, metabolism slows, especially when any stress, such as cold or hunger, increases the concentration of free fatty acids in the blood stream. Stress and hypothyroidism increase the formation of serotonin, which is an important factor in producing the torpor of hibernation, and lowering the body temperature. The polyunsaturated fatty acids themselves directly contribute to the formation of serotonin, for example by increasing the ability of tryptophan to enter the brain. In a certain cold climate, the PUFA are essential for hibernation, but under other conditions, the rodent would be able to continue gathering food and eating, instead of hibernating.

The direct effects of the PUFA on the endocrine and nervous systems, as illustrated by the hibernating squirrel, interact with their effects on intercellular communication (including the formation of prostaglandins and related substances), and the effects of their oxidative breakdown products, such as acrolein. But the people who claim that they are absolutely, rather than conditionally, essential, base their argument on the idea that they are needed for the formation of prostaglandins and cell membranes. The fact that cells can replicate in fat free conditions shows that the argument from membranes is unfounded. The argument from prostaglandins is more complex, but has no firmer foundation.

When a dose of PUFA is administered to a lizard, which isn't a hibernator, the lizard's body temperature is lowered by several degrees. There are probably many ways in which the PUFA produce that effect, besides increasing serotonin and decreasing thyroid. The PUFA are increased by estrogen, and they increase estrogen, and have some directly estrogen-like effects. Estrogen itself tends to lower body temperature and shift metabolism away from oxidative energy production. Aging, like estrogen, increases the body's content of the PUFA: Linoleic, linolenic, dihomo-gamma-linolenic, docosahexaenoic and docosapentaenoic acids are increased by age, and the longer chain acids increase more rapidly in women than in men (Bolton-Smith, et al., 1997). (Women are apparently relatively protected by progesterone, which inhibits lipolysis and prostaglandin formation, and protects the brain, thymus, and other tissues from lipid peroxidation and other effects of the PUFA.)

Aging involves a decreasing metabolic rate, an increased tendency toward inflammation, and a decreased ability to synthesize proteins. Inflammation contributes to the decreasing ability to use oxygen, and the slowed renewal of proteins combined with lower ability to produce energy impair the organism's ability to control peroxidative damage and inflammation.

The fragments of deteriorating PUFA combine with proteins and other cell materials, producing immunogenic substances. The so-called "advanced glycation end products," that have been blamed on glucose excess, are mostly derived from the peroxidation of the "essential fatty acids." The name, glycation, indicates the addition of sugar groups to proteins, such as occurs in diabetes and old age, but when tested in a controlled experiment, lipid peroxidation of polyunsaturated fatty acids produces the protein damage about 23 times faster than the simple sugars do (Fu, et al., 1996).

Several autoimmune disease models in animals (involving the eye, kidney, and pancreas) have been prevented by a deficiency of the EFA (Schreiner, et al., 1989, Bazan, et al., 1990, Benhamou, et al., 1995).

Besides causing a general slowing of metabolism, aging and toxic PUFA have specific actions on the detoxifying system. The enzymes that help to detoxify PUFA and estrogen and serotonin are inhibited by both PUFA and estrogen. All systems, including blood vessels and the intestine, are made leaky by estrogen and the PUFA and their products. A reduced ability to regulate the excitatory amino acids, resulting from PUFA toxins, tends to produce excitotoxicity, damaging nerves (Ou, et al., 2002).

Although the interplay of the various types of nerve is very complex, a variety of experiments suggest that the PUFA are acting directly on serotonergic nerves, rather than just increasing the conversion of tryptophan to serotonin.

For example, a deficiency of the so-called essential fatty acids, EFA, makes animals more sensitive to some anesthetics, and more resistant to others. It makes them resistant to the anesthetics that act by promoting the actions of serotonin, but it prolongs the effects of those that don't act through serotonin, and these are the anesthetics such as xenon and nitrous oxide, that apparently act by stabilizing the structure of water, as described by Linus Pauling. Progesterone and the saturated fats seem to act partly through the stabilizing of cell water, and estrogen and the PUFA have opposing effects, creating cellular excitation while interfering with the stable cellular water structure.

Serotonin interferes with slow wave sleep, and promotes cortisol, both of which can be harmful to brain cells. (Hypothyroidism is one of the causes of a decrease in slow wave sleep.) Babies whose mothers' serum contained more DHA were more wakeful on their second day of life, than the babies of low-DHA mothers. The amide of oleic acid is a sleep promoter, with apparent antiserotonin activity (Yang, et al., 2003), and since oleic acid tends to be displaced by diets high in PUFA, this suggests another way in which the highly unsaturated fatty acids could promote serotonin's effects.

People who don't have a normal amount of slow wave sleep are likely to have slow reaction times when they are awake, and quickness of reactions is a good indicator of general intelligence.

Manufacturers of baby formulas are claiming that the highly unsaturated fatty acids accelerate brain development, but they neglect to mention studies that show either no effect, or retardation of development. In some of the tests that are used to measure infant development, a generalized state of arousal or anxiety could be interpreted as "more mature."

In one experiment, animals that received less than 0.32% of their calories as EFA grew slightly less than rats on a standard diet, but their brains were as large as those of normal rats (Bruckner, et al., 1984). That is, their brain to body ratio was a little larger than normal, which is a typical feature of individuals with a higher metabolic rate. That result is very different from the claims of the baby food industry, that the brain is the organ most easily damaged by a PUFA deficiency.

One of the standard signs of toxicity is the enlargement of the spleen and liver, and that effect is produced by larger amounts of the EFA. The weight of the thymus is reduced by PUFA in the diet (Guimarães, et al., 1990). Thymus cells tend to be easily killed by a combination of stress and EFA, and bone marrow cells, though less sensitive than thymic cells, are damaged by lipid peroxidation of the PUFA. The effects of PUFA on the thymus were compared to those of radiation by Soviet researchers. Immunodeficiency, produced largely by damage to thymic cells, increases when larger amounts of PUFA are eaten for a prolonged time.

The growth and metastasis of a variety of tumors are inhibited by saturated fatty acids, and increased by fish oil--as much as 10 times in number of metastases, 1000 times in size (Griffini, et al., 1998).

Mothers whose breast milk contains more long-chain n-3 fatty acids are more likely to have allergic children (Stoney, et al., 2004). (And children whose mothers are allergic have higher levels of DHA and EPA in their tissues.) These associations aren't mentioned by the manufacturers who speak of those fats as essential.

When animals have been "deprived" of the EFA during gestation and nursing, and then given a standard diet, they develop larger bones, with a thicker cortex and more trabecular bone, both of which would suggest a lower level of stress. Many types of inflammation and stress are significantly reduced in "EFA deficient" animals. Inflammation caused by the injection of carrageenan is decreased, partly because of the absence of prostaglandins in these animals. The absence of the EFA protects against colitis and nephritis ( ). The kidneys are more effective in several ways in the deficient animals.

Shock, caused by the injection of endotoxin, which is 100% lethal to normally fed animals, is only 24% lethal to the deficient animals.

Poisons are much less harmful to deficient animals, for example, a cobra venom factor causes less tissue damage to their lungs.

Concussive trauma and burns cause much less damage to deficient animals.

The endothelial lining of blood vessels is protected by saturated fats and oleic acid, damaged by polyunsaturated, and their barrier function is improved by the absence of PUFA.

Alzheimer's disease, retinal degeneration, cataracts, and liver cirrhosis all involve reactions of oxidized PUFA with proteins. Saturated fats help to heal alcoholic liver cirrhosis.

The lesions of atherosclerosis and cataracts contain some of the same oxidized lipids as the age pigment itself. When large deposits of age pigment become visible, it's probably because the general reduction of metabolism and protein synthesis has interfered with the normal processes for removing debris. The age pigment contributes to degeneration by wasting energy and oxygen, weakening the antioxidation, antiglycation, and other defensive systems.

The EFA amplify nearly all kinds of injury and stress, and the results of many recent publications make it look as though serotonin interacts harmfully with the EFA in most of these situations. The specific balance of polyunsaturated fatty acids, and their various breakdown products, from carbon monoxide, glyoxal, and acrolein, to the larger aldehydes and radicals, and the stress-induced substances such as serotonin, histamine, estrogens, can produce an immense variety of biological problems.

When the various claims of an EFA "deficiency disease" or syndrome or symptom are examined, their inconsistency over the years makes skepticism seem increasingly justified. The Burrs' publications were typical of others, in failing to describe and account for the evidence that contradicted their claims. Claiming that certain fatty acids are essential, a scientific approach would require showing what was wrong with the experiments that showed that they were not essential, and especially, those that showed that they were positively harmful.

In this culture that repeatedly makes such claims of essentiality, the growing number of reports of biological superiority of "deficient" animals suggests that nutritional research may be near the point at which it can resume the line of study begun by Northrup, Osborne, Mendel, Drummond, Bernstein, Elias, and others, that was interrupted for 60 years by industrial interests that promoted antiscientific opinions.

For example, in 1914 F.P. Rous showed that limiting food intake reduced the incidence of cancer, and then in 1915 and 1917, Osborne and Mendel showed that food restriction extended the fertility and longevity of female rats. The association between estrogen and cancer had become known during this time, and vitamin E, which was originally known as the fertility vitamin, was soon recognized to have antiestrogenic properties, as well as to prevent the deadly effects of excessive polyunsaturated fats in the diet. My endocrinology professor, A.S. Soderwall, who had found that excess estrogen prevented (or interrupted) pregnancy, demonstrated that increased vitamin E extended fertility in aging female rodents.

By the time I began my research, it seemed clear that it had been the reduction of PUFA in the diet which, like the addition of vitamin E, had prevented sterility in the calorie restriction experiments, and that those treatments had limited the effects of estrogen in the aging organisms.

Estrogen, by activating phospholipase A2, acts to amplify the toxic effects of PUFA in the tissues, and these effects increase with age, and with decreased amounts of thyroid and progesterone.

Antioxidants can slightly retard the cumulative degenerative effects of the fats interacting with estrogen, serotonin, and other mediators of inflammation, but real elimination of the degenerative diseases will require an exploration of the effects of the entire series of lipid signalling substances derived from the saturated and omega minus 9 fatty acids.

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Br J Nutr. 2003 Aug;90(2):385-94. Dietary docosahexaenoic acid-induced production of tissue lipid peroxides is not suppressed by higher intake of ascorbic acid in genetically scorbutic Osteogenic Disorder Shionogi/Shi-od/od rats. Sekine S, Kubo K, Tadokoro T, Maekawa A, Saito M.

Cancer Res. 2004 Sep 15;64(18):6482-8. Estrogen enhances angiogenesis through a pathway involving platelet-activating factor-mediated nuclear factor-kappaB activation. Seo KH, Lee HS, Jung B, Ko HM, Choi JH, Park SJ, Choi IH, Lee HK, Im SY.

Clin Exp Allergy. 2004 Feb;34(2):194-200. Maternal breast milk long-chain n-3 fatty acids are associated with increased risk of atopy in breastfed infants. Stoney RM, Woods RK, Hosking CS, Hill DJ, Abramson MJ, Thien FC.

Proc Natl Acad Sci U S A. 1988 Aug;85(16):6137-41. Essential fatty acid deficiency prevents multiple low-dose streptozotocin-induced diabetes in CD-1 mice. Wright JR Jr, Lefkowith JB, Schreiner G, Lacy PE.

Mech Ageing Dev. 2005 May 10; [Epub ahead of print] Membrane alteration as a basis of aging and the protective effects of calorie restriction. Yu BP.

Acta Paediatr 1996 Jun;85(6):679-83. Phospholipid fatty acids in cord blood: family history and development of allergy. Yu G, Kjellman NI, Bjorksten B.

Fiziol Cheloveka. 2005 Mar-Apr;31(2):108-15. [Age-related changes in lipid peroxidation in various regions of the central nervous system] [Article in Russian] Volchegorskii IA, Shemiakov SE, Telesheva IB, Malinovskaia NV, Turygin VV.

Surg Today. 2003;33(8):600-5. Beneficial effects of n-9 eicosatrienoic acid on experimental bowel lesions. Yoshida H, Soh H, Sando K, Wasa M, Takagi Y, Okada A. PURPOSE: Dietary fortification of n-9 polyunsaturated fatty acids (PUFA) or 5,8,11-eicosatrienoic acid (ETrA) as well as n-3 PUFA might contribute to the suppression of leukotriene B4 (LTB4) synthesis and thereby reduce inflammatory bowel lesions. As a result, the effect of an ETrA-enriched diet on experimental bowel lesions was examined in this study. METHODS: In Expt. 1, rats were freely fed either an ETrA-enriched or a standard diet. After 7 days of feeding, acute bowel lesions were induced by the subcutaneous injection of 10 mg/kg indomethacin. In Expt. 2, chronic bowel lesions were made by performing subcutaneous injections of 7.5 mg/kg indomethacin twice. After the first injection, the rats were freely fed either an ETrA-enriched or a standard diet for 7 days. RESULTS: In both experiments, the rats fed an ETrA-enriched diet showed increased levels of ETrA in the plasma and intestinal mucosa, and a decreased inflammation score. However, there was no significant decrease in plasma and intestinal mucosal LTB4 in the ETrA-enriched diet-fed rats. CONCLUSION: These results suggest that the dietary supplementation of ETrA may have both prophylactic and therapeutic effects on experimentally produced bowel lesions. Further investigations are necessary to clarify the effects of ETrA on bowel lesions and its mechanisms.

© Ray Peat Ph.D. 2007. All Rights Reserved. www.RayPeat.com

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<span class="koboSpan" id="kobo.1.1">Aging, estrogen, and progesterone</span> A R T I C L E

Aging, estrogen, and progesterone

Estrogen refers not just to a family of steroids but to a class of substances that can produce approximately the same effects as estradiol and its metabolites.

Even before the pure substance was isolated in the 1930s, the effects of fluid from ovarian follicles were studied. It was soon discovered that many chemicals could produce similar effects.

By the middle of the century, many toxic effects of the estrogens were known, and more are being discovered.

Cancer, abnormal blood clotting, and infertility were known to be caused by estrogen before 1940, but at the same time the drug companies began calling estrogen the female hormone, and claiming that it would improve fertility.

Since the 19th century, some people argued that aging was caused by hormonal deficiency; for example, the symptoms of thyroid deficiency resembled aging. The estrogen industry exploited this idea to create the hormone replacement business.

Some hormones do decrease with aging, but others increase.

All of the unpleasant consequences of estrogen excess happen to resemble some of the events of aging.

If aging involves the same processes that are created by estrogen, then our knowledge of how to protect ourselves against estrogen can be used to protect ourselves against aging.

Estrogen steals oxygen from mitochondria, shifting patterns of growth and adaptation.

The balance between what a tissue needs and what it gets will govern the way that tissue functions, in both the short term and the long term. When a cell emits lactic acid and free radicals and the products of lipid peroxidation, it's reasonable to assume that it isn't getting everything that it needs, such as oxygen and glucose. With time, the cell will either die or adapt in some way to its deprived conditions.

In aging, tissues generally atrophy, with loss of both substance and activity. Ordinarily, organisms react to stress with increased activity of the appropriate functional system, but when the stress is inescapable, organisms adopt the strategy of decreasing their demands, as in hibernation or the defensive inhibition that has been called parabiosis, the state of being not fully alive. In many situations, serotonin (which is closely associated with estrogen) seems to be an important inducer of this state. There are many indications that estrogen is a factor [e.g., Shvareva & Nevretdinova, 1989, Saltzman, et al., 1989] in functionally suppressed states such as hibernation, social subordination, learned helplessness and depression. Social subordination in animals often involves high estrogen and reduced fertility.

In good health, an animal's systems are designed so that certain tissues will be intensely but briefly stimulated by estrogen. This stimulation by estrogen doesn't produce the normal amount of carbon dioxide, so the tissue experiences oxygen deprivation, leading to swelling and cell division. (Along with the reduced carbon dioxide production, there is increased lipid peroxidation). Any similar stimulaton, whether it's produced by soot, or suffocation, or irradiation, will produce the broad range of estrogen's effects, beginning with inflammation but ending with atrophy or cancer if it is too prolonged.

Although, as the 21st century begins, the US government hasn't decided whether to classify estrogen as a carcinogen, it was identified as a carcinogen in the first half of the 20th century--and a variety of carcinogens were found to be estrogenic.

Many people studying estrogen's biological effects observed that certain of its effects resembled the changes seen in aging, such as fibrotic changes of connective tissues, accelerated accumulation of age pigment, a tendency to miscarry, or the production of degenerative changes in various organs. But as far as I know, I was the first one to suggest that aging itself involves increased estrogen dominance. (Taking this perspective suggests many specific things to do for aging. And, if radiation injury, and stress, are estrogenic, it suggests that specific anti-estrogenic treatments could be appropriate.) I based my argument on the identity of the biochemical and tissue effects produced by aging and by estrogenic excess. At that time, techniques for the accurate measurement of very small amounts of estrogen hadn't been fully developed. I felt that the situation should have been clear, because of the previous decades of research, and I used that as the context for arguing that the reason for age-related infertility was the same as for estrogen-induced infertility or stress-related infertility, namely, the inability to deliver oxygen to the embryo. I thought of the developing embryo as a sensitive indicator of processes that occur throughout the body during aging and stress, and that the destruction of the embryo by the excessive estrogen of the birth control pill was closely analogous to the progressive loss of function that occus in so many tissues during normal aging.

After I wrote my dissertation, Terry Parkening, who had worked in the same lab, sent me data from rats, showing that his measurements confirmed the increase of estrogen with aging. Since then, many others have shown that either the absolute levels of estrogen, or the ratio of estrogen to the antiestrogens, increases with aging in a wide variety of organisms of both sexes, including humans.

In the 1970s, the claims about estrogen curing osteoporosis apparently had been debunked. At the time, that appeared to be the last of the major claims for the therapeutic properties of estrogen. Studies in dogs were starting to show that estrogen was an important cause of degenerative bone disease, as well as kidney disease, liver disease, thyroid disease, etc. Hormones used in contraceptives were producing cancer in dogs, as well as many other diseases, so dog research was widely abandoned by the drug industry/FDA, in favor of animals that were less sensitive, or differently sensitive, to the hormones. The claims that the industry was making were contradicted by the dog research, so they sought new animal models that wouldn't so clearly contradict their claims.

A great advantage, for the drug industry, of using rats instead of dogs is that expensive, and often embarrassing, long-term experiments aren't possible in such short-lived animals. Rats die when their tissues still appear to be relatively young. Although excess prolactin (resulting from excess estrogen) in humans is an important cause of osteoporosis, in rats at a certain age and on a certain diet, hyperprolactinemia can stimulate bone growth. [Piyabhan, et al., 2000, Yeh, et al., 1996] This trait of rats could be very advantageous to the estrogen industry.

All of the maladies caused by estrogen excess appear to develop in the same way that it interferes with pregnancy, by driving the tissue to require more energy and oxygen than can be delivered to it. Necrosis, the death of sections of tissue, was produced acutely by extreme overdoses of estrogen, or gradually by less extreme overdoses, and if the estrogenic stimulation was milder but very prolonged, the result would usually be tumors, sometimes developing in the midst of atrophy or necrosis. An overdose of estrogen was used to shrink breasts and prevent lactation, and an even larger dose was used to kill breast tissue in treating cancer. A recent study (Toth, et al., 2000) shows that, at least in women, estrogen is closely associated with the general loss of fat-free tissue with aging. This shows a close association between the generalized atrophy of aging and the amount of estrogen in the tissues.

In the case of the embryo that can't implant in the aged or estrogenized uterus, it is because oxygen is being consumed so fast by the uterus that very little is available for the embryo. The uterus is, effectively, in an inflamed state, and the embryo is in a state that requires abundant oxygen. The general loss of tissue that Toth associated with increased estrogen follows many of the same steps that occur in the failure of the embryo to implant in the uterus: Glycogen is depleted in futile oxidative cycles, protein synthesis is inhibited, lipid peroxides and free radicals accumulate, cellular defensive and repair processes replace normal functioning.

(With aging, the loss of glycogen in the brain has serious consequences, including insomnia. Estrogen's depletion of glycogen in other tissues is probably important for their functioning, and thyroid and progesterone are known to help maintain the glycogen stores.)

In the last several years, according to the medical literature estrogen would seem to have outgrown nearly all of its bad traits. It protects the brain, the heart, the blood vessels, even the fetus, and it prevents many kinds of cancer, and improves memory, mood, and immunity. And it would still seem to be of great promise in treating breast cancer and prostate cancer, if we took some medical journals seriously. It achieves many of these nice things by functioning as an antioxidant and by increasing circulation, often acting through nitric oxide and serotonin or melatonin. Even though I have read thousands of the articles that said otherwise, the near unanimity of the current research literature can almost give me the feeling that things might not be exactly as they had seemed.

In fact they aren't, but the change is in what passes for science, rather than in the way organisms respond to estrogen. Many little pictures are being presented, that seem to add up to a very different big picture. It is clear that this new picture is being painted by those who fund the research, and by some of those whose careers depend on that funding. The people who do the odd little studies of estrogen and cytokines, nitric oxide, regulatory genes, and so on, are usually getting the data they claim to get, and if they draw speculative conclusions about what their study means medically, that's their privilege. But hundreds of these little publications that would be harmless individually, add up to national policy endorsed by the FDA and other powerful agencies--they add up to the same sort of criminal conspiracy that the tobacco industry and its researchers perpretrated throughout the twentieth century.

Journals that are considered to be the best in their field publish many papers that simply misrepresent some of the basic facts, while interpreting experimental results that would otherwise have unpleasant commercial implications.

For example, the follicular phase is a time of low steroid production by the ovary, until near the end of the phase, just before ovulation, when estrogen rises. The luteal phase is a time of high estrogen and high progesterone synthesis. Many publications describe the follicular phase as a time of high estrogen, and the luteal phase as a time of low estrogen, roughly the opposite of the actual situation. And an even larger number of studies get the results they want by using a short exposure to estrogen to study something which takes a long time to develop.

In the last few years, one of the most common tricks of estrogen promotion is to argue that estrogen protects against heart disease and Alzheimer's disease because it relaxes blood vessels, by increasing the formation of nitric oxide. It does generally increase the formation of nitric oxide, but nitric oxide is a toxic free radical that plays a major role in degenerative diseases. And the inappropriate relaxation of blood vessels, coupled with increased clottability of the blood, is a major cause of pulmonary embolisms and venous disorders.

In studies of tendons, excess estrogen, aging, and cooking (the phenomenon of the curling pork chop) all caused hardening and contraction of the collagen. When people get to be 90 or 100 years old, the opening between their eyelids is sometimes contracted, presumably because of this process of collagen shrinkage. If this shrinkage of connective tissue affects the large blood vessels, they become narrower and stiffer, so that the blood has to travel faster if the same amount is to be delivered in the same time.

Ultrasound can be used to measure the velocity of the blood flow, and increased velocity will correspond to constriction of the channel, if the same amount of blood is being delivered. But many people praise estrogen's vascular benefits on the basis of tests showing increased blood velocity in large arteries such as the aorta, without evidence that more blood is being circulated. With aging, as arteries become constricted, increased blood velocity is taken as evidence of the pathology. Velocity measurements have to be interpreted in the contexts of tissue perfusion, cardiac output, etc. When the diameter of the artery is considered along with the velocity of the blood, the volume of flow can be determined, and then it appears that progesterone increases blood flow, while estrogen can decrease it. [Dickey and Hower, 1996.] This would be consistent with the known ability of an estrogen excess to cause retarded growth of the fetus, as well as specific birth defects.

Estrogen does increase the blood flow to particular organs, but apparently less than it increases their oxygen demand, as can be seen from the color change of estrogenized tissues, toward purple, rather than pink. Measurements of oxygen tension in the tissue show that estrogen decreases the relative availability of oxygen. And when the level of estrogen is very high, metabolically demanding tissues, such as the kidney and adrenal cortex, simply die, especially under conditions that restrict blood flow. [E.g., Kocsis, et al., 1988, McCaig, et al., 1998, Yang, et al., 1999.] When estrogen's effects overlap with the stimulating effects of other hormones, such as pituitary hormones, particular organs undergo something similar to excitotoxicity. When estrogen overlaps with endotoxin (as it tends to do), multiple organ failure is the result.

The simple need for more oxygen is a stimulus to increase the growth of blood vessels, and estrogen's stimulation of non-mitochondrial oxygen consumption with the production of lactic acid stimulates blood vessel formation. Progesterone, by increasing oxidative efficiency, opposes this angiogenic (neovascularization) effect of estrogen.

Szent-Gyorgyi spent most of his career studying muscles--from the anal sphincter to pigeon breast to tense goats. One of his most interesting experiments investigated the effects of estrogen and progesterone on the heart muscle. He showed that estrogen excess prevents the increase of stroke volume as the speed increases, but that progesterone increases the stroke volume as the heart accelerates, making pumping more effective without unnecessary acceleration of the heart rate. These effects are parallel to Selye's observation that estrogen imitates the shock reaction.

In shock, the blood pressure decreases, mainly because the blood volume decreases. Water is taken up by the tissues, out of the blood. Much of the remaining blood volume is accumulated in the relaxed veins, and little is returned to the heart, yet the increased need for circulation accelerates the heart, causing each stroke to pump only a small amount. The reduced blood pressure caused many people to think that adrenaline would help to improve the circulation, but actually the resistance arteries, small arteries that provide blood to the arterioles and capillaries, are constricted in shock, (Lin, et al., 1998,) and adrenaline usually makes the situation worse. When tissue is poorly oxygenated (or is exposed to estrogen) it takes up water, swelling and becoming more rigid, turgid. (It also takes up calcium, especially under the influence of estrogen, causing muscles to contract.) This swelling effect will be much more noticeable in small arteries than in major arteries with very large channels, but when the effect is prolonged, it will affect even the heart, causing it to stiffen, weakening its ability to pump. There is some evidence that estrogen can make large arteries stiffen, over a span of a few months. (Giltay, et al., 1999)

Estrogen, by creating an oxygen deficiency, stimulates first swelling, and then collagen synthesis. Collagen tends to accumulate with aging.

In shock, the cells are in a very low energy state, and infusions of ATP have been found to be therapeutic, but simple hypertonic solutions of glucose and salt are probably safer, and are very effective. The low energy of cells causes them to take up water, but it also causes the veins (which always receive blood after most of its oxygen and nutrients have been extracted) to lose their tone, allowing blood to pool in them, instead of returning to the heart. (Abel and Longnecker, 1978) This contributes to varicose veins (Ciardullo, et al., 2000), and to orthostatic hypotension, which is seen in women who are exposed to too much estrogen, and very frequently in old people.

The energy failure resulting from estrogen excess has been remarkably well characterized (but the meaning of this for the cell hasn't been explored). The electron transfer process of the mitochondria is interrupted by the futile redox cycling catalyzed by estrogens.

Good sleep requires fairly vigorous metabolism and a normal body temperature. In old age, the metabolic rate is decreased, and sleep becomes defective. Protein synthesis declines with aging, as the metabolic rate slows. At least in the brain, protein synthesis occurs most rapidly in deep sleep. [Nakanishi, et al., 1997; Ramm and Smith, 1990]

In old age, the catabolic hormones such as cortisol are relatively dominant [Deuschle, et al., 1998], and even in youth, cortisol rises during darkness, reaching its peak around dawn. Even in young women, bone loss occurs almost entirely during the night, when cortisol is high. The hormones that are commonly said to prevent bone loss, estrogen and growth hormone, are high at night, rising along with cortisol. Estrogen causes growth hormone to increase, and in the morning, young women's growth hormone has been found to be 28 times higher than men's.[Engstrom, et al., 1999] The growth hormone response to estrogen is probably the result of the changed use of glucose under estrogen's influence, making it necessary to mobilize free fatty acids from tissues. While estrogen is usually highest at night, progesterone is lowest during the night. These observations should suggest that progesterone, not estrogen, is the bone protective substance.

The disappearance of water from the blood, as it moves into the tissues during the night, makes sleep resemble a state of shock or inflammation. Since rats, that are active at night, experience the same blood thickening, it's actually the darkness, rather than sleep, that creates this inflammatory state. Estrogen increases, and acts through, the inflammatory mediators, serotonin and histamine, to increase vascular leakiness, at the same time that it causes cells to take up water and calcium. The formation of lactic acid, in place of carbon dioxide, tends to coordinate these effects.

In sleep, as in shock, hyperventilation is common, and it sometimes produces extreme vasoconstriction, because of the loss of carbon dioxide.

Since glucose and salt are used to treat shock (intravenous 7.5% salt solutions are effective), it seems appropriate to use carbohydrate (preferably sugar, rather than starch) and salty foods during the night, to minimize the stress reaction. They lower adrenalin and cortisol, and help to maintain the volume and fluidity of blood. Thyroid, to maintain adequate carbon dioxide, is often all it takes to improve the blood levels of salt, glucose, and adrenalin.

Temperature falls during sleep. Recent experiments show that hypothermia during surgery exacerbates the edema produced by stress, and that hypertonic (hyperosmotic or hyperoncotic) solutions alleviate the swelling. It is possible that light's action directly on the cells helps them to prevent swelling, and that the body's infrared emissions have a similar function. Whatever the mechanism is, adequate temperature improves sleep, and an excessive nocturnal temperature drop probably increases edema, with all of its harmful consequences.

At least some of the redox cycles involving NAD/NADH and NADP/NADPH keep electrons from moving beyond ubiquinone (coQ10) and energizing the mitochondria. The cycle that makes nitric oxide is one of these, but some forms of estrogen participate directly as catalysts in this energy-stealing process. One of the effects of blocking electron transfer in the mitochondria is to lower the energy charge of the cells, mimicking the function of the age-damaged mitochondria. Glutathione and protein sulfhydryls are oxidized, because the normal energy pathways that maintain them have been disrupted.

Estrogen directly lowers the temperature, while progesterone raises the temperature. Estrogen sets the brain's temperature regulator lower, but, acting through serotonin and other mediators, it can actually lower the metabolic rate, too.

Far from being just the hormone of estrus, estrogen, in the form of estradiol and the related steroids, plays a role in organisms as diverse as yeasts, worms and mollusks, and in modifying the function of practically every type of animal cell--skin, nerve, muscle, bone, hair, gland, etc. But, as more and more of its functions come to be understood, it turns out that many toxic chemicals and stressful physical processes can activate the same functions, and that estrogen's association with the functions of stress makes it a kind of window into some universal biological functions.

When Hans Selye brought it to our attention that stress was a general life process, he began a process of generalization that led people to be able to see that the changes of aging were also the result of complex interactions between organisms and their environment, rather than some genetic program that operates like a clock running down.

When W. Donner Denckla demonstrated that the removal of an animal's pituitary (or, in the case of an octopus, its equivalent optic gland) radically extended the animal's life span, he proposed the existence of a death hormone in the pituitary gland. But the case of the octopus makes it clear that the catabolic, death-inducing hormone is produced by the ovary, under the influence of the optic gland's gonadotropins. This sacrifice of the old (the individual) for the new (the progeny) is analogous to the tissue wasting we see under the influence of estrogen, as it stimulates cell division.

In Selye's classical stress, the destruction of tissues by the catabolic hormones makes sense in terms of the functional system described by Anokhin, in which the hormones of adaptation dissolve one tissue for use by the system which is adaptively functioning, with the production of carbon dioxide by the functional tissue, stabilizing it and regulating the adequate delivery of blood.

Progesterone is both an anticatabolic hormone and an antiestrogenic hormone, and in both cases, it protects the functional systems from atrophy.

The extreme generality of the phenomenon of estrogenicity that was built up during the twentieth century has taken the concept beyond the specific functions of estrus, and reproduction, and the activation of genetic programs of the female animal, to make it necessary to see it as a way that living substance responds to certain kinds of stimulus. And these ways of responding turn out to be involved in the complex but coherent ways that organisms respond to aging.

Selye gave various names to the biology of stress, but the general adaptation syndrome expressed the idea accurately. But the biology of estrogenicity, like the biology of aging, is so central that any name is likely to be misleading. The historical accident of naming a hormone for estrus shouldn't keep us from thinking about the way estrogen affects our energetics and structure, and how those processes relate to aging, atrophy, cancerization, etc.

While progesterone is probably the most perfect antiestrogenic hormone, and therefore an anti-stress and anti-aging hormone, the recognition of a wide variety of estrogen's effects has made it possible to adjust many things in our diet and environment to more perfectly oppose the estrogenic and age-accelerating influences.

REFERENCES

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Acta Physiol Scand 1990 Sep;140(1):85-94. Effects of hypertonic NaCl solution on microvascular haemodynamics in normo- and hypovolaemia. Bouskela E, Grampp W, Mellander S. The aims of this study were to investigate possible resuscitation effects of a single, 10-min, 350-microliters intravenous infusion of 7.5% NaCl in hamsters in hemorrhagic shock and to compare the effects of such infusion with an identical one of 0.9% NaCl on the hamster cheek pouch microcirculation during normovolaemia and after acute bleeding to a hypotension level of about 40 mmHg. No significant differences could be detected between the effects of either infusion given to normovolaemic normotensive hamsters. In the animals subjected to haemorrhage, upon bleeding, arterioles larger than 40 microns constricted, arterioles smaller than 40 microns dilated and venular diameter did not change, while blood flow decreased in all vessels. Central nervous and/or reflex excitation of the sympathetic nervous system could account for the constriction of venules and larger arterioles, while a direct effect of hyperosmolarity could explain the dilatation of the smaller arterioles. The study can therefore help to explain some of the mechanisms underlying the reported resuscitation effect of 7.5% NaCl infusion in animals during severe haemorrhagic hypovolaemia.

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Br J Exp Pathol 1987 Feb;68(1):35-43. Histochemical and ultrastructural study of renal cortical necrosis in rats treated with oestrone + vasopressin, and its prevention with a vasopressin antagonist. Kocsis J, Karacsony G, Karcsu S, Laszlo FA. Renal cortical necrosis was induced by the administration of vasopressin to oestrogen-pretreated rats. Histochemical (succinic dehydrogenase, trichrome, perjod acid Schiff) and electronmicroscopic methods were applied to examine how the vasopressin antagonist d(CH2)5Tyr(Met)AVP influences the development of this renal cortical necrosis. The experiments revealed that vasopressin did not induce hypoxia or necrosis in the renal tubules if the antagonist was administered simultaneously, even after oestrogen pretreatment. The conclusion is drawn that this pressor antagonist may be of value for the prevention of renal cortical necrosis in rats or in human beings.

Invest Radiol 1979 Jul-Aug;14(4):295-9. Serioangiographic study of renal cortical necrosis induced by administration of estrin and vasopressin in rats. Kocsis J, Szabo E, Laszlo FA. We report a serioangiographic method in rats which permits assessment of the course and dimensions of the renal arteries, the durations of the arterial and venous phases, and the intensity and uniformity of the renal parenchymal filling. The procedure was employed to study the mechanism by which administration of vasopressin to rats pretreated with estrin leads to renal cortical necrosis. The pathogenetic significance of the spasm localized on the larger renal arteries was proved directly; the possible role of the arteriovenous shunt in the development of the renal ischemia was excluded.

Contrib Nephrol 1981;28:1-216. Renal cortical necrosis. Experimental induction by hormones. Laszlo FA.

Morphol Igazsagugyi Orv Sz 1974 Jan;14(1):8-12 [The effect os estrogen, ACTH and cortisone administration, as well as hypophysectomy on histological changes in unilateral renal hilus ligation]. [Article in Hungarian] Laszlo F, Monus Z.

Eur J Neurosci 1997 Feb;9(2):271-9. Positive correlations between cerebral protein synthesis rates and deep sleep in Macaca mulatta. Nakanishi H, Sun Y, Nakamura RK, Mori K, Ito M, Suda S, Namba H, Storch FI, Dang TP, Mendelson W, Mishkin M, Kennedy C, Gillin JC, Smith CB, Sokoloff L.

Can J Physiol Pharmacol 2000 Oct;78(10):757-65. Changes in the regulation of calcium metabolism and bone calcium content during growth in the absence of endogenous prolactin and during hyperprolactinemia: a longitudinal study in male and female Wistar rats. Piyabhan P, Krishnamra N, Limlomwongse L Since endogenous prolactin has been shown to enhance food consumption, calcium absorption, and bone calcium turnover in the pregnant rat, the role of endogenous prolactin in the regulation of calcium metabolism was investigated in 3-day balance studies of female Wistar rats from the age of 3 to 11 weeks. Results showed that rapid growth occurred between 3 and 6 weeks with maximum fractional calcium absorption and calcium retention at 5 weeks of age in both sexes. The data also showed a physiological significance of endogenous prolactin in enhancing calcium absorption and retention in 5 week old rats. In an absence of prolactin, peak calcium absorption was delayed in 7-week old animals, and vertebral calcium content of 11-week old animals was reduced by 18%. Hyperprolactinemia in the AP group was found to enhance fractional calcium absorption and calcium retention at 7, 9, and 11 weeks and increased the femoral calcium content by 16%. It could be concluded that a physiological role of prolactin is the stimulation of calcium absorption and maintainance of bone calcium content during growth and development.

Physiol Behav 1990 Nov;48(5):749-53. Rates of cerebral protein synthesis are linked to slow wave sleep in the rat. Ramm P, Smith CT. Using L-[1-14C]leucine autoradiography, rates of cerebral and local cerebral protein synthesis were studied during wakefulness, slow wave sleep (SWS) and REM sleep in the rat. In the cerebrum as a whole, the rate at which labelled leucine was incorporated into tissues was positively correlated with the occurrence of slow wave sleep. We failed to observe a significant correlation of protein synthesis rate with either wakefulness or REM sleep. As in the cerebrum as a whole, most discrete brain regions showed moderate positive correlations between the occurrence of SWS and rates of protein synthesis. There were no brain regions in which rates of protein synthesis showed striking correlations with sleep-wake states. Thus, the occurrence of SWS is associated with higher rates of protein synthesis throughout the brain. These data suggest that SWS sleep favors the restoration of cerebral proteins.

Surgery 1991 Oct;110(4):685-8; discussion 688-90. The effect of hypertonic saline resuscitation on bacterial translocation after hemorrhagic shock in rats. Reed LL, Manglano R, Martin M, Hochman M, Kocka F, Barrett J. Recent work suggests that moderate hypovolemia causes gut arteriolar constriction, which is ameliorated by hypertonic saline resuscitation. Bacterial translocation should, therefore, be reduced when hypertonic saline (HS) is used as the resuscitative fluid. Compared to autotransfusion, hemodilutional resuscitation from hemorrhagic shock with hypertonic saline resulted in a significant reduction in bacterial translocation (p values were 0.03 and 0.04 for 3% and 7.5% hypertonic saline, respectively). The reduction in translocation after hypertonic saline resuscitation may be the consequence of microcirculatory alterations preventing gut hypoperfusion.

Am J Physiol 1999 Feb;276(2 Pt 2):H563-71. Changes in resistance vessels during hemorrhagic shock and resuscitation in conscious hamster model. Sakai H, Hara H, Tsai AG, Tsuchida E, Johnson PC, Intaglietta M. The unanesthetized hamster dorsal skinfold preparation was used to monitor diameters and blood flow rates in resistance arteries (small arteries, A0: diameter, 156 +/- 23 micrometers) and capacitance vessels (small veins, V0: 365 +/- 64 micrometers), during 45 min of hemorrhagic shock at 40 mmHg mean arterial pressure (MAP) and resuscitation. A0 and V0 vessels constricted significantly to 52 and 70% of the basal values, respectively, whereas precapillary arterioles (A1-A4, 8-60 micrometers) and collecting venules (VC-VL, 26-80 micrometers) did not change or tended to dilate. Blood flow rates in the microvessels declined to <20% of the basal values.

Horm Behav 1998 Feb;33(1):58-74. Suppression of cortisol levels in subordinate female marmosets: reproductive and social contributions. Saltzman W, Schultz-Darken NJ, Wegner FH, Wittwer DJ, Abbott DH Cortisol levels of cycling females were significantly higher than those of subordinates at all parts of the cycle, but were significantly higher than those of ovariectomized females only during the midcycle elevation. Unexpectedly, subordinates had significantly lower cortisol levels than ovariectomized females, as well as higher estradiol and estrone levels and lower progesterone and luteinizing hormone (LH) levels.

Zh Evol Biokhim Fiziol 1989 Jan-Feb;25(1):52-9. [Seasonal characteristics of the functioning of the hypophysis-gonad system in the suslik Citellus parryi]. Shvareva NV, Nevretdinova ZG In experiments on the arctic ground squirrel C. parryi, studies have been made on seasonal changes in the weight of testes, follicular diameter in the ovaries and the content of sex and gonadotropic hormones in the peripheral blood. Testicular involution and arrest of follicular development were observed in prehibernation period. During hibernation, follicular growth and the increase in the weight of testes take place. Estradiol secretion was noted in hibernating females, whereas progesterone was found in the blood only in May.

Maturitas 1984 Nov;6(3):269-78. Spontaneous skin flushing episodes in the aging female rat. Simpkins JW. It is well known that with the loss of gonadal function most women experience hot flushes, characterized by a rapid regional increase in cutaneous blood flow. Animal models for this vasomotor syndrome have been elusive, thus hampering efforts to evaluate the endocrine and neuronal substrates of the hot flush. In this report, evidence is reported for the occurrence in aging female rats of spontaneous tail skin temperature (TST) fluctuations which are similar in amplitude, duration and frequency to hot flushes reported for peri-menopausal women. Paradoxically, these TST pulses occur in animals with senescent reproductive states in which serum estrogen levels are moderately elevated and ovariectomy eliminates these rat flushing episodes. This demonstration of steroid-dependent, spontaneous flushing episodes indicates that the aging female rat can be used to evaluate the neuronal and hormonal basis of vasomotor instability.

Carcinogenesis 1994 Nov;15(11):2637-43. The metabolism of 17 beta-estradiol by lactoperoxidase: a possible source of oxidative stress in breast cancer. Sipe HJ Jr, Jordan SJ, Hanna PM, Mason RP. Electron spin resonance (ESR) spectroscopy and oxygen consumption measurements using a Clark-type oxygen electrode have been used to study the metabolism of the estrogen 17 beta-estradiol by lactoperoxidase. Evidence for a one-electron oxidation of estradiol to its reactive phenoxyl radical intermediate is presented. The phenoxyl radical metabolite abstracts hydrogen from reduced glutathione generating the glutathione thiyl radical, which is spin trapped by 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and subsequently detected by ESR spectroscopy. In the absence of DMPO, molecular oxygen is consumed by a sequence of reactions initiated by the glutathione thiyl radical. Similarly, the estradiol phenoxyl radical abstracts hydrogen from reduced beta-nicotinamide-adenine dinucleotide (NADH) to generate the NAD. radical. The NAD. radical is not spin trapped by DMPO, but instead reduces molecular oxygen to the superoxide radical, which is then spin-trapped by DMPO. The superoxide generated may either spontaneously dismutate to form hydrogen peroxide or react with another NADH to form NAD., thus propagating a chain reaction leading to oxygen consumption and hydrogen peroxide accumulation. Ascorbate inhibits oxygen consumption when estradiol is metabolized in the presence of either glutathione or NADH by reducing radical intermediates back to their parent molecules and forming the relatively stable ascorbate radical. These results demonstrate that the futile metabolism of micromolar quantities of estradiol catalyzes the oxidation of much greater concentrations of biochemical reducing cofactors, such as glutathione and NADH, with hydrogen peroxide produced as a consequence. The accumulation of intracellular hydrogen peroxide could explain the hydroxyl radical-induced DNA base lesions recently reported for female breast cancer tissue.

Endocrinol Metab Clin North Am 1995 Sep;24(3):531-47. Idiopathic edema. Pathogenesis, clinical features, and treatment. Streeten DH. Idiopathic edema is usually orthostatic. It occurs almost exclusively in post-pubertal women. . . .

Carcinogenesis 1995 Apr;16(4):891-5. Mitochondrial enzyme-catalyzed oxidation and reduction reactions of stilbene estrogen. Thomas RD, Roy D. We have demonstrated for the first time that mitoplasts (i.e. mitochondria without outer membrane) were able to convert stilbene estrogen (diethylstilbestrol, DES) to reactive metabolites, which covalently bind to mitochondrial (mt)DNA. Depending on the cofactor used, mitochondrial enzymes catalyzed the oxidation and/or reduction of DES. DES was oxidized to DES quinone by peroxide-supported mitochondrial enzyme. DES quinone was reduced to DES by mitoplasts in the presence of NADH. DES quinone was also reduced to DES by pure diaphorase, a mitochondrial reducing enzyme, in the presence of NADH. These data provide direct evidence of mitochondrial enzyme-catalyzed oxidation and reduction reactions of DES. In the cell, activation of DES in the mitochondria (the organelle in which mtDNA synthesis, mtDNA repair and transcription systems are localized) is of utmost importance, because an analogous in vivo mitochondrial metabolism of DES through covalent modifications in mitochondrial genome may produce instability in the mitochondrial genome of the cells. These modifications may in turn play a role in the development of DES-induced hepatocarcinogenicity.

J Clin Endocrinol Metab 2000 Apr;85(4):1382-7. Regulation of protein metabolism in middle-aged, premenopausal women: roles of adiposity and estradiol. Toth MJ, Tchernof A, Rosen CJ, Matthews DE, Poehlman ET. The age-related loss of fat-free mass (FFM) is accelerated in women during the middle-age years and continues at an increased rate throughout the postmenopausal period. Because protein is the primary structural component of fat-free tissue, changes in FFM are largely due to alterations in protein metabolism. Knowledge of the hormonal and physiological correlates of protein metabolism in middle-aged women, therefore, has important implications for understanding the mechanisms underlying changes in FFM. We measured leucine kinetics (expressed relative to FFM: micromol/kg FFM/h) in 46 middle-aged, premenopausal women (mean +/- SD, 47 +/- 3 yr) after an overnight fast (i.e. basal) and during euglycemic hyperinsulinemia (40 mU/m2/min) using a 5.5-h nfusion of [1-13C]leucine. Additionally, we measured insulin-stimulated glucose disposal by euglycemic hyperinsulinemic clamp, body composition by dual energy -ray absorptiometry, abdominal fat distribution by computed tomography, and hormone levels by RIA as possible correlates of protein metabolism. Under basal onditions, stepwise regression analysis showed that leucine appearance (i.e. protein breakdown) was related to percent body fat and serum estradiol (r2 = 40%; P < 0.01), and leucine oxidation was related to serum estradiol and percent ody fat (r2 = 26%; P < 0.05). Under euglycemic hyperinsulinemic conditions, no variables correlated with the percent change in leucine appearance. The percent change in leucine oxidation was related to intraabdominal adipose tissue area and glucose disposal rate (r2 = 48%; P < 0.01). Correlates and r2 values for nonoxidative leucine disposal (i.e. protein synthesis) under basal and euglycemic hyperinsulinemic conditions were similar to those observed for leucine appearance. From these results, we conclude that adiposity and/or serum estradiol may contribute to the regulation of protein metabolism and FFM in middle-aged, premenopausal women.

J Korean Med Sci 1999 Jun;14(3):277-85. The metabolic effects of estriol in female rat liver. Yang JM, Kim SS, Kim JI, Ahn BM, Choi SW, Kim JK, Lee CD, Chung KW, Sun HS, Park DH, Thurman RG. Basal oxygen consumption of perfused liver increased significantly in estriol or ethanol-treated rats. These findings suggest that the metabolic effects of estriol (two mg per 100 mg body wt) can be summarized to be highly toxic in rat liver, and these findings suggest that oral administration of estrogens may induce hepatic dysfunctions and play a role in the development of liver disease.

Bone 1996 May;18(5):443-50. Ovariectomy-induced high turnover in cortical bone is dependent on pituitary hormone in rats. Yeh JK, Chen MM, Aloia JF.. Our results confirmed that OV increased and HX suppressed systemic and periosteal bone formation parameters in both bone sites, OV increased and HX suppressed the gain in bone size and bone mass. When OV rats were HX, the serum levels of osteocalcin and periosteal bone formation parameters of the tibial shaft and the fifth lumbar vertebrae were, however, depressed and did not differ from that of the HX alone. DXA results show that the effect of OV on bone size and bone mass is also abolished by HX. In conclusion, we have demonstrated that OV increases tibial and lumbar vertebral bone formation and bone growth and this effect is pituitary hormone dependent.

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<span class="koboSpan" id="kobo.1.1">Aging Eyes, Infant Eyes, and Excitable Tissues</span> A R T I C L E

Aging Eyes, Infant Eyes, and Excitable Tissues

The eyes and the lungs are sensitive tissues that are easily harmed by inappropriate environmental exposure. They are especially sensitive in infancy and old age.

For 60 years there have been controversies about the cause of retinopathy of prematurity, which has blinded tens of thousands of people.

Degeneration of the retina is the main cause of blindness in old people. Retinal injury is caused by ordinary light, when the eyes are sensitized by melatonin, prolactin, and polyunsaturated fats. Bright light isn't harmful to the retina, even when it is continuous, if the retina isn't sensitized.

Melatonin and prolactin are induced by stress, and darkness is a stress because it impairs mitochondrial energy production.

The polyunsaturated fats which accumulate in the brain and retina damage mitochondria.

Iron, which accumulates prenatally, and then again with aging, reacts with unsaturated fats during stress to destroy cells.

The popular supplements melatonin, tryptophan, fish oils, St. John's wort, and the various omega -3 oils, all increase the risk of retinal light damage and macular degeneration. Serotonin uptake inhibiting antidepressants are suspected to be able to cause it.

Processes similar to those that damage the over-sensitized retina can occur in other cells, as a result of stress. The substances that sensitize the retina to light-damage, can also increase the incidence of new or metastatic cancers.

Iron supplements and the use of supplemental oxygen, especially with a vitamin E deficiency exacerbated by excessive unsaturated fats in the diet, are still commonly used exactly when they can do the most damage.

One of the recognized achievements of biology has been the demonstration of lifes universality, in the sense that organisms of all sorts use the same fundamental genetic code, and that yeasts, lizards, apes, and people have remarkably similar cellular systems, as well as a great amount of genetic similarity.

There has been another, less well recognized, sort of convergence going on in physiology and pathophysiology. Hans Selyes concept of stress, the syndrome of being sick, Otto Warburgs argument that a respiratory defect was behind all kinds of cancer, and the idea of free radical damage as a common factor in disease and aging, helped to create a more general way of looking at the nature of disease that superceded medicines theories of disease pathogens and genetic mutations, which created thousands of disease entities, none of which had much to do with the individuality of the patient or his environment.

The understanding that plants and animals have much biochemistry in common has gradually changed the assumptions of the science establishment, which until recently insisted that only ionizing radiation could affect animals or other organisms that lacked chlorophyll--and insisted that ionizing rays acted only on the DNA. Visible light, the textbooks said, was not chemically active, and so couldnt possibly affect animals cells. In animals, coloration was seen mainly as decoration and disguise, rather than as a functional part of their biochemistry.

(Chemically, the meaning of a pigment is that its a chemical which selectively absorbs radiation. Old observations such as Warburgs, that visible light can restore the activity of the respiratory pigments, showed without doubt that visible light is biochemically active. By the 1960s, several studies had been published showing the inhibition of respiratory enzymes by blue light, and their activation by red light. The problem to be explained is why the science culture simply couldnt accept crucial facts of that sort.)

The retina, of course, was allowed (in the views of mainline science) to respond to ordinary light, but the few people who studied the biological effects of seasonal or daily cycles of light have until recently stayed very close to the nerve pathways leading from the retina to the pineal gland, because those pathways could be described in terms of an evolutionarily specialized third eye. Even with a doctrine of a genetically specialized link between the retina and a little of the animals physiological chemistry, the great, slow-witted science establishment has done its best to avoid thoughts of any deep interaction between an organism and its environment, by insisting that the organism runs according to a genetically determined clock which is located in a few cells in a certain area of the brain, and that nervous impulses from the retina have only the small privilege of setting the clock.

It didnt matter to the academic and medical worlds that a professor, Frank A. Brown, had long ago disproved the idea of an innate genetic clock, because philosophy is much stronger than evidence. Leibniz had said that everything in the world runs on its own inner clock, without needing to perceive its surroundings, and this idea that everything in the world is a windowless monad resonated through the world of science, because it justified the pompous authoritarian attitudes of the experts who knew that anything that wasnt already in their heads couldnt be considered knowledge. If an organisms essence is contained in its genes, then it clearly doesnt interact in any meaningful way with most of its environment. This is the sort of culture that imbued research on the biology of light cycles.

When I moved from Mexico, first to Montana and then to Oregon in 1966, I became very conscious of how light affects the hormones and the health. (For example, in Montana I experienced an interesting springtime shedding of body hair.) Many people who came to cloudy Eugene to study, and who often lived in cheap basement apartments, would develop chronic health problems within a few months. Women who had been healthy when they arrived would often develop premenstrual syndrome or arthritis or colitis during their first winter in Eugene.

The absence of bright light would create a progesterone deficiency, and would leave estrogen and prolactin unopposed. Beginning in 1966, I started calling the syndrome winter sickness, but over the next few years, because of the prominence of the premenstrual syndrome and fertility problems in these seasonally exacerbated disorders, I began calling it the pathology of estrogen dominance. In the endocrinology classes I taught at the National College of Naturopathic Medicine, I emphasized the importance of light, and suggested that medicine could be reorganized around these estrogen-related processes. If the sparrows of Times Square mated in the winter because of the bright lights, it seemed clear that bright artificial light would be helpful in regulating human hormones.

In our lab at the University of Oregon, our hamsters would try to hibernate, even though they were in temperature-controlled laboratories with regular cycles of artificial light. (The ceiling lights provided only dim illumination inside their cage boxes, so they were probably in a chronic state of light deprivation, which probably increased their sensitivity to the weak environmental cues that Frank Brown had investigated, possibly microwaves that easily penetrated the lab walls.) During the winter, when they were infertile, I found that their thymus glands practically disappeared. The mechanism seemed to include the increase of pineal gland activity (probably increasing melatonin synthesis) in the winter, under the intensified activity of the sympathetic nervous system (with increased activity of adrenalin and other catecholamines), and the melatonin was apparently a signal for suppressing fertility during the stressful winter. In some animals (Shvareva and Nevretdinova, 1989), estrogen is increased during hibernation, contributing to the reduction of body temperature.

In 1994 A.V. Sirotkin found that melatonin inhibits progesterone production but stimulates estrogen production, and its widely recognized that melatonin generally inhibits the thyroid hormones, creating an environment in which fertilization, implantation, and development of the embryo are not possible. This combination of high estrogen with low progesterone and low thyroid decreases the resistance of the organism, predisposing it to seizures and excitotoxic damage, and causing the thymus gland to atrophy.

Cyclical exposure to melatonin can have an effect on the reproductive system opposite to that of chronic exposure, and the way exogenous melatonin is delivered to the animal can have unexpected effects on the actual amount of melatonin circulating in the blood (Wright and Alves, 2001). The actual amount of melatonin in the tissues, its relation to the normal cycling of the animal, and the influence of temperature, are often disregarded in melatonin research, making it hard to interpret many of the publications.

There is a lot of talk about melatonins function as an antioxidant, but, like so many other antioxidants, melatonin can act as a pro-oxidant at physiologically relevant concentrations; some studies have found that it, like estrogen, increases the activity of the pro-oxidative free radical nitric oxide (which acts like melatonin on pigment cells, causing them to lighten). The promoters of estrogen are also making claims that estrogen is a protective antioxidant, though that isnt true of physiological concentrations of estrogen, which can catalyze intense oxidations. The market culture seems to guide most research in these substances.

Almost any kind of stress increases the formation of melatonin.

In some animals, melatonin has been shown to be responsible for whitening of the hair during the winter. In some species it acts directly on the pigment cells, but in other species it seems to inhibit the action of the melanocyte stimulating hormone.

In snowy climates, its ecologically rational for animals to turn white in the winter, for camouflage. But tadpoles also turn white in the dark, or under the influence of melatonin, and the biological meaning of that isnt so clear. Its possible that being white would reduce their loss of heat through radiation, but I think it is more likely that it relates to an increased ability of weak radiation to penetrate their tissues, rather than being stopped near the surface by the melanin in the skin. The absence of melanin makes them more sensitive to light. Bright light suppresses their melatonin, and makes them turn dark brown or black, and this protects them from bright sunlight.

In the retina, melatonin increases the sensitivity of the cells to dim light. It, along with prolactin, another nocturnal hormone, helps to produce dark adaptation of the eyes.

Melatonin increases the concentration of free fatty acids during the night (John, et al., 1983; John and George, 1976)), so its interesting that one of the long-chain highly unsaturated fatty acids, DHA (docosahexaenoic acid), also increases the light sensitivity of the retina.

Melatonin lowers body temperature, causes vasoconstriction in the brain, heart, and other organs, and slows reactions. An antagonist to melatonin acts as an antidepressant, reducing behavioral despair resulting from stress. (Dubocovich, et al., 1990.) So, in the behavioral sense, melatonin reduces sensitivity, yet it increases the eyes sensitivity to light, causing them to be injured by light that would otherwise be harmless.

Since a hibernating animal under the influence of melatonin can become very cold, the light-sensitizing function of melatonin is probably related to the biological need to be roused out of the torpor occasionally. (Hibernators apparently have to warm up occasionally to sleep in the ordinary manner.) Melatonin is said to intensify dreaming, which is part of the process of arousal from sleep.

All of the stress-related hormones increase during the night. One of the ways these hormones of darkness act is to increase the sensitivity to light, in a process that is an important adaptation for organisms in dim light. In the night, our ability to see (and respond to) dim light is increased. But dark-adapted eyes are very sensitive to injury by bright light. Light that ordinarily wouldnt harm the eyes, will do serious damage when the eyes are dark adapted.

In thinking about the effects of stress and oxygen deprivation, I read the studies demonstrating that the formation of the oxygen-wasting age pigment, lipofuscin, is increased by estrogen, by oxygen deprivation (in carp living below the ice, or even in fetuses), by metals such as iron, by x-rays, and by highly unsaturated fats.

Free fatty acids that are mobilized from storage tissues in the night and in the winter also tend to increase with aging, as the ability to tolerate stress decreases. Poor circulation and lipofuscin tend to be associated, in a vicious cycle. This means that the retina becomes easier to injure by light in old age, for some of the same reasons that the infants retina is susceptible.

The fetus accumulates a very large amount of iron, and it absorbs melatonin from the maternal circulation. Prolactin is sometimes elevated in the newborn. Premature babies are often given extra oxygen, which tends to cause vasoconstriction by displacing carbon dioxide. Melatonins ability to cause vasoconstriction means that stress makes supplemental oxygen more toxic. Synthetic glucocorticoids are often given to premature babies, adding to the risk of retinal damage.

When the mother has been given iron supplements during pregnancy, along with unsaturated oils in the diet, the baby is likely to be born with a vitamin E deficiency and suppressed thyroid function, increasing the probability that it will be jaundiced, leading to treatment of the jaundice with exposure to very bright light.

Although Yandell Henderson had already, in 1928, explained the need for carbon dioxide to be used with oxygen for resuscitating infants or adults, medical researchers and hospital workers could never accept the idea, probably because of a fundamental misunderstanding of the Henderson-Hasselbalch equation. Animal experiments show that supplemental oxygen, without carbon dioxide, causes vasoconstriction, reducing the tissues supply of glucose as well as oxygen. In combination with too much light, especially blue light, it damages the retina. At hyperbaric pressure, oxygen causes seizures, as well as damage to the lungs and other tissues.

The contribution of bright light to retinal damage in babies has been denied in several recent publications, and these articles undoubtedly provide useful material for defense lawyers to use when hospitals are sued for causing blindness. One publication based on experiments with kittens concludes that bright light does not harm the newborns retina, but the comparison is between continuous light and intermittent light, rather than between bright light and dim light. Twelve hours of total darkness, rather than sparing the eye by reducing its exposure to light, would sensitize the eye. The only reason such appalling things can be published is that their conclusions protect the hospitals.

A few good studies of the effect of bright light on the retina, and the fact that dark-skinned people with more protective pigment in their eyes have a lower incidence of retinopathy of prematurity, make it clear that the ordinary laws of physics and chemistry actually do apply to the infant eye.

Light and stress, especially with excess iron, damage the retina when the cells contain too much PUFA, since these fats react with light and free radicals. The nocturnal/stress hormones, especially prolactin and melatonin, make the retina more sensitive to light, and more easily damaged. (It's too much darkness that sets up the problem, since the eyes will adapt to excess light, but darkness increases their sensitivity.)

The use of lasers to operate on eyes produces intense inflammation of the eye, but even at low dose the diffusing light causes retinal/macular damage.

Cytochrome oxidase is one of the enzymes damaged by stress and by blue light, and activated or restored by red light, thyroid, and progesterone. It's a copper enzyme, so it's likely to be damaged by excess iron. It is most active when it is associated with a mitochondrial lipid, cardiolipin, that contains saturated palmitic acid; the substitution of polyunsaturated fats lowers its activity. Mitochonrial function in general is poisoned by the unsaturated fats, especially arachidonic acid and DHA.

Creating a deficiency of DHA, even when an oil of known toxicity is used to replace the omega -3 oils, prevents retinal damage from light. Despite evidence of this sort, Mead Johnson is going ahead with the marketing of its baby formula containing added DHA which is industrially extracted from algae. (Although the researchers who claim that DHA is beneficial havent answered my letters, a representative of the company that manufactures it did answer my question about the actual composition of the oil, and acknowledged that they dont have any idea what the minor ingredients might be.)

When animals are made deficient in all the exogenous polyunsaturated fatty acids, linoleic and arachidonic acid as well as linolenic and DHA, they become remarkably resistant to all sorts of stress and toxins.

The polyunsaturated fats make the lungs more sensitive to excess oxygen or hyperventilation, they make the eyes more sensitive to light, and they make the brain more sensitive to fatigue.

The use of synthetic glucocorticoid hormone is standard in treating very premature babies, although it is known to contribute to eye damage. This is because it is considered necessary to improve the lung function of premature babies with respiratory distress. But there is no clear evidence that it is beneficial for lung function in the long run, and very clear evidence that it damages the brain and other organs. There is widespread agreement regarding the use of the glucocorticoids prenatally to accelerate lung development in women who seem likely to deliver prematurely. Natural cortisol is a factor that promotes lung development prenatally. But cortisol is also a signal produced by a stressed fetus, that triggers the birth process. Cortisol, or the synthetic glucocorticoid, inhibits progesterone production, and stimulates estrogen production, activating uterine contractions and other processes that terminate the pregnancy.

Apparently, it doesnt occur to many people that administering the glucocorticoid triggers premature birth, creating the problem they are intending to treat.

Recognizing causal connections between premature birth and respiratory distress and retinopathy of prematurity, it would be obvious that the greatest effort should be made to prevent the problems by improving the health of pregnant women. Hospitals, however, are invested in high technology systems for treating these problems, and even though their results are dismal, they cant make money by getting pregnant women to eat enough protein to prevent preeclampsia, which is a major cause of premature birth, or by treating the problems with salt, magnesium, progesterone, thyroid, and aspirin when the women havent had a good diet.

Historically, preeclampsia has been blamed on the mothers or fetuss bad genes, and that cultural bias was the setting in which these high technology prenatal and neonatal systems developed. High technology neonatology derives from the same ideology that motivated Josef Mengeles genetic research in Auschwitz. The idea of genetic determination is still motivating resistance to reasonable preventive approaches.

Thyroid, i.e., T3, is very effective in accelerating lung development in the fetus, and it doesnt have any of the harmful effects of the synthetic glucocorticoids. It normalizes the hormones, increasing progesterone and decreasing estrogen, which are needed for full-term gestation, the opposite of the glucocorticoids effects. While the cortisol-like drugs damage the brain and other organs, thyroid and progesterone protect them.

Old organisms, like newborns, are easily injured by all sorts of inappropriate excitation. As in premature babies, the aged eyes, lungs, and brain are especially sensitive to damage by stress. But all organs are subject to the same kinds of damage. Medical treatments for respiratory distress and macular degeneration in old people are often the same as those used so inappropriately for babies. The good health practices that can prevent the inflammatory and degenerative diseases can often make it possible for damaged tissues to recover, even in old age.

The pituitary hormones, especially prolactin and TSH, are pro-inflammatory, and darkness increases TSH along with prolactin, so to compensate for a light deficiency, the pituitary should be well-suppressed by adequate thyroid. Armour thyroid or Thyrolar or Cynoplus, Cytomel, would probably be helpful. (Eye-drops containing T3 might be a way to restore metabolic activity more quickly.) Limiting water intake (or using salt generously) helps to inhibit prolactin secretion. The saturated fats protect against the body's stored PUFA, and keeping the blood sugar up keeps the stored fats from being mobilized. Aspirin (or indomethacin) is generally protective to the retina, analogously to its protection against sunburn. Adequate vitamin E is extremely important. There are several prescription drugs that protect against serotonin excess, but thyroid and gelatin (or glycine, as in magnesium glycinate) are protective against the serotonin and melatonin toxicities. Copper and magnesium deficiencies predispose to retinal damage. Red light is protective, blue light (or u.v.) is harmful, so wearing orange lenses would be helpful. Progesterone and pregnenolone, by reducing the stress reactions, should be helpful--in the eye diseases of infancy and old age, as they are in the respiratory distress syndromes.

REFERENCES

Eksp Klin Farmakol 1999 Mar-Apr; 62(2):58-60. [Melatonin lowers the threshold of light sensitivity of the human retina] ; Arushanian EB, Ovanesov KB. Department of Pharmacology, Stavropol State Medical Academy, Russia. After chronic use of melatonin (3 mg before night-time for 14 days) campimetry showed a significant decrease of the threshold of brilliance sensitiveness of the retina in the absence of authentic changes of the sensorimotor response latency in individuals of the older age group. A connection between the eye light sensitivity and the direct effect of the hormone on the photoreceptors is suggested.

Cochrane Database Syst Rev 2001;4:CD001077. Restricted versus liberal oxygen exposure for preventing morbidity and mortality in preterm or low birth weight infants (Cochrane Review). Askie LM, Henderson-Smart DJ.

Prog Clin Biol Res 1989;312:95-112. The metabolism of omega-3 polyunsaturated fatty acids in the eye: the possible role of docosahexaenoic acid and docosanoids in retinal physiology and ocular pathology. Bazan NG.

Biull Eksp Biol Med 1976 Oct;82(10):1181-3. [Role of the biological activity of serotonin in the production of the "shock lung" syndrome.] ; Bazarevich GI, Deviataev AM, Likhtenshtein AO, Natsvlishvili BP, Sadeko MK.

Invest Ophthalmol Vis Sci 1993 Sep;34(10):2878-80. An elevated hematogenous photosensitizer in the preterm neonate. Bynoe LA, Gottsch JD, Sadda SR, Panton RW, Haller EM, Gleason CA.

Eur J Endocrinol 1995 Dec;133(6):691-5. Melatonin enhances cortisol levels in aged but not young women. Cagnacci A, Soldani R, Yen SS

Am J Psychiatry 1976 Oct;133(10):1181-6. Negative effects of melatonin on depression. Carman JS, Post RM, Buswell R, Goodwin FK. In order to test the efficacy of the pineal neurohumor melatonin on depression, the hormone was administered in varying doses to six moderately to severely depressed patients and two patients with Huntington's chorea in double-blind crossover study. Melatonin exacerbated symptoms of dysphoria in these patients, as well as causing a loss of sleep and weight and a drop in oral temperature. Melatonin increased cerebrospinal fluid 5-hydroxyindoleacetic acid and calcium in three of four patients studied. The authors discuss the implications of this finding.

Neuroendocrinol Lett 2001 Dec;22(6):432-4. Melatonin shortens the survival rate of Ehrlich ascites-inoculated mice. Catrina SB, Curca E, Catrina AI, Radu C, Coculescu M. Dept. Endocrinology II, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania. sergiu-bogdan.catrina@molmed.ki.se The average survival rate of the animals treated with melatonin was shorter (14.8+/-2.23 days) compared to control animals (21.9+/-2.21 days)(p=0.01). CONCLUSION: In our model, melatonin had a deleterious effect on the survival rate raising the question whether it is correct to assume that the hormone shows lack of adverse reactions.

J Neurochem 1988 Apr;50(4):1185-93. Induction of intracellular superoxide radical formation by arachidonic acid and by polyunsaturated fatty acids in primary astrocytic cultures. Chan PH, Chen SF, Yu AC.

Graefes Arch Clin Exp Ophthalmol 1993 Jul;231(7):416-23. Inhibition of cytochrome oxidase and blue-light damage in rat retina. Chen E. St. Erik's Eye Hospital, Karolinska Institute, Stockholm, Sweden. The activity of cytochrome oxidase, outer nuclear layer thickness, and edema were quantitatively evaluated in the blue-light exposed rat retina. Dark-adapted or cyclic-light reared rats were exposed to blue light with a retinal dose of 380 kJ/m2. Immediately, 1, 2, and 3 day(s) after exposure, the retinas of six rats from each adaptation group were examined. There was no difference between the dark-adapted and cyclic-light reared rats. Immediately after light exposure, cytochrome oxidase activity decreased. The activity in the inner segments remained low at day 1, while severe edema was observed in the inner and outer segments. The outer nuclear layer thickness decreased 1-3 days after exposure. The blue-light exposure inhibited cytochrome oxidase activity and caused retinal injury. Similarity of the injury process in the dark-adapted and cyclic-light reared retinas suggests that rhodopsin was not involved. The inhibition of cytochrome oxidase could be a cause of retinal damage.

Acta Ophthalmol Suppl 1993;(208):1-50. Inhibition of enzymes by short-wave optical radiation and its effect on the retina. Chen E. Eye Laboratory, St. Erik's Eye Hospital, Stockholm, Sweden. Exposure to short-wave optical radiation is a potential hazard for vision. In the present study, blue-light damage is studied in rat retina. Blue light inhibited cytochrome oxidase at a retinal dose of about 110 kJ/m2. This inhibition was reversible, and is probably related to the light regulation of retinal metabolism. At a retinal dose of about 380 kJ/m2, the inhibition of cytochrome oxidase was followed consecutively by a probable redistribution of chlorine and potassium in the inner and outer segments, damage to the mitochondria in the inner segments, edema in the inner and outer segments, and progressive degeneration of photoreceptor cells. Dark adaptation did not increase the blue-light retinal injury. These findings support the hypothesis that inhibition of cytochrome oxidase is one of the causes of blue-light retinal damage.

Aust N Z J Ophthalmol 1997 May;25 Suppl 1:S73-5. Retinal control of scleral precursor synthesis. Devadas M, Morgan

Eur J Pharmacol 1990 Jul 3;182(2):313-25. Antidepressant-like activity of the melatonin receptor antagonist, luzindole (N-0774), in the mouse behavioral despair test. Dubocovich ML, Mogilnicka E, Areso PM.

J Pharmacol Exp Ther 1988 Sep;246(3):902-10. Luzindole (N-0774): a novel melatonin receptor antagonist. Dubocovich ML.

Exp Eye Res 1985 Oct;41(4):497-507. The diurnal susceptibility of rat retinal photoreceptors to light-induced damage. Duncan TE, O'Steen WK. Exposure of albino rats to high intensity light results in rapid, graded loss of photoreceptors. The hormonal status and age of an animal at the time of exposure affect the severity of light-induced retinal damage. The adrenal axis and pituitary hormones (prolactin) have been demonstrated previously to affect the degree of cell death in the retina. Because circadian rhythms for adrenal and pituitary secretion have been demonstrated in the rat, a series of experiments was undertaken to determine if a diurnal pattern of retinal susceptibility to light damage exists which might be related to endogenous endocrine rhythms. Male Sprague-Dawley rats were exposed to 4 hr of high intensity fluorescent light for 8 consecutive days during different phases of the 14:10 hr light: dark animal room light cycle. Morphometric analysis performed at the light microscopic level 2 weeks after exposure demonstrated a differential susceptibility to light-induced cell death depending upon the period during the light-dark cycle when animals received their daily light exposure. Neuronal cell death was confined to the outer nuclear layer as previously described. The retinas of animals exposed during the middle of the dark period or during the first 5 hr of the light period were significantly more damaged than the retinas of animals exposed during the last 9 hr of the light period. Control groups for the relative amounts of dark-adaptation between groups suggested that the diurnal susceptibility to light damage was not solely dependent upon the degree of dark adaptation. These results demonstrate a diurnal susceptibility of photoreceptors to light-induced cell death.

Nature 1983 Dec 22-1984 Jan 4;306(5945):782-4. Melatonin is a potent modulator of dopamine release in the retina. Dubocovich ML.

Semin Perinatol 2000 Aug;24(4):291-8. Environmental light and the preterm infant. Fielder AR, Moseley MJ. The lighting environment of the preterm baby is quite unlike that experienced at any other time of life. Physical and physiological factors control how much light reaches the retina of the preterm baby. With respect to the former, although many neonatal intensive care units are brightly and continuously lit, there is a trend to employ lower levels of illumination and to introduce cycling regimens. Physiological determinants of the retinal light dose include: eyelid opening and transmission, pupil diameter and the transmission characteristics of the ocular media. Early exposure to light does not significantly hasten or retard normal visual development, and it is not a factor in the development of retinopathy of prematurity. However, ambient neonatal intensive care unit illumination may be implicated in some of the more subtle visual pathway sequelae that cannot be attributed to other major complications of preterm birth including altered visual functions and arrested eye growth.

Pediatrics 1992 Apr;89(4 Pt 1):648-53. Light and retinopathy of prematurity: does retinal location offer a clue? Fielder AR, Robinson J, Shaw DE, Ng YK, Moseley MJ. Nursery illumination has been implicated in the pathogenesis of retinopathy of prematurity (ROP), although the results of recent studies are conflicting. The data base for this article is a prospective ROP study on 607 infants of birth weight less than or equal to 1700 g including 35 larger siblings from multiple births when 1 infant fulfilled the birth weight criteria. Retinopathy commences preferentially in the nasal retina of the most immature neonate and is less likely to develop, or its onset is delayed, in the superior and inferior regions. These findings cannot be fully accounted for by regional vascular and neuroanatomical variations. Radiometric and physiological evidence suggests that the very immature neonate, most at risk of developing severe ROP, receives the greatest retinal irradiance. Furthermore, ROP commences in the areas of the retina receiving the highest light dose, and its onset is either retarded or inhibited in the darker retinal regions. Further studies are required to determine whether early exposure to light is a factor in the development of ROP. If a causal relationship is proven, here at least is one modality that can easily and immediately be controlled.

N Engl J Med 1985 Aug 15;313(7):401-4. Effect of bright light in the hospital nursery on the incidence of retinopathy of prematurity. Glass P, Avery GB, Subramanian KN, Keys MP, Sostek AM, Friendly DS. The preterm infant is subjected to prolonged exposure to ambient nursery illumination at levels that have been found to produce retinal damage in animals. We prospectively investigated the effect of exposure to light in two intensive care nurseries by comparing the incidence of retinopathy of prematurity among 74 infants from the standard bright nursery environment (median light level, 60 foot-candles [ftc]) with the incidence among 154 infants of similar birth weight for whom the light levels were reduced (median, 25 ftc). There was a higher incidence of retinopathy of prematurity in the group of infants who had been exposed to the brighter nursery lights, particularly in those with birth weights below 1000 g (86 percent vs. 54 per cent, P less than 0.01 by chi-square test). We conclude that the high level of ambient illumination commonly found in the hospital nursery may be one factor contributing to retinopathy of prematurity and that safety standards with regard to current lighting practices should be reassessed.

Doc Ophthalmol 1990 Mar;74(3):195-203. Light and the developing retina. Glass P. George Washington University School of Medicine & Health Sciences, Washington, DC. Retinopathy of prematurity (ROP) has increased in the United States in the past decade.

Pediatr Res 1987 Oct;22(4):414-6. Calcemic responses to photic and pharmacologic manipulation of serum melatonin. Hakanson DO, Penny R, Bergstrom WH.

Pediatr Res 1990 Jun;27(6):571-3. Pineal and adrenal effects on calcium homeostasis in the rat. Hakanson DO, Bergstrom WH.

Science 1981 Nov 13;214(4522):807-9. Phototherapy-induced hypocalcemia in newborn rats: prevention by melatonin. Hakanson DO, Bergstrom WH.

Doc Ophthalmol 1992;79(2):141-50. Diurnal variations in the electroretinographic c-wave and retinal melatonin content in rats with inherited retinal dystrophy. Hawlina M, Jenkins HG, Ikeda H.

J.A.M.A. 90:353 (Feb. 25) 1928. The Prevention and Treatment of Asphyxia in the New-Born, Henderson, Yandell.

Neuroendocrinology 2001 Feb;73(2):111-22. Estrogen modulates alpha(1)/beta-adrenoceptor- induced signaling and melatonin production in female rat pinealocytes. Hernandez-Diaz FJ, Sanchez JJ, Abreu P, Lopez-Coviella I, Tabares L, Prieto L, Alonso R.

J Neurosci Res 1989 Oct;24(2):247-50. Brain mitochondrial swelling induced by arachidonic acid and other long chain free fatty acids. Hillered L, Chan PH.

J Neurosci Res 1988;19(1):94-100. Effects of arachidonic acid on respiratory activities in isolated brain mitochondria. Hillered L, Chan PH.

J Neurosci Res 1988 Aug;20(4):451-6. Role of arachidonic acid and other free fatty acids in mitochondrial dysfunction in brain ischemia. Hillered L, Chan PH.

J Neurosci Res 1989 Oct;24(2):247-50. Brain mitochondrial swelling induced by arachidonic acid and other long chain free fatty acids. Hillered L, Chan PH.

J Clin Epidemiol 1992 Nov;45(11):1265-87. Oxygen as a cause of blindness in premature infants: "autopsy" of a decade of errors in clinical epidemiologic research. Jacobson RM, Feinstein AR. Clinical Epidemiology Unit, Yale University School of Medicine, New Haven, CT 06510. Several intellectual "autopsies" have recently reviewed errors in clinical epidemiologic studies of causation, such as the original claim that amyl nitrite "poppers" caused AIDS. The current autopsy was done to determine why it took more than a decade--1942 to 1954--to end an iatrogenic epidemic in which high-dose oxygen therapy led to retrolental fibroplasia (RLF) in premature infants, blinding about 10,000 of them. The autopsy revealed a museum of diverse intellectual pathology.

Curr Eye Res 2001 Jul;23(1):11-9. Rod outer segments mediate mitochondrial DNA damage and apoptosis in human retinal pigment epithelium. Jin GF, Hurst JS, Godley BF.

Endocrinol Exp 1976 Jun;10(2):131-7. Diurnal variation in the effect of melatonin on plasma and muscle free fatty acid levels in the pigeon. John TM, George JC. Pigeons maintained on standard diet and held under 12 h daily photo-period in a controlled environmental room, were given intravenous injections of melatonin. A low dose (1.25 mg/kg body weight) of melatonin when given in the middle of the scotophase, produced a significant increase in plasma FFA when estimated at 20 min and 90 min post-injection, whereas no significant change was seen with injections given in the middle of the photophase. No significant change in muscle FFA level was obtained either during the photophase or the scotophase when estimated at 90 min postinjection. With a higher dose (5 mg/kg body weight) of melatonin given in the scotophase, on the other hand, a significant increase in both plasma as well as muscle FFA levels was obtained at 90 min post-injection but there was no effect on plasma FFA at 20 min or 90 min post-injection in the photophase and at 20 min in the scotophase. It is concluded that melatonin has a lipid mobilizing action in the pigeon when administered during the scotophase.

Arch Int Physiol Biochim 1983 Jul;91(2):115-20. Diurnal impact of locomotory activity and melatonin and N-acetylserotonin treatment on blood metabolite levels in the rainbow trout. John TM, Beamish FW, George JC. In rainbow trout forced to swim continuously at sustained speeds for six weeks, selected doses of melatonin or N-acetylserotonin (1.25 and 5.0 mg/kg body weight) injections caused no change in haematocrit. Melatonin did not produce any significant change in plasma glucose level either in the photophase or in the scotophase. However, diurnal variations were observed in the effect of melatonin on plasma free fatty acids (FFA). Melatonin was ineffective in causing any change in plasma FFA level during photophase but during scotophase, the higher dose (5.0 mg/kg) produced an increase in FFA while the lower dose (1.25 mg/kg) had no effect, N-acetylserotonin administration produced diurnal variation in its effect on both plasma glucose and FFA. The higher dose of N-acetylserotonin brought about a drop in plasma glucose level during photophase, but both doses were ineffective during scotophase. N-acetylserotonin produced no change in FFA during photophase, but during scotophase tended to lower FFA level. It is suggested that exercise shortens the time required to cause a hypoglycemic effect of N-acetylserotonin during photophase, blocks FFA release-inhibiting action of melatonin observed in photophase, and minimizes the time required for the FFA mobilizing action of melatonin in scotophase.

J Neural Transm 1977;40(2):87-97. The adrenal medulla may mediate the increase in pineal melatonin synthesis induced by stress, but not that caused by exposure to darkness. Lynch HJ, Ho M, Wurtman RJ.

Bull Acad Natl Med 2000;184(2):415-28; discussion 428-30. [Pulmonary toxicity of oxygen] [Article in French] Mantz JM, Stoeckel ME.

Br J Pharmacol 1977 Dec;61(4):607-14. The action of melatonin on single amphibian pigment cells in tissue culture. Messenger EA, Warner AE.

Oftalmol Zh 1989;(8):469-73. [The early diagnosis, evaluation of treatment results and modelling of certain aspects of the pathogenesis of retinal dystrophy] ; Mironova EM, Pavlova ON, Ronkina TI. The paper analyses results after a study of the functional state of pigmented epithelium and the retina in patients with a dry form of senile macular dystrophy as well as of experimental simulation of retinal dystrophy with the help of melatonin and its treatment by taurine. Melatonin in 10(-3) M concentration leads to development of dystrophic changes in pigmented epithelium and interacting with it structures, this being testified by remarkable lowering of EOG parameters and electron microscopic findings. Taurine in 10(-3) M concentration blocks the action of exogenic melatonin as well as has a pronounced positive action on metabolism of dystrophic changes in the pigmented epithelium and photoreceptors. Examination of patients with different stages of a dry form of senile macular dystrophy revealed statistically significant reduction of KA cEOG at the initial stage of the disease in the presence of normal ERG parameters. In 18% of patients, supernormal values of KA were recorded, that are likely to reflect the presence of "predystrophic hyperactivity" of the pigmented epithelium cells. In progression of the process, the further reduction of electrophysiologic values was recorded. The data obtained speaks about the important role of pigmented epithelium pathology in the pathogenesis of senile macular dystrophy and about high information value of the cEOG method for detection of early stages of the disease. It is believed that disturbances in melatonin metabolism can be one of causes leading to development of retinal dystrophy.

J Clin Endocrinol Metab 1977 Oct;45(4):768-74. The effects of oral melatonin on skin color and on the release of pituitary hormones. Nordlund JJ, Lerner AB. We studied the effects of prolonged ingestion of melatonin, 1 g per day, on skin color and the serum levels of pituitary hormones in 5 human subjects with hyperpigmented skin. Melatonin lightened hyperpigmented skin of one patient with untreated adrenogenital syndrome, but had no effect on three patients' skin with idiopathic hyperpigmentation and one patient with treated Addison's disease.

Invest Ophthalmol 1976 Oct;15(10):869-72. Hormonal influences on photoreceptor damage: the pituitary gland and ovaries. Olafson RP, O'Steen WK. To determine whether the absence of pituitary or ovarian hormones would influence retinal degeneration, female albino rats were either hypophysectomized (HYPEX) or ovariectomized (OVEX) before pubery. Later, they were exposed to continuous light for periods up to 45 days. Retinas evaluated by light microscopic measurements showed damage to the outer nuclear layer (ONL) and photoreceptor layer in both the operated and intact, control rats. However, the degree of damage observed in retinas of HYPEX and OVEX rats was significantly less than that observed in retinas of intact rats exposed to the same lighting conditions. Therefore, hypophysectomy and ovariectomy, which influence the normal development of sexual maturation when performed on immature rats, significantly reduce photoreceptor damage in adult rats exposed to continuous light.

Invest Ophthalmol Vis Sci 1996 Oct;37(11):2243-57. Retinal light damage in rats with altered levels of rod outer segment docosahexaenoate. Organisciak DT, Darrow RM, Jiang YL, Blanks JC. PURPOSE: To compare retinal light damage in rats with either normal or reduced levels of rod outer segment (ROS) docosahexaenoic acid. METHODS: Weanling male albino rats were maintained in a weak cyclic light environment and fed either a nonpurified control diet or a purified diet deficient in the linolenic acid precursor of docosahexaenoic acid (DHA). Half the rats on the deficient diet were given linseed oil, containing more than 50 mol% linolenic acid, once a week to maintain ROS DHA at near normal levels. Diets and linseed oil supplementation were continued for 7 to 12 weeks. To replenish DHA in their ROS, some 10-week-old rats on the deficient diet were given linseed oil three times a week for up to 3 additional weeks. Groups of animals were killed at various times for ROS fatty acid determinations or were exposed to intense green light using intermittent or hyperthermic light treatments. The extent of retinal light damage was determined biochemically by rhodopsin or photoreceptor cell DNA measurements 2 weeks after exposure and morphologically by light and electron microscopy at various times after light treatment. RESULTS: Rats maintained for 7 to 12 weeks on the linolenic acid-deficient diet had significantly lower levels of DHA and significantly higher levels of n-6 docosapentaenoic acid (22:5n-6) in their ROS than deficient-diet animals supplemented once a week with linseed oil or those fed the nonpurified control diet. As determined by rhodopsin levels and photoreceptor cell DNA measurements, deficient diet rats exhibited protection against retinal damage from either intermittent or hyperthermic light exposure. However, the unsaturated fatty acid content of ROS from all three dietary groups was the same and greater than 60 mol%. In 10 week-old deficient-diet rats given linseed oil three times a week, ROS DHA was unchanged for the first 10 days, whereas 22:5n-6 levels declined by 50%. After 3 weeks of treatment with linseed oil, ROS DHA and 22:5n-6 were nearly the same as in rats supplemented with linseed oil from weaning. The time course of susceptibility to retinal light damage, however, was different. Hyperthermic light damage in rats given linseed oil for only 2 days was the same as for rats always fed the deficient diet. Six days after the start of linseed oil treatment, retinal light damage was the same as in rats given the linseed oil supplement from weaning. Morphologic alterations in ROS of linseed oil-supplemented rats immediately after intermittent light exposure were more extensive than in either the deficient-diet animals or those fed the control diet. The deficient-diet rats also exhibited better preservation of photoreceptor cell nuclei and structure 2 weeks after exposure. CONCLUSIONS: Rats fed a diet deficient in the linolenic acid precursor of DHA are protected against experimental retinal light damage. The relationship between retinal light damage and ROS lipids does not depend on the total unsaturated fatty acid content of ROS; the damage appears to be related to the relative levels of DHA and 22:5n-6.

Exp Neurol 1970 May;27(2):194-205. Retinal and optic nerve serotonin and retinal degeneration as influenced by photoperiod. O'Steen WK.

Invest Ophthalmol Vis Sci 1982 Jan;22(1):1-7. Antagonistic effects of adrenalectomy and ether/surgical stress on light-induced photoreceptor damage. O'Steen WK, Donnelly JE. Light-induced damage to retinal photoreceptors in influenced by the endocrine status of the animal during the period of exposure. Experimental manipulation of the pituitary gland and of prolactin levels has been shown to affect retinal damage in rats exposed to visible light. When rats are experimentally stressed, prolactin secretion from the pituitary gland occurs as does secretion of adrenocorticotropic hormone (ACTH), which stimulates the release of adrenal cortical hormones. Since prolactin appears to influence retinal damage and since stressed animals have increased serum levels of prolactin, a comparison of photoreceptor damage in animals in which the adrenal glands were removed or which had been experimentally stressed was undertaken in this study. Adrenalectomized rats had thicker outer nuclear layer (ONL) measurements than those found in sham-operated animals. Stressed rats had severely damaged retinas with cystic degeneration and significantly reduced ONL thickness measurements as compared to retinas of unstressed and adrenalectomized rats. Therefore hormones of the pituitary-adrenal system appear to be involved in the damage to the retina by light, and this response may be related to an interaction or synergism between the adrenal gland, stress, and prolactin secretion.

Brain Res 1990 Nov 26;534(1-2):99-105. Water deprivation protects photoreceptors against light damage. O'Steen WK, Bare DJ, Tytell M, Morris M, Gower DJ. Photoreceptor cell death after light-damage and during aging in rats is associated with the hormonal status of the animal, as well as other environmental and intrinsic factors. Restricted caloric intake extends the life of rodents and is usually accompanied by a reduction in water consumption. In this study, male and female rats were placed on restricted water intake for either 3 or 7 days to induce dehydration. Photoreceptor cells of 7-day, dehydrated male and female rats survived light-damage significantly better than those allowed water ad libitum; however, after 3 days of water restriction, only the male rats demonstrated protection from photodamage. AVP increased by 350% during the 7-day period of dehydration. Protection of photoreceptors from light-damage in this study may be correlated with osmotically stimulated changes in the retinas of dehydrated animals.

Brain Res 1985 Oct 7;344(2):231-9. Neuronal damage in the rat retina after chronic stress. O'Steen WK, Brodish A. Long-term exposure to escapable foot shock has been used to determine if chronic stress influences neuronal cell death in the retina of albino and pigmented rats. Histopathologic and morphometric approaches analyzed changes in photoreceptors and neurons of the bipolar and ganglion cell layers of the retina. Albino Fischer rats when exposed to chronic stress for 4-8 h daily for 1 week to 6 months, developed severe retinal damage, as compared to unstressed control retinas, with reduction in photoreceptor and bipolar neurons, particularly in the superior central retina. The damage was observed in male and female rats, but males appeared to be more susceptible to the influence of stress than female animals. Ganglion cells were unaffected. Photoreceptor destruction did not occur in Long-Evans pigmented rats under identical experimental conditions. The results suggest that: input of the sensory stimulus, light, to the retina of stressed rats augmented neuronal damage and might be required for its initiation; and hormones and/or neurotransmitters associated with long-term chronic stress might be related to increased neuronal cell death in the mammalian retina.

Invest Ophthalmol Vis Sci 1977 Oct;16(10):940-6. Effects of hypophysectomy, pituitary gland homogenates and transplants, and prolactin on photoreceptor destruction. O'Steen WK, Kraeer SL. Prepubertal removal of the pituitary gland, which in young animals influences sexual maturation, reduces significantly the amount of retinal photoreceptor destruction when the rats are exposed to continuous illumination in adulthood. When crude pituitary gland homogenate is administered to adult rats hypophysectomized prior to puberty, photoreceptor destruction is more severe. Transplantation of whole pituitary glands to the kidney capsule of hypophysectomized rats also reduces the effect of pituitary gland removal and results in more extensive damage to receptor cells than found in hypophysectomized, adult animals. Hypophysectomized rats treated with prolactin had more severe retinal damage than untreated, hypophysectomized rats. Results of these studies indicate the hormones of the pituitary gland have a regulatory influence on the severity of light-induced, retinal photoreceptor damage in the rat.

Life Sci 1985 Nov 4;37(18):1743-6. Stress-induced synthesis of melatonin: possible involvement of the endogenous monoamine oxidase inhibitor (tribulin). Oxenkrug GF, McIntyre IM.

Mech Ageing Dev 2000 Jan 10;112(3):169-83. Double bond content of phospholipids and lipid peroxidation negatively correlate with maximum longevity in the heart of mammals. Pamplona R, Portero-Otin M, Ruiz C, Gredilla R, Herrero A, Barja G.

Prostaglandins Leukot Essent Fatty Acids 2001 Feb;64(2):75-80. Comparative studies on lipid peroxidation of microsomes and mitochondria obtained from different rat tissues: effect of retinyl palmitate. Piergiacomi VA, Palacios A, Catala A.

Curr Eye Res 1992 Oct;11(10):939-53. Oxygen-induced retinopathy in the rat: hemorrhages and dysplasias may lead to retinal detachment. Penn JS, Tolman BL, Lowery LA, Koutz CA.

Vision Res 1995 May;35(9):1247-64. Studies on the role of the retinal dopamine/melatonin system in experimental refractive errors in chickens. Schaeffel F, Bartmann M, Hagel G, Zrenner E.

Exp Clin Endocrinol Diabetes 1997;105(2): 109-12. Melatonin and serotonin regulate the release of insulin-like growth factor-I, oxytocin and progesterone by cultured human granulosa cells. Schaeffer HJ, Sirotkin AV.

Zh Evol Biokhim Fiziol 1989 Jan-Feb;25(1):52-9. [Seasonal characteristics of the functioning of the hypophysis-gonad system in the suslik Citellus parryi] Shvareva NV, Nevretdinova ZG. In females, FSH was found in the blood in October, being absent from November to January; beginning from February, it may be found both in sleeping and active animals. Estradiol secretion was noted in hibernating females, whereas progesterone was found in the blood only in May.

J Pineal Res 1985;2(1):39-49. Melatonin and N-acetylserotonin stress responses: effects of type of stimulation and housing conditions. Seggie J, Campbell L, Brown GM, Grota LJ.

Acta Ophthalmol Scand 2001 Aug;79(4):428-30. Presumed sertraline maculopathy. Sener EC, Kiratli H.

Paediatr Perinat Epidemiol 1999 Apr;13(2):128-30. Effects of premature exposure to light: a credibility struggle. Silverman WA.

J Pineal Res 1994 Oct;17(3):112-7. Direct influence of melatonin on steroid, nonapeptide hormones, and cyclic nucleotide secretion by granulosa cells isolated from porcine ovaries. Sirotkin AV. It was found that melatonin is able to inhibit progesterone and stimulate estradiol secretion. The present observations suggest a direct effect of melatonin on the steroid, nonapeptide hormone, and cyclic nucleotide release from porcine ovarian cells.

J Pineal Res 1994 Oct;17(3):112-7. Direct influence of melatonin on steroid, nonapeptide hormones, and cyclic nucleotide secretion by granulosa cells isolated from porcine ovaries. Sirotkin AV.

Prog Clin Biol Res 1989;312:229-49. Inhibitors of the arachidonic acid cascade in the management of ocular inflammation. Srinivasan BD, Kulkarni PS.

J Nutr 2000 Dec;130(12):3028-33. Polyunsaturated (n-3) fatty acids susceptible to peroxidation are increased in plasma and tissue lipids of rats fed docosahexaenoic acid-containing oils. Song JH, Fujimoto K, Miyazawa T. Thus, high incorporation of (n-3) fatty acids (mainly DHA) into plasma and tissue lipids due to DHA-containing oil ingestion may undesirably affect tissues by enhancing susceptibility of membranes to lipid peroxidation and by disrupting the antioxidant system.

Acta Ophthalmol (Copenh) 1992 Feb;70(1):115-22. Effects of steady electric fields on human retinal pigment epithelial cell orientation and migration in culture. Sulik GL, Soong HK, Chang PC, Parkinson WC, Elner SG, Elner VM

Ned Tijdschr Geneeskd 2001 Dec 29;145(52):2521-5. [Administration of glucocorticosteroids to premature infants: increasing evidence of adverse effects] [Article in Dutch] van Bel F. Neonatal glucocorticosteroid therapy is increasingly being used for the prevention of chronic lung disease in very premature infants. In the short term this therapy is usually successful. There is, however, increasing evidence for long-term adverse effects. In particular there seems to be an increased chance of abnormal brain development, which later results in locomotory dysfunction, developmental delay and cerebral palsy.

Brain Res 1984 Feb 27;294(1):166-8. Pineal methoxyindoles depress calcium uptake by rat brain synaptosomes. Vacas MI, Keller Sarmiento MI, Cardinali DP.

Ann N Y Acad Sci 1994 Nov 17;738:408-18. Serotonin binding proteins: an in vitro model system for monoamine-related neurotoxicity. Vauquelin G, Del Rio MJ, Pardo CV.

J Hypertens Suppl 1985 Dec;3 Suppl 3:S107-9. Seasonal variation in the development of stress-induced systolic hypertension in the rat. Weinstock M, Blotnick S, Segal M. Seasonal variation in blood pressure in human hypertensives prompted us to investigate whether such a phenomenon also occurs in rats made hypertensive by environmental stress. Systolic pressure increased by 14-25 mmHg after 6-8 weeks of stress from October to January. Artificial environmental light for 15 h prevented development of hypertension by stress, which could also be reversed by acute administration of propranolol. Hypertensive rats had significantly greater relative heart and adrenal weights. This phenomenon can be explained by amplification of sympathetic pressor activity by stress hormones, adrenaline, corticosterone and prolactin, under the influence of melatonin.

Invest Ophthalmol Vis Sci 1992 May;33(6):1894-902. Melatonin increases photoreceptor susceptibility to light-induced damage. Wiechmann AF, O'Steen WK. Pinealectomy has been shown to protect photoreceptors from light-induced damage, and melatonin treatment has been reported to increase the degree of photoreceptor damage in albino rats. The animals that received daily melatonin injections (100 micrograms) in the late afternoon (3 hr before lights off) for 1-3 days before photodamage showed an approximate 30% greater reduction compared with sham control animals in ONL thickness in the superior quadrant, the area most susceptible to light damage. Melatonin injections given after the photodamage did not affect ONL thickness. Although retinal susceptibility to light damage varied with time of day, the degree to which melatonin increased the degree of damage appeared unaffected by the time of day. These results suggest that melatonin may be involved in some aspects of photoreceptor sensitivity to light damage.

J Neurochem 1986 Oct;47(4):1181-9. Effects of arachidonic acid on glutamate and gamma-aminobutyric acid uptake in primary cultures of rat cerebral cortical astrocytes and neurons. Yu AC, Chan PH, Fishman RA.

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<span class="koboSpan" id="kobo.1.1">Altitude and Mortality</span> A R T I C L E

Altitude and Mortality

Breathing pure oxygen lowers the oxygen content of tissues; breathing rarefied air, or air with carbon dioxide, oxygenates and energizes the tissues; if this seems upside down, it's because medical physiology has been taught upside down. And respiratory physiology holds the key to the special functions of all the organs, and to many of their basic pathological changes.

Stress, shock, inflammation, aging, and organ failure are, in important ways, respiratory problems.

Definitions Haldane effect: Oxygen displaces carbon dioxide from hemoglobin, in proportion to its partial (specific) pressure. Bohr effect: Carbon dioxide (or acidity) displaces oxygen from hemoglobin. Lactic acidemia: The presence of lactic acid in the blood. Alkalosis: A pH of the blood above 7.4. Acidosis: A blood pH below 7.4. Lactate paradox: The reduced production of lactic acid at a given work rate at high altitude. Muscle work efficiency may be 50% greater at high altitude. ATP wastage is decreased.

There are some popular medical ideas that obstruct clear thinking about respiration. One is that high altitude deprives you of oxygen, and is likely to be bad for people with heart disease and cancer. Another is that breathing pure oxygen helps sick people to oxygenate their tissues while exerting less effort in breathing. These are both exactly wrong, and the errors have been explored in quite a few publications, but the ideas persist in the culture to such a degree that our perceptions and intuitions have been misled, making closely related things seem to be unrelated. In this culture, it is hard to see that heart disease, cancer, and cataracts all involve a crucial respiratory defect, with the production of too much lactic acid and too little carbon dioxide, which leads to a swelling pathology: A pathological retention of water. The swollen heart beats poorly, the swollen lens turns milky, other cells divide rapidly as a result of swelling.

People who live at very high altitudes live significantly longer; they have a lower incidence of cancer (Weinberg, et al., 1987) and heart disease (Mortimer, et al., 1977), and other degenerative conditions, than people who live near sea level. As I have written earlier, I think the lower energy transfer from cosmic radiation is likely to be a factor in their longevity, but several kinds of evidence indicate that it is the lower oxygen pressure itself that makes the biggest contribution to their longevity.

Mountain sickness is a potentially deadly condition that develops in some people when they ascend too rapidly to a high altitude. Edema of the lungs and brain can develop rapidly, leading to convulsions and death. The standard drug for preventing it is acetazolamide, which inhibits carbonic anhydrase and causes carbon dioxide to be retained, creating a slight tendency toward acidosis. This treatment probably mimics the retention of carbon dioxide that occurs naturally in altitude adapted people. The reasons for mountain sickness, and the reasons for the low incidence of heart disease, cancer, cataracts, etc., at high altitude, offer clues to the prevention of death and deterioration from many other causes.

When the weather in a particular place is cool, sunny and dry (which in itself is very good for the health) the atmospheric pressure usually is higher than average. Although sunny dry weather is healthful, periods of higher pressure correspond to an increased incidence of death from heart disease and strokes.

The Haldane-Bohr effect describes the fact that oxygen and carbon dioxide destabilize each others binding to hemoglobin. When oxygen pressure is high, the blood releases its carbon dioxide more easily. In stormy weather, or at high altitude, the lower oxygen pressure allows the body to retain more carbon dioxide. Carbon dioxide, produced in the cells, releases oxygen into the tissues, relaxes blood vessels, prevents edema, eliminates ammonia, and increases the efficiency of oxidative metabolism.

Hyperventilation, breathing excessively and causing too much carbon dioxide to be lost, is similar to being in the presence of too much oxygen; its similar to being at low altitude with high atmospheric pressure, only worse. Therefore, the physiological events produced by hyperventilation can give us an insight into what happens when the atmospheric pressure is low, by looking at the events in reverse. Likewise, breathing 100% oxygen has known harmful consequences, which are very similar to those produced by hyperventilation.

Hyperventilation is defined as breathing enough to produce respiratory alkalosis from the loss of carbon dioxide. Lactic acid is produced in response to the alkalosis of hyperventilation.

Breathing too much oxygen displaces too much carbon dioxide, provoking an increase in lactic acid; too much lactate displaces both oxygen and carbon dioxide. Lactate itself tends to suppress respiration.

Oxygen toxicity and hyperventilation create a systemic deficiency of carbon dioxide. It is this carbon dioxide deficiency that makes breathing more difficult in pure oxygen, that impairs the hearts ability to work, and that increases the resistance of blood vessels, impairing circulation and oxygen delivery to tissues. In conditions that permit greater carbon dioxide retention, circulation is improved and the heart works more effectively. Carbon dioxide inhibits the production of lactic acid, and lactic acid lowers carbon dioxide's concentratrion in a variety of ways..

When carbon dioxide production is low, because of hypothyroidism, there will usually be some lactate entering the blood even at rest, because adrenalin and noradrenalin are produced in large amounts to compensate for hypothyroidism, and the adrenergic stimulation, besides mobilizing glucose from the glycogen stores, stimulates the production of lactate. The excess production of lactate displaces carbon dioxide from the blood, partly as a compensation for acidity. The increased impulse to breath (ventilatory drive) produced by adrenalin makes the problem worse, and lactate can promote the adrenergic response, in a vicious circle..

Since the 1920s when A. V. Hill proposed that the prolonged increase in oxygen consumption after a short period of intense work, the oxygen debt, was equivalent to the amount of lactic acid that had entered the circulation from the muscles anaerobic work, and that it had to be disposed of by oxidative processes, physiology textbooks have given the impression that lactic acid accumulation was exactly the same as the oxygen debt. In reality, several things are involved, especially the elevation of temperature produced by the intense work. Increased temperature raises oxygen consumption independently of lactic acid, and lower temperature decreases oxygen consump-tion, even when lactic acid is present.

The idea of the oxygen debt produced by exercise or stress as being equivalent to the accumulation of lactic acid is far from accurate, but its true that activity increases the need for oxygen, and also increases the tendency to accumulate lactic acid, which can then be disposed of over an extended time, with the consumption of oxygen. This relationship between work and lactic acidemia and oxygen deficit led to the term lactate paradox to describe the lower production of lactic acid during maximal work at high altitude when people are adapted to the altiude. Carbon dioxide, retained through the Haldane effect, accounts for the lactate paradox, by inhibiting cellular excitation and sustaining oxidative metabolism to consume lactate efficiently.

The loss of carbon dioxide from the lungs in the presence of high oxygen pressure, the shift toward alkalosis, by the Bohr-Haldane effect increases the bloods affinity for oxygen, and restricts its delivery to the tissues, but because of the abundance of oxygen in the lungs, the blood is almost competely saturated with oxygen.

At high altitude, the slight tendency toward carbon dioxide-retention acidosis decreases the bloods affinity for oxygen, making it more available to the tissues. It happens that lactic acid also affects the bloods oxygen affinity, though not as strongly as carbon dioxide. However, lactic acid doesnt vaporize as the blood passes through the lungs, so its effect on the lungs ability to oxygenate the blood is the opposite of the easily exchangeable carbon dioxides. Besides dissociating oxygen from hemoglobin, lactate also displaces carbon dioxide from its (carbamino) binding sites on hemoglobin. If it does this in hemoglobin, it probably does it in many other places in the body.

According to Meerson, ascending more than 200 feet per day produces measurable stress. People seldom notice the effects of ascending a few thousand feet in a day, but it has been found that a large proportion of people have bleeding into the retina when they ascend to 10,000 feet without adequate adaptation. Presumably, similar symptomless bleeding occurs in other organs, but the retina can be easily inspected.

If hypothyroid people, with increased adrenalin and lactate, are hyperventilating even at rest and at sea level, when they go to a high altitude where less oxygen is available, and their absorption of oxygen is impaired by lactic acidemia, their oxygen debt, conceived as circulating lactic acid, is easily increased, intensifying their already excessive ventilatory drive, and in proportion to the lactic acid oxygen debt, oxygen absorption is further inhibited.

The lactic acid has to be disposed of, but their ability to extract oxygen is reduced. The poor oxygenation, and the increased lactic acid and free fatty acids cause blood vessels to become leaky, producing edema in the lungs and brain. This is very similar to the multiple organ failure that occurs in inflammatory conditions, bacteremia, congestive heart failure, cancer, and trauma.

Otto Warburg established that lactic acid production even in the presence of oxygen is a fundamental property of cancer. It is, to a great degree, the lactic acid which triggers the defensive reactions of the organism, leading to tissue wasting from excessive glucocorticoid hormone. The cancers production of lactic acid creates the same kind of internal imbalance produced by hyperventilation, and if we look at the physiology of hyperventilation in the light of Warburgs description of cancer, hyperventilation imitates cancer metabolism, by producing lactic acid even in the presence of oxygen. Lactate, a supposedly benign metabolite of the cancer cells, which appears in all the other degenerative conditions, including obesity, diabetes, Alzheimers disease, multiple sclerosis, is itself a central factor in the degenerative process.

Working out the mechanisms involved in susceptibility to altitude sickness will clarify the issues involved in the things that cause most people to die. At first, all of these changes occur in the regulatory systems, and so can be corrected.

The vitality of the mitochondria, their capacity for oxidative energy production, is influenced by nutrition and hormones. In healthy people, mitochondria work efficiently at almost any altitude, but people with damaged or poorly regulated mitochondria are extremely susceptible to stress and hyperventilation. Progesterone, testosterone, and thyroid (T3 and T2) are protective of normal mitochondrial function, by both local and systemic effects.

The changes that occur in malnutrition and hypothyroidism affect the mitochondria in a multitude of ways, besides the local effects of the thyroid and progesterone deficiency.

Increased estrogen, nitric oxide, excitatory amino acids, cortisol, lactate, free unsaturated fatty acids, prolactin, growth hormone, histamine, serotonin, tumor necrosis factor and other pro-inflammatory cytokines and kinins, and a variety of prostaglandins and eicosanoids, have been identified as anti-mitochondrial, anti-respiratory agents. Edema itself can be counted among these agents. (Carbon dioxide itself directly reduces tissue edema, as can be seen in studies of the cornea.) Thyroid, progesterone, magnesium, glucose, and saturated fatty acids are among the central protective elements.

The similarity of the changes occurring under the influence of estrogen excess, oxygen deprivation, aging, and ionizing radiation are remarkable. People who think that radiations biological effects are mainly on the DNA, and that estrogen acts through estrogen receptors, arent interested in the parallels, but the idea of a common respiratory defect, activating common pathways, suggests that there is something useful in the perception that irradiation, hypoxia, and aging have estrogenic effects.

Irradiation by ultraviolet, gamma, or x-rays, and even by blue light, is damaging to mitochondrial respiration. All of the ionizing radiations produce immediate and lingering edema, which continues to damage metabolism in a more or less permanent way, apart from any detectable mutagenic actions. The amount of water taken up following irradiation can be 20% to 30% of the normal weight, which is similar to the amount of swelling that intense work produces in a muscle, and to the weight increase under hormonal imbalances. The energy changes produced by irradiation in, for example, the heart, appear to accelerate the changes produced by aging. Since unsaturated fats accumulate in the respiratory system with aging, and are targets for radiation damage, the involvement of these fats in all sorts of antirespiratory degenerative processes deserves more attention. Darkness, like irradiation, excess lactate, and unsaturated fats, has the diabetes-like effect of greatly reducing the ability of muscle to absorb sugar, while light stimulates respiration..

When the ideas of stress, respiratory defect, and hyperventilation are considered together, they seem practically interchangeable.

The presence of lactic acid, which indicates stress or defective respiration, interferes with energy metabolism in ways that tend to be self-promoting. Harry Rubins experiments demonstrated that cells become cancerous before genetic changes appear. The mere presence of lactic acid can make cells more susceptible to the transformation into cancer cells. (Mothersill, et al., 1983.) The implications of this for the increased susceptibility to cancer during stress, and for the increased resistance to cancer at high altitude, are obvious.

Blocking the production of lactic acid can make cells more resistant (Seymour and Mothersill, 1988); if lactic acid were merely a useful fuel, its hard to see how poisoning its formation could improve cell survival. But it happens to be an energy-disruptive fuel, interfering with carbon dioxide metabolism, among other things.

Hyperventilation is present in hypothyroidism, and is driven by adrenalin, lactate, and free fatty acids. Free fatty acids and lactate impair glucose use, and promote edema, especially in the lungs. Edema in the lungs limits oxygen absorption. Swelling of the brain, resulting from increased vascular permeability and the entry of free fatty acids, reduces its circulation and oxygenation; lactic acidemia causes swelling of glial cells. Swelling of the endothelium increases vascular resistance by making the channel narrower, eventually affecting all organs. Cells of the immune system release tumor necrosis factor and other inflammatory cytokines, and the bowel becomes more permeable, allowing endotoxin and even bacteria to enter the blood. Endotoxin impairs mitochondria, increases estrogen levels, causes Kupffer cells in the liver to produce more tumor necrosis factor, etc.. Despite its name, tumor necrosis factor stimulates the growth and metastasis of some types of cancer. Dilution of the body fluids, which occurs in hypothyroidsim, hyperestrogenism, etc., stimulates tumor growth.

The inflammatory factors that can promote cell growth can, with just slight variation, deplete cellular energy to the extent that the cells die from the energetic cost of the repair process, or mutate from defective repairs. Niacinamide can have an antiinflammatory function, preventing death from multiple organ failure, by interupting the reactions to nitric oxide and peroxynitrile (Cuzzocrea, et al., 1999). The cells type, environment, and history determine the different outcomes.

Cataracts, cancer, congestive heart failure, seemingly such different degenerative problems, have the same sort of metabolic problem, leading to the abnormal absorption of water by cells, disrupting their normal functions.

The same simple metabolic therapies, such as thyroid, progesterone, magnesium, and carbon dioxide, are appropriate for a great range of seemingly different diseases. Other biochemicals, such as adenosine and niacinamide, have more specific protective effects, farther downstream in the "cascade" effects of stress.

There are many little cliches in the medical culture that prevent serious thought about integral therapy: Progesterone is the pregnancy hormone, thyroid makes your heart work too hard, thyroid uncouples mitochondrial phosphorylation, magnesium has nothing to do with thyroid or progesterone, lactate provides energy, etc. But many of these minor cliches are held in place by deep theoretical errors about the nature of cells and organisms. Once those have been corrected, there should be progress toward more powerful integral therapies.

REFERENCES

Cell Biol Int Rep 1983 Nov;7(11):971-80. Lactate-mediated changes in growth morphology and transformation frequency of irradiated C3H 10T1/2 cells. Mothersill C, Seymour CB, Moriarty M. Treatment of mammalian cells with lactate or inhibitors of glycolysis alters their radiation response, particularly in the low dose region of the dose response curve. The occurrence of both high lactate levels and high glycolytic metabolism in tumours is well known and therefore the effect of lactate on a cell line sensitive to radiation induced transformation was examined using a single exposure to Cobalt 60 gamma rays as the carcinogen challenge. The results indicate that cells treated with 5mM lactate before irradiation exhibit changes in morphology and growth rate and that the transformation frequency is increased by three to ten fold following 24 hours lactate treatment just prior to irradiation. Examination of radiation survival curves showed a positive correlation between transformation frequency and size of the shoulder, but increasing transformation frequency was associated with a decrease in Do. A mechanism involving altered Redox potential in lactate treated cells is suggested. The results are discussed in terms of their possible significance for radiotherapy.

Radiat Environ Biophys 1988;27(1):49-57. The effect of glycolysis inhibitors on the radiation response of CHO-K1 cells. Seymour CB, Mothersill C Saint Luke's Hospital, Rathgar, Dublin, Ireland. Exposure of CHO-K1 cells to three different inhibitors of glycolysis, prior to treatment with a single dose of ionising radiation, reduced their survival. The effects were concentration-dependent but occurred under all conditions where cells were exposed to the inhibitors prior to irradiation. The results are similar to those obtained by this group when glycolysis was altered using analogues of D-glucose or by blocking the pyruvate----lactate reaction using added lactate or oxamate. They support data from other workers suggesting a role for energy metabolism in the final expression of radiation damage.

Crit Care Med 1999 Aug;27(8):1517-23. Protective effect of poly(ADP-ribose) synthetase inhibition on multiple organ failure after zymosan-induced peritonitis in the rat. Cuzzocrea S, Zingarelli B, Costantino G, Sottile A, Teti D, Caputi AP

Eur J Cancer 1975 May;11(5):365-371. Cancer and altitude. Does intracellular pH regulate cell division? Burton AC.

Monaldi Arch Chest Dis 1999 Aug;54(4):365-72. The pathophysiology of hyperventilation syndrome. Folgering H. Dept Pulmonology Dekkerswald, University of Nijmegen, Groesbeek, The Netherlands.. Hyperventilation is defined as breathing in excess of the metabolic needs of the body, eliminating more carbon dioxide than is produced, and, consequently, resulting in respiratory alkalosis and an elevated blood pH. The traditional definition of hyperventilation syndrome describes "a syndrome, characterized by a variety of somatic symptoms induced by physiologically inappropriate hyperventilation and usually reproduced by voluntary hyperventilation". The spectrum of symptoms ascribed to hyperventilation syndrome is extremely broad, aspecific and varying. They stem from virtually every tract, and can be caused by physiological mechanisms such as low Pa,CO2, or the increased sympathetic adrenergic tone. Psychological mechanisms also contribute to the symptomatology, or even generate some of the symptoms. Taking the traditional definition of hyperventilation syndrome as a starting point, there should be three elements to the diagnostic criterion: 1) the patient should hyperventilate and have low Pa,CO2, 2) somatic diseases causing hyperventilation should have been excluded, and 3) the patient should have a number of complaints which are, or have been, related to the hypocapnia. Recent studies have questioned the tight relationship between hypocapnia and complaints. However, the latter can be maintained and/or elicited when situations in the absence of hypocapnia in which the first hyperventilation and hypocapnia was present recur. Thus, the main approach to diagnosis is the detection of signs of (possible) dysregulation of breathing leading to hypocapnia. The therapeutic approach to hyperventilation syndrome has several stages and/or degrees of intervention: psychological counselling, physiotherapy and relaxation, and finally drug therapy. Depending on the severity of the problem, one or more therapeutic strategies can be chosen.

N Engl J Med 1977 Mar 17;296(11):581-585. Reduction in mortality from coronary heart disease in men residing at high altitude. Mortimer EA Jr, Monson RR, MacMahon B In New Mexico, where inhabited areas vary from 914 to over 2135 m above sea level, we compared age-adjusted mortality rates for arteriosclerotic heart disease for white men and women for the years 1957-1970 in five sets of counties, grouped by altitude in 305-m (1000-foot) increments. The results show a serial decline in mortality from the lowest to the highest altitude for males but not for females. Mortality rates for males residing in the county groups higher than 1220 m in order of ascending altitude were 98, 90, 86 and 72 per cent of that for the county group below 1220-m altitude (P less than 0.0001). The results do not appear to be explained by artifacts in ascertainment, variations in ethnicity or urbanization. A possible explanation of the trend is that adjustment to residence at high altitude is incomplete and daily activities therefore represent greater exercise than when undertaken at lower altitudes.

Br Med J 1980 Jan 5;280(6206):5. Cardiovascular mortality and altitude.

Radiat Res 1987 Nov;112(2):381-390. Altitude, radiation, and mortality from cancer and heart disease. Weinberg CR, Brown KG, Hoel DG. The variation in background radiation levels is an important source of information for estimating human risks associated with low-level exposure to ionizing radiation. Several studies conducted in the United States, correlating mortality rates for cancer with estimated background radiation levels, found an unexpected inverse relationship. Such results have been interpreted as suggesting that low levels of ionizing radiation may actually confer some benefit. An environmental factor strongly correlated with background radiation is altitude. Since there are important physiological adaptations associated with breathing thinner air, such changes may themselves influence risk. We therefore fit models that simultaneously incorporated altitude and background radiation as predictors of mortality. The negative correlations with background radiation seen for mortality from arteriosclerotic heart disease and cancers of the lung, the intestine, and the breast disappeared or became positive once altitude was included in the models. By contrast, the significant negative correlations with altitude persisted with adjustment for radiation. Interpretation of these results is problematic, but recent evidence implicating reactive forms of oxygen in carcinogenesis and atherosclerosis may be relevant. We conclude that the cancer correlational studies carried out in the United States using vital statistics data do not in themselves demonstrate a lack of carcinogenic effect of low radiation levels, and that reduced oxygen pressure of inspired air may be protective against certain causes of death.

Biull Eksp Biol Med 1993 Jun;115(6):576-578. [The effect of high-altitude ecological and experimental stresses on the thrombocyte-vascular wall system]. [Article in Russian]. Bekbolotova AK, Lemeshenko VA, Aliev MA. Experiments in animals (rats) and examinations of the population of high-altitude shepherds were used to study the functional system "Thrombocytes-Vessel Wall" (STVW) for evaluation of the organism ecological adaptation to "pure" high-altitude stress, with and without combination with experimental-adrenergic cardionecrosogenic stress (ACNS, in rats). The adaptive increase of antiaggregation prostacyclin activity of the aorta in rats and PGI2 reaction of vessels in human population of high-altitude in mountains (2000, 3000-3500 m) were found to be a common biologist regularity. The adaptive increase of coronary reserve of the heart and vasodilatator-antiaggregation status in high-altitude shepherds correlated with an increase of antiaggregation activity of the aorta and decrease of spontaneous aggregation of the thrombocytes in rats under conditions of more prolonged adaptation to high-altitude ecological stress.

Diabetologia 1982 Jun;22(6):493. Measurement of glycosylated haemoglobin at high altitudes. Paisey R, Valles V, Arredondo G, Wong B, Lozano-Castaneda O.

[Change in the ultrastructure of rat myocardium under the influence of 12-months' adaptation to high altitude] Zhaparov B; Mirrakhimov MM. Biull Eksp Biol Med, 1977 Jul, 84:7, 109-12. The right and left ventricle myocardium of rats was studied in the course of a 12-month period of adaptation to high altitude (3200 m above the sea level). A long-term exposure of the animals to the high altitude led the development of ventricular hypertrophy mostly of the right, and partly of the left ventricle. Hyperplasia and hypertrophy of individual organellae, particularly mitochondria, were found in most cardiomyocytes of both ventricles. In animals adapted to the high altitude the mitochondrial succinic dehydrogenase activity was more pronounced than in control ones. The results obtained testified to the enhanced intracellular metabolism reflecting myocardial compensatory adaptive responses.

[Morphologic characteristics of the hearts of argali continuously dwelling at high mountain altitudes], Zhaparov B; Kamitov SKh; Mirrakhimov MM, Biull Eksp Biol Med, 1980 Apr, 89:4, 498-501 The hearts of argali [wild sheep] living at 3800-5000 m above the sea level were examined. Macroscopy showed complete absence of fatty tissue under the epicardium. Increased number of the capillaries surrounding cardiomyocytes, intercalated discs in many zones of the myocardium, sharp thickening giving pronounced cross lines of myofibrils were revealed on semithin and ultrathin sections. The data obtained demonstrate specificity of the heart structure of argali and are discussed from the standpoint of increased compensatory-adaptive changes in the test organ, these changes being associated with its enhanced function provoked by high altitude conditions.

J Dev Physiol 1990 Sep;14(3):139-46. Effect of lactate and beta-hydroxybutyrate infusions on brain metabolism in the fetal sheep. Harding JE, Charlton VE Department of Pediatrics, University of California, San Francisco 94143. Brain uptake of substrates other than glucose has been demonstrated in neonatal but not fetal animals in vivo. This study was undertaken to investigate the ability of the fetal sheep brain to use potential alternative substrates when they were provided in increased amounts. Brain substrate uptake was measured in chronically catheterised fetal sheep during 2-h infusions of neutralised lactate (n = 12) or beta-hydroxybutyrate (n = 12). Despite large increases in fetal arterial lactate and beta-hydroxybutyrate during the respective infusions, no significant uptake of either substrate was demonstrated. However during both types of infusion, the brain arterio-venous difference for glucose decreased 30% (P less than 0.05). Since the brain arterio-venous difference for oxygen was unchanged, and blood flow to the cerebral hemispheres (measured in 11 studies) was also unchanged, the infusions appeared to cause a true decrease in brain glucose uptake. This decrease paralleled the rise in lactate concentration during lactate infusions, and the rise in lactate and butyrate concentrations during the butyrate infusions. Both substrates have metabolic actions that may inhibit brain glucose uptake. We speculate that the deleterious effects of high lactate and ketone states in the perinatal period may in part be due to inhibition of brain glucose uptake.

Hypertens 1995 Feb;9(2):119-22. Pressor effect of hyperventilation in healthy subjects. Todd GP, Chadwick IG, Yeo WW, Jackson PR, Ramsay LE University Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield, UK Hyperventilation is an important feature of panic disorder, and an association has been reported between panic disorder and hypertension. We have examined the effect of hyperventilation on the blood pressure (BP) of healthy subjects. Twenty six subjects were randomised in a balanced two-period cross-over study to compare the effects of hyperventilation with that of normal breathing on sitting BP, heart rate and the electrocardiogram. Each study phase lasted 40 min, with 15 min of baseline observation, 5 min of hyperventilation or normal breathing, and 20 min of continued observation. Hyperventilation significantly increased SBP by 8.9 mm Hg (95% CI 3.8-13.8, P < 0.01), diastolic blood pressure by 8.2 mm Hg (95% CI 1.7-14.7, P < 0.05), mean arterial pressure by 10.0 mm Hg (95% CI 3.3-16.7, P < 0.01) and heart rate by 36 beats/min (95% CI 31-44, P < 0.01). The changes in diastolic and mean arterial pressure correlated significantly with the total volume of air expired during hyperventilation (r = 0.57, p < 0.01 and r = 0.50 P < 0.01, Arch Biol Med Exp (Santiago) 1989 Dec;22(4):379-85 Pulmonary response to free fatty acid intravenous infusion in the rabbit: role of leukotrienes and the effect of prostacyclin. Arenas G, Del Buono R, Oyarzun MJ, Donoso P, Quijada D Departamento de Ciencias Preclinicas, Facultad de Medicina, Universidad de Chile, Santiago. Intravenous infusion of free fatty acid (FFA) 20 mg.kg-1.min-1 produces pulmonary edema, hypoxemia, hyperventilation and increase in the alveolar surfactant content in rabbits in less than 15 min.

Respiration 1986;49(3):187-94. Role of hypocapnia in the alveolar surfactant increase induced by free fatty acid intravenous infusion in the rabbit. Oyarzun MJ, Donoso P, Quijada D. Intravenous infusion of free fatty acid (FFA) produces an increase in the alveolar surfactant pool of the rabbit and pulmonary edema, hyperventilation, hypoxemia and hypocapnia. Previous studies suggested that alveolar PCO2 would be a regulator of intracellular storages of surfactant. In order to study the role of hypocapnia in the increase of lung surfactant in our experiments we administered 20 mg FFA X kg-1 X min-1 i.v. to rabbits breathing room air (n = 10) or 5% CO2, 21% O2, 74% N2 (n = 7). Disaturated phosphatidylcholine (DSPC) was determined in bronchial-alveolar lavage fluid as index of alveolar surfactant content, 5% CO2 in the inspired air prevented the hypocapnia and blocked the increase in DSPC induced by FFA (p less than 0.01). Pulmonary edema post-FFA was not changed by 5% CO2 administration. We conclude that hypocapnia produced by hyperventilation during FFA infusion would be an important factor in the increase of DSPC observed after FFA infusion.

Farmakol Toksikol 1977. Sep-Oct; 40(5):620-3.. [Effect of combinations of apressin, obsidan, diprazin, adenosine, NAD and nicotinamide on the resistance of rats to hypoxia and on carbohydrate metabolic indices]. [Article in Russian] Abakumov GZ As evidenced from experiments on rats, a combined application of apressin with obsidan and diprazine, and also of adenozine with nicotine-amidadenine-dinucleotide (NAD), as well as of adeozine with nicotine amide potentiates the protective effect of these substances in hypobaric hypoxia, increases the resistance of the animals to cerebral ischemia, brings down the excess lactate level and raises the redoz potential of the system lactic-acid-pyruvic acid in the brain of rats exposed to the effects of rarefied atmosphere.

Schweiz Med Wochenschr 1977 Nov 5;107(44):1585-6. [Protective effect of pyridoxilate on the hypoxic myocardium. Experimental studies]. [Article in French] Moret PR, Lutzen U The protective action of piridoxilate on hypoxic myocardium has been studied on rats in acute hypoxia (isolated heart, perfused with a non-oxygenated solution) and in prolonged hypoxia (3 days at high [3454 m] altitude). Piridoxilate maintained a higher ATP level with a much lower production of lactate. The mechanisms of action of piridoxilate are probably fairly similar to those of Na dichloracetate.

J. Appl Physiol 1991 Apr;70(4):1720-30. .Metabolic and work efficiencies during exercise in Andean natives. Hochachka PW, Stanley C, Matheson GO, McKenzie DC, Allen PS, Parkhouse WS Department of Zoology, University of British Columbia, Vancouver, Canada. Maximum O2 and CO2 fluxes during exercise were less perturbed by hypoxia in Quechua natives from the Andes than in lowlanders. In exploring how this was achieved, we found that, for a given work rate, Quechua highlanders at 4,200 m accumulated substantially less lactate than lowlanders at sea level normoxia (approximately 5-7 vs. 10-14 mM) despite hypobaric hypoxia. This phenomenon, known as the lactate paradox, was entirely refractory to normoxia-hypoxia transitions. In lowlanders, the lactate paradox is an acclimation; however, in Quechuas, the lactate paradox is an expression of metabolic organization that did not deacclimate, at least over the 6-wk period of our study. Thus it was concluded that this metabolic organization is a developmentally or genetically fixed characteristic selected because of the efficiency advantage of aerobic metabolism (high ATP yield per mol of substrate metabolized) compared with anaerobic glycolysis. Measurements of respiratory quotient indicated preferential use of carbohydrate as fuel for muscle work, which is also advantageous in hypoxia because it maximizes the yield of ATP per mol of O2 consumed. Finally, minimizing the cost of muscle work was also reflected in energetic efficiency as classically defined (power output per metabolic power input); this was evident at all work rates but was most pronounced at submaximal work rates (efficiency approximately 1.5 times higher than in lowlander athletes). Because plots of power output vs. metabolic power input did not extrapolate to the origin, it was concluded 1) that exercise in both groups sustained a significant ATP expenditure not convertible to mechanical work but 2) that this expenditure was downregulated in Andean natives by thus far unexplained mechanisms.

Br J Anaesth 1975 Jun;47(6):669-78. Effect of CO2 on myocardial contractility and aortic input impedance during anaesthesia. Foex P, Prys-Roberts C. The haemodynamic responses to hypocapnia and hypercapnia have been studied in the dog during intermittent positive pressure ventilation under halothane anaesthesia (1% halothane in oxygen) and under nitrous oxide anaesthesia (30% oxygen in nitrous oxide). In the absence of significant variations of either myocardial contractility or left ventricular end-diastolic pressure, the changes of stroke volume and cardiac output (diminution because of hypocapnia, augmentation because of hypercapnia) were determined by alterations of systemic vascular resistance (augmentation because of hypocapnia, diminution because of hypercapnia).

J Appl Physiol 1991 May;70(5):1963-76. Skeletal muscle metabolism and work capacity: a 31P-NMR study of Andean natives and lowlanders. Matheson GO, Allen PS, Ellinger DC, Hanstock CC, Gheorghiu D, McKenzie DC, Stanley C, Parkhouse WS, Hochachka PW Sports Medicine Division, University of British Columbia, Vancouver, Canada. Two metabolic features of altitude-adapted humans are the maximal O2 consumption (VO2max) paradox (higher work rates following acclimatization without increases in VO2max) and the lactate paradox (progressive reductions in muscle and blood lactate with exercise at increasing altitude). To

J Hum Hypertens 1995 Feb;9(2):119-22. Pressor effect of hyperventilation in healthy subjects.Todd GP, Chadwick IG, Yeo WW, Jackson PR, Ramsay LE.

J Infect Dis 1998 May;177(5):1418-21.The effect of lactic acid on mononuclear cell secretion of proinflammatory cytokines in response to group B streptococci. Steele PM, Augustine NH, Hill HR Department of Pathology, University of Utah School of Medicine, Salt Lake City 84132, USA.This study found that lactate alone had a stimulatory effect (207.1 +/- 16.3%; P = .001) on tumor necrosis factor (TNF)-alpha production by human mononuclear cells with the most profound secretion being at pathologic concentrations of 4-8 mM lactate. Furthermore, exposure of these mononuclear cells to group B streptococci (GBS, 10(5) cfu) resulted in TNF-alpha production of up to 621.1 +/- 42% of control; the combination of lactic acid and GBS increased TNF-alpha production up to 1019.3 +/- 16.1% (P = .001). The combination of GBS and lactate also enhanced the secretion of interleukin (IL)-1beta and IL-6. Lactate in pathologic concentrations, therefore, likely enhances the secretion of these inflammatory mediators and contributes to septic shock and meningitis caused by GBS.

J Appl Physiol 1994 Apr;76(4):1462-7. Lactic acidosis as a facilitator of oxyhemoglobin dissociation during exercise. Stringer W, Wasserman K, Casaburi R, Porszasz J, Maehara K, French W.

Involvement of nitric oxide and N-methyl- D-aspartate in acute hypoxic altitude convulsion in mice. Chen CH; Chen AC; Liu HJ. Aviat Space Environ Med, 1997 Apr, 68:4, 296-9. Altitude convulsion is a rather specific form of experimental convulsion which is induced by acute exposure to a hypobaric hypoxic condition. Several neurotransmitters have been shown to be involved in the mechanisms of altitude convulsions. The novel neurotransmitter nitric oxide (NO) may be involved in the mechanisms of altitude convulsion through its neuronal signalling roles in relation to the NMDA receptor. NO synthesis precursor, L-arginine (20, 40, 200, 800 mg/kg), resulted in a dose-dependent decrease in the ACT in mice, while the NO synthase (NOS) inhibitor, NG-nitro-L-arginine-methyl ester (L-NAME, 1.25, 2.50, 5.00 mg/kg, i.p.) increased the ACT. CONCLUSIONS: These findings suggest an important signalling role for nitric oxide and NMDA in the development of altitude convulsion and further support the hypothesized relationship between NMDA-receptor mediated neurotoxicity and nitric oxide.

Excitotoxicity in the lung: N-methyl-D-aspartate- induced, nitric oxide-dependent, pulmonary edema is attenuated by vasoactive intestinal peptide and by inhibitors of poly(ADP-ribose) polymerase. Said SI; Berisha HI; Pakbaz H. Proc Natl Acad Sci U S A, 1996 May 14, 93:10, 4688-92. Excitatory amino acid toxicity, resulting from overactivation of N-methyl-D-aspartate (NMDA) glutamate receptors, is a major mechanism of neuronal cell death in acute and chronic neurological diseases. We have investigated whether excitotoxicity may occur in peripheral organs, causing tissue injury, and report that NMDA receptor activation in perfused, ventilated rat lungs triggered acute injury, marked by increased pressures needed to ventilate and perfuse the lung, and by high-permeability edema." The injury was prevented by competitive NMDA receptor antagonists or by channel-blocker MK-801, and was reduced in the presence of Mg2+. As with NMDA toxicity to central neurons, the lung injury was nitric oxide (NO) dependent: it required L-arginine, was associated with increased production of NO, and was attenuated by either of two NO synthase inhibitors. The neuropeptide vasoactive intestinal peptide and inhibitors of poly(ADP-ribose) polymerase also prevented this injury, but without inhibiting NO synthesis, both acting by inhibiting a toxic action of NO that is critical to tissue injury. The findings indicate that: (i) NMDA receptors exist in the lung (and probably elsewhere outside the central nervous system), (ii) excessive activation of these receptors may provoke acute edematous lung injury as seen in the "adult respiratory distress syndrome," and (iii) this injury can be modulated by blockade of one of three critical steps: NMDA receptor binding, inhibition of NO synthesis, or activation of poly(ADP-ribose) polymerase.

Adenosine modulates N-methyl-D- aspartate- stimulated hippocampal nitric oxide production in vivo. Bhardwaj A; Northington FJ; Koehler RC; Stiefel T; Hanley DF; Traystman RJ. Stroke, 1995 Sep, 26:9, 1627-33. "Adenosine acts presynaptically to inhibit release of excitatory amino acids (EAAs) and is thus considered to be neuroprotective. Because EAA-stimulated synthesis of nitric oxide (NO) may play an important role in long-term potentiation and excitotoxic-mediated injury, we tested the hypotheses that adenosine agonists attenuate basal and EAA-induced NO production in the hippocampus in vivo and that adenosine A1 receptors mediate this response." "...these data are consistent with in vitro results showing that NMDA receptor stimulation enhances NO production. Furthermore, we conclude that stimulation of A1 receptors can attenuate the basal as well as NMDA-induced production of NO. Because NMDA receptor stimulation amplifies glutamate release, our data are consistent with presynaptic A1 receptor-mediated inhibition of EAA release and consequent downregulation of NO production."

Anesthesiology 1993 Jan;78(1):91-9. Hypocapnia worsens arterial blood oxygenation and increases VA/Q heterogeneity in canine pulmonary edema. Domino KB, Lu Y, Eisenstein BL, Hlastala MP. University of Washington Medical School, Seattle. "Hyperventilation frequently is employed to reduce carbon dioxide partial pressure in patients in the operating room and intensive care unit. However the effect of hypocapnia on oxygenation is complex and may result in worsening in patients with preexisting intrapulmonary shunt." "Both hypocapnia and hypercapnia were associated with an increased VA/Q inequality. However, PaO2 decreased and P[A-a]O2 increased with only hypocapnia. These results suggest that hyperventilation to reduce PaCO2 may be detrimental to arterial PO2 in some patients with lung disease."

Acta Anaesthesiol Scand 1996 Jan;40(1):133-4 Hyperlactatemia associated with hypocarbic hyperventilation. Cheung PY

Am J Physiol 1999 May;276(5 Pt 1):E922-9 Hyperlactatemia reduces muscle glucose uptake and GLUT-4 mRNA while increasing (E1alpha)PDH gene expression in rat. Lombardi AM, Fabris R, Bassetto F, Serra R, Leturque A, Federspil G, Girard J, Vettor R Endocrine Metabolic Laboratory, Department of Medical and Surgical Sciences, University of Padova, 35100 Padova, Italy. An increased basal plasma lactate concentration is present in many physiological and pathological conditions, including obesity and diabetes. We previously demonstrated that acute lactate infusion in rats produced a decrease in overall glucose uptake. The present study was carried out to further investigate the effect of lactate on glucose transport and utilization in skeletal muscle. In chronically catheterized rats, a 24-h sodium lactate or bicarbonate infusion was performed. To study glucose uptake in muscle, a bolus of 2-deoxy-[3H]glucose was injected in basal condition and during euglycemic-hyperinsulinemic clamp. Our results show that hyperlactatemia decreased glucose uptake in muscles (i.e., red quadriceps; P < 0.05). Moreover in red muscles, both GLUT-4 mRNA (-30% in red quadriceps and -60% in soleus; P < 0.025) and protein (-40% in red quadriceps; P < 0.05) were decreased, whereas the (E1alpha)pyruvate dehydrogenase (PDH) mRNA was increased (+40% in red quadriceps; P < 0.001) in lactate-infused animals. PDH protein was also increased (4-fold in red gastrocnemius and 2-fold in red quadriceps). These results indicate that chronic hyperlactatemia reduces glucose uptake by affecting the expression of genes involved in glucose metabolism in muscle, suggesting a role for lactate in the development of insulin resistance.

Radiat Res 1993 Apr;134(1):79-85 Effects of in vivo heart irradiation on myocardial energy metabolism in rats. Franken NA, Hollaar L, Bosker FJ, van Ravels FJ, van der Laarse A, Wondergem J Department of Clinical Oncology, University Hospital, Leiden, The Netherlands. To investigate the effect of in vivo heart irradiation on myocardial energy metabolism, we measured myocardial adenosine nucleotide concentrations and mitochondrial oxygen consumption in left ventricular tissue of rats 0-16 months after local heart irradiation (20 Gy). At 24 h and 2 months no difference in myocardial adenosine nucleotide concentration was apparent between irradiated and control hearts. The total myocardial adenosine nucleotide concentrations in irradiated hearts compared to those of nonirradiated controls tended to be lower from 4 months onward. The rate of oxidative energy production (state 3 respiration) in irradiated hearts was significantly reduced ompared with that of age-matched controls from 2 months onward. Moreover, as a result of aging, time-dependent decrease in the rate of oxidative energy production was observed in both rradiated and control hearts (P < 0.001). The respiratory control index (RCI = oxygen consumption n state 3/oxygen consumption in state 4) in irradiated hearts was not different from the RCI easured in age-matched control animals. During the period of study the RCI diminished significantly wth age in both groups (P < 0.005). The number of oxygen atoms used per molecule of ADP phosphorylated (P/O ratio) was not influenced by the irradiation. The P/O ratio for the AD(+)-linked substrates remained unchanged at a value of about 3 during the period studied. At 6 months after irradiation activities of myocardial enzymes such as lactate dehydrogenase, creatine kinase, citrate synthase, and cytochrome c oxidase were reduced. The reduction in myocardial energy production and the changes in energy supplies provide a mechanism to explain impaired contractility after local heart irradiation.

J Radiat Res (Tokyo) 1993 Sep;34(3):195-203. Radiosensitization of human lung fibroblasts by chemical that decrease ATP levels. Kumar A, Kimura H, Aoyama T. "Radiosensitization by lactate, pyruvate, nalidixic acid and novobiocin was studied in exponentially growing SH-18L human lung fibroblasts. All the chemicals had a slight radiosensitizing effect at a low concentration and a definite effect at a higher one." "Fibroblasts incubated with the low concentration of each chemical for 24 hrs after X irradiation showed no reduction in intracellular ATP content, whereas, the higher concentration produced a significant decrease. These observations suggest that the decrease in the ATP content may be involved in the radiosensitization of human fibroblasts at high concentrations of these chemicals. In contrast, radiosensitization at a low concentration is not explained by a relationship to ATP content. Different mechanisms may be involved in radiosensitization at low and high concentrations of these chemicals."

J Exp Med 1993 May 1;177(5):1391-8. Enhancement of experimental metastasis by tumor necrosis factor. Orosz P, Echtenacher B, Falk W, Ruschoff J, Weber D, Mannel D.N. Institute for Immunology and Genetics, German Cancer Research Center, Heidelberg. "The influence of endogenous and exogenous tumor necrosis factor (TNF) on metastasis was investigated in an experimental fibrosarcoma metastasis model." "This effect was time dependent, as administration of rmTNF 5 h before or 1 h but not 24 h after tumor cell inoculation caused an increase of tumor cell colony formation on the lung surface, suggesting an influence of TNF on the vascular adhesion and diapedesis of tumor cells. Since tumor-bearing mice showed an enhanced ability to produce TNF after endotoxin injection compared to control mice, tumor-bearing mice were treated with anti-mTNF antibodies. Neutralization of endogenous tumor-induced TNF led to a significant decrease of the number of pulmonary metastases. Histological analysis of micrometastases in the lung on day 5 by silver staining of proteins associated with nucleolar organizer regions revealed more metastatic foci and augmented proliferative activity of the tumor cells after rmTNF pretreatment of mice. However, no direct effect of rmTNF on the proliferation rate of tumor cells was seen in vitro."

Nippon Geka Gakkai Zasshi 1996 Sep;97(9):726-32. [Energy substrate metabolism during stress]. Sugimoto H. Department of Traumatology and Critical Care Medicine, Osaka University School of Medicine, Suita, Japan. "Energy substrate metabolism during stress is characterized by increased REE (resting energy expenditure), hyperglycemia, hyperlactatemia and protein catabolism. This stress-induced hypermetabolic responses are closely related to increased secretion of neurohormonal and cytokine mediators. The insulin resistance hyperglycemia has been called "stress diabetes" or 'surgical diabetes.' Glucose disposal has been thought to be impaired in this condition." "This hyperglycemia in stress diabetes results from a postreceptor mechanism. Stress hyperlactatemia is thought to be caused by decreased pyruvate dehydrogenase activity rather than tissue hypoperfusion."

Clin Physiol 1995 Nov;15(6):581-95. Effects of lactate infusion on hepatic gluconeogenesis and glycogenolysis. Haesler E, Schneiter P, Temler E, Jequier E, Tappy L.

Cancer Res 1993 Apr. 15;53(8):1939-44.. Tumor necrosis factor alpha as an autocrine and paracrine growth factor for ovarian cancer: monokine induction of tumor cell proliferation and tumor necrosis factor alpha expression. Wu S, Boyer CM, Whitaker RS, Berchuck A, Wiener JR, Weinberg JB, Bast RC Jr.

Klin Med (Mosk) 1989 May;67(5):38-41. ["Dry" carbon dioxide baths in treating patients with myocardial infarction at the sanatorium stage of rehabilitation]. [Article in Russian] Barashkova NL, Kartamysheva NL, Krasnova VP, Kriuchkova LN, Miasoedova E.S. A group of 75 patients with a history of myocardial infarction and repeated myocardial infarction were subjected to treatment involving dry carbon dioxide baths. Its results demonstrated normalization of IHD manifestations, such as coronary and heart failure, functional state of the cardiovascular system, its reserve potentialities and adaptation to physical effort. Under the influence of a course treatment with dry carbon dioxide baths hemodynamic parameters of cardiac output (cardiac and stroke volume) underwent favourable changes, rhythm slowed down, diastole became longer and systolic and diastolic arterial pressure decreased. The data obtained substantiate application of dry carbon dioxide baths in the recovery period to I-III functional classes patients with a history of myocardial infarction.

J Dev Physiol 1989 Nov;12(5):283-6. Haemodynamic effects of respiratory alkalosis independent of changes in airway pressure in anaesthetized newborn dogs. Reuter JH, Donovan EF, Kotagal U.R. "We have recently reported a decrease in cardiac output in newborn dogs during respiratory alkalosis which is independent of changes in airway pressure."

Undersea Hyperb Med 1994 Jun;21(2):169-83. Influence of hyperbaric oxygen on left ventricular contractility, total coronary blood flow, and myocardial oxygen consumption in the conscious dog. Savitt MA, Rankin JS, Elberry JR, Owen CH, Camporesi E.M. "It is known that hyperbaric oxygenation (HBO) decreases total coronary blood flow (TCBF) and cardiac output (CO)."

Heart rhythm disturbances in the inhabitants of mountainous regions. Mirrakhimov MM; Meimanaliev TS Cor Vasa, 1981, 23:5, 359-65. "During exercise heart arrhythmias appeared conspicuously less frequently in the high mountain than in the low altitude inhabitants."

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<span class="koboSpan" id="kobo.1.1">The problem of Alzheimer's disease as a clue to immortality</span> A R T I C L E

The problem of Alzheimer's disease as a clue to immortality - Part 1

I. INTRODUCTION

II. COMMON FACTORS IN INJURY DURING GROWTH AND AGING

III. A VIEW OF ENTROPY--RENEWAL OF THE BRAIN

IV. FALSE SIGNALS FROM THE ENVIRONMENT

A. EDUCATION, DIET AND MEDICINE INTERACT

B. SIGNALS IN THE ABSTRACT

V. HORMONE IMBALANCE, LEADING TO FAILURE OF PROTECTIVE INHIBITION AND ALZHEIMER'S DISEASE

A. THE FUNCTION OF ENERGY

B. EFFECTS OF ESTROGEN AND UNSATURATED FATTY ACIDS

C. VITAMIN A AND STEROIDS

D. THE NATURE OF ALZHEIMER'S DISEASE

E. AN EXAMPLE; DIET AFFECTS HORMONES WHICH AFFECT STRUCTURE AND LEAD TO APPARENT SELF- DESTRUCTION

VI. STRUCTURE AS A REGULATORY SYSTEM--AN EMERGING VISION OF PERVASIVE EPIGENESIS

I. INTRODUCTION

The toxicity of estrogen and of the unsaturated fats has been known for most of the twentieth century, and much has been learned about their interactions in the aging process. The body, during this time, has been understood as a dynamic interaction of cellular trophic influences which govern both form and function. My argument here will be that some of our adaptive, protective regulatory processes are overridden by the excessive supply of unsaturated fats--supported by a few other toxins--in our diet, acting as a false-signal system, and that cholesterol, pregnenolone, and progesterone which are our main long-range defenses, are overcome by the effects of the unsaturated fats, and that the resulting cascade of ineffective and defective reactions (including various estrogen-stimulated processes) leads to lower and lower energy production, reduced function, and death. At certain times, especially childhood and old age, iron (which also has important regulatory roles) accumulates to the point that its signal functions may be inappropriate.

It interacts with estrogen and unsaturated fats in ways that can change restraint and adaptation into sudden self-destruction, apoptotic cell death. If we look at the human organism from one perspective, it seems coherent and intelligible, but from the perspective of established academic biological doctrine, it seems appallingly complex, lacking any visible integrating principle, and as a result simplistic mechanical, pharmaceutical, or religious ideas are increasingly offered to fill the gap. But experimental data can be taken out of the muddle, and put to coherent human use. In what follows, I am acting as though the doctrines of genetic determination and regulation by membranes were mere historical relics. The emerging control systems are now clear enough that we can begin to use them to reverse the degenerative diseases: Alzheimer's dementia, epileptic dementia, arthritis, osteoporosis, depression, hypertension, hardening of the heart and blood vessels, diabetes, and some types of tumor, immunodeficiencies, reflex problems, and special atrophic problems, including clearing of amyloid and mucoid deposits. I think many people experience regenerative age-regressing when many circumstances are just right; for example, taking a trip to the mountains in the spring with friends can optimize several basic regulatory systems.

II. COMMON FACTORS IN BRAIN INJURY DURING GROWTH AND AGING

Most people are surprised by the number of cells in the prenatal brain, and in the very old brain: In the human fetus at 6 months of development, there are about twice as many brain cells as there are at the time of birth, and in old age the number of cells in the brain keeps increasing with age, so that at the age of 90 the amount of DNA in the brain (36.94 grams) is about 50%.greater than at the age of 16-20 (23.04 grams). In the aged brain, glial cells multiply while neurons die. In the fetus, the cells that die are apparently nerve cells that haven't yet matured. The factors that are known to reduce the brain size at birth are also factors that are involved in the degenerating brain in old age or Alzheimer's disease: lack of oxygen, excess unsaturated fats or deficiency of saturated fats, estrogen excess, progesterone deficiency, and lack of glucose. A lack of carbon dioxide is probably harmful in both. Inflammation and blood clots may be factors in the aging brain, and bleeding with vascular spasm is sometimes a contributing factor to brain damage in both the old and the fetal brain. Endotoxemia may be a factor in nerve degeneration only during adult life, but it is sometimes present during pregnancy.

M. C. Diamond, Enriching Heredity: The Importance of the Environment on the Anatomy of the Brain. Free Press, N.Y., 1988. C. Finch and L. Hayflick, Handbook of the Biology of Aging. Van Nostrand Reinhold, N.Y., 1977.

III. A VIEW OF ENTROPY: RENEWAL OF THE BRAIN

When a fertilized egg is developing into a person, each cell division creates a new environment for the daughter cells, to which they adapt. They may run into limits and resistances (sometimes a certain gene doesn't meet the need of the situation, or toxins are present, or nutrients and hormones are imperfectly supplied), but the process is flexible, and a way is normally found to get around the limitation. The embryo's brain development is my favorite example of the ways genes interact with the environment. We might think of the "optimal brain development" of a person, or a rat, or a chicken, as something which is clearly limited by "the genes." But if rats are given a stimulating environment, each generation gets a slightly bigger, slightly more intelligent brain. If rats are treated during pregnancy to increase the amount of progesterone, the offspring have bigger brains and learn more efficiently. Still, that might just be restoring a condition that was natural for rats in some perfect environment. Chickens develop inside an egg shell, and so the nutrients needed for their development are all present when the egg is laid.

The brain, like the other organs, stops growing when the food supply is used up. But an experimenter (Zamenhof) opened the egg shells at the stage of development when the brain normally stops growing, and added glucose, and found that the brain continued growing, producing chickens with bigger brains. The "genes" of a chicken, as part of a system, have something to do with the development of that system, but the environment existing in and around the organism is able to guide and support the way the system develops. The size, complexity, and intelligence of the brain represents a very large part of the "information" contained in the organism, and Zamenhof's experiment showed that the ability to realize this potential, to create this complexity, comes from the support of the environment, and that the "genetic nature of the chicken" didn't constitute a limit to the development of its brain.

I am going to argue that Alzheimer's disease is analogous to the situation confronted by the developing chicken embryo or the rat or human fetus, when the environment is unable to meet the needs of the highly energetic, demanding and sensitive brain cells, and the brain cells begin to die, instead of developing into a more complex state, passing beyond various barriers and limitations. There are two stereotypes that are in conflict with this view: (1) That the structure of the brain is determined at an early point in life, sometimes explicitly stated as the age of 12 or 16, and (2) that the structure of the brain goes into an "entropic" deterioration during the process of aging. My position is that the brain cells are in a vital developmental process at all times, and that the same things that injure the brain of a fetus also injure the brain of an aging person.

If novelty is really appearing during development, then it is hard to maintain that "entropy increases" during the development of an individual. Isn't a child a richer organization than a fertilized egg? Isn't an adult more individualized or realized than an infant? Seen from the inside, our known world gets richer with experience. Learning is certainly anti-entropic. Where does the idea of "increasing entropy with living" come from? Many things contribute, including a doctrine of genetic determinism, the old Platonic idea of the imperfection of the concrete, the unreality of the existent, and the medieval idea of the "corruption of the body." These philosophies still motivate some people in aging research. The astrophysicist, N. A. Kozyrev, showed that the idea of an "entropic cosmos" derived simply from the assumptions of 19th century deism, "God set the clockwork universe in motion, and left it to run down." Early in this century, Raymond Pearl argued that the "rate of living" governed the life-span, so that "fast living" meant a short life. He based his argument on cantaloupe seeds: the faster they grew, the sooner they died. This was because he didn't give them anything but water, so they had to live on their stored energy; if they grew quickly, obviously they ran out of stored energy sooner. I have never heard that described as a stupid idea, but I think politeness is sometimes carried too far. In the clock analogy, or the seed analogy, the available energy is used up.

The clock with its wound-up spring and the seed in a dish of water may be considered as closed systems, and we can understand their fate. But if it is foolish to argue from a confined seed to free-living organisms, then it is just as foolish to argue from a clock to a cosmos. Unfortunately, these inferences about closed systems are often applied to real situations that aren't energetically closed.

The "rate of living" theory of aging picked up the idea of aging as a natural physical property of time, and gave it expression in mathematical form, arguing (Hershey, "Entropy, basal metabolism and life expectancy," Gerontologia 7, 245-250, 1963) that "the total lifetime entropy production" could be calculated, to give insight into "life expectancy and evolutional development." Unfortunately, the equation Hershey used assumed that the flow of heat out of the body into the surroundings is reversible. This suggests an image of Dr. Frankenstein vivifying his monster with lightning, putting the heat back into the body. If heat is to be "put back into the body," it is necessary to make sure that it is appropriate for the structure as it exists.

Actually, it is just the directed flow of energy which generates the structures. If any biological argument can be made from the idea of entropy, it is that it would be extremely difficult to regenerate food, by putting heat into a person. In a few situations, it is possible to show that living structures can directly absorb heat from their environment (causing the temperature to fall)--"negative heat production"--but the exact meaning of this isn't clear. (B. C. Abbott, et al., "The positive and negative heat production associated with a nerve impulse," Proc. R. Soc. B 148, 149, 1958; R. D. Keynes and J. M. Ritchie, "The initial heat production of amphibian myelinated nerve fibres," Proc. Physiol. Soc., June 1970, page 29P-30P: "It is now clear that in both crustacean...and mammalian (Howarth, et al., 1968) non-myelinated fibres there is an initial production of heat during (or soon after) the action potential, 80% of which is rapidly reabsorbed.") A. I. Zotin ("Aging and rejuvenation from the standpoint of the thermodynamics of irreversible processes," Priroda, No. 9, 49-55, 1970), citing the theory of Prigogine-Wiame, argued that the aging process involves both a decrease in entropy and a decrease in the rate of heat production.

Regeneration involves a production of entropy, as when an egg is formed. (The temperature fluctuation at the time of ovulation might make a contribution to the construction of the entropic egg.) The argument that aging of the animal (like aging of the cosmos) is governed by "the tendency of entropy to increase" has led people to say that rejuvenation would be like unscrambling an egg. Zotin's argument is interesting, because he says that an egg is a "scrambled animal." This view is very much like Warburg's and Szent-Gyorgyi's theory of cancer, that it is like a reversion to a simpler state of life. To sketch out what I have argued in different contexts, water is the part of the living substance that we can most meaningfully discuss in terms of entropy. In fact, much of the concept of entropy has derived from the study of water, as it changed state in steam engines, etc. Cancer cells, like egg cells, have a higher water content than the differentiated, functioning cells of an adult, and the water is less rigidly ordered by the cellular molecules. This different, more mobile state of the water, can be measured by the NMR (nuclear magnetic resonance) machines which are used for MRI (magnetic resonance imaging).

Estrogen has a special place in relation to the water in an organism. It is intimately involved with the formation of the egg cell, and wherever it operates, it increases both the quantity of water and, apparently, the disorder of the water. Its function, I believe, is to promote regeneration, as in Zotin's scheme, by increasing entropy, or "scrambling the animal." The way it promotes regeneration is by promoting water uptake, stimulating cell division, and erasing the differentiated state to one degree or another, providing a new supply of "stem cells," or cells at the beginning of a certain sequence of differentiation. These more numerous cells then must find a hospitable environment in which to develop and adapt. If the proper support can't be found, then they will be recycled, like the unfed cells in the brain of a fetus. If we imagine the course of development as a summary of evolution ("ontogeny recapitulating phylogeny"), then the egg, as it "unscrambles" itself in embryonic development, passing through stages resembling jelly fish, worm, fish, reptile, bird, baboon, keeps finding that the available energy allows it to, in effect, say "I want this, I don't want that," until it emerges as a human baby, saying "I want," and begins eating and learning, and with luck continues the unscrambling, or self-actualization.. Degenerative aging, rather than being "physically derived from the properties of time," seems to be produced situationally, by various types of contamination of our energy supply. Unsaturated fats, interacting with an excess of iron and a deficiency of oxygen or usable energy, redirect our developmental path.

The saturated fats, in themselves, seem to have no "signalling" functions, and when they are naturally modified by our desaturating enzymes, the substances produced behave very differently from the plant-derived "eicosanoids." As far as their effects have been observed, it seems that they are adaptive, rather than dysadaptive. All of the factors that affect the brain of a fetus should be examined in relation to the aging brain. Besides estrogen and fats, I am thinking of oxygen and carbon dioxide, glucose, iron and calcium, cholesterol, progesterone, pregnenolone, DHEA, the endorphins, GABA, thyroid, and vitamin A. An additional factor, endotoxin poisoning, eventually tends to intervene during stress and aging, exacerbating the trend begun under the influence of the other factors.

IV. FALSE SIGNALS FROM THE ENVIRONMENT

The environment can be supportive, but it can also divert development from an optimal course.

Passively taking whatever you are given, by history and nature, is entropic; choosing intelligently from possible diets, selecting courses of action, will create pattern and reduce entropy. If education contains an element of choice and self-actualization, then the results seen in several Alzheimer's studies could have a significance larger than what has been suggested by the investigators. A diagnostic bias has been reported to result from the use of standardized tests based on vocabulary, because education increases vocabulary, and tends to cover up the loss of vocabulary that occurs in dementia. In the Framingham study, it was concluded that there was a real association of lower educational level with dementia, but the suggestion was made that self-destructive practices such as smoking were more common among the less educated.

The Seattle study of the patients in a health maintenance organization showed a very distinct difference in educational level between the demented and the non-demented, both of whom had roughly similar frequency of prescriptions for estrogen. The features that seemed important to me, that weren't discussed by the authors, were that the demented women had a much lower rate of progestogen use, and a much higher incidence of hysterectomy, which interferes with natural progesterone production. Although Brenner, et al., in the Seattle study concluded that "this study provides no evidence that estrogen replacement therapy has an effect on the risk of Alzheimer's disease in postmenopausal women," they reported that "Current estrogen use of both the oral and the vaginal routes had odds ratios below 1, while former use of both types yielded odds ratios above 1...." (They seem to neglect the fact that Alzheimer's-type disease in old people has a long developmental history, so it is precisely the "former" use that is relevent. 31% of the demented women had formerly used estrogen, and only 20% of the control group. Since estrogen is a brain excitant, present use creates exactly the same sort of effect on verbal fluency and other signs of awareness of the environment that a little cocaine does. Anyone who neglects this effect is probably deliberately constructing a propaganda study.)

This observation, that the demented had 155% as much former estrogen use as the normal group, as well as the difference in rates of progestogen use (normal patients had 50% more progestogen use than demented) and hysterectomy (demented had 44.1% vs. 17% in the normals, i.e., 259% as many; the incidence of hysterectomies after the age of 55, which is a strong indication of a natural excess of estrogen, in the demented was 374% of the incidence in the non-demented), should call for a larger study to clarify these observatons, which tend to indicate that exposure to estrogen in middle-age increases the risk of Alzheimer's disease in old age, and that even medical progestogens offer some protection against it..

(Although this study might have been bigger and better, it is far better than the junk-studies that have been promoted by the pharmaceutical publicity machine. I have seen or heard roughly 100 mentions of the pro-estrogen anti-scientific "studies," and none mentioning this one.)

D. E. Brenner, et al., Postmenopausal estrogen replacement therapy and the risk of Alzheimer's disease: A population-based case-control study," Am. J. Epidemiol. 140, 262-267, 1994. "Women tend to have higher age-specific prevalence and incidence rates of Alzheimer's disease than do men." A.F. Jorm, The Epidemiology of Alzheimer's disease and related disorders, Chapman and Hall, London, 1990, and W. A. Rocca, et al., Ann. Neurol. 30, 381-190, 1991.

H. C. Liu, et al., "Performance on a dementia screening test in relation to demographic variables--study of 5297 community residents in Taiwan," Arch. Neurol. 51(9), 910-915, 1994. "Commonly used dementia screening tests may be unfair to poorly educated individuals, especially women and rural residents."

SIGNALS IN THE ABSTRACT

When I taught endocrinology, I annoyed my tidy-minded students by urging them to consider the potential hormone-like action of everything in the body, and to think of layers of control, ranging from sugar, salt, and carbon dioxide, through the "official hormones," to complex nervous system actions such as expectancy, and biorhythms. Certain things that are active in very important processes deserve special attention as "signals," but they still have to be understood in context. In this sense, we can think of Ca2+ as a signal substance, in its many contexts; it is strongly regulated by the cell's energy charge. Magnesium and sodium antagonize it in certain situations. Linoleic acid, linolenic acid, arachidonic acid: Their toxicity is potentially prevented by the Mead acids, and their eicosanoid derivatives, which behave very differently from the familiar prostaglandins, as far as they have been compared; can be drastically reduced by dietary changes. Prostaglandins, prostacyclin, thromboxane: Formation is blocked by aspirin and other antiinflammatory drugs.

Adenosine: Sleep inducing protective effect. Adenosine is structurally very similar to inosine, another natural substance (found in meat, for example) which is a component of "inosiplex," an antiviral drug (Brown and Gordon, Fed. Proc. 29, 684, 1970, and Can. J. Microbiol. 18, 1463, 1972) or immunostimulant which has also been found to have an anti-senility effect (Doty and Gordon, Fed. Proc. 29). Adenosine is a free radical scavenger, and protects against calcium and glutamate excitotoxicity. (I. Yokoi, et al., "Adenosines scavenged hydroxyl radicals and prevented posttraumatic epilepsy," Free Radical Biol. Med. 19(4), 473-479, 1995; M. P. Abbracchio, et al., "Adenosine A(1) receptors in rat brain synaptosomes: Transductional mechanisms, efects on glutamate release, and preservation after metabolic inhibition," Drug Develop. Res. 35(3), 119-129, 1995.) It also appears to protect against the relative hyperventilation that wastes carbon dioxide, and endotoxin can interfere with its protective action. Guanosine, in this same group of substances, might have some similar properties. Thymidine and cytidine, which are pyrimidine-based, are endogenous analogs of the barbiturates, and like them, they might be regulators of the cytochrome P450 enzymes. Uridine, in this group, promotes glycogen synthesis, and is released from bacteria in the presence of penicillin.

Iron: Regulator of mRNA stability, heme synthesis; reacts with reductants and unsaturated oils, to produce free radicals and lipid peroxides; its absorption is increased by estrogen, hypothyroidism, anemia or lack of oxygen. Glutamate and aspartate, excitotoxins, and GABA, an inhibitory transmitter.

These have metabolic links with each other, with ammonia, and with stress and energy metabolism.

Estrogen and acetylcholine, excitotoxins; see Savolainen, et al., 1994. The information on this is overwhelmingly clear, and the publicity to the contrary is a horrifying example of the corruption of the mass media by the drug industry.

Endorphins: Stress induced, laterally specific, involved in estrogen action, antagonized by naloxone and similar anti-opiate drugs. I have proposed that the endorphins can cause or sustain some of the symptoms of aging. Naloxone appears to be a useful treatment for senility. E. Roberts, Ann. N. Y. Acad. Sci. 396, 165, 1982; B. Reisberg, et al., N. Engl. J. Med. 308, 721, 1983.

Endotoxin: Antimitochondrial action, causes elevation of estrogen. It synergizes with unsaturated fats, and naloxone opposes some of its toxic effects.

Urea, cholesterol: Structural stability of proteins and lipid-protein complexes.

Things that act directly on the water structure: I think all of the natural regulators have an effect on the structure of water, but some unusual substances seem to act primarily on the water. Noble gases, for example, have no chemical effects, but they tend to form "cages" of water molecules around themselves. Camphor, adamantane, and the antiviral drug amantadine, probably have a similar water-structuring effect, and amantadine, which is widely used as a therapy in Parkinson's disease, has an anti-excitotoxic action.

Article continued in Part 2 - click here

Raymond Peat, Ph.D.

Copyright 1997

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J. M. Pasquini and A. M. Adamo, "Thyroid hormones and the central nervous system," Dev. Neurosci. 12(1-2), 1-8, 1994. "Among their actions, T3 and T4 have effects on the differentiation of various cell types in the rat brain and cerebellum as well as on the process of myelination. Recently, several investigators have shown effects of thyroid hormones on myelin protein gene expression."

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T. Yamada, et al., "Apolipoprotein E mRNA in the brains of patients with Alzheimer's disease," J. Neurol. Sci. 129(1), 56-61, 1995. In A.D. Apo E "was decreased in relation to the apoE-epsilon 4 gene dosage." "AD patients who had long survival times showed high expression of apoE and low expression of GFAP [glial fibrillary acidic protein]. These results suggest that apoE suppresses the progression of AD, including gliosis, in the brain."

G. P. Jarvik, et al., "Genetic influences on age-related change in total cholesterol, low density lipoprotein-cholesterol, and triglyceride levels: Longitudinal apolipoprotein E genotype effects," Genet. Epidemiol. 11(4), 375-384, 1994. "Apo E is a component of LDL, is a ligand for the LDL receptor, and apo E genotype has been consistently associated with variation in mean levels of total cholesterol and LDL-C...." With aging, total cholesterol and LDL-C became significantly lower in the "epsilon 4 genotype" group; this is the group at risk for AD.

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D. L. Williams, et al., "Cell surface 'blanket' of apolipoprotein E on rat adrenocortical cells," J. Lipid Res. 36(4), 745-758, 1995. "...the zona fasciculata cell is encircled or covered with apoE on all faces of the cell. ...this cell surface 'blanket' of apoE participates in the uptake of lipoprotein cholesterol by either the endocytic or selective uptake pathways." C. A. Frye and J. D. Sturgis, "Neurosteroids affect spatial reference, working, and long-term memory of female rats," Neurobiol. Learn. Memory 64(1), 83-96, 1995. [Female rats take longer to acquire a spatial task during behavioral estrus.)]

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P. Robel, et al., "Biosynthesis and assay of neurosteroids in rats and mice: Functional correlates," J. Steroid Biochem. Mol. Biol. 53(1-6), 355-360, 1995. [Discusses the effects of pregnenolone and progesterone on aggression and learning. The animals which learned most easily had the highest levels of pregnenolone sulfate.] K. W. Lange and P. Riederer, "Glutamatergic drugs in Parkinson's disease," Life Sci. 55(25-26, 2067-2075, 1994. "...excitatory amino acids such as glutamate are involved in the pathophysiological cascade of MPTP...-induced neuronal cell death." "The 1-amino-adamantanes amantadine and memantine have recently been shown to be non-competitive NMDA antagonists and are widely used in Europe as antiparkinsonian agents."

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T. Reed, et al., "Lower cognitive performance in normal older adult male twins carrying the apolipoprotein E epsilon 4 allele," Arch. Neurol. 51(12), 1189-1182, 1994.

S.Y. Tan and M. B. Pepys, "Amyloidosis," Histopathology 25(5), 403-414, 1994. "...abnormal protein fibrils which are derived from different proteins in different forms of the disease. Asymptomatic amyloid deposition in a variety of tissues is a universal accompaniment of ageing, and clinical amyloidosis is not rare. Intracerebral and cerebrovascular beta-protein amyloid deposits are a hallmark of the pathology of ... Alzheimer's disease...." "Amyloid deposits are in a state of dynamic turnover and can regress if new fibril formation is halted." A. V. Sirotkin, "Direct influence of melatonin on steroid, nonapeptide hormones, and cyclic nucleotide secretion by granulosa cells isolated from porcine ovaries," J. Pineal Res. 17(3), 112-117, 1994. "It was found that melatonin is able to inhibit progesterone and stimulate estradiol secretion." "Some inhibition of vasopressin and cAMP and significant stimulation of cGMP also resulted from melatonin treatment." R. M. Sapolsky, "Glucocorticoid toxicity in the hippocampus: Reversal with supplementation with brain fuels," J. Neurosci. 6, 2240-2245, 1986. R. M. Sapolsky, "Glucocorticoids, hippocampal damage and the glutaminergic synapse," Prog. Brain Res. 86, 13-23, 1990. M. Schwartz, et al., "Growth-associated triggering factors and central nervous system regeneration," p. 47 in Trophic Factors and the Nervous System, edited by L. A. Horrocks, et al., Raven Press, NY, 1990. R. W. Ordway, et al., "Direct regulation of ion channels by fatty acids," Trends Neurosci. 14, 96-100, 1991.

H. G. P. Swarts, et al., "Binding of unsaturated fatty acids to Na+,K+-ATPase leading to inhibition and inactivation," Biochim. Biophys. Acta 1024, 32-40, 1990.

G. Autore, et al., "Essential fatty acid-deficient diet modifies PAF levels in stomach and duodenum of endotoxin-treated rats," J. Lipid Mediators Cell Signalling 9, 145-153, 1994. J. Rafael, et al., "The effect of essential fatty acid deficiency on basal respiration and function of liver mitochondria in rats," J. Nutr. 114, 255-262, 1984.

A. M. Weiner, et al., "Nonviral retroposons, genes, pseudogenes, and transposable elements generated by the reverse flow of genetic information," Ann. Rev. Biochem. 55, 631-661, 1986. I. Zs.-Nagy, "Semiconduction of proteins as an attribute of the living state: The ideas of Albert Szent-Gyorgyi revisited in light of the recent knowledge regarding oxygen free radicals," Exp. Gerontology 30(3-4), 327-335, 1995. "In this assumption, the continuous radical flux is as important for the maintenance of the living state, as the voltage power supply is essential for the functioning of the computer."

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<span class="koboSpan" id="kobo.1.1">The problem of Alzheimer's disease as a clue to immortality - part 2</span> A R T I C L E

The problem of Alzheimer's disease as a clue to immortality - Part 2

V. HORMONE IMBALANCE, LEADING TO FAILURE OF PROTECTIVE INHIBITION AND ALZHEIMER'S DISEASE

"All cell death is characterized by an increase of intracellular calcium...." "Increase of cytoplasmic free calcium may therefore be called 'the final common path' of cell disease and cell death. Aging as a background of diseases is also characterized by an increase of intracellular calcium. Diseases typically associated with aging include hypertension, arteriosclerosis, diabetes mellitus and dementia."

T. Fujita, "Calcium, parathyroids and aging," in Calcium-Regulating Hormones. 1. Role in Disease and Aging, H. Morii, editor, Contrib. Nephrol. Basel, Karger, 1991, vol. 90, pp. 206-211.

THE FUNCTION OF ENERGY

Most people are slightly demented now and then, when they are very sleepy or tired, or sick, or drunk, or having a hormone imbalance or extreme anxiety state. Sometimes physicians have described people as demented, implying that the condition would never improve, when the person was depressed or hypothyroid. If the person has a history of epilepsy, or is very old, the physician is more likely to diagnose dementia than if the same loss of mental function occurs in a younger person without a history of a nervous disorder. Even people with less education are at increased risk of being diagnosed as "demented."

In 1976, I saw a 52 year-old woman who had the diagnosis of epileptic dementia. After 3 or 4 days of taking progesterone, her mental function returned to the extent that she could find her way around town by herself, and could work. A few months later, she returned to graduate school, got straight As and a master's degree. A few years later, a man in his 80s showed the classical signs of senile dementia, with childishness, confusion, self-centeredness, and unstable emotions. A few days after getting a mixture of thyroid, pregnenolone, and progesterone, his mind was again clear, and he was able to work on a research project he had set aside years before.

When the body temperature is very much below normal, mental functioning is seriously limited. I think the first question that should be asked about a demented person is "is this the cold brain syndrome, or is something else involved?" When it is known that the brain has shrunken drastically, and filled up with plaques and developed gliosis, we know that something more than a "cold brain" is involved, but we don't know how much function could be regained if the hormones were normalized. Every moment of malfunction probably leaves its structural mark. Early or late, it is good to prevent the functional errors that lead to further damage, and to give the regenerative systems an opportunity to work. Before the final "calcium death" described (above) by Fujita, there are many opportunities for intervening to stop or reverse the process. The older the person is, the more emphasis should be put on protective inhibition, rather than immediately increasing energy production. Magnesium, carbon dioxide, sleep, red light, and naloxone might be appropriate at the beginning of therapy.

The resting state of a cell is a highly energized state. To the old Pavlovians, the resting state existed at two energy levels, and they applied the term "protective inhibition" generally to the depleted state (parabiosis) that occurs in exhaustion or coma, but I am using the phrase in a more general sense, that seems reasonable now that the concept of "excitotoxic" injury has become current. I mean it to include everything which protects against excitotoxic injury. This definition therefore has the virtue of being biochemically and physiologically very specific, while retaining the functional and therapeutic significance that it had for the Pavlovians. (My book, Mind and Tissue, and the chapter "A unifying principle" in Generative Energy, discussed the idea of the resting state and protective inhibition.)

Ordinary healthy sleep is an example of restorative, protective inhibition. The energy charge, including levels of ATP, creatine phosphate, and glycogen storage, regulates many restorative enzyme systems. I have suggested (1975, J. Orthomol. Psychiatry) how the entropy-sensitivity or cold-inactivation of an enzyme could be involved in shifting the brain toward a state of inhibition. A recent publication (J. H. Benington and H. C. Heller, "Restoration of brain energy metabolism as the function of sleep," Progress in Neurobiol. 45, 347-360, 1995) has proposed that reduction of energy charge and depolarization of cells act through adenosine secretion to restore glycogen stores. Since glycogen stores decrease with aging, this work supports the idea that protective inhibition is weakened with aging. (L. N. Simanovskiy and Zh. A. Chotoyev, "The effect of hypoxia on glycogenolysis and glycolysis rates in the rat brain," Zhurnal Evolyutsionnoy Biokhimii i Fiziologii 6(5), 577-579, 1970.)

J. H. Benington and H. C. Heller, "Restoration of brain energy metabolism as the function of sleep," Prog. in Neurobiology 45, 347-360, 1995. "...the conditions that have been demonstrated to stimulate adenosine release from neural tissue represent either increases in metabolic demand (...activation of excitatory receptors) or decreases in metabolic supply (hypoxia, ischaemia, hypoglycemia)...." "In the brain, adenosine-stimulated increases in potassium conductance produce hyperpolarization, thereby reducing neuronal responsiveness...." "Adenosine release is triggered globally in response to changes in cerebral energy homeostasis." "A number of findings provide indirect support for the hypothesis that glycogen stores are depleted during waking and restored during sleep." "Reduced availability of glycogen to astrocytes must...increase adenosine release...." "Because ATP concentration is 100-fold greater than AMP concentration, a minute decrease in cellular energy charge...is translated into a large proportional increase in extracellular adenosine cencentration...."

The terms "functional quiescence" and "G0 quiescence" are similar in meaning to the resting state; I think of cells in the state of "G0 quiescence" as being stem cells, waiting for use in regeneration, but I don't subscribe to the idea that they can't be reconstituted from functioning, differentiated cells. In plants, dedifferentiation is achieved fairly easily, and in the study of animal cells the trend in that direction seems very obvious, though many people keep saying that it just isn't possible. In general, the things such as lipid peroxidation or calcium influx which cause cell replication at one level, cause cell death at a higher level.

Energy to resist stress makes quiescence possible, and prevents the deterioration of cells, of the sort that occurs in aging. O. Toussaint, et al., "Cellular aging and energetic factors," Exp. Gerontology 30(1), 1-22, 1995. "Experiments performed with endothelial cells in the context of the ischemia-reperfusion toxicity of free radicals, also offer good examples of the impact of cell energy on cell resistance to these toxic molecules." "...if a supplement of energy is given...the toxic effect of the free radicals is much reduced...."

The specific approaches of this orientation --to energize but quiet the brain--are diametrically opposed to some of the "therapies" for Alzheimer's disease that have been promoted recently by the drug industries: Things to increase stimulation, especially to increase cholinergic excitation; even the excitotoxic amino acids themselves and their analogs; and estrogen, which is a multiple brain excitant, proconvulsant, excitotoxic promoter, and anti-memory agent. Those product-centered publications stand out distinctly from the actual research.

There are many energy-related vicious circles associated with aging, but the central one seems to be the fat-thyroid-estrogen-free-radical-calcium sequence, in which the ability to produce stabilizing substances including carbon dioxide and progesterone is progressively lost, increasing susceptibility to the unstable unsaturated fats.

EFFECTS OF ESTROGEN AND UNSATURATED FATTY ACIDS

Estrogen production is facilitated when tissue is cooler, and it lowers body temperature. Estrogen and the endorphins act together in many ways (including the behavior of estrus), and naloxone (the antagonist of morphine and the endorphins) raises body temperature and in other ways opposes estrogen. Naloxone has been found to improve the symptoms of demented people, and I have seen it quickly, and dramatically, improve the mental clarity of a 60 year old woman who had used estrogen. It, like clonidine (the anti-adrenaline drug), is a good candidate for controlling the hot flashes and other symptoms of menopause.

In various degenerative brain conditions, blood clotting has been implicated either as a cause or a complication. Many people are promoting unsaturated oils for their "anti-clotting" value, in spite of the older literature showing that they inhibit proteolytic enzymes and slow clot removal. Several newer publications have revealed other aspects of their involvement in thrombus formation. A. J. Honour, et al., "The effects of changes in diet on lipid levels and platelet thrombus formation in living blood vessels," Br. J. Expt. Pathol. 59(4), 390-394, 1978--corn oil caused platelets to be more sensitive to ADP.

Although there is a lot of talk about "membrane fluidity," as a desirable thing, and the loss of unsaturated lipids in the aged brain, there are some interesting observations related to "viscosity" in Alzheimer's disease. The platelets of Alzheimer's patients are less viscous, and lipids extracted from the brain are more fluid, and contain 30% less cholesterol than normal (on a molar basis, in relation to phospholipids). (G. S. Roth, et al., 1995.) In general, lipid peroxidation causes cellular viscosity to increase, apparently by causing cross-linking of proteins, but I think the significance of the decreased cholesterol relates to its significance as precursor to pregnenolone and progesterone, and to the known association with Alzheimer's disease of a variant form of the cholesterol transporter protein, ApoE, which I suppose is a slightly less stable molecular form that is more susceptible to malfunction in stress.

The extracellular matrix is a major factor in the function and stability of brain cells. (L. F. Agnati, et al., "The concept of trophic units in the central nervous system," Prog. in Neurobiol. 46, 561-574, 1995. Any factor producing edema tends to disrupt the extracellular matrix (Chan and Fishman, 1978, 1980, and L. Loeb, 1948.)

Seizures are known to be promoted by estrogen, by unsaturated fats, and by lipid peroxidation, and to cause an increase in the size of the free fatty acid pool in the brain. Prolonged seizures cause nerve damage in certain areas, especially the hippocampus, thalamus, and neocortex (Siesjo, et al., 1989). Dementia is known to be produced by prolonged seizures.

Prenatal exposure to estrogen, to oxygen deficiency, or to unsaturated fats decreases the size of the brain at birth. There is apparently a requirement for saturated fats during development (J. M. Bourre, N. Gozlan-Devillierre, O. Morand, and N. Baumann, "Importance of exogenous saturated fatty acids during brain development and myelination in mice," Ann. Biol. Anim., Biochim., Biophys. 19(1B), 172-180, 1979.

Under the influence of estrogen, or unsaturated fats, brain cells swell, and their shape and interactions are altered. Memory is impaired by an excess of estrogen. Estrogen and unsaturated fat and excess iron kill cells by lipid peroxidation, and this process is promoted by oxygen deficiency. The fetus and the very old have high levels of iron in the cells. Estrogen increases iron uptake. Estrogen treatment produces elevation of free fatty acids in the blood, and lipid peroxidation in tissues. This tends to accelerate the accumulation of lipofuscin, age-pigment. Lactic acid, the production of which is promoted by estrogen, lowers the availability of carbon dioxide, leading to impairment of blood supply to the brain.

Estrogen stimulates cell division, but can also increase the rate of cell death. Unsaturated fatty acids can also stimulate or kill.

Both estrogen and unsaturated fats promote the formation of age-pigment. Besides increasing the free fatty acid concentration, estrogen possibly depresses the level of cholesterol, both of which are changes seen in the senile brain.

Estrogen causes massive alterations of extracellular matrix, and seems to promote dissolution of microtubules (Nemetschek-Gannsler), as calcium does. Unsaturated fats increase calcium uptake by at least some brain cells (H. Katsuki and S. Okuda, 1995.) Unsaturated fats, like estrogen, increase the permeability of blood vessels. The unsaturated fat causes edema of the brain, inhibits choline uptake, blocking acetylcholine production.

Progesterone is a nerve growth factor, produced by glial cells (oligodendrocytes). It promotes the production of myelin, protects against seizures, and protects cells against free radicals. It protects before conception, during gestation, during growth and puberty, and during aging. It promotes regeneration. Its production is blocked by stress, lipid peroxidation, and an excess of estrogen and iron.

Aspirin protects against iron toxicity, clot formation, and reduces lipid peroxidation while blocking prostaglandin formation. Aspirin and other antiinflammatory drugs, taken for arthritis, have been clearly associated with a reduced incidence of Alzheimer's disease. Aspirin reduces the formation of prostaglandins from arachidonic acid.

Unsaturated fatty acids, but not saturated fatty acids, are signals which activate cell systems.

Many different stimuli can induce cell activity, cell death, or change to another cell type. (J. Niquet, et al., "Glial reaction after seizure induced hippocampal lesion: Immunohistochemical characterization of proliferating glial cells," J. Neurocytol. 23(10), 641-656, 1994: "...hippocampal astrocytes from kainate-treated rats experess A2B5 immunoreactivity, a marker of type-2 astrocytes." "This suggests that in the CNS, normal resident astrocytes acquire the phenotypic properties of type-2 astrocytes.")

A "deficiency" of polyunsaturated fatty acids leads to altered rates of cellular regeneration and differentiation, a larger brain at birth, improved function of the immune system, decreased inflammation, decreased mortality from endotoxin poisoining, lower susceptibility to lipid peroxidation, increased basal metabolic rate and respiration, increased thyroid function, later puberty and decreases other signs of estrogen dominance. When dietary PUFA are not available, the body produces a small amount of unsaturated fatty acid (Mead acids), but these do not activate cell systems in the same way that plant-derived PUFAs do, and they are the precursors for an entirely different group of prostaglandins.

VITAMIN A AND THE STEROIDS

In a variety of cell types, vitamin A functions as an estrogen antagonist, inhibiting cell division and promoting or maintaining the functioning state. It promotes protein synthesis, regulates lysosomes, and protects against lipid peroxidation. Just as stress and estrogen-toxicity resemble aging, so does a vitamin A deficiency. While its known functions are varied, I think the largest use of vitamin A is for the production of pregnenolone, progesterone, and the other youth-associated steroids. One of vitamin E's important functions is protecting vitamin A from destructive oxidation. Although little attention has been given to the effects of unsaturated fats on vitamin A, their destruction of vitamin E will necessarily lead to the destruction of vitamin A. The increased lipid peroxidation of old age represents a vicious circle, in which the loss of the antioxidants and vitamin A leads to their further destruction.

To produce pregnenolone, thyroid, vitamin A, and cholesterol have to be delivered to the mitochondria in the right proportion and sufficient quantity. Normally, stress is balanced by increased synthesis of pregnenolone, which improves the ability to cope with stress. Lipid peroxidation, resulting from the accumulation of unsaturated fatty acids, iron, and energy deficiency, damages the mitochondrias' ability to produce pregnenolone. When pregnenolone is inadequate, cortisol is over-produced. When progesterone is deficient, estrogen's effect is largely unopposed. When both thyroid and progesterone are deficient, even fat cells synthesize estrogen.

THE NATURE OF ALZHEIMER'S DISEASE

Although Alzheimer's disease until recently referred to a certain type of organic dementia occuring in people in their thirties, forties and fifties (presenile dementia), structural similarities seen in senile dementia have caused the term to lose its original meaning. Alzheimer's sclerosis of blood vessels, and even the death of nerve cells, are sometimes neglected in favor of the more stylish ideas, emphasizing certain proteins that cause the tangles and plaques. Until recently, the "tangles" were commonly interpreted as the debris left after the death of a cell, rather than as one of the processes causing the death of the cell.

Alzheimer-type dementia is different from other dementias, but it overlaps with them, and with age-related and stress-related changes in other organs.

Physical signs (seen at autopsy) of AD:

1) Death of neurons (increase of glial cells),

2) Amyloid plaques (extracellular), associated with a particular variant of apolipoprotein E, the epsilon 4 allele,

3) Fibrillary tangles (intracellular, or remaining after the rest of the cell has disappeared),

4) Amyloid in blood vessels.

Functional and biochemical observations:

1) The mitochondrial energy problem, cytochrome oxidase and its regulation; body temperature/pulse-rate cycle disturbance; lipid peroxidation; respiratory defect; altered amino acid uptake; memory impairment; dominance of the excitatory systems vs. the inhibitory adenosine/GABA/progesterone/pregnenolone system. Increased calcium uptake, which is associated with lipid peroxidation and cell death. Increased cortisol and DHEA.

2) Deposit of abnormal proteins, such as transthyretin-amyloid; albumin binding of PUFA, vs. transport of thyroid and retinol. Beta-glucuronidase increases, depositing estrogen in cells. (A. J. Cross, et al., "Cortical neurochemistry in Alzheimer-type dementia," Chapter 10, pages 153-170 in Aging of the Brain and Alzheimer's Disease, Prog. in Brain Res. 70, edited by D. F. Swaab, et al., Elsevier, N.Y., 1986.)

3) Abnormally phosphorylated (tau) proteins; association with the variant form of Apo E; tau microtubule organizing proteins, microtubules are involved in transporting cholesterol; phosphorylation, by the kinase systems, regulated by PUFA; the intermediate filaments are generally stress-associated.

4) ApoE, in cytoplasm, involved in cholesterol delivery for pregnenolone synthesis, as in the adrenal; its expression regulated by thyroid. Regulation of the side-chain cleaving enzymes; regulation of the cholesterol intake and conversion to pregnenolone by the endozepine receptor/GABA receptor, modified by progesterone.

AN EXAMPLE OF A REGULATORY PROBLEM

Vegetable oil suppresses the thyroid, increasing estrogen. Estrogen and calcium depolymerize microtubules. Microtubule transport for Apo E, transthyretin, thyroid, and cholesterol for pregnenolone synthesis is disrupted. Transthyretin and Apo E accumulate unused, and deposit in blood vessels, around nerves, and in cytoplasm. Pregnenolone and progesterone deficiency (aggravating thyroid deficiency) causes memory loss, destabilization of nerve cells, failure of myelin formation, and excess cortisol synthesis. Free radicals and calcium cause multiple cell injuries including nerve-death. Estrogen is released by elevated beta-glucuronidase. Imbalances of other steroids, including cortisol and DHEA, develop as cells compensate for pregnenolone deficiency, causing shifts in balance of glial cells. Hypothyroidism, estrogen excess, free unsaturated fats cause increased vascular permeability and brain edema, protein leakage, and alteration of the matrix..

VIII: STRUCTURE AS A REGULATORY SYSTEM--AN EMERGING VISION OF PERVASIVE EPIGENESIS

In the introduction I mentioned that membranous regulation and genetic determination should be considered as defunct theories. What I have been saying about self-actualizing systems and the factors that disrupt them derives from a view of cell function that has been developing since the 1920s.

Around 1940, a Russian biochemist (Oparin, I think) proposed that the enzymes of glycolysis were bound to the structure of the cell when they were not in use, and that they were "desorbed" under the conditions that required abundant glycolysis. Knowing that concept, in 1970 I proposed that the cell water itself underwent a transition under such conditions (which could include increased temperature, reduced oxygen, or nervous or hormonal stimulation). Activation of glycolysis is usually explained by the availability of regulatory substances such as ammonia, phosphate, and NAD, and many biochemists were content to understand cells in terms of test-tube models. But in the last few years, it has become clear that some of these basic regulatory molecules do bind to structural components of the cell. (T. Henics, "Thoughts over cell biology: A commentary," Physiol. Chem. Phys. & Med. NMR 27, 139-140, 1995.) Although the details aren't clear, it is known that hormones and other factors stabilize or destabilize RNA, and that during some of these events relevant enzymes bind to the RNA. When these facts are combined with the information that is accumulating on splicing and modification of RNA, and the copying of RNA back into DNA, the hereditary system is seen to be much more flexible than it was believed to be.

A global change of state is able to steer each part of the process, continuously. In this way, the cell resembles an analog, rather than a digital, control system: each part is momentarily guided, rather than waiting for "feedback."

Where before, cellular "regulatory mechanisms" referred to certain feedback mechanisms based on interactions of randomly diffusing molecules, the new understanding of the cell sees a highly structured system in which very little is random, and the cell's adaptive possibilities, instead of being limited to a certain number of genetic switches, are shaped by every imaginable environmental influence. The cell's structure, far from being "read out of the genome," is sensitively reshaped constantly by processes that incorporate some of the environment in establishing each new stability. The old-model-geneticists have been forced to admit that the genes can't specify everything in the organism's structure, and it was the brain's complexity that forced this recognition that certain things are developed "epigenetically." But the new fact that most biologists are reluctant to accept is that the structure of the cell itself is developed very largely on the basis of information received from the environment--that is, "epigenetically."

Traditionally, epigenesis has meant that the form of an embryo or organism didn't preexist, or wasn't completely specified by the genes. That is, it has had to do with the relationships between cells. It involved a recognition that "cells are clever enough to design an organism." It is a significant step beyond that to the recognition that "cells are clever enough to redesign themselves to meet situations never seen before."

Biologists working with bacteria and yeasts have seen them adapt in non-random ways to novel conditions. "Directed mutations" are impossible, according to the "central dogma" that has the support of textbooks and most biology professors, but they do occur in those single-celled organisms. Barbara McClintock showed that in corn her mobile genes were mobilized by stress. Although this isn't exactly "directed mutation," it is an example of a mechanism for increasing adaptation when adaptation is need. There is a certain type of enzyme which makes specific cuts in the DNA chain. Biotechnologists find them convenient for their purposes, but their presence serves physiological purposes, presumably in all organisms, like those described by McClintock in corn. During the terminal stress that produces the special kind of cell death known as apoptosis, these enzymes make confetti of the genome.

Poisons, such as estrogen, unsaturated fatty acids, or even radiation, produce different effects at different doses. Low doses typically stimulate cell division, larger doses produce changes of cell type and altered states of differentiation, and finally, adequate doses produce apoptotic cell death. There is a special ideology around apoptosis, which holds that it is "genetically programmed," implying that whenever it occurs in the brain, it was destined to happen sooner or later. But in fact, "growth factors" of various sorts can prevent it. It is increasingly clear that it represents excessive stress and deficient resources. The involvement of the genetic apparatus in differentiation and radical adaptation suggests that the (epigenetic) resources of cells are unlimited.

The changes that are known to be produced by the poisons that we are habitually exposed to are exactly the changes that occur in the aging brain. As I scan over hundreds of studies that define the effects of estrogen, unsaturated fats, excess iron, and lipid peroxidation, my argument seems commonplace, even trivial, except that I know that it clearly relates to therapies for most of the degenerative diseases, and that the great culture-machine is propagating a different view at several points that are essential for my argument.

They are advancing a myth about human nature, so I will advance a counter-myth. At the time people were growing their large brains they lived in the tropics. I suggest that in this time before the development of grain-based agriculture, they ate a diet that was relatively free of unsaturated fats and low in iron--based on tropical fruits. I suggest that the Boskop skull from Mt. Kilimanjaro was representative of people under those conditions, and that just by our present knowledge of the association of brain size with longevity, they--as various "Golden Age" myths claim--must have had a very long life-span. As people moved north and developed new ways of living, their consumption of unsaturated fats increased, their brain size decreased, and they aged rapidly. Neanderthal relics show that flaxseed was a staple of their diet.

Even living in the tropics, there are many possibilities for diets rich in signal-disrupting substances, including iron, and in high latitudes there are opportunities for reducing our exposure to them. As a source of protein, milk is uniquely low in its iron content. Potatoes, because of the high quality of their protein, are probably relatively free of toxic signal-substances. Many tropical fruits, besides having relatively saturated fats, are also low in iron, and often contain important quantities of amino acids and proteins. In this context, Jeanne Calment's life-long, daily consumption of chocolate comes to mind: As she approaches her 121st birthday, she is still eating chocolate, though she has stopped smoking and drinking wine. The saturated fats in chocolate have been found to block the toxicity of oils rich in linoleic acid, and its odd proteins seem to have an anabolic action.

If we really take seriously even the traditional sort of epigenesis, and especially if we accept the deeper idea of epigenesis on the level of cellular structure and function, we have to see the organism as a sort of "whirlwind of cells," made up of whirlwinds of atoms (in Vernadsky's phrase) in which our way of life sets the boundaries within which our cells will restructure themselves.

The random production of free radicals, rather than acting only by way of genetic damage or protein cross-linking, is also able to act as a signalling process, that is, on a strictly physiological level. An excess of unsaturated fatty acids itself constitutes a massive distortion of the regulatory systems, but it also leads to distortions in the "eicosanoid" system and the increasingly uncontrolled production of free radicals, and to changes in energy, thyroid activity, and steroid balance. The aging body, rather than being like a car that needs more and more repairs until it collapses from simple wear, is more like a car traveling a road that becomes increasingly rough and muddy, until the road becomes an impassable swamp.

The suggested therapy is a correction of the signalling process, rather than "genetic surgery," transplantation, etc., which is the pessimistic implication of the doctrine that oxidative damage is simply a matter of "wear and tear," "somatic mutations," and "cross-linking." Those problems are reparable, and our emphasis should be on the production of energy and the avoidance of the conditions that allow the undesirable signals to accumulate.

The absence of cancer on a diet lacking unsaturated fats, the increased rate of metabolism, decreased free radical production, resistance to stress and poisoning by iron, alcohol, endotoxin, alloxan and streptozotocin, etc., improvement of brain structure and function, decreased susceptibility to blood clots, and lack of obesity and age pigment on a diet using coconut oil rather than unsaturated fats, indicates that something very simple can be done to reduce the suffering from the major degenerative diseases, and that it is very likely acting by reducing the aging process itself at its physiological core.

Copyright: Raymond Peat, PhD 1997

PO Box 5764 Eugene, OR 97405

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G. C. Ness and Z. H. Zhao, "Thyroid hormone rapidly induces hepatic LDL receptor mRNA levels in hypophysectomized rats," Arch. Biochem. Biophys. 315(1), 199-202, 1994.

E. M. Mutisya, et al., "Cortical cytochrome oxidase activity is reduced in Alzheimer's disease," J. Neurochem. 63(6), 2170-2184, 1994. "These results provide further evidence of a cytochrome oxidase defect in Alzheimer's disease postmortem brain tissue. A deficiency in this key energy-metabolizing enzyme could lead to a reduction in energy stores and thereby contribute to the neurodegenerative process."

G. J. Bu, et al., "Subcellular localization and endocytic function of low density lipoprotein receptor-related protein in human glioblastoma cells," J. Biol. Chem. 269(47), 29874-29882, 1994. "Our results thus strongly suggest several potential roles for LRP in brain protein and lipoprotein metabolism, as well as control of extracellular protease activity."

V. Vandenbrouck, et al., "The modulation of apolipoprotein E gene expression by 3,3'-5-triiodothyronine in HepG(2) cells occurs at transcriptional and post-transcriptional levels," Eur. J. Biochem. 224(2), 463-471, 1994. "...thyroid hormone stimulated apoE gene transcription threefold in 24 hours."

M. J. Ignatius, et al. "Expression of apolipoprotein-E during nerve degeneration and regeneration," Proc. Natl. Acad. Sci. (USA) 83, 1125-1129, 1986.

B. T. Stokes, et al., "Energy depletion, calcium and the cytoskeleton: A model for trophic intervention," pp. 279-292, in Trophic Factors and the Nervous System, L. A. Horrocks, et al., editors, Raven Press, NY, 1990. "Injury to neuronal cells is associated with a decline in high energy phosphates, a loss of cation homeostasis, and possibly, an increase in reactive oxygen radicals." "Virtually all components of the cytoskeleton are either directly or indirectly affected by alterations in calcium metabolism." "...calcium-activated proteases may also specifically modulate components of the cytoskeleton." "...ATP depletion itself may directly alter the structural components of the neuronal cytoskeleton." "...major neurodegenerative diseases such as Alzheimer's, Parkinsonian syndrome, amyotrophic lateral sclerosis...are also characterized by changes in the neuronal cytoskeleton."

T. Gunther, et al., "Effects of magnesium and iron on lipid peroxidation in cultured hepatocytes," Mol. Cell Biochem. 144(2), 141-145, 1995. (Magnesium protects against iron.)

K. D. Croft, et al., "Oxidation of low-density lipoproteins: Effect of antioxidant content, fatty acid composition and intrinsic phospholipase activity on susceptibility to metal ion-induced oxidation," BBA-Lipid Lipid Metab. 1254(3), 250-256, 1995.

J. H. Choi and B. P. Yu, "Brain synaptosomal aging: Free radicals and membrane fluidity," Free Radical Biol. Med. 18(2), 133-139, 1995 ("...fluidity loss may be influenced by factors other than cholesterol. We suggest that lipid peroxidation may be a major factor in the change in fluidity during the aging process.")

J. H. Choi and B. P. Yu, "Modification of age-related alterations of iron, ferritin, and lipid peroxidation in rat serum," Age 17(3), 93-97, 1994.

E. Chiarpotto, et al., "Metabolism of 4-hydroxy-2-nonenal and aging," Biochem. Biophys. Res. Commun. 297(2), 477-484, 1995. (Accumulation of unsaturated fat breakdown product in old animals.)

H. J. Sipe, et al., "The metabolism of beta-estradiol by lactoperoxidase: A possible source of oxidative stress in breast cancer," Carcinogenesis 15(11), 2637-2643, 1994.

M. J. Endresen, et al., "Effects of free fatty acids found increased in women who develop pre-eclampsia on the ability of endothelial cells to produce prostacyclin, cGMP and inhibit platelet aggregation," Scan. J. Clin. Lab. Invest. 54(7), 549-557, 1994. "...levels of circulating free fatty acids are increased in women who later develop pre-eclampsia long before the clinical onset of the disease." "...linoleic acid reduced the thrombin-stimulated prostacyclin release by 30-60%, oleic acid by 10-30%, wheras palmitic acid had no effect." "Linoleic acid reduced the endothelial cells" ability to inhibit platelet aggregation by 10-45%...."

L. A. Norris and J. Bonnar, "Effect of oestrogen dose on whole blood platelet activation in women taking new low dose oral contraceptives," Thromb. Haemost. 72(6), 926-930, 1994: "Increased levels of ADP and arachidonic acid-induced aggregation were observed in women taking the 30 microgram ethinyloestradiol combination. Platelet release of beta-thromboglobulin (beta TG) was also significantly increased. Increased collagen-induced aggregation was observed but this failed to reach statistical significance for the individual treatment groups.") Estrogen dominance is an essential factor in preeclampsia. Women who have died of (eclamptic) convulsions have been found to have massive clots in their brain blood vessels. Much of this work had its origin in the 1930s (Shute and others), and was buried by the power of the estrogen industry.

H. Darmani, et al., "Interferon-gamma and polyunsaturated fatty acids increase the binding of lipopolysaccharide to macrophages," Int. J. Exp. Pathol. 75(5), 363-368, 1994.

G. Autore, et al., "Essential fatty acid-deficient diet modifies PAF levels in stomach and duodenum of endotoxin-treated rats," J. Lipid Mediators Cell Signalling 9, 145-153, 1994. Deficiency of "essential" fats decreases damage from endotoxin.

N. Auge, et al., "Proliferative and cytotoxic effects of mildly oxidized low-density lipoproteins on vascular smooth-muscle cells," Biochem. J. 309(Part 3), 1015-1020, 1995. "The proliferative effect on smooth-muscle cells is counterbalanced at high concentrations of mildly oxidized LDLs (or at high oxidation levels) by their cytotoxic effect."

S. K. Clinton, et al., "The combined effects of dietary fat and estrogen on survival, 7,12-dimethyl- benz(a)-anthracene-induced breast cancer and prolactin metabolism in rats," J. Nutr. 125(5), 1192-1204, 1995. "Mortality in controls was doubled by feeding a high fat diet...." "...the presence of estrogen may be a prerequisite for significant dietary modulation."

R. Sanchez Olea, et al., "Inhibition by polyunsaturated fatty acids of cell volume regulation and osmolyte fluxes in astrocytes," Amer. J. of Physiology--cell physiology 38(1), C96-C102, 1995. "...potent blockers of regulatory volume decrease and of the swelling-activated efflux of taurine, D-aspartate, inositol, and I-125 (used as marker of Cl). ...oleic and ricinoleic acids and saturated fatty acids were ineffective." "...polyunsaturated fatty acids directly inhibit the permeability pathways correcting cell volume after swelling in cultured astrocytes."

M. E. Miller, et al., "Influence of hormones on platelet intracellular calcium," Thrombosis Research 77(6), 515-530, 1995. "Platelet intracellular calcium concentration and release was significantly decreased in women ingesting tamoxifen compared to controls and significantly increased, as was platelet adhesion, in oral contraceptive users." "Only oral contraceptive users had increased sensitivity to aggregating agents. (...platelet calcium levels are closely related to the degree of platelet adhesion and aggregation in vivo."

F. Mercure and G. Vanderkraak, "Inhibition of gonadotropin-stimulated ovarian steroid production by PUFA in teleost fish," Lipids 30(6), 547-554, 1995. "EPA and DHA inhibited gonadotropin-stimulated testosterone production in a dose-related manner...."

A A Farooqui, K Wells, L A Horrocks, "Breakdown of membrane phospholipids in Alzheimer disease--involvement of excitatory amino acid receptors," Mol Chem Neuropathol 25(2-3) 155-173, 1995. "The release of arachidonate from the sn-2 position of glycerophospholipids is catalyzed by phospholipases and lipases. These enzymes are coupled to EAA receptors. Overstimulation of these receptors may be involved in abnormal calcium homeostasis, degradation of membrane phospholipids, and the accumulation of free fatty acids, prostaglandins, and lipid peroxides. Accumulation of the mentioned metabolites, as well as abnormalities in signal transduction owing to stimulation of lipases and phospholipases, may be involved in the pathogenesis of the neurodegeneration in AD."

Leo Loeb, V. Suntzeff, and E. L. Burns, "Changes in the nature of the stroma in vagina, cervix and uterus of the mouse produced by long-continued injections of estrogen and by advancing age," The American Journal of Cancer 35(2), 159-174, 1939. Loeb, et al., speak of collagenous deposits as fibrous-hyaline tissue, varying from a fibrillar to a homogeneous appearance, and varying in consistency from very dense and glassy in appearance, to the softer gelatinous substance between cells and around arteries and glands. This material increases with aging and eventually appears between cells in the muscular part of the uterus. With the injection of moderate amounts of estrogen, the quantity of the material is increased. When large amounts of estrogen are injected, "The connective tissue and muscle appear rarefied, almost as though they were perforated by a large number of small holes." "...this condition is presumably due to a deposit of a mixture of hyaline material and edematous fluid...." "This process of hyalinization...is counteracted by invasion by connective tissue." In this way there may take place in many areas a substitution and organization of the hyaline material by connective tissue, in which dilated capillaries may also be visible." "There is a second process which in many cases accompanies the invasion and organization of hyaline substance by connective tissue, namely a formation, at the margin of the hyaline material, of epithelioid and of small giant cells possessing more than one nucleus." "As a rule, the epithelioid cells are seen alone; giant cells are more rare." "...the connective-tissue fibrils may in places appear somewhat separated, perhaps by edematous fluid." "The first changes consist very likely in the transudation of fluid from the vessels into the connective tissue." "It seems, then, that at a very early stage after the beginning of the injections of effective doses of estrogen, a liquid substance which separates the connective-tissue elements makes its appearance, and that this represents one of the earliest changes induced by the hormone. It may be accompanied, or soon followed, by the deposit of a hyaline substance which occurs first between the connective-tissue cells, but may extend also to the muscle fibers." "...the deposit of hyaline which progressively becomes more and more devoid of connective-tissue cells and blood vessels, is so marked that the material acts like a foreign body...." "While it may be found also around blood vessels, such deposits are less conspicuous than in other organs in mice, such as the mammary gland.... There is a tendency for the hyaline substance to form sheaths around various organs and it is more prominent at the border separating different tissues and organs." "In its appearance and in the foreign body reactions which it initiates this substance somewhat resembles amyloid, which is readily produced in mice in various groups. The application of stains differentiating amyloid from other hyaline material, however, gave negative results."

Leo Loeb, V. Suntzeff, and E. L. Burns, "The effects of age and estrogen on the stroma of vagina, cervix and uterus in the mouse," Science 88(22, Nov. 4), 1938. "...large amounts of a hyaline substance are deposited, which act as foreign bodies and cause the formation of epithelioid and giant cells and an ingrowth of connective tissue. Thus an organization of this substance is attempted, which is interrupted, however, by renewed deposition of this hyaline material." "No definite statement can be made at present as to the chemical nature of this substance and its possible relation to a plasma constituent, except that it is not amyloid." "...a very intense fibrosis and hyalinization of the stroma which may induce abnormal reactions in the surrounding tissue. In this way it seems to be possible to accelerate and intensify very much some of the old age changes in certain organs."

P. H. Chan and R. A. Fishman, "Brain edema: Induction in cortical slices by polyunsaturated fatty acids," Science 201, 358-369, 1978. "This cellular edema was specific, since neither saturated fatty acids nor a fatty acid containing a single double bond had such effect."

C. LarssonBackstrom, et al., "Effects of dietary alpha- and gamma-linolenic acids on liver fatty acids, lipid metabolism, and survival in sepsis," Shock 4(1), 11-20, 1995. "Dietary GLA reduced survival from sepsis."

D. Chemla, et al., "Influence of dietary polyunsaturated fatty acids on contractility, inotropy and compliance of isolated rat myocardium, J mol Cell Cardiol 27(8), 1745-1755, 1995. "There was a trend towards a lower peak lengthening velocity at preload in the LC (n-3) group...together with an unchanged peak rate of isometric force decline. This resulted in a significant impairment of the two mechanical indexes testing the load dependence of myocardial relaxation." See B. Pieske, Circul. 92(5), 1169-78

R. Lerner, et al., "Development and characterization of essential fatty acid deficiency in human endothelial cells in culture," Proc Natl Acad Sci USA 92(4), 1147-1151, 1995. Oleic acid derivative 5,8,11-eicosatrienoic acid (20:3 omega 9) (5,8,11,14,17 eicosapentaenoic, 20-5 omega 3)); 20:3 omega 9 impaired the Ca2(i) response, indicating a suppressive effect of it. (Agonist-induced increases in concentrations of prostacycline PGI 2, and cytosolic Ca2+ were reduced in efad cells.)

K. Imaizumi, et al., "Dissociation of protein kinase C activities and diacylglycerol levels in liver plasma membranes of rats on coconut oil and safflower oil diets," J. Nutr Biochem 6(10), 528-533, 1995. "The activation of PKC is affected differently in vitro by different fatty acids." "Rats on coconut oil...had a markedly lower PKC activity in liver plasma membranes with slight but significant reduction of the activity in the cytosol than did rats fed safflower oil...." "...coconut oil resulted in a higher content of diacylglycerols in these membranes than did ingestion of safflower oil, whereas the proportions of saturated fatty acids and phospholipids and membrane fluidity were similar between rats ingesting different fats." "It seems likely that saturated fats exert various physiological effects on lipid and lipoprotein metabolism, in part through PKC pathways."

V. Boutard, et al., "Fish oil supplementation and essential fatty acid deficiency reduce nitric oxide synthesis by rat macrophages," Kidney Int. 46(5), 1280-1286, 1994. "Both...have been shown to exert anti-inflammatory effects...."

A A Farooqui, K Wells, L A Horrocks, "Breakdown of membrane phospholipids in Alzheimer disease--involvement of excitatory amino acid receptors," Mol Chem Neuropathol 25(2-3) 155-173, 1995. "The release of arachidonate from the sn-2 position of glycerophospholipids is catalyzed by phospholipases and lipases. These enzymes are coupled to EAA receptors. Overstimulation of these receptors may be involved in abnormal calcium homeostasis, degradation of membrane phospholipids, and the accumulation of free fatty acids, prostaglandins, and lipid peroxides. Accumulation of the mentioned metabolites, as well as abnormalities in signal transduction owing to stimulation of lipases and phospholipases, may be involved in the pathogenesis of the neurodegeneration in AD."

P. H. Chan and R. A. Fishman, "Transient formation of superoxide radicals in polyunsaturated fatty acid-induced brain swelling," J. of Neurochemistry 35, 1004-1007, 1980.

J. S. Jensen, et al., "Microalbuminuria reflects a generalized transvascular albumin leakiness in clinically healthy subjects," Clin Sci 88(6), 629-633, 1995. "In epidemiological studies microalbuminuria, i.e., slightly elevated urinary albumin excretion rate, predicts increased atherosclerotic vascular morbidity and mortality." "In animal experiments the outflux of albumin and lipids to the arterial wall are highly correlated, and both are elevated in atherosclerosis." "...microalbuminuria is an independent marker of systemic transvascular albumin leakiness in clinically healthy subjects."

H. M. Wisniewski and P. B. Kozlowski, "Evidence for blood-brain barrier changes in senile dementia of the alzheimer type (SDAT)", Ann. N. Y. Acad. Sci. 396, 119-129, 1982. "...one would expect that the chronic "flooding" of the neuronal elements with serum proteins would affect their performance." "The cause of the increased BBB permeability in SDAT is unknown."

F. Laszlo, et al., "Association of microvascular leakage with induction of nitric oxide synthase: Effects of nitric oxide synthase inhibitors in various organs," Eur. J. Pharmacol. 283(1-3), 47-53, 1995. "...assessed by the vascular leakage of ... albumin." "Endotoxin...induced the expression of a calcium-independent nitric oxide synthase...."

C. Nilsson, et al., "The nocturnal increase in human cerebrospinal fluid production is inhibited by a beta(1)-receptor antagonist," Amer. J. Physiol.--Regul. Integr. C 36(6), R1445-R1448, 1994.

S. Capsoni, et al., "Reduction of regional cerebral blood flow by melatonin in young rats," Neuroreport 6(9), 1346-1348, 1995. "...reduced in the cerebral areas supplied by circle of Willis and the basilar arteries. [Also to the] ...choroid plexuses."

A. C. Bowling and M. F. Beal, "Bioenergetic and oxidative stress in neurodegenerative diseases," Life Sci. 56(14), 1151-1171, 1995. "Defects in energy metabolism and increased cortical lactate levels have been detected in Huntington's disease patients. Studies of Alzheimer's disease patients have identified decreased [mitochondrial] complex IV activity...." "The age-related onset and progressive course of these neurodegenerative diseases may be due to a cycling process betwen impaired energy metabolism and oxidative stress."

K. Nakai, et al., "Regeneration of norepinephrine-containing fibers in occipital cortex of adult cats," Brain Res. Bull. 35(5-6), 409-412, 1994. "The present results indicate that the regenerative ability of the central NE neurons is universal, not limited to the immature brain. ...equipped with a transmitter-specific repair mechanism throughout life."

A. Bhatnagar, "Biochemical mechanism, of irreversible cell injury caused by free radical-initiated reactions," Mol. Cell. Biochem. 137(1), 9-16, 1994. "...free radical-induced irreversible cell injury results from a loss of protein thiols."

L. Balazs and M. Leon, "Evidence of an oxidative challenge in the Alzheimer's brain," Neurochem. Res. 19(9), 1131-1137, 1994. "These data suggest that the entire Alzheimer's brain may be subject to an oxidative challenge, but that some brain areas may be more vulnerable than others to the consequent neural damage that characterizes the disease."

J. A. Court and E. K. Perry, "CNS nicotinic receptors--possible therapeutic targets in neurodegenerative disorders," CNS Drugs 2(3), 216-233, 1994. "...epidemiological evidence suggests that later in life tobacco smoking may offer some protection against Parkinson's and Alzheimer's diseases."

N. A. Simonian and B. T. Hyman, "Functional alterations in Alzheimer's disease: Selective loss of mitochondrial-encoded cytochrome oxidase mRNA in the hippocampal formation," J. Neuropathol. Exp. Neurol. 53(5), 508-512, 1994.

A. M. Proenze, et al., "Estrogen effects on blood amino acid compartmentation," Life Sci. 57(17), 1589-1587, 1995.

S. S. Smith, "Sensorimotor-correlated discharge recorded from ensembles of cerebellar Purkinje cells varies across the estrous cycle of the rat," J. Neurophysiol. 74(3), 1095-1108, 1995. "...estradiol augments excitatory responses of cerebellar Purkinje cells to...glutamate...."

C. F. Lim, et al., "Influence of nonesterified fatty acid and lysolecithins on thyroxine binding to thyroxine-binding globulin and transthyretin," Thyroid 5(4), 319-324, 1995. "Unsaturated nonesterified fatty acids...inhibited T4 binding to TBG." "Saturated NEFAs...were inactive."

O. V. Sviridov, "Specific binding of thyroid hormones by human plasma apolipoproteins: A new property of known proteins," Biochemistry (Engl. translation) 59(5), 457-466, 1884.

T. Parasassi, et al., "Cholesterol protects the phospholipid bilayer from oxidative damage," Free Radical Biology & Medicine 19(4), 511-516, 1995.

A. G. Herzog, "Progesterone therapy in women with complex partial and secondary generalized seizures," Neurology 45(9), 1660-1662, 1995.

Z. Q. Ma, et al., Estrogenic control of monoamine oxidase A activity in human neuroblastoma cells expressing physiological concentrations of estrogen receptor," Eur. J. Pharmacol. 284(1-2), 171-176, 1995.

J. G. Belasco and G. Brawerman, Control of Messenger RNA Stability, Academic Press, NY, 1994.

Leo Loeb, V. Suntzeff, and E. L. Burns, "Changes in the nature of the stroma in vagina, cervix and uterus of the mouse produced by long-continued injections of estrogen and by advancing age," The American Journal of Cancer 35(2), 159-174, 1939. Loeb, et al., speak of collagenous deposits as fibrous-hyaline tissue, varying from a fibrillar to a homogeneous appearance, and varying in consistency from very dense and glassy in appearance, to the softer gelatinous substance between cells and around arteries and glands. This material increases with aging and eventually appears between cells in the muscular part of the uterus. With the injection of moderate amounts of estrogen, the quantity of the material is increased. When large amounts of estrogen are injected, "The connective tissue and muscle appear rarefied, almost as though they were perforated by a large number of small holes." "...this condition is presumably due to a deposit of a mixture of hyaline material and edematous fluid...." "This process of hyalinization...is counteracted by invasion by connective tissue." In this way there may take place in many areas a substitution and organization of the hyaline material by connective tissue, in which dilated capillaries may also be visible." "There is a second process which in many cases accompanies the invasion and organization of hyaline substance by connective tissue, namely a formation, at the margin of the hyaline material, of epithelioid and of small giant cells possessing more than one nucleus." "As a rule, the epithelioid cells are seen alone; giant cells are more rare." "...the connective-tissue fibrils may in places appear somewhat separated, perhaps by edematous fluid." "The first changes consist very likely in the transudation of fluid from the vessels into the connective tissue." "It seems, then, that at a very early stage after the beginning of the injections of effective doses of estrogen, a liquid substance which separates the connective-tissue elements makes its appearance, and that this represents one of the earliest changes induced by the hormone. It may be accompanied, or soon followed, by the deposit of a hyaline substance which occurs first between the connective-tissue cells, but may extend also to the muscle fibers." "...the deposit of hyaline which progressively becomes more and more devoid of connective-tissue cells and blood vessels, is so marked that the material acts like a foreign body...." "While it may be found also around blood vessels, such deposits are less conspicuous than in other organs in mice, such as the mammary gland.... There is a tendency for the hyaline substance to form sheaths around various organs and it is more prominent at the border separating different tissues and organs." "In its appearance and in the foreign body reactions which it initiates this substance somewhat resembles amyloid, which is readily produced in mice in various groups. The application of stains differentiating amyloid from other hyaline material, however, gave negative results."

Leo Loeb, V. Suntzeff, and E. L. Burns, "The effects of age and estrogen on the stroma of vagina, cervix and uterus in the mouse," Science 88(22, Nov. 4), 1938. "...large amounts of a hyaline substance are deposited, which act as foreign bodies and cause the formation of epithelioed and giant cells and an ingrowth of connective tissue. Thus an organization of this substance is attempted, which is interrupted, however, by renewed deposition of this hyaline material." "No definite statement can be made at present as to the chemical nature of this substance and its possible relation to a plasma constituent, except that it is not amyloid." "...a very intense fibrosis and hyalinization of the stroma which may induce abnormal reactions in the surrounding tissue. In this way it seems to be possible to accelerate and intensify very much some of the old age changes in certain organs."

Winfried G. Rossmanith, "Gonadotropin secretion during aging in women: Review article," Exp. Gerontology 30(3/4) 369-381, 1995. "...major functional derangements, primarily at a hypothalamic rather than a pituitary site, have been determined as concomitants of aging in women." "...aging may impair the negative feedback sensitivity to ovarian sex steroids...." Hormonal changes at menopause "may represent the sum of functional aberrations that were initiated much earlier in life...." "...prolonged estrogen exposure facilitates the loss of hypothalamic neurons...."

J. R. Brawer, et al., "Ovary-dependent degeneration in the hypothalamic arcuate nucleus," Endocrinology 107, 274-279, 1980.

G. C. Desjardins, "Estrogen-induced hypothalamic beta-endorphin neuron loss: A possible model of hypothalamic aging," Exp. Gerontology 30(3/4), 253-267, 1995. "This loss of opioid neurons is prevented by treatment with antioxidants indicating that it results from estradiol-induced formation of free radicals." "...this beta-endorphin cell loss is followed by a compensatory upregulation of mu opioid receptors in the vicinity of LHRH cell bodies." Resulting supersensitivity of the cells results "in chronic opioid suppression of the pattern of LHRH release, and subsequently that of LH." The neurotoxic effects of estradiol causes a "cascade of neuroendocrine aberrations resulting in anovulatory acyclicity." Treatment with an opiod antagonist "reversed the cystic morphology of ovaries and restored normal ovarian cycles" in estrogen-treated rats.

G. B. Melis, et al., "Evidence that estrogens inhibit LH secretion through opioids in postmenopausal women using naloxone," Neuroendocrinology 39, 60-63, 1984.

H. J. Sipe, et al., "The metabolism of 17 beta-estradiol by lactoperoxidase: A possible source of oxidative stress in breast cancer," Carcinogenesis 15(11), 2637-2643, 1994. "...molecular oxygen is consumed by a sequence of reactions initiated by the glutathione thiyl radical. ...the estradiol phenoxyl radical abstracts hydrogen from...NADH to generate the NAD radical." "...the futile metabolism of micromolar quantities of estradiol catalyzes the oxidation of much greater concentrations of biochemical reducing cofactors, such as glutathione and NADH, with hydrogen peroxide produced as a consequence."

S. Santagati, et al., "Estrogen receptor is expressed in different types of glial cells in culture," J. Neurochem. 63(6), 2058-2064, 1994. "...in all three types of glial cell analyzed in almost equal amounts..."

D. X. Liu and L. P. Li, "Prostaglandin F-2 alpha rises in response to hydroxyl radical generated in vivo," Free Radical Biol. Med. 18(3), 571-576, 1995. "Free radicals and some free fatty acids, such as arachidonic acid metabolites...may form a feedback loop in which generation of one type leads to formation of the other." "Prostaglandin F-2 alpha dramatically increased in response to hydroxyl radical generation...."

J. Owens and P. A. Schwartzkroin, "Suppression of evoked IPSPs by arachidonic acid and prostaglandin F-2 alpha," Brain Res. 691(1-2), 223-228, 1995. "These findings suggest that high levels of AA and its metabolites may bias neurons towards excitation."

E. A. Quail and G. C. T. Yeoh, "The effect of iron status on glyceraldehyde 3-phosphate dehydrogenase expression in rat liver," FEBS Lett. 359(2-3), 126-128, 1995. "...the overexpression of GAPDH mRNA in iron deficiency is probably due to increased message stability." [This is one of the points discussed by Henics. Estrogen, which increases iron retention, also modifies mRNA stability.]

J. G. Liehr, et al., "4-hydroxylation of estradiol by human uterine myometrium and myoma microsomes: Implications for the mechanism of uterine tumorigenesis," Proc Natl Acad Sci USA 92(20), 9220-9224, 1995. "... elicits biological activities distinct from estradiol, most notably an oxidant stress response induced by free radicals generated by metabolic redox cycling reactions."

J. G. Liehr and D. Roy, "Free radical generation by redox cycling of estrogens," Free Rad. Biol. Med. 8, 415-423, 1990.

F. Fourrier, Circ. Shock 43(4), 171-178, 1994, "High estrogen levels were specifically observed in patients with sepsis and septic shock, either males or females." "Circulating T levels were decreased in all male patients."

J. A. Jarvis, et al., "H-1 NMR analysis of fibril-forming peptide fragments of transthyretin," Int. J. Pept. Protein Res. 44(4), 388-398, 1994. "...fragments of the protein transthyretin, previously shown to form cross beta-sheet amyloid-like fibrils in vitro, were investigated...."

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<span class="koboSpan" id="kobo.1.1">Aspirin, brain, and cancer</span> A R T I C L E

Aspirin, brain, and cancer

When a drug such as caffeine or aspirin turns out to have a great variety of protective effects, it's important to understand what it's doing.

Because aspirin has been abused by pharmaceutical companies that have competing products to sell, as well as by the original efforts to promote aspirin itself, people can easily find reasons why they shouldn't take it.

Early in the 20th century, people were told that fevers were very bad, and that aspirin should be used whenever there is a fever.

In the 1980s, there was a big publicity campaign warning parents that giving aspirin to a child with the flu could cause the potentially deadly Reye syndrome. Aspirin sales declined sharply, as sales of acetaminophen (Tylenol, etc.) increased tremendously. But in Australia, a study of Reye syndrome cases found that six times as many of them had been using acetaminophen as had used aspirin. (Orlowski, et al., 1987)

Until the 1950s and 1960s, when new products were being promoted, little was said about the possibility of stomach ulceration from aspirin. Lately, there has been more publicity about the damage it can do to the stomach and intestine, much of it in connection with the sale of the new "COX-2 inhibitors." (These new drugs, rather than protecting the circulatory system as aspirin does, damage it.) Aspirin rapidly breaks down into acetic acid and salicylic acid (which is found in many fruits), and salicylic acid is protective to the stomach and intestine, and other organs. When aspirin was compared with the other common antiinflammatory drugs, it was found that the salicylic acid it releases protects against the damage done by another drug. (Takeuchi, et al, 2001; Ligumsky, et al., 1985.) Repeated use of aspirin protects the stomach against very strong irritants. The experiments in which aspirin produces stomach ulcers are designed to produce ulcers, not to realistically model the way aspirin is used.

Recently, the public has been led to believe that drugs are being designed to fit certain cellular "receptors." The history of the "COX-2 inhibitors" is instructive, in a perverse way. The structures of DES and other synthetic estrogens were said to relate to "the estrogen receptor." Making these estrogenic molecules more soluble in water made them somewhat anti-estrogenic, leading to products such as Tamoxifen. But some of the molecules in this group were found to be antiinflammatory. The structure of Celecoxib and other "COX-2 inhibitors" is remarkably similar to the "designer estrogens." Considering this, it's a little odd that so few in the U.S. are openly discussing the possibility that estrogen's function is directly related to inflammation, and involves the production of many inflammatory mediators, including COX-2. (See Lerner, et al., 1975; Luo, et al., 2001; Cushman, et al, 2001; Wu, et al., 2000; Herrington, et al., 2001.)

Soot and smoke contain many chemicals that produce inflammation (Brune, et al., 1978). In the 1930s, soot was known to be both carcinogenic and estrogenic, and analysis of its components led to the production of the early commercial estrogens. Any intelligent person reading the chemical and biological publications of that time will see how closely associated cancer, inflammation, and estrogen are.

Soon after vitamin E was discovered, tocopherol was defined as a brain-protective, pregnancy protective, male fertility protective, antithrombotic, antiestrogenic agent. But very soon, the estrogen industry made it impossible to present ideas that explained vitamin E, progesterone, vitamin A, or thyroid hormone in terms of the protection they provide against estrogenic substances. Since the polyunsaturated fats caused the same conditions that were caused by unopposed estrogen, vitamin E came to be known as an "antioxidant," because it reduced their toxicity. (Vitamin E is now known to suppress COX-2, synergizing with aspirin and opposing estrogen.)

In 1970, when I was beginning to see the ways in which unopposed estrogen and accumulated polyunsaturated fats interacted with a vitamin E deficiency during aging and in infertility, I got some prostaglandins to experiment with, since they are products of the oxidation of linoleic acid. The prostaglandins are an interesting link between estrogens and inflammation, in normal physiology as well as in disease.

I wanted to test their effects on the uterus, especially the sites where the embryos implant. There was a theory that the electrical charge of the surface of the uterus was decreased at the implantation sites, to reduce the repulsion between two negatively charged things. Although there were regions of lower surface charge along the lining of the uterus, the charge changed as waves of muscle contraction moved along the uterus, and the prostaglandins affected the contractions.

To understand the differences between the different types of prostaglandin, I tested them on my arm, and those with the most hydroxyl groups produced regions with an increased negative charge. For comparison, I exposed another spot to sunlight for an hour, and found that there was a similar increase in the negative charge in that spot. Apparently the prostaglandins were causing an injury or excitation, a mild inflammation, in the skin cells.

A few years later, aspirin was found to inactivate the enzyme that forms prostaglandins, by the transfer of the acetyl radical to the enzyme. This became the orthodox "explanation" for what aspirin does, though it neglected to explain that salicylic acid (lacking the acetyl radical) had been widely known in the previous century for its very useful antiinflammatory actions. The new theory did explain (at least to the satisfaction of editors of medical magazines) one of aspirin's effects, but it distracted attention from all the other effects of aspirin and salicylic acid.

Aspirin is an antioxidant that protects against lipid peroxidation, but it also stimulates mitochondrial respiration. It can inhibit abnormal cell division, but promote normal cell division. It can facilitate learning, while preventing excitotoxic nerve injury. It reduces clotting, but it can decrease excessive menstrual bleeding. These, and many other strangely beneficial effects of aspirin, strongly suggest that it is acting on very basic biological processes, in a coherent way.

In explaining aspirin's effects, as in explaining those of estrogen and progesterone, or polyunsaturated fats and vitamin E, I think we need concepts of a very broad sort, such as "stability and instability."

The COX (cyclooxygenase) enzymes, that make prostaglandins, are just one system among many that are activated by stress. Aromatase, that makes estrogen, enzymes that make histamine, serotonin and nitric oxide, the cytokines, and the stress-induced hormones of the pituitary and adrenal glands, are turned on in difficult situations, and have to be turned off when the threat has been overcome. The production of energy is the basis for overcoming all threats, and it has to be conserved in readiness for future needs.

The fetus produces saturated fats such as palmitic acid, and the monounsaturated fat, oleic acid, which can be turned into the Mead acid, ETrA (5,8,11-eicosatrienoic acid), and its derivatives, which are antiinflammatory, and some of which act on the "bliss receptor," or the cannibinoid receptor. In the adult, tissues such as cartilage, which are protected by their structure or composition from the entry of exogenous fats, contain the Mead acid despite the presence of linoleic acid in the blood.

At birth, the baby's mitochondria contain a phospholipid, cardiolipin, containing palmitic acid, but as the baby eats foods containing polyunsaturated fatty acids, the palmitic acid in cardiolipin is replaced by the unsaturated fats. As the cardiolipin becomes more unsaturated, it becomes less stable, and less able to support the activity of the crucial respiratory enzyme, cytochrome oxidase.

The respiratory activity of the mitochondria declines as the polyunsaturated oils replace palmitic acid, and this change corresponds to the life-long decline of the person's metabolic rate.

In old age, a person's life expectancy strongly depends on the amount of oxygen that can be used. When the mitochondria can't use oxygen vigorously, cells must depend on inefficient glycolysis for their energy.

Estrogen activates the glycolytic pathway, while interfering with mitochondrial respiration. This resembles the aged or stressed metabolism, in which lactic acid is produced instead of carbon dioxide.

Aspirin activates both glycolysis and mitochondrial respiration, and this means that it shifts the mitochondria away from the oxidation of fats, toward the oxidation of glucose, resulting in the increased production of carbon dioxide. Its action on the glycolytic enzyme, GAPDH, is the opposite of estrogen's.

The shift away from fat oxidation under the influence of aspirin doesn't lead to an accumulation of free fatty acids in the circulation, since aspirin inhibits the release of fatty acids from both phospholipids and triglycerides. Estrogen has the opposite effects, increasing fat oxidation while increasing the level of circulating free fatty acids, since it activates lipolysis, as do several other stress-related hormones.

The polyunsaturated fatty acids, such as linolenic, linoleic, arachidonic, EPA, and DHA, have many directly toxic, antirespiratory actions, apart from the production of the prostaglandins or eicosanoids. Just by preventing the release of these fatty acids, aspirin would have broadly antiinflammatory effects.

Since the polyunsaturated fats and prostaglandins stimulate the expression of aromatase, the enzyme that synthesizes estrogen, aspirin decreases the production of estrogen. So many of aspirin's effects oppose those of estrogen, it would be tempting to suggest that its "basic action" is the suppression of estrogen. But I think it's more likely that both estrogen and aspirin are acting on some basic processes, in approximately opposite ways.

Bioelectrical functions, and the opposition between carbon dioxide and lactic acid, and the way water is handled in cells, are basic conditions that have a general or global effect on all of the other more specific biochemical and physiological processes. Originally, estrogen and progesterone were each thought to affect only one or a few biochemical events, but it has turned out that each has a multitude of different biochemical actions, which are integrated in globally meaningful ways. The salicylic acid molecule is much smaller and simpler than progesterone, but the range of its beneficial effects is similar. Because of aspirin's medical antiquity, there has been no inclination to explain its actions in terms of an "aspirin receptor," as for valium and the opiates, leaving its biochemistry, except for the inadequate idea of COX-inhibition, simply unexplained.

If we didn't eat linoleic acid and the other so-called "essential fatty acids," we would produce large amounts of the "Mead acid," n-9 eicosatrienoic acid, and its derivatives. This acid in itself is antiinflammatory, and its derivatives have a variety of antistress actions. The universal toxicity of the polyunsaturated fats that suppress the Mead fats as they accumulate, and the remarkable vitality of the animals that live on a diet deficient in the essential fatty acids, indicate that the Mead fats are important factors in the stability of our mammalian tissues. This protective lipid system probably interacts with cellular proteins, modifying the way they bind water and carbon dioxide and ions, affecting their electrons and their chemical reactivity.

If salicylic acid and the structurally similar antiinflammatories, local anesthetics, muscle relaxants, expectorants, and antihistamines, act as surrogates for the absent Mead acid family, and thereby act as defenses against all the toxic effects of the unstable fats, it would explain the breadth and apparent coherence of their usefulness. And at the same time it explains some of the ways that estrogen goes out of control, when it exacerbates the toxicity of the accumulated unstable fats.

The competition between aspirin and salicylic acid, and other antiinflammatories, for the active site on the COX enzyme (Rao, et al., 1982), shows that the structural features of these molecules are in some ways analogous to those of the polyunsaturated fatty acids. Wherever there are phospholipids, free fatty acids, fatty acid esters, ethers, etc. (i.e., in mitochondria, chromosomes, cytoskeleton, collagen networks--essentially everywhere in and around the cell), the regulatory influence of specific fatty acids--or their surrogates--will be felt.

Although it would undoubtedly be best to grow up eating foods with relatively saturated fats, the use of aspirin preventively and therapeutically seems very reasonable under the present circumstances, in which, for example, clean and well ripened fruits are not generally available in abundance. Preventing blindness, degenerative brain diseases, heart and lung diseases, and cancer with aspirin should get as much support as the crazy public health recommendations are now getting from government and foundations and the medical businesses.

When people with cancer ask for my recommendations, they usually think I'm joking when I tell them to use aspirin, and very often they don't take it, on the basis of what seems to be a very strong cultural prejudice. Several years ago, a woman whose doctors said it would be impossible to operate on her extremely painful "inflammatory breast cancer," had overnight complete relief of the pain and swelling from taking a few aspirins. The recognized anti-metastatic effect of aspirin, and its ability to inhibit the development of new blood vessels that would support the tumor's growth, make it an appropriate drug to use for pain control, even if it doesn't shrink the tumor. In studies of many kinds of tumor, though, it does cause regression, or at least slows tumor growth. And it protects against many of the systemic consequences of cancer, including wasting (cachexia), immunosuppression, and strokes.

Opiates are the standard medical prescription for pain control in cancer, but they are usually prescribed in inadequate quantities, "to prevent addiction." Biologically, they are the most inappropriate means of pain control, since they increase the release of histamine, which synergizes with the tumor-derived factors to suppress immunity and stimulate tumor growth.

It has recently become standard practice in most places to advise a person who is having a heart attack to immediately chew and swallow an aspirin tablet.

The same better-late-than-never philosophy can be applied to Alzheimer's disease, Parkinson's disease, and other degenerative nerve diseases. Aspirin protects against several kinds of toxicity, including excitotoxicity (glutamate), dopamine toxicity, and oxidative free radical toxicity. Since its effects on the mitochondria are similar to those of thyroid (T3), using both of them might improve brain energy production more than just thyroid. (By activating T3, aspirin can sometimes increase the temperature and pulse rate.) Magnesium, niacinamide, and other nerve protective substances work together.

In multiple organ failure, which can be caused by profound shock caused by trauma, infection, or other stress, aspirin is often helpful, but carbon dioxide and hypertonic glucose and sodium are more important.

Aspirin, like progesterone or vitamin E, can improve fertility, by suppressing a prostaglandin, and improving uterine circulation.

Although the animal studies that showed stomach damage from aspirin often used single doses equivalent to 10 or 100 aspirin tablets, the slight irritation produced by a normal dose of aspirin can be minimized by dissolving the aspirin in water. The stomach develops a tolerance for aspirin over a period of a few days, allowing the dose to be increased if necessary. And both aspirin and salicylic acid can be absorbed through the skin, so rheumatic problems have been treated by adding the drug to bath water.

The unsaturated (n-6 and n-3) fats that accumulate in our tissues, instead of being part of the system for reestablishing order and stability, tend to amplify the instability that is triggered by excitation, by estrogen, or by external stresses.

I think it's important that we don't allow the drug publicists to obscure the broad importance of substances such as aspirin, vitamin E, progesterone, and thyroid. For 60 years, a myth that was created to sell estrogen has harmed both science and the health of many people.

REFERENCES

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J Pharmacol Exp Ther 1981 Aug;218(2):464-9. Protective effects of aspirin in endotoxic shock. Halushka PV, Wise WC, Cook JA.

J Pharmacol Exp Ther 2000 May; 293(2):417-25. Cyclooxygenase-2 contributes to N-methyl-D-aspartate-mediated neuronal cell death in primary cortical cell culture. Hewett SJ, Uliasz TF, Vidwans AS, Hewett JA

Med Hypotheses 1999 Apr;52(4):291-2. Genetic induction and upregulation of cyclooxygenase (COX) and aromatase (CYP19): an extension of the dietary fat hypothesis of breast cancer. Harris RE, Robertson FM, Abou-Issa HM, Farrar WB, Brueggemeier R A novel model of mammary carcinogenesis is proposed involving sequential induction and upregulation of cyclooxygenase and aromatase genes by essential fatty acids prominent in the US diet.

J Clin Endocrinol Metab 2001 Sep; 86(9):4216-22. Differential effects of E and droloxifene on C-reactive protein and other markers of inflammation in healthy postmenopausal women. Herrington DM, Brosnihan KB, Pusser BE, Seely EW, Ridker PM, Rifai N, MacLean DB. "E treatment resulted in 65.8% higher levels of C-reactive protein (P = 0.0002) and 48.1% higher levels of IL-6...." "These data provide additional evidence of a proinflammatory effect of E that may have adverse cardiovascular consequences."

J Natl Cancer Inst 1998 Mar 18;90(6):455-60. Expression of cyclooxygenase-1 and cyclooxygenase-2 in human breast cancer. Hwang D, Scollard D, Byrne J, Levine E "Our results suggest that overexpression of COX may not be unique to colon cancer and may be a feature common to other epithelial tumors."

Ginekol Pol 1999 Mar;70(3):126-34. [Evaluation of the effectiveness of a low-dose aspirin in the treatment of intrauterine growth retardation (IUGR)]. Kalinka J, Sieroszewski P, Hanke W, Laudanski T, Suzin J

J Cardiovasc Pharmacol 1995 Feb;25(2):273-81. Inhibitory effects of aspirin on coronary hyperreactivity to autacoids after arterial balloon injury in miniature pigs. Kuga T, Ohara Y, Shimokawa H, Ibayashi S, Tomoike H, Takeshita A. "Coronary vasoconstriction induced by histamine and serotonin were examined angiographically before, 1 h, 1 week, and 1 month after balloon injury in 29 hypercholesterolemic miniature pigs." "Hyperconstriction induced by the autacoids 1 h after injury were significantly less in groups B and C than in group A (p < 0.01). Hyperconstriction induced by autacoids 1 week after injury were significantly less in group B than in group A (p < 0.01) and were significantly less in group C than in group A (p < 0.01) or group B (p < 0.05)."

Proc Soc Exp Biol Med 1975 Feb;148(2):329-32. Correlation of anti-inflammatory activity with inhibition of prostaglandin synthesis activity of nonsteroidal anti-estrogens and estrogens (38532). Lerner EJ, Carminati P, Schiatti P.

Proc Soc Exp Biol Med 1985 Feb;178(2):250-3. Salicylic acid blocks indomethacin-induced cyclooxygenase inhibition and lesion formation in rat gastric mucosa. Ligumsky M, Guth PH, Elashoff J, Kauffman GL Jr, Hansen D, Paulsen G. "Salicylic acid has been shown to decrease gastric mucosal lesions induced by indomethacin in the rat."

Z Naturforsch [C] 2001 May-Jun; 56(5-6):455-63. Constant expression of cyclooxygenase-2 gene in prostate and the lower urinary tract of estrogen-treated male rats. Luo C, Strauss L, Ristimaki A, Streng T, Santti R.

Neuropharmacology 2000 Apr 27;39(7):1309-18. Mechanisms of the neuroprotective effect of aspirin after oxygen and glucose deprivation in rat forebrain slices. Moro MA, De Alba J, Cardenas A, De Cristobal J, Leza JC, Lizasoain I, Diaz-Guerra MJ, Bosca L, Lorenzo P "Apart from its preventive actions against stroke due to its antithrombotic properties, recent data in the literature suggest that high concentrations of ASA also exert direct neuroprotective effects." "We have found that ASA inhibits neuronal damage at concentrations lower than those previously reported (0.1-0.5 mM), and that these effects correlate with the inhibition of excitatory amino acid release, of NF-kappaB translocation to the nucleus and iNOS expression caused by ASA." "Our results also show that the effects of ASA are independent of COX inhibition. Taken together, our present findings show that ASA is neuroprotective in an in vitro model of brain ischaemia at doses close to those recommended for its antithrombotic effects."

Pediatrics 1987 Nov;80(5):638-42. A catch in the Reye. Orlowski JP, Gillis J, Kilham HA.

Prostaglandins Leukot Med 1982 Jul;9(1):109-15. Effect of acetaminophen and salicylate on aspirin-induced inhibition of human platelet cyclo-oxygenase. Rao GH, Reddy KR, White JG. "Recent studies have shown that salicylic acid, a metabolite of aspirin, effectively competes for the same site on the platelet cyclo-oxygenase enzyme."

Stroke 1997 Oct;28(10):2006-11. Acetylsalicylic acid increases tolerance against hypoxic and chemical hypoxia. Riepe MW, Kasischke K, Raupach A.

Cancer Res 1998 Dec 1;58(23):5354-60. Prevention of NNK-induced lung tumorigenesis in A/J mice by acetylsalicylic acid and NS-398. Rioux N, Castonguay A

J Endocrinol 1989 Jun;121(3):513-9. Indomethacin inhibits the effects of oestrogen in the anterior pituitary gland of the rat. Rosental DG, Machiavelli GA, Chernavsky AC, Speziale NS, Burdman JA.

Int J Cancer 2001 Aug 15;93(4):497-506. Cyclooxygenase inhibitors retard murine mammary tumor progression by reducing tumor cell migration, invasiveness and angiogenesis. Rozic JG, Chakraborty C, Lala PK.

Res Commun Mol Pathol Pharmacol 1998 Sep;101(3):259-68. Protective ability of acetylsalicylic acid (aspirin) to scavenge radiation induced free radicals in J774A.1 macrophage cells. Saini T, Bagchi M, Bagchi D, Jaeger S, Hosoyama S, Stohs SJ.

Mol Cell Biochem 1999 Sep;199(1-2):93-102. Antioxidant properties of aspirin: characterization of the ability of aspirin to inhibit silica-induced lipid peroxidation, DNA damage, NF-kappaB activation, and TNF-alpha production. Shi X, Ding M, Dong Z, Chen F, Ye J, Wang S, Leonard SS, Castranova V, Vallyathan V

J Physiol Paris 2001 Jan-Dec;95(1-6):51-7. Protection by aspirin of indomethacin-induced small intestinal damage in rats: mediation by salicylic acid. Takeuchi K, Hase S, Mizoguchi H, Komoike Y, Tanaka A. "Most of non-steroidal anti-inflammatory drugs (NSAIDs) except aspirin (ASA) produce intestinal damage in rats." "ASA did not provoke any damage, despite inhibiting (prostaglandin) PG production, and prevented the occurrence of intestinal lesions induced by indomethacin, in a dose-related manner."

FASEB J 2001 Oct;15(12):2057-72. Cyclooxygenase-independent actions of cyclooxygenase inhibitors. Tegeder I, Pfeilschifter J, Geisslinger G.

J Indian Med Assoc 1997 Feb;95(2):43-4, 47. Role of low dose aspirin in prevention of pregnancy induced hypertension. Tewari S, Kaushish R, Sharma S, Gulati N

J Chromatogr B Biomed Appl 1995 Jul 21;669(2):404-7. Aspirin inhibits collagen-induced platelet serotonin release, as measured by microbore high-performance liquid chromatography with electrochemical detection. Tsai TH, Tsai WJ, Chen CF.

Clin Exp Immunol 1991 Nov;86(2):315-21. Piroxicam, indomethacin and aspirin action on a murine fibrosarcoma. Effects on tumour-associated and peritoneal macrophages. Valdez JC, Perdigon G. "We also studied the effect on tumour development of three inhibitors of prostaglandin synthesis: indomethacin, piroxicam and aspirin. Intraperitoneal administration of these drugs during 8 d was followed by the regression of palpable tumours. Indomethacin (90 mg/d) induced 45% regression, while with piroxicam (two 400 mg/d doses and six 200 mg/d doses) and aspirin (1 mg/d) 32% and 30% regressions, respectively, were observed. The growth rate of nonregressing tumours, which had reached different volumes by the end of the treatment, was delayed to a similar extent by the three anti-inflammatory non-steroidal drugs (NSAID)."

Int J Radiat Biol 1995 May;67(5):587-96. Amelioration of radiation nephropathy by acetylsalicylic acid. Verheij M, Stewart FA, Oussoren Y, Weening JJ, Dewit L.

Semin Perinatol 1986 Oct;10(4):334-55. The role of arachidonic acid metabolites in preeclampsia. Walsh SW, Parisi VM.

Proc Natl Acad Sci U S A 1999 Apr 27;96(9):5292-7. Suppression of inducible cyclooxygenase 2 gene transcription by aspirin and sodium salicylate. Xu XM, Sansores-Garcia L, Chen XM, Matijevic-Aleksic N, Du M, Wu KK. "Aspirin and sodium salicylate at therapeutic concentrations equipotently blocked COX-2 mRNA and protein levels induced by interleukin-1beta and phorbol 12-myristate 13-acetate."

Hum Reprod 1994 Oct;9(10):1954-7. The benefits of low-dose aspirin therapy in women with impaired uterine perfusion during assisted conception. Wada I, Hsu CC, Williams G, Macnamee MC, Brinsden PR. "Higher pregnancy rates (47 versus 17%) were achieved in those taking aspirin from day 1 of HRT." "The addition of low-dose aspirin to a standard HRT protocol in women with impaired uterine perfusion is associated with improved blood flow and satisfactory pregnancy rates."

J Ethnopharmacol 1991 Sep;34(2-3):215-9. Radiation-protective and platelet aggregation inhibitory effects of five traditional Chinese drugs and acetylsalicylic acid following high-dose gamma-irradiation. Wang HF, Li XD, Chen YM, Yuan LB, Foye WO.

Fertil Steril 1997 Nov;68(5):927-30. Low-dose aspirin for oocyte donation recipients with a thin endometrium: prospective, randomized study. Weckstein LN, Jacobson A, Galen D, Hampton K, Hammel J. "Low-dose aspirin therapy improves implantation rates in oocyte donation recipients with a thin endometrium."

Dermatologica 1978;156(2):89-96. Effect of topical salicylic acid on animal epidermopoiesis. Weirich EG, Longauer JK, Kirkwood AH. In contrast to its antihyperplastic effect on pathological proliferation of the epidermis, salicylic acid promotes epidermopoiesis in the normal guinea pig skin. After the application of 1% w/w salicylic acid in acetone-ethanol for 4 weeks, the thickness of the surface epithelium was increased by 40% and that of the deep epithelium by 19%. The mitotic index rose by 17%.

Arch Exp Veterinarmed 1981;35(3):465-70. [Control of implantation in rats and sows by peroral administration of prostaglandin synthetase inhibitors. 2. Effects of prostaglandin F2 alpha, progesterone/estrone, and acetylsalicylic acid on implantation and various biochemical parameters of amniotic fluid in the rat] Wollenhaupt K, Steger H. "The highest number of normally developed (97 per cent) and the lowest number of degenerated foetuses (three per cent) were recorded following acetylsalicylic acid treatment, as compared to the control group (91 and nine per cent)."

Biomed Pharmacother 1999 Aug;53(7):315-8. Aspirin induced apoptosis in gastric cancer cells. Wong BC, Zhu GH, Lam SK

Scand J Immunol 2000 Oct;52(4):393-400. Tamoxifen decreases renal inflammation and alleviates disease severity in autoimmune NZB/W F1 mice. Wu WM, Lin BF, Su YC, Suen JL, Chiang BL. "It has been documented that sex hormone may play a role in the pathogenesis of murine lupus."

Science 2001 Aug 31;293(5535):1673-7. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE.

Since the 1970s, aspirin has been thought of as an inhibitor of prostaglandin synthesis, but that is only part of its effect. Sometimes its effect is the opposite of the effects of other prostaglandin inhibitors.

It protects against the harmful effects of estrogen, prolactin, serotonin, cortisol, histamine, and radiation (u.v., x-rays, gamma rays).

It prevents cancer, and can cause its regression. It inhibits vascular proliferation. It inhibits interleukin 6 (and other inflammatory cytokines), which is a factor in heart disease and breast and liver cancer.

It protects the brain, and can improve learning. It's an antioxidant, prevents cataracts, and protects against glycation in diabetes.

It prevents premature birth and prevents birth defects caused by diabetes, preeclampsia, and exposure to alcohol. It prevents recurrence of neural tube defects and protects against many of the gestational problems associated with lupus.

Although aspirin protects against uncontrolled cell proliferation, as in cancer and psoriasis, salicylic acid increases normal cell division in the skin.

Aspirin protects against many forms of shock and stess, and corrects imbalances in the nervous system.

It protects against several kinds of toxins involved in brain degeneration.

"Aspirin elevated ATP levels not only in intact cortical neurons but also in isolated brain mitochondria, an effect concomitant with an increase in NADH-dependent respiration by brain submitochondrial particles."

De Cristobal, et al., 2002

"The pharmacological action of salicylate cannot be explained by its inhibition of cyclooxygenase (COX) activity." ". . . salicylate exerts its antiinflammatory action in part by suppressing COX-2 induction. . . ." XM Xu, et al., 1999

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<span class="koboSpan" id="kobo.1.1">Autonomic systems</span> A R T I C L E

Autonomic systems

Historically, functions such as reason, emotion, and instinct were associated with particular nervous structures, and there was a reluctance to think that consciousness, like instinct, could be based on "reflexes." Eventually, this led to the idea of an autonomous nervous system which produced emotions and adjusted the body's functions, while the "central nervous system" was the seat of conscious thought, perception, and behavior.

Our individual cells have a degree of autonomy, consisting of the ability to sense their situation, integrate stimuli, and act adaptively. Their behavior is intelligently adaptive. The cells that make up the nervous system have this basic capacity for complex adaptive integration, but they also have the specialized role of serving as links between cells, and between cells and the environment.

The integration of the organism is most complete when the energy of each cell is optimal. The "autonomic nervous system," including nerves that are closely associated with the diverse organs and tissues, is easiest to understand as a system for integrating and optimizing energy throughout the organism.

This view suggests new ways of understanding imbalance in these nervous functions, and the diseases that develop under the imbalanced conditions--e.g., asthma, polycystic ovaries, menopausal symptoms, some skin diseases, multiple sclerosis, heart disease, and tumors.

Every organ has its own intrinsic nerve net, and the cortex of the brain adjusts each system to meet the adaptive needs of the organism.

When every cell is functioning optimally, and the organism is adapted to its environment, there is little need for intervention by the "transmitter substances."

People like Walter Cannon and Wilhelm Reich popularized the idea of the autonomic nervous system, but they were just systematizing ideas that had been developing since the beginning of the century. Their views were the context in which Selyes idea of stress developed.

The anatomical components of the nervous system that were called the sympathetic (fight or flight, adrenergic) system and the parasympathetic (vegetative) system are still important factors in physiological thinking, and despite the great complexity that has grown up around them, there is still a tendency to identify the systems with polarities of mood or emotion. The idea of polarities is useful, but it easily leads to error.

(The sympathetic system includes a chain of ganglia along the spine, and its functions include dilating the pupils and accelerating the heart. The parasympathetic system is also called the cranio-sacral system, from the location of its ganglia, and among its functions are slowing the heart and constricting the pupils. However, despite several decades of research, the actions of sympathetic and parasympathetic nerves in most organs arent understood.)

If the adrenaline side of the nervous system is responsible for the reactions to pain and threat, reactions of fear and rage, then the opposite side tends to be given attributes such as peace and pleasure, and the fact that these oppositions are often true has led to a climate in which the adrenergic reactions are seen as bad, and the opposite reactions as good. When adrenalin was identified as an agent of the sympathetic nervous system, there was a search for the opposing agent of the parasympathetic system. Histamine was an early candidate, before acetylcholine was discovered to be the main parasympathetic agent. This view of histamine was fostered by the older idea of trophic nerves, which easily became identified with the parasympathetic system. When acetylcholine was identified as the transmitter or agent of the parasympathetic system, it tended to take on many of the qualities, including the trophic functions, that had grown up around the idea of the parasympathetic system, but the emphasis on acetylcholine led to a general neglect of the associations of histamine, and the mast cells that produce much of it, with the autonomic nervous system. (The current trend seems to be emphasizing a close integration of mast cell function with nervous function.) Nitric oxide has recently been identified as another parasympathetic transmitter. Nitric oxide and histamine are both very important factors in degenerative inflammatory diseases, but their association with the parasympathetic nervous system has given them an aura of benevolence.

I think its useful to compare the autonomic nervous system with the pituitary, not just because some of the pituitary hormones are called trophic hormones (e.g., luteotrophic, adrenocorticotrophic), but because their important adaptive functions can themselves be the cause of serious problems. An excess of the thyroid stimulating hormone, for example, causes degeneration and cancer development in the thyroid gland, and animals deprived of their pituitary gland, but given thyroid, live longer than intact animals.

If slaves are starved and beaten frequently, they arent very productive, they dont live long, and they might rebel. Workers that are healthy and working for a common goal that they understand are more productive. Cells that are well energized perform their functions with minimal cues, but deprived cells that have to be forced to function are likely to die unexpectedly, or to reproduce inappropriately, or to change their identity.

Professors often make a strong impression on their students, but, especially in technical or scientific fields, they usually do this by controlling the discourse, so that radical questioning is excluded. What they dont know isnt knowledge. Under the pressure of getting a professional education, students appreciate organizing principles and mnemonic devices, but this gives traditional ways of systematizing knowledge tremendous power that, in practice, is far more important than mere experimental results. (Experiments that dont acknowledge the ruling metaphors are almost universally considered inadmissable, unpublishable.)

Some obvious questions about the autonomic system have been commonly ignored or minimized by physiologists. If stress is the stimulus that causes the sympathetic system to increase its activity, what is the stimulus for increased activity of the parasympathetic system? What accounts for the relative balance between the two sides of the system, or their imbalance? The fact that the answers arent obvious has left the questions largely to psychiatrists and psychologists. Wilhelm Reich, who tried to provide answers in terms of developmental interactions between the organism and its environment, found that the question led him to investigate psychosomatic disease, sexual repression, cancer, and fascism, with disastrous results for himself.

Chinese medicine was familiar with many of the functions of the autonomic nervous system at a time when western medicine was organized around the humors. Its easy for contemporary western people to see that the winds and the hot and cold principles of Chinese tradition are metaphors, but they are reluctant to see that their own system has grown up within very similar traditional metaphoric polarities.

The successes of even a good metaphor can cause people to neglect details that could support a more complete and accurate image of reality.

Contemporary science carries a load of bad metaphors, because the educational system doesnt tolerate a critical attitude. Potentially, a good metaphor (e.g., Vernadskys suggestion that an organism is a whirlwind of atoms) could blow away many bad metaphors, but the present organization of science is tending in the other direction: Commercial interests are creating a culture in which their metaphors are replacing the traditional science in which there was a certain amount of honest intellectual exploration.

In talking about consciousness, sleep, stress, biological rhythms, aging, and energy, I have often focussed on the efficient use of oxygen for energy production by the mitochondria, i.e., cellular respiration. Every situation demands a special kind of adaptation, and each kind of adaptation requires a special distribution of cellular and organic activity, with its supporting local respiratory activity.

There is a lot of local self-regulation in the adapting organism, for example when the activated tissue produces increased amounts of carbon dioxide, which dilates blood vessels, delivering more oxygen and nutrients to the tissue. But the distribution of excitation, and the harmonious balancing of the organisms resources and activities, is achieved by the actions of the cortex of the brain, acting on the subordinate nerve nets, adjusting many factors relating to energy production and use.

On the level of the mitochondria, adrenaline and acetylcholine have slightly different effects. (Metabolic studies with isolated mitochondria are so remote from the normal cellular condition that their results are nothing more than a hint of what might be occurring in the cell.) Acetylcholine appears to shift the proportion of the fuels used (increasing the oxidation of alpha-ketoglutarate, with the production of carbon dioxide) and increasing the efficiency of energy conservation (phosphorylation, producing ATP) so that less oxygen is needed, while adrenaline increases the rate of oxygen consumption (and succinate oxidation). This would be consistent with F. Z. Meersons conception of the parasympathetic function as one of the stress limiting systems.

On the level of the whole cell, organ, and organism, the parasympathetic function limits oxygen consumption in a variety of ways, including the reduction of blood flow. Acetylcholine, like histamine and serotonin, activates glycolysis, the conversion of glucose to lactic acid, which provides energy in the absence of oxygen.

The effects of a little adrenaline, and a lot of adrenaline, are very different, with a high concentration of adrenaline decreasing the efficiency of phosphorylation. In the stressed heart, this effect of excess adrenaline can be fatal, especially when it is combined with adrenalines acceleration of clotting, liberation of fatty acids, and frequently of calcium, and constriction of blood vessels.

Seventy years ago, autonomic control of blood vessels seemed to be a matter of nerve fibers that constrict them, and other fibers that cause them to dilate, but that idea hasnt worked for a long time.

Ever since I noticed that the students in our physiology lab who tried to use adrenaline to revive their rats werent successful, I have wondered about the television shows in which adrenaline is given to patients with heart problems. Under some conditions adrenaline does increase circulation to the heart, but extreme stress doesnt seem to be among those conditions.

Too much serotonin, histamine, acetylcholine, and polyunsaturated fatty acids, like too much adrenalin, can cause spasms of the coronary arteries, along with disturbances of mitochondrial respiration. In stress, these substances are almost sure to be present in excess. (Anti-serotonin drugs are effective for a variety of heart problems, and other degenerative diseases.)

By increasing the production of lactic acid and the loss of carbon dioxide, exaggerated nervous stimulation (especially the excess of acetylcholine, histamine, and serotonin) can cause a variety of problems, including generalized vasoconstriction and systemic alkalosis, as well as increased intracellular alkalinity. This metabolic pattern is characteristic of many kinds of stress, including cancer. (Elsewhere, I have referred to this pattern as relative hyperventilation.) The metabolic effects probably account for some of the paradoxical effects of the autonomic agents.

When nutrition and thyroid function, light, atmospheric pressure, and other conditions are favorable, the autonomic transmitters (e.g., acetylcholine, histamine, serotonin, adrenalin) and pituitary hormones and other signal substances are kept within safe limits.

Because the substances released from various cells under the influence of the autonomic nerves (histamine and serotonin, for example) stimulate cell division, injuries which produce clots and vascular spasms will also stimulate the formation of new blood vessels, a process that is essential for the adaptation of tissues to prolonged stress.

These stress-induced agents are appropriately included in the vegetative (parasympathetic) nervous system, because they promote vegetation, i.e., the proliferation of substance.

Adrenaline, and the sympathetic nerves, have the opposite function, of restraining cell division, and they also oppose the pro-inflammatory functions of those parasympathetic agents.

Estrogen tends to shift autonomic balance toward the parasympathetic side, away from the sympathetic/adrenergic. Recalling that stress, hypothyroidism, and aging increase the activity of aromatase in various tissues, with local production of estrogen, and that tissue-bound estrogen stays at a high level in postmenopausal women despite the lower level of estrogen in the serum, its worthwhile looking at the effects of estrogen on the various components of the so-called autonomic nervous system.

One injection of estrogen can induce a large increase in the number of sympathetic nerves in the ovaries. At menopause, a similar invasion of sympathetic nerves occurs. The polycystic ovary (which is even more common after menopause than before, and some studies have found the condition in 20% of premenopausal women) responds to estrogen by producing nerve growth factor(s), and growing a large number of new sympathetic nerves. Although the hyperestrogenism associated with the polycystic ovary syndrome has many harmful effects, the invasion of the ovary by adrenergic nerves apparently protects it from the development of cancer.

Parasympathetic nerves, pituitary hormones and mast cells activate the ovaries. The number of mast cells in the ovaries is increased by the pituitary hormones (including the thyroid stimulating hormone), and by estrogen (Jaiswal and Krishna, 1996). Estrogen is the most potent of these hormones in causing the cells to release histamine. The overgrowth of the sympathetic nerves in the polycystic ovary causes the number and activity of mast cells to decrease, possibly as a protective adaptation against excessive stimulation from the many pro-inflammatory factors. The mast cells are needed for the follicles to rupture, so their suppression prevents ovulation.

The nervous system is closely involved in controlling the growth of tissues, and it has been argued (R.E. Kavetsky reviewed the subject in his book, emphasizing the role of depression in development of cancer) that cancer results from reduced activity of the sympathetic nerves, or unopposed action of the parasympathetic system. That stress has a role in cancer is acknowledged by the scientific establishment, but the nervous systems direct involvement in the regulation of cellular metabolism, cell division, and other processes that are central to the cancerous state is either flatly denied or simply ignored.

Although mast cells have been known to be a common component of tumors for many years, it is only recently that antihistamines and other antiinflammatory drugs have been recognized as valuable therapies in cancer. The whole issue of the role of nerves in tumor development and physiology has been submerged by the mystique of the intrinsically bad cancer cell.

In Alzheimers disease, there has been a great investment in the doctrine that drugs to promote the function of cholinergic (acetylcholine forming) nerves will restore lost mental function, or at least retard the progression of the disease. The success of anticholinergic drugs in treating several degenerative brain diseases is probably embarrassing to the companies whose cholinergic-intensifying drugs arent very successful. Conveniently for them, these formerly anticholinergic drugs are now being called anti-excitotoxic or anti-glutamatergic drugs. There is no serious conflict in the terminology, since the cholinergic processes (like the serotonergic processes) are closely associated with excitotoxic nerve damage. The cholinergic drugs will probably be sold as long as their patents are effective, and then will be quietly forgotten.

The modern conception of pharmacology, with receptors and transmitters turning functions on or off, has turned into an unproductive and dangerous scholasticism. No one will ever successfully count the number of transmitter angels dancing on the variable sites of the variable receptor molecules. The functional meaning of a receptor or transmitter changes according to circumstances, and the effect of activating a particular nerve depends on surrounding conditions, and on preceding conditions. Each cell integrates stimuli adaptively.

If no reflex is simply mechanical and innate, then all reflexes are conditional. (M. Merleau-Ponty argued against the validity of the reflex concept itself, because of this conditionality.) P. K. Anokhins concept of the Acceptor of Action (described in my book, Mind and Tissue) provides an image in which we can see the set-points for the relatively autonomic reflexes as reflections of the general needs of the organism. The local tissue reflexes, the organ reflexes, the spinal reflexes, etc., are variable, according to their energetic resources, and according to the way in which they are organized under the influence of the cerebral cortex and the environment.

The reality is more complex than the philosophy of the drug industry imagines, but the solutions of problems can be much simpler, if we think in terms of energetic support, rather than the over-concretized interventions of the pharmacologists. In hypothyroidism, it is common for there to be an excess of adrenalin/noradrenalin, serotonin, histamine, and some of the pituitary hormones. Correcting thyroid function can immediately correct many problems, but especially when the energy deficiency has caused anatomical adjustments (redistribution of blood vessels and mast cells, for example) its important to make the environment supportive in as many ways as possible.

In polycystic ovaries, menopausal symptoms, arthritis, angina pectoris, multiple sclerosis, some kinds of dementia, migraine, and emphysema, the relief achieved with a simple improvement of cellular energy can be rapid and complete. Presumably a similar process of biological reorganization is involved in the occasional spontaneous regression of tumors.

Although I dont think the autonomic nervous system, with its sympathetic and parasympathetic divisions, exists in the way it has traditionally been conceived, the idea can be useful if we think of using drugs and other factors in ways that tend to quiet an overactive autonomic nervous system.

REFERENCES

Am J Emerg Med 1989 Sep;7(5):485-8. Coronary artery spasm induced by intravenous epinephrine overdose. Karch SB. A 27-year-old man was accidentally given 2 mg intravenous epinephrine instead of 2 mg naloxone. He immediately developed chest pain, nausea, and diaphoresis. An ECG taken shortly after the epinephrine administration showed widespread ischemia. Forty-five minutes later the tracing still showed an early repolarization pattern, but ST elevation was less marked and the patient was asymptomatic. Serum potassium was 3.2 mEq/L and serum catecholamines, drawn approximately 20 minutes after the epinephrine administration, were 10 times normal (dopamine, 173 ng/L; epinephrine, 1,628 ng/L; norepinephrine, 1,972 ng/L). There are seven other reports of intravenous epinephrine overdose in the English literature. Two of the previously reported cases had 12-lead ECGs within the first hour. In both there was evidence of transient ischemia similar to that observed in this case. Most of the patients had symptoms consistent with angina, and several developed pulmonary edema. These findings suggest that, in humans, large intravenous doses of epinephrine are likely to produce coronary artery spasm and may decrease coronary artery perfusion.

Res Exp Med (Berl) 1987;187(5):385-93. Possible interaction of platelets and adrenaline in the early phase of myocardial infarction. Seitz R, Leising H, Liebermann A, Rohner I, Gerdes H, Egbring R. It is known that in most cases of transmural acute myocardial infarction a platelet clot originates within a coronary artery. In acute myocardial infarction patients increased levels of the plasma catecholamines adrenaline and noradrenaline as well as the platelet release proteins platelet factor 4 and beta-thromboglobulin have been reported.

Anesthesiology 1991 Jun;74(6):973-9. Comment in: Anesthesiology. 1992 Mar;76(3):475. Magnesium inhibits the hypertensive but not the cardiotonic actions of low-dose epinephrine. Prielipp RC, Zaloga GP, Butterworth JF 4th, Robertie PG, Dudas LM, Black KW, Royster RL. Intravenous magnesium supplementation is often used to control cardiac arrhythmias and coronary artery vasospasm resulting from disturbances of magnesium homeostasis after coronary artery bypass surgery. Many such patients also require inotropic drug support of depressed myocardial function. However, increased serum magnesium concentrations directly depress cardiac contractility in animals and may interfere with catecholamine actions. To determine whether small intravenous doses of magnesium sulfate (MgSO4) interfere with the cardiotonic actions of epinephrine, we examined the hemodynamic effects of MgSO4 and epinephrine infusion in 17 cardiac surgical patients on their 1st postoperative day in a prospective, controlled study. In 11 patients, infusion of MgSO4 (7-mg.kg-1 bolus followed by 10 mg.kg-1.h-1 as a continuous infusion) increased serum magnesium concentrations by 44% (mean +/- standard error of the mean [SEM] of 0.8 +/- 0.1 to 1.2 +/- 0.1 mM; P less than 0.01) but had no significant effect on heart rate; mean arterial, central venous, or pulmonary arterial occlusion pressures; or cardiac output. Epinephrine infusion (30 ng.kg-1.min-1) significantly increased cardiac index (2.7 +/- 0.1 to 3.1 +/- 0.21.min-1.m-2; P less than 0.05); this effect was not altered by MgSO4 administration (n = 11). However, MgSO4 significantly blunted epinephrine's hypertensive action and prevented a significant increase in mean arterial pressure during concurrent MgSO4-epinephrine administration. Six placebo control patients were given two sequential infusions of epinephrine separated by a placebo infusion to rule out an effect of time on the hemodynamic response to epinephrine. Mean arterial pressure and cardiac index responses to epinephrine were identical before and after placebo infusion.

Jpn Heart J 1979 Jan;20(1):75-82. Inhibition of constrictor responses of dog coronary artery by atropine. A possible effectiveness of atropine on variant form of angina pectoris. Sakanashi M, Furukawa T, Horio Y. A possible effectiveness of atropine on variant form of angina pectoris was investigated using the left circumflex coronary arterial strips of dogs. Acetylcholine 10(-5)--10(-3) Gm/ml dose-dependently constricted the isolated arterial strips during potassium-contracture in 6 cases, and repetitive applications of acetylcholine could produce the similar contractions to the control. In 18 strips atropine 10(-6) Gm/ml significantly depressed the contractions of coronary arteries induced by acetylcholine 10(-5)--10(-3) Gm/ml. In 5 arterial strips atropine 10(-6) Gm/ml significantly inhibited norepinephrine-induced responses of these arteries, and by 10(-5) Gm/ml further suppression of the responses was obtained. The results suggest that atropine may suppress the contractile responses of the coronary artery induce by acetylcholine and nonrepinephrine through a muscarinic-receptor blocking action and simultaneously partly through an adrenergic alpha-receptor blocking action.

Eur J Clin Pharmacol 1981;20(4):245-50. Effect of long-term beta-blockade with alprenolol on platelet function and fibrinolytic activity in patients with coronary heart disease. Jurgensen HJ, Dalsgaard-Nielsen J, Kjoller E, Gormsen J.

C R Seances Soc Biol Fil 1987;181(3):242-8. [Adrenaline activates oxidative phosphorylation of rat liver mitochondria through alpha 1-receptors]. Breton L, Clot JP, Bouriannes J, Baudry M. We studied the effects and mode of action of epinephrine on the oxidative phosphorylation of rat liver mitochondria. With either succinate or beta-hydroxybutyrate as substrate, i.v. injection of 1.5 microgram/100 g epinephrine increased the respiratory rates by 30-40% in state 3 (with ADP), and by 20-30% in state 4 (after ADP phosphorylation), so that the respiratory control ratio (state 3/state 4) changed little. The respiratory stimulation by epinephrine was maximal 20 minutes after its injection. The action of epinephrine on mitochondria was blocked by pretreatment of the animals with the alpha 1-antagonist prazosin but not by treatment with the beta-antagonist propranolol. I. v. injection of 10 micrograms/100 g phenylephrine evoked the same mitochondrial response as epinephrine. I. v. administration of 50 micrograms/100 g dibutyryl cyclic AMP enhanced glycaemia but did not affect mitochondrial respiration. Epinephrine therefore has an alpha 1-type of action on mitochondrial oxidative phosphorylation.

Biochimie 1975;57(6-7):797-802. Effects of catecholamines on rat myocardial metabolism. I. Influence of catecholamines on energy-rich nucleotides and phosphorylated fraction contents. Merouze P, Gaudemer Y. 1. The influence of catecholamines (adrenaline and noradrenaline) on energy metabolism of the rat myocardium has been studied by incubating slices of this tissue with these hormones and by following the levels of the different phosphorylated fractions and adenylic nucleotides. 2. Similar effects are obtained with both hormones, adrenaline being more effective. 3. Catecholamines decrease significantly the total amount of phosphate while Pi content increases during the first 10 minutes of incubation; labile and residual phosphate contents increase at the beginning of incubation and decrease to the initial values afterwards. 4. ATP and ADP levels decrease significantly with both hormones; however, the effect of noradrenalin on the ATP level needs a longer time of incubation. The ATP/ADP ratios decrease after 5 minutes incubation and the total adenylic nucleotide content is severely decreased (35 per cent with adrenalin, after 20 minutes incubation). 5. Similar results have been obtained with other tissues; these results can explain the decrease of aerobic metabolism we observed under the same conditions.

Eur J Pharmacol 1982 Jul 30;81(4):569-76. Actions of serotonin antagonists on dog coronary artery. Brazenor RM, Angus JA. Serotonin released from platelets may initiate coronary vasospasm in patients with variant angina. If this hypothesis is correct, serotonin antagonists without constrictor activity may be useful in this form of angina. We have investigated drugs classified as serotonin antagonists on dog circumflex coronary artery ring segments in vitro. Ergotamine, dihydroergotamine, bromocriptine, lisuride, ergometrine, ketanserin, trazodone, cyproheptadine and pizotifen caused non-competitive antagonism of serotonin concentration-response curves. In addition, ketanserin, trazodone, bromocriptine and pizotifen inhibited noradrenaline responses in concentrations similar to those required for serotonin antagonism. All drugs with the exception of ketanserin, cyproheptadine and pizotifen showed some degree of intrinsic constrictor activity. Of the drugs tested, ketanserin may be the most useful in variant angina since it is a potent 5HT antagonist, lacks agonist activity and has alpha-adrenoceptor blocking activity.

Arch Mal Coeur Vaiss 1983 Feb;76 Spec No:3-6. Role of autonomic nervous system in the pathogenesis of angina pectoris. Yasue H. The attacks of vasospastic angina or coronary spasm can be induced by injection of epinephrine, cold pressor test, Valsalva maneuver, and exercise. The attacks of vasospastic angina can also be induced by injection of methacholine, a parasympathomimetic agent, and this reaction is suppressed by atropine, a parasympathetic blocking agent. Thus, parasympathetic nervous system also seems to play a role in the production of vasospastic angina. The attacks of vasospastic angina can be easily induced by adrenergic or parasympathetic stimuli from midnight to early morning but is usually not provoked by these stimuli in the daytime. Thus, there is circadian variation in the reactivity of coronary arteries to adrenergic or parasympathetic stimuli. There are also weekly, monthly and yearly variations of the reactivity of coronary arteries to these stimuli. Thus, alpha adrenergic or parasympathetic activity is not the sole factor in the production of vasospastic angina. Angina pectoris caused by increased myocardial oxygen demand is induced by infusion of isoproterenol, a beta adrenergic stimulant, and is suppressed by propranolol but not by phentolamine.

Nippon Yakurigaku Zasshi 1986 Mar;87(3):281-90. [Vasoconstrictor responses of isolated pig coronary arteries]. [Article in Japanese] Ikenoue K, Kawakita S, Toda N. In helical strips of pig coronary arteries, histamine, serotonin, acetylcholine and a stable analogue of thromboxane A2 (9, 11-epithio-11, 12-methano TXA2: s-TXA2) produced a dose-dependent contraction. The histamine-induced contraction was suppressed by treatment with chlorpheniramine, suggesting an involvement of H1 receptors. Contractile responses to serotonin were attenuated by not only ketanserin, an S2 antagonist, but also by cinanserin and methysergide. Contractile responses to histamine were potentiated by treatment with low concentrations of serotonin or s-TXA2. Contractile responses to serotonin were also potentiated by low concentrations of histamine or s-TXA2. Removal of the endothelium from pig coronary arterial strips potentiated contractions induced by serotonin, histamine and norepinephrine. These results suggest that, in addition to damaged endothelium, integrating action of endogenous vasoconstrictors, including histamine, serotonin, TXA2 and norepinephrine, may play an important role in producing coronary vasospasm.

Jpn Heart J 1987 Sep;28(5):649-61. The role of parasympathetic nerve activity in the pathogenesis of coronary vasospasm. Suematsu M, Ito Y, Fukuzaki H. To evaluate the role of the autonomic nervous system, especially the parasympathetic nervous system, in the initiation mechanism of vasospastic angina pectoris (AP), the coefficient of R-R interval variation (CV) on the electrocardiogram (ECG) and plasma catecholamine concentration were measured in 25 patients with vasospastic AP, 10 patients with effort AP and 12 control subjects. CV which has been recognized as reflecting parasympathetic nervous system activity was calculated from 100 consecutive heart beats on the ECG and represented as the percentage of standard deviation of the R-R interval per mean R-R interval. Repeated measurements of plasma catecholamine concentration revealed higher values at any sampling point throughout a day in patients with vasospastic AP than those in control subjects. A distinctly higher CV was observed at night in the vasospastic AP group. This elevated CV was abolished by atropine sulfate (1.5 mg/day per os). Pilocarpine injection (1.3 mg/10 kg B.W. subcutaneously) induced a marked increase in CV that preceded the occurrence of chest pain and/or ischemic ECG changes in 5 patients with vasospastic AP. The increment in CV at 10 min after pilocarpine administration was greater in vasospastic AP than in control subjects (p less than 0.05). It is concluded that enhanced parasympathetic activity may play a role in the initiation of coronary vasospasm associated with sympathetic hyperactivity.

Science 1984 Mar 30;223(4643):1435-7. Coronary arteries of cardiac patients are hyperreactive and contain stores of amines: a mechanism for coronary spasm. Kalsner S, Richards R. Coronary arteries from hearts of cardiac patients contain significantly higher concentrations of histamine than do those from noncardiac patients. The coronary vessels of cardiac patients are also hyperresponsive to histamine and serotonin. These differences between groups of patients suggest an explanation for coronary artery spasm in heart disease.

Fed Proc 1985 Feb;44(2):321-5. Coronary artery reactivity in human vessels: some questions and some answers. Kalsner S. It is now clear that human coronary arteries in vitro contract to acetylcholine but that relaxation is the only response observed in dog coronary vessels. Acetylcholine is as powerful a constrictor of human coronary arteries, in terms of tension induced, as 5-hydroxytryptamine (5-HT) or histamine and is a substantially more powerful constrictor than norepinephrine. Field stimulation of coronary artery strips caused a vasoconstriction that was partially antagonized by atropine (3.45 X 10(-6) M). Coronary tissue from cardiac patients also contains stores of 5-HT and histamine, and the histamine levels are substantially increased above the values in vessels from noncardiac patients. Coronary artery spasm or contraction probably can be initiated by diverse intrinsic and extrinsic influences, including autonomic discharge from either the parasympathetic or sympathetic nervous system or from histamine or 5-HT, and probably no one agent or entity is causative in all cases.

Ann N Y Acad Sci 1969 Oct 14;164(2):517-9. Induced carcinogenesis under various influences on the hypothalamus. Kavetsky RE, Turkevich NM, Akimova RN, Khayetsky IK, Matveichuck YD.

Kavetsky RE, (editor) The Neoplastic Process and the Nervous System,Kiev, 1958.

Ann N Y Acad Sci 1966 Jan 21;125(3):933-45. On the psychophysiological mechanism of the organism's resistance to tumor growth. Kavetsky RE, Turkevich NM, Balitsky KP.

Patol Fiziol Eksp Ter 1971 Sep-Oct;15(5):3-10. [Role of disorders in intra-cellular and neuro-humoral regulation in the development of the tumor process]. [Article in Russian] Kavetskii RE, Balitskii KP.

Milman, M.S., The sympathetic nervous system and the source of tumors, Problems of Oncology IX, 162-173, 1936.

Obstet Gynecol Surv 1977 May;32(5):267-81. Estrogen and endometrial carcinoma. Knab DR. 1. It has become evident that the estrogen secreting tumors of the ovary are associated with endometrial carcinoma, but this association is most easily observed in the postmenopausal patient where the incidence of carcinoma has been reported at 10.3% (1. 02) to 24% (83). 2. The most consistent association of endometrial carcinoma is with polycystic ovarian disease, where 19 (34), 21 (152), and 25% (150) of young women with endometrial carcinoma had Stein-Leventhal syndrome (67). 3. A very significant discovery became known in 1967 when the peripheral aromatization of delta4 androstenedione to estrone was reported by Kase (94) and MacDonald (111,112). Since that time we have learned that endometrial carcinoma patients have an increased peripheral conversion (139) (0.1% compared to 0.027%), which is similar to that found in obese and aging patients, by Hemsell, et al (77). This can be 2 to 4 times greater than the young adult or the patient without cancer. Similarly patients with polycystic ovary disease, hyperthecosis and lipoid cell tumors of the ovary demonstrate androgen excess with extraglandular conversion to estrone (2). 4. It has become apparent that the principal estrogen in the postmenopausal patient is estrone and that the estrone-estradiol ratio in the serum is higher in postmenopausal women with corpus cancer than similar patients without cancer (135). 5. With the lack of ovarian estrogen there is a relative excess of adrenal testosterone, dihydrotestosterone and delta4 androstenedione, the available precursors of extraglandular estrone (1). 6. With the passage of time it appears that endometrial carcinoma is associated with hypothalamic "hyperactivity" (31)....

Endocrinology 2000 Mar;141(3):1059-72. An increased intraovarian synthesis of nerve growth factor and its low affinity receptor is a principal component of steroid-induced polycystic ovary in the rat. Lara HE, Dissen GA, Leyton V, Paredes A, Fuenzalida H, Fiedler JL, Ojeda SR. A form of polycystic ovary (PCO) resembling some aspects of the human PCO syndrome can be induced in rats by a single injection of estradiol valerate (EV). An increase in sympathetic outflow to the ovary precedes, by several weeks, the appearance of cysts, suggesting the involvement of a neurogenic component in the pathology of this ovarian dysfunction. The present study was carried out to test the hypotheses that this change in sympathetic tone is related to an augmented production of ovarian nerve growth factor (NGF), and that this abnormally elevated production of NGF contributes to the formation of ovarian cysts induced by EV. Injection of the steroid resulted in increased intraovarian synthesis of NGF and its low affinity receptor, p75 NGFR. The increase was maximal 30 days after EV, coinciding with the elevation in sympathetic tone to the ovary and preceding the appearance of follicular cysts. Intraovarian injections of the retrograde tracer fluorogold combined with in situ hybridization to detect tyrosine hydroxylase (TH) messenger RNA-containing neurons in the celiac ganglion revealed that these changes in NGF/p75 NGFR synthesis are accompanied by selective activation of noradrenergic neurons projecting to the ovary. The levels of RBT2 messenger RNA, which encodes a beta-tubulin presumably involved in slow axonal transport, were markedly elevated, indicating that EV-induced formation of ovarian cysts is preceded by functional activation ofceliac ganglion neurons, including those innervating the ovary. Intraovarian administration of a neutralizing antiserum to NGF in conjunction with an antisense oligodeoxynucleotide to p75 NGFR, via Alzet osmotic minipumps, restored estrous cyclicity and ovulatory capacity in a majority of EV-treated rats. These functional changes were accompanied by restoration of the number of antral follicles per ovary that had been depleted by EV and a significant reduction in the number of both precystic follicles and follicular cysts. The results indicate that the hyperactivation of ovarian sympathetic nerves seen in EV-induced PCO is related to an overproduction of NGF and its low affinity receptor in the gland. They also suggest that activation of this neurotrophic-neurogenic regulatory loop is a component of the pathological process by which EV induces cyst formation and anovulation in rodents. The possibility exists that a similar alteration in neurotrophic input to the ovary contributes to the etiology and/or maintenance of the PCO syndrome in humans.

Acta Physiol Hung 1996;84(2):183-90. Effects of hormones on the number, distribution and degranulation of mast cells in the ovarian complex of mice. Jaiswal K, Krishna A. The changes in the number and degranulation pattern of mast cells varied with the types of hormonal treatment and ovarian compartment. Luteinizing hormone (LH), follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH) and 17-beta estradiol (E2) treatment caused increase (P < 0.05) in the number of mast cells in the hilum as compared with the controls. Increase (P < 0.05) in the number of mast cells in the whole ovarian complex was observed only following FSH and E2 treatment. All the hormones used in the present study increased the percentage degranulation of mast cells in the hilum. However, only LH, FSH and E2 increased the percentage degranulation of mast cells in other compartments of the ovary (medulla, bursa and cortex). TSH and ACTH failed to cause any increase in the percentage degranulation of mast cells in these compartments. The present findings indicate E2 to be the most potent among the hormones tested in causing degranulation of mast cells in all ovarian compartments.

Fertil Steril 2001 Jun;75(6):1141-7. Increase in nerve fibers and loss of mast cells in polycystic and postmenopausal ovaries. Heider U, Pedal I, Spanel-Borowski K. OBJECTIVE: To quantify nerve fibers and mast cells in human ovaries at different functional stages. DESIGN: Retrospective study. SETTING: Research laboratory of the university. SPECIMEN(S): 8 human ovaries in the follicular (cyclic) phase, 7 polycystic ovaries, and postmenopausal ovaries with (n=5) or without (n=7) hyperthecosis. MAIN OUTCOME MEASURE(S): Single- and double immunohistology for the S100 antigen in glial cells of autonomic nerve fibers, for chymase and tryptase in mast cells, and for the common leukocyte antigen on leukocytes. Histometric evaluation was also performed. INTERVENTION(S): None. RESULT(S): Polycystic ovaries contained significantly more S100-positive nerve fibers in the corticomedullary region than did cyclic ovaries (mean +/- SD per 2-mm(2) area, 476 +/- 136 and 224 +/- 133; P<.01). Postmenopausal ovaries with or without hyperthecosis had the highest density of nerve fibers. In cyclic and polycystic ovaries, more tryptase-positive mast cells than chymase-positive mast cells were found in the interstitial cortex and the medulla. In cyclic ovaries, areas with a moderate density of nerve fibers contained many mast cells. Hence, with increasing nerve fiber density in polycystic ovaries, the number of mast cells decreased strikingly compared with cyclic ovaries (p<.001). Almost no mast cells were seen in postmenopausal ovaries with and without hyperthecosis. The number of leukocyte antigen-positive leukocytes was similar in all groups. CONCLUSION(S): The high density of nerve fibers in polycystic and postmenopausal ovaries, together with a conspicuous decrease in mast cells, indicates altered neuroimmune communication.

Endocrinology 1993 Dec;133(6):2696-703. Ovarian steroidal response to gonadotropins and beta-adrenergic stimulation is enhanced in polycystic ovary syndrome: role of sympathetic innervation. Barria A, Leyton V, Ojeda SR, Lara HE. Experimental induction of a polycystic ovarian syndrome (PCOS) in rodents by the administration of a single dose of estradiol valerate (EV) results in activation of the peripheral sympathetic neurons that innervate the ovary. This activation is evidenced by an increased capacity of ovarian nerve terminals to incorporate and release norepinephrine (NE), an increase in ovarian NE content, and a decrease in ovarian beta-adrenergic receptor number in the ovarian compartments receiving catecholaminergic innervation. The present experiments were undertaken to examine the functional consequences of this enhanced sympathetic outflow to the ovary. The steroidal responses of the gland to beta-adrenergic receptor stimulation and hCG were examined in vitro 60 days after EV administration, i.e. at the time when follicular cysts are well established. EV-treated rats exhibited a remarkable increase in ovarian progesterone and androgen responses to isoproterenol, a beta-adrenergic receptor agonist, with no changes in estradiol responsiveness. Basal estradiol release was, however, 50-fold higher than the highest levels released from normal ovaries at any phase of the estrous cycle. The ovarian progesterone and androgen responses to hCG were enhanced in EV-treated rats, as were the responses to a combination of isoproterenol and hCG. Transection of the superior ovarian nerve (SON), which carries most of the catecholaminergic fibers innervating endocrine ovarian cells, dramatically reduced the exaggerated responses of all three steroids to both beta-adrenergic and gonadotropin stimulation. SON transection also reduced the elevated levels of ovarian NE resulting from EV treatment and caused up-regulation of beta-adrenoreceptors. Most importantly, SON transection restored estrous cyclicity and ovulatory capacity. The results indicate that the increased output of ovarian steroids in PCOS is at least in part due to an enhanced responsiveness of the gland to both catecholaminergic and gonadotropin stimulation. The ability of SON transection to restore a normal response indicates that the alteration in steroid output results from a deranged activation of selective components of the noradrenergic innervation to the ovary. These findings support the concept that an alteration in the neurogenic control of the ovary contributes to the etiology of PCOS.

Wilderness Environ Med 2001 Spring;12(1):8-12. Alterations in autonomic nervous control of heart rate among tourists at 2700 and 3700 m above sea level. Kanai M, Nishihara F, Shiga T, Shimada H, Saito S. RESULTS: Both HF and LF heart rate variability decreased according to the elevation of altitude. CONCLUSIONS: At 2700 and 3700 m, the activity of the autonomic nervous system measured by heart rate variability was decreased in untrained office workers. The sympathetic nervous system was dominant to the parasympathetic at 3700 m. These alterations in the autonomic nervous system might play some role in physical fitness at high altitudes.

Acta Neuroveg (Wien) 1967;30(1):557-63. [Neuroautonomic reactivity of the skin during high mountain climate treatment of skin diseases]. [Article in German] Chlebarov S.

Munch Med Wochenschr 1966 Mar 18;108(11):589-92. [Changes of the neurovegetative reactivity of the skin after Alpine climatic therapy]. [Article in German] Borelli S, Chlebarov S.

J Appl Physiol 1978 May;44(5):647-51. Mechanism of the attenuated cardiac response to beta-adrenergic stimulation in chronic hypoxia. Maher JT, Deniiston JC, Wolfe DL, Cymerman A. A blunting of the chronotropic and inotropic responses of the heart to beta-adrenergic stimulation occurs following chronic exposure to hypobaric hypoxia. Neither monoamine oxidase activity nor norepinephrine level of any region of the heart was altered by chronic hypoxia. However, a twofold increase (P less than 0.001) in catechol O-methyltransferase activity above sea-level values was found in both the atria and ventricles of the hypoxic animals. Thus, the attenuation in cardiac responsiveness to beta-adrenoceptor stimulation in chronic hypoxia appears unrelated to the level of vagal activity, but may be attributable to enhanced enzymatic inactivation of catecholamines.

Acta Physiol Scand 1976 Jun;97(2):158-65. Effects of respiratory alkalosis and acidosis on myocardial excitation. Samuelsson RG, Nagy G. In anesthetized dogs electrocardiogram and monophasic action potentials (MAPs) were recorded from the right atrium and the right ventricle by intracardiac suction electrode technique. The animals were subjected, by means of ventilation with CO2 and hyperventilation, to periods of respiratory acidosis and respiratory alkalosis, respectively. Pronounced respiratory acidosis induced an increased sympathetic activity followed by a decrease in heart rate and prolongation of the A-V conduction time whereas the shape and duration of the atrial and ventricular MAPs remained unaltered. Arterial hypoxia in combination with pronounced respiratory acidosis did not influence the MAP durations. Respiratory alkalosis resulted in an increased sympathetic influence on the heart activity whereas the shape and duration of the atrial and the ventricular MAPs remained unaffected. During pronounced hyperventilation with increasing central venous pressure an increased parasympathetic influence on the heart activity with decrease in the heart rate, prolongation of the A-V conduction time and shortening of the atrial MAP duration was recorded.

Biull Eksp Biol Med 1978 Nov;86(11):525-8. [Effect of neuromediators on acid-base status]. [Article in Russian] Lazareva LV, Bazarevich GI, Makarova LV. A relationship between the state of adrenergic, cholinergic, and serotoninergic systems, on the one hand, and the acid-alkaline balance of the organism, on the other hand, was revealed in sharp and chronic experiments on dogs. A surplus of each of the mediators was accompanied by respiratory alkalosis, and its deficiency--by combined respiratory and metabolic acidosis.

Can J Physiol Pharmacol 1987 May;65(5):1078-85. Pathophysiology of pH and Ca2+ in bloodstream and brain. Somjen GG, Allen BW, Balestrino M, Aitken PG. The highlights of the literature and our work on tetany and hyperventilation are reviewed. Our studies concern the following: (1) the changes of [Ca2+] in circulating plasma caused by respiratory and "metabolic" acidosis and alkalosis; (2) critical plasma [Ca2+] levels associated with signs of tetany and neuromuscular blockade; (3) changes in cerebral [Ca2+]o caused by hypo- and hyper-calcaemia, and the changes in cerebral [Ca2+]o and pHo caused by acute systemic acidosis and alkalosis; and (4) effects of changing [Ca2+]o and pHo levels on synaptic transmission in hippocampal formation. Our main conclusions are (1) changes of plasma [Ca2+] caused by "metabolic" pH changes are greater than those associated with varying CO2 concentration; (2) acute systemic [Ca2+] changes are associated with small cerebral [Ca2+]o changes; (3) the decreases in systemic and cerebral [Ca2+]o caused by hyperventilation are too small to account for the signs and symptoms of hypocapnic tetany; (4) moderate decrease of [Ca2+]o depresses and its increase enhances synaptic transmission in hippocampal formation; and (5) H+ ions in extracellular fluid have a weak depressant effect on neuronal excitability. CO2 is a strong depressant, which is only partly explained by the acidity of its solution. CO2 concentration is a significant factor in controlling cerebral function.

J Hirnforsch 1991;32(5):659-664. Normalization of protein synthesis and the structure of brain dystrophic neurons after the action of hypoxia, 10% NaCl and organ-specific RNA. Polezhaev LV, Cherkasova LV, Vitvitsky VN, Timonin AV N. I. Vavilov Institute of General Genetics, USSR Academy of Sciences, Moscow. It was shown previously (Polezhaev and Alexandrova, 1986) that hypoxic hypoxia causes mass (up to 30%) diffuse dystrophy of brain cortex and hippocamp neurons in rats, disturbances in the higher nervous activity, reduction of protein, RNA synthesis in neurons and of DNA synthesis in the whole brain cortex. Transplantation of embryonic nervous tissue (ENT) in one of the hemispheres normalizes all the above abnormalities observed in some neurologic and mental diseases in humans. However, transplantation may entail injuries of parenchyma and brain blood vessels. This forces researchers to search for another biological method similar by its action but safer and simpler. ENT transplantation has a dual action: 1) formation of biologically active substances (BAS) releasing from the ENT transplant and from the host brain nervous tissue upon operation; 2) establishment of synaptic connections between the transplant and host neurons. Previously we (Vitvitsky, 1987) described the isolation of BAS from rat forebrain in the form of organ-specific RNA. The latter was injected intraperitoneally several times to post-hypoxic rats in which 30 min prior to that the blood-brain barrier (BBB) was opened by injecting intravenously and intraperitoneally 10% NaCl solution without damaging the host brain. At the beginning 10% NaCl increased the destruction of brain cortical neurons and then stimulated protein synthesis in them. RNA injections stimulated the synthesis in cortical neurons and normalized their structure. Thus, we propose a safe and simple method for normalization of dystrophic neurons which can be used after certain improvement for curing neurodegenerative and neuropsychic diseases in humans.

Group processes

The trouble with writing and painting is that they are considered to be solitary and individualistic activities. In the 20th century, the idea developed that they were expressive, rather than communicative, as if there could be any sane distinction between those. The result was that much of 20th century poetry and painting was insane. The products of insanity arent necessarily worthless, but they are less than they could be.

When the writer and painter are in close contact with responsive people, their product is adjusted to, and enriched by, the reactions they evoke.

J Cardiovasc Pharmacol 1987;10 Suppl 2:S94-8; discussion S99. The effect of beta-blockade on platelet function and fibrinolytic activity. Winther K. Department of Clinical Chemistry, Rigshospitalet, Copenhagen, Denmark. Two groups of hypertensives and a group of migraine sufferers were tested during treatment with the nonselective beta-blocker propranolol and the beta 1-selective metoprolol. During treatment with propranolol, an increased platelet aggregability and a decrease in platelet content of cyclic AMP were seen when compared with metoprolol treatment. In addition, propranolol treatment increased the plasma level of adrenaline as well as the euglobulin clot lysis time. types of monoamine oxidase, adrenaline

45: Br J Pharmacol 1982 Feb;75(2):269-86

Coronary vasoconstrictor and vasodilator actions of arachidonic acid in the

isolated perfused heart of the rat.

Belo SE, Talesnik J.

The administration of arachidonic acid (AA) to the isolated perfused heart of

the rat usually produced biphasic coronary responses characterized by initial

vasoconstriction followed by prolonged vasodilatation. However, some responses

were predominantly vasoconstrictor or vasodilator. The non-steroidal

anti-inflammatory agents (NSAA) indomethacin (1-5 mg/l) and naproxen (12.5-25

mg/1) reversibly inhibited both phases of the response induced by AA.

Pretreatment of animals with indomethacin (5 mg/kg) or naproxen (25 mg/kg)

daily, resulted in unaltered coronary response to AA. Subsequent addition of

NSAA to the perfusate produced inhibition of the AA effect. Short infusions of

acetylsalicylic acid at low concentrations (2.9 micrograms/ml), dipyridamole

(0.6 micrograms/ml) and sulphinpyrazone (28.7 micrograms/ml) selectively

inhibited the vasoconstrictor phase of the response to AA. It was confirmed that

metabolic coronary dilatation induced by cardiostimulation was inhibited by

prolonged AA administration; this effect was prevented by NSAA pretreatment.

Reactive hyperaemic responses to short lasting occlusions of coronary inflow

were unaffected by NSAA. Linolenic, linoleic, dihomo-gamma-linolenic and oleic

acid usually produced decreases in coronary flow which were unaffected by NSAA,

dipyridamole or sulphinpyrazone. Intra-aortic injections of AA, prostacyclin

(PGI2) and prostaglandin E2 (PGE2) in the intact rat produced a dose-dependent

decrease in blood pressure with the AA response inhibited by indomethacin. PGI2

and PGE2 produced long lasting coronary vasodilatation in the isolated heart.

The coronary actions of AA appear to be due to its transformation, within the

easily accessible vascular wall, into prostaglandin and thromboxane-like

substances. We suggest that a vasoconstrictor thromboxane A2-like substance may

be responsible for coronary vasospasm. Coronary insufficiency may also result

from an inhibition of compensatory metabolic coronary dilatation by increased

synthesis of PGE2 within the myocardial cell.

42: Br Heart J 1983 Jan;49(1):20-5

Platelet reactivity and its dependence on alpha-adrenergic receptor function in

patients with ischaemic heart disease.

Yokoyama M, Kawashima S, Sakamoto S, Akita H, Okada T, Mizutani T, Fukuzaki H.

We studied 57 patients admitted to hospital with ischaemic heart disease,

including nine patients with variant angina, to evaluate platelet reactivity and

its dependence on alpha-adrenergic receptor function. The threshold

concentration for biphasic platelet aggregation in response to adrenaline and

adenosine diphosphate was measured in fresh platelet rich plasma. There were age

related alterations in platelet responsiveness to adrenaline. In 27 age matched

control subjects platelets showed adrenaline induced aggregation at a

concentration higher than 0.1 mumol. The threshold concentrations for adrenaline

and adenosine diphosphate were 0.91 mumol and 4.68 mumol. In 16 patients with

acute infarction, 14 with old infarction, nine with effort angina, and nine with

rest angina, mean values of platelet aggregation threshold for both adrenaline

and adenosine diphosphate were not altered significantly when compared with

control subjects. In contrast, the values for adrenaline and adenosine

diphosphate in nine patients with variant angina were 0.012 mumol and 2.24 mumol

and seven of them showed obvious platelet hyperactivity to adrenaline at a concentration lower than 0.1 mumol. The threshold concentration for adrenaline induced aggregation did not correlate with serum cholesterol and triglyceride

levels.

Am Heart J 1985 Jun;109(6):1264-8. Reduction of plasma norepinephrine levels in response to brief coronary occlusion in experimental dogs. Haneda T, Arai T, Kanda H, Ikeda J, Takishima T. Although an increased plasma norepinephrine (NE) level is sometimes observed

during angina pectoris, it is difficult to say whether sympathetic overflow is

its cause. The left anterior descending coronary artery was occluded by

intracoronary balloon for 3 minutes in 12 closed-chest anesthetized dogs. During

occlusion, heart rate did not change but aortic pressure slightly decreased.

Occlusion caused a significant reduction in both NE levels in the aorta (177 +/-

17 to 134 +/- 16 pg/ml, p less than 0.01) and in the great cardiac vein (GCV)

296 +/- 44 to 249 +/- 44 pg/ml, p less than 0.01). After surgical vagotomy, the

occlusion increased NE levels in the aorta (227 +/- 44 to 278 +/- 43 pg/ml, p

less than 0.01) and in GCV (384 +/- 76 to 444 +/- 81 pg/ml, p less than 0.01),

showing the release of vagal inhibition. These results may be applicable to

patients with transient anterior myocardial ischemia; if plasma NE increases

without marked hemodynamic changes, it is suggested that the sympathetic

overflow is not a result but a possible cause of the ischemia.

25: Exp Mol Pathol 1986 Apr;44(2):138-46

Intimal thickening and the distribution of vasomotor nerves in the mechanically

injured dog coronary artery.

Taguchi T, Ishii Y, Matsubara F, Tanaka K.

Intimal injury and atherosclerotic change seem to be causative factors linked to

spasm of the coronary artery. Intimal thickening was produced by mechanical

injury to the endothelium of the canine coronary artery and we investigated the

distribution of adrenergic, cholinergic, and peptidergic nerves in the coronary

arteries. Although adrenergic and cholinergic nerves were not altered in

density, neuron specific enolase positive nerve fibers were increased in number

in dogs killed 1 and 3 months after injury. Substance P-containing fibers were

also increased at 3 months after the induced injury.

24: J Am Coll Cardiol 1986 Jul;8(1 Suppl A):42A-49A

Mechanisms of coronary spasm of isolated human epicardial coronary segments

excised 3 to 5 hours after sudden death.

Vedernikov YP.

Isolated segments of epicardial coronary artery with and without severe

atherosclerotic lesions excised from human hearts 3 to 5 hours after sudden

coronary death demonstrated spontaneous contractile activity that was dependent

on the external calcium level and was inhibited by calcium antagonists and

activation of beta-adrenoceptors (isoproterenol and high concentrations of

norepinephrine). Isoproterenol, with a median effective dose (ED50) of 6.3 X

10(-7) M, relaxed coronary segments that had been precontracted with 30 mM

potassium. Stimulation of the alpha-adrenoceptors activated spontaneous

contractions and increased tension. Norepinephrine ED50 (in the presence of

10(-6) M propranolol) was 2.3 X 10(-7) M, and tension at a maximal concentration

of 10(-4) M was 385.4 +/- 51.4 mg. The ED50 for acetylcholine and histamine, the

potent activators of coronary segment tone and phasic contractility, was 3.98 X

10(-7) and 8.9 X 10(-7) M, respectively; the maximal increase in tension was

1,079.5 +/- 175 (at 10(-4) M) and 1,131.3 +/- 302 mg (at 10(-5) M),

respectively. Acetylcholine and histamine increased whereas high concentrations

of norepinephrine failed to inhibit rhythmic activity and tension of coronary

artery segments with severe atherosclerotic lesions. Membrane electrogenic

mechanisms and ways of activating the contractile elements of human coronary

artery smooth muscle are discussed.

Pharmacol Rev 2000 Dec;52(4):595-638. The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system. Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. Inflammatory Joint Diseases Section, Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA. The brain and the immune system are the two major adaptive systems of the body. During an immune response the brain and the immune system "talk to each other" and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs. Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation. Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest. In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta. Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 production. Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages. The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth. Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome.

Am J Physiol Cell Physiol 2000 Nov;279(5):C1665-74. beta-adrenergic receptor/cAMP-mediated signaling and apoptosis of S49 lymphoma cells. Yan L, Herrmann V, Hofer JK, Insel PA. Department of Pharmacology, University of California, San Diego, La Jolla, California 92093-0636, USA. beta-Adrenergic receptor (betaAR) activation and/or increases in cAMP regulate growth and proliferation of a variety of cells and, in some cells, promote cell death. In the current studies we addressed the mechanism of this growth reduction by examining betaAR-mediated effects in the murine T-lymphoma cell line S49. Wild-type S49 cells, derived from immature thymocytes (CD4(+)/CD8(+)) undergo growth arrest and subsequent death when treated with agents that increase cAMP levels (e.g., betaAR agonists, 8-bromo-cAMP, cholera toxin, forskolin). Morphological and biochemical criteria indicate that this cell death is a result of apoptosis. In cyc(-) and kin(-) S49 cells, which lack G(s)alpha and functional protein kinase A (PKA), respectively, betaAR activation of G(s)alpha and cAMP action via PKA are critical steps in this apoptotic pathway. S49 cells that overexpress Bcl-2 are resistant to cAMP-induced apoptosis. We conclude that betaAR activation induces apoptosis in immature T lymphocytes via G(s)alpha and PKA, while overexpression of Bcl-2 prevents cell death. betaAR/cAMP/PKA-mediated apoptosis may provide a means to control proliferation of immature T cells in vivo.

Carcinogenesis 2001 Mar;22(3):473-9. Beta-adrenergic growth regulation of human cancer cell lines derived from pancreatic ductal carcinomas. Weddle DL, Tithoff P, Williams M, Schuller HM. Carcinogenesis and Developmental Therapeutics Program, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA. Exocrine ductal carcinoma of the pancreas has been associated with smoking, and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) causes this cancer type in laboratory rodents. Current knowledge on the growth regulation of this malignancy is extremely limited. Recent studies have shown overexpression of cyclooxygenase 2 (COX 2) and 5-lipoxygenase (5-lipox) in exocrine pancreatic carcinomas, suggesting a potential role of the arachidonic acid (AA) cascade in the regulation of this cancer type. In support of this interpretation, our data show high basal levels of AA release in two human cell lines derived from exocrine ductal pancreatic carcinomas. Both cell lines expressed m-RNA for beta2-adrenergic receptors and beta1-adrenergic receptors. Radio-receptor assays showed that beta2-adrenergic receptors predominated over beta1-adrenergic receptors. beta2-Adrenergic antagonist ICI118,551 significantly reduced basal AA release and DNA synthesis when the cells were maintained in complete medium. DNA synthesis of the cell line (Panc-1) with an activating point mutation in codon 12 of the ki-ras gene was significantly stimulated by NNK when cells were maintained in complete medium and this response was inhibited by the beta-blocker ICI118,551, the COX-inhibitor aspirin, or the 5-lipox-inhibitor MK-886. The cell line without ras mutations (BXPC-3) did not show a significant response to NNK in complete medium. When the assays were conducted in serum-free medium, both cell lines demonstrated increased DNA synthesis in response to NNK, an effect inhibited by the beta2-blocker, aspirin, or MK-886. Panc-1 cells were more sensitive to the stimulating effects of NNK and less responsive to the inhibitors than BXPC-3 cells. Our findings are in accord with a recent report which has identified NNK as a beta-adrenergic agonist and suggest beta-adrenergic, AA-dependent regulatory pathways in pancreatic cancer as a novel target for cancer intervention strategies.

Shock 2000 Jul;14(1):60-7. Terbutaline prevents circulatory failure and mitigates mortality in rodents with endotoxemia. Wu CC, Liao MH, Chen SJ, Chou TC, Chen A, Yen MH. Department of Pharmacology, National Defense Medical Center, Taipei, ROC, Taiwan. Septic shock is characterized by a decrease in systemic vascular resistance. Nevertheless, regional increases in vascular resistance can occur that may predispose mammals to organ dysfunction, including the acute respiratory distress syndrome. In the host infected by endotoxin (lipopolysaccharide, LPS), the expression and release of proinflammatory tumor necrosis factor-alpha (TNFalpha) rapidly increases, and this cytokine production is regulated by agents elevating cyclic AMP. In this report, we present evidence that terbutaline, a beta2-agonist, inhibits TNFalpha production and enhances interleukin-10 (IL-10) release in the anesthetized rat treated with LPS. In addition, an overproduction of nitric oxide (NO, examined by its metabolites nitrite/nitrate) by inducible NO synthase (iNOS, examined by western blot analysis) is attenuated by pretreatment of LPS rats with terbutaline. Overall, pretreatment of rats with terbutaline attenuates the delayed hypotension and prevents vascular hyporeactivity to norepinephrine. In addition, pretreatment of mice with terbutaline also improves the survival in a model of severe endotoxemia. The infiltration of polymorphonuclear neutrophils into organs (e.g., lung and liver) from the surviving LPS mice treated with terbutaline was reduced almost to that seen in the normal controls. These findings suggest that the inhibition of TNFalpha and NO (via iNOS) production as well as the increment of IL-10 production contribute to the beneficial effect of terbutaline in animals with endotoxic shock.

Ann Endocrinol (Paris) 1977;38(6):421-6. [Hyperestrogenism in the woman during the reproductive period]. [Article in French] Kuttenn F.

Br J Obstet Gynaecol 1976 Aug;83(8):593-602. Polycystic ovarian disease. Duignan NM. Sex hormone binding globulin (SHBG) capacity was reduced in 9 of 31 patients with polycystic ovarian (PCO) disease and the mean level in PCO patients was significantly less (p less than 0.001) than normal. Serum testosterone levels were elevated in 21 of 32 PCO patients and the mean level was significantly elevated (p less than 0.001). Serum androstenedione values were raised in 17 of 31 patients and the mean value was also significantly raised (p less than 0.001). Serum dehydroepiandrosterone sulphate (DHAS) concentrations were elevated in only 2 of 14 patients. Urinary 17-oxo and 17-oxogenic steroids were normal in all patients studied. Basal follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were normal but LH release following injection of luteinizing hormone-releasing hormone (LH-RH) was enhanced. A highly significant negative correlation (r=--0.449; p less than 0.01) was found between the logarithm of testosterone and the logarithm of LH levels. Serum prolactin concentrations were elevated in 4 of 21 PCO patients. Thyroid-stimulating hormone (TSH) values were normal. Eighteen of 20 patients ovulated following treatment with clomiphene and nine became pregnant. Five of 12 of patients treated with oestrogen/progesterone preparations noticed an improvement in their hirsutism. It is suggested that the normal cyclical release of LH is inhibited in PCO disease by a negative feedback by androgens to the hypothalamus or the pituitary, and that wedge resection should be reserved for patients in whom other forms of treatment have failed.

Nouv Presse Med 1976 Apr 10;5(15):975-9. [Secretion of gonadotropins during sleep. Changes during secondary amenorrheas]. [Article in French] Passouant P, Crastes de Paulet A, Descomps B, Besset A, Billiard M. 4 females with secondary amenorrheas underwent sleep polygraphic recordings together with blood samples for measurements of LH, FSH and GH, 3 normal females served as controls. Among normal subjects LH and FSH secretion showed a pulsating pattern around the time of ovulation, appearing as secretory episodes throughout the night, without any relationship with sleep stages. In amenorrheas, 3 types of abnormalities could be identified: the first was a lack of secretory episodes of LH and FSH associated with an abnormal pattern of GH (9 subjects). The second was an hypersecretion of LH and a decrease of FSH secretion together with a normal secretion of GH in 4 subjects with a Stein-Leventhal syndrome. The last one was an hypersecretion of LH and FSH together with a normal pattern of GH in a subject with an early menopause. These results are discussed according to the present data on the part of neurotransmission in the regulation of ovulation and the 2 types of sleep. Furthermore secretory abnormalities of LH and FSH together with a disconnection between GH secretion and the stages of sleep lead to question the possibility of interrelationships in the secretory mechanisms of these different hormones.

Cancer 1997 Feb 1;79(3):494-9. Comment in: Cancer. 1997 Oct 1;80(7):1360-2. Association of Stein-Leventhal syndrome with the incidence of postmenopausal breast carcinoma in a large prospective study of women in Iowa. Anderson KE, Sellers TA, Chen PL, Rich SS, Hong CP, Folsom AR. Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, USA. BACKGROUND: The Stein-Leventhal syndrome (SLS), first described in 1935, is characterized by infertility, hyperandrogenization, and obesity. Because this phenotype represents an aggregation of risk factors for postmenopausal breast carcinoma, and because in general, a hormonal imbalance underlies the disorder, the authors examined the association between self-reported SLS and breast carcinoma incidence in a cohort of 34,835 cancer-free women assembled in 1986 and followed through 1992. METHODS: All participants were between the ages of 55 and 69 and held a valid Iowa driver's license. A total of 472 women in the cohort (1.35%) reported a history of SLS at baseline. Incident cases of breast carcinoma were identified annually using the State Health Registry of Iowa. Data were analyzed using Cox proportional hazards regression. RESULTS: During the follow-up period, there were 883 incident breast carcinomas, 14 among women reporting a history of SLS. Women with SLS were more likely than women without SLS to report fertility problems and menstrual irregularities, but there were no significant differences observed regarding body mass index (BMI). Although women with SLS were 1.8 times as likely to report benign breast disease than women without SLS (P < 0.01), they were not more likely to develop breast carcinoma (relative risk [RR] = 1.2; 95% confidence interval [CI] = 0.7-2). Adjustment for age at menarche, age at menopause, parity, oral contraceptive use, BMI, waist-to-hip ratio, and family history of breast carcinoma lowered the RR to 1 (95% CI = 0.6-1.9. CONCLUSIONS: Despite the high risk profiles of some women with SLS, these results do not suggest that the syndrome per se is associated with an increased risk of postmenopausal breast carcinoma.

Am J Epidemiol 1991 Oct 15;134(8):818-24. Comment in: Am J Epidemiol. 1992 Aug 1;136(3):372-3. Polycystic ovaries and the risk of breast cancer. Gammon MD, Thompson WD. Division of Epidemiology, Columbia University School of Public Health, New York, NY. Data from a case-control study that was conducted between 1980 and 1982 were analyzed to investigate the possible association between polycystic ovaries and the risk of breast cancer. The multicenter, population-based study included in-home interviews with 4,730 women with breast cancer and 4,688 control women aged 20-54 years. The age-adjusted odds ratio for breast cancer among women with a self-reported history of physician-diagnosed polycystic ovaries was 0.52 (95% confidence interval 0.32-0.87). The inverse association was not an artifact of infertility, age at first birth, or surgical menopause. Because women with this syndrome have abnormal levels of certain endogenous hormones, the observation of a low risk of breast cancer in this group may provide new insights into hormonal influences on breast cancer.

Clin Endocrinol (Oxf) 1996 Mar;44(3):269-76. Polycystic ovaries in pre and post-menopausal women. Birdsall MA, Farquhar CM. Department of Obstetrics and Gynaecology, National Women's Hospital, Auckland, New Zealand. OBJECTIVE: Polycystic ovaries have been diagnosed in more than 20% of premenopausal women using ultrasound. The aim of this study was to determine whether polycystic ovaries exist in post-menopausal women. DESIGN: Two groups of women were studied; group 1 consisted of 18 post-menopausal volunteers and group 2 comprised 142 women, 94 of whom were post-menopausal who had recently undergone coronary angiography. MEASUREMENTS: Transabdominal and transvaginal ultrasound scans were performed and measurements made of uterine area, endometrial thickness and ovarian volume. The morphological appearance of the ovaries was also noted. Fasting blood samples were taken. Medical and menstrual questionnaires were completed. RESULTS: Polycystic ovaries were found in 8/18 (44%) of group 1 and 60/142 (42%) in group 2. Polycystic ovaries were detected in 35/94 (37%) of the post-menopausal women in group 2. Post-menopausal women with polycystic ovaries had larger ovaries containing more follicles compared with post-menopausal women with normal ovaries. Post-menopausal women with polycystic ovaries had higher serum concentrations of testosterone and triglycerides than had post-menopausal women with normal ovaries. CONCLUSIONS: Polycystic ovaries can be detected in post-menopausal women and have some of the same endocrine abnormalities which are evident in premenopausal women with polycystic ovaries, that is, raised serum concentrations of testosterone and triglycerides.

Cancer Causes Control 1996 Nov;7(6):605-25. Comment in: Cancer Causes Control. 1996 Nov;7(6):569-71. Nutrition, hormones, and breast cancer: is insulin the missing link? Kaaks R. International Agency for Research on Cancer, Lyon, France. Breast cancer incidence rates are high in societies with a Western lifestyle characterized by low levels of physical activity, and by an energy-dense diet rich in total and saturated fat and refined carbohydrates. Epidemiologic studies, so far mostly on postmenopausal women, have shown that breast cancer risk is increased in hyperandrogenic women, with decreased levels of plasma sex-hormone binding globulin, and with increased levels of testosterone and of free estrogens. This paper describes the role of hyperinsulinemia as a hysiologic link between nutritional lifestyle factors, obesity, and the development of a hyperandrogenic endocrine profile, and reviews evidence that may or may not support the theory that chronic hyperinsulinemia is an underlying cause of breast cancer. An hypothesis is presented, stipulating that breast cancer risk is increased not only in hyperandrogenic postmenopausal women, but also in premenopausal women with mild hyperandrogenism and normal (ovulatory) menstrual cycles. The author suggests further investigation as to whether there is a positive association between risk of breast cancer before menopause and ubclinical forms of the polycystic ovary syndrome (PCOS), and to what extent iet and physical activity during childhood, by modulating the degree of insulin esistance during adolescence, may or may not be determinants of a PCO-like hyperandrogenic endocrine profile persisting into adulthood.

Akush Ginekol (Mosk) 1990 Sep;(9):61-3. [The therapeutic effect of parlodel in the polycystic ovary syndrome]. [Article in Russian] Soboleva EL, Komarov EK, Potin VV, Svechnikova FA. Parlodel (2.5-50 mg/day) has been given for 1 to 7 days to 33 patients with the polycystic ovary syndrome (POS). The ovulatory menstrual cycle returned in 10 (30%) patients and 4 of them conceived. Pretreatment cycle disturbance persisted in 6 (18%) patients. Parlodel reduced mid-follicular mean blood LH levels to values of normal women. Some decrease in blood testosterone levels occurred only in the second phase of the cycle. Estradiol test in 6 patients showed normal positive and negative feedbacks in the hypothalamic-pituitary-ovarian axis. Parlodel treatment reduced basal and estradiol stimulated pituitary gonadotropin secretion. It is suggested that parlodel may be used in ovulation induction in a proportion of POS patients.

polycystic menopausal sympathetic
estrogen parasympathetic, antimitochondrial, both can have a protective function, though in excess the inhibition itself is toxic.

Mast cells: hair growth, angiogenesis, cancer, MS, asthma. Nervous control of insulin,7:

Am J Obstet Gynecol 1993 Nov;169(5):1223-6. Comment in: Am J Obstet Gynecol. 1994 Dec;171(6):1673 Excessive estradiol secretion in polycystic ovarian disease. Benjamin F, Toles AW, Seltzer VL, Deutsch S. Department of Obstetrics and Gynecology, Queens Hospital Center, Jamaica, NY 11432. Polycystic ovarian disease is both a hyperestrogenic and a hyperandrogenic syndrome, and all studies have shown that hyperestrogenemia is the result of an elevation of estrone with plasma estradiol levels in the normal follicular range. Because a literature search failed to reveal any report of polycystic ovarian disease with significantly elevated estradiol levels, we report a case in which the plasma estradiol was so massively elevated as to mimic an estrogen-producing neoplasm. This case also suggests that although polycystic ovarian disease is a very rare cause of such excessive estradiol production, it should be included in the differential diagnosis of estrogen-producing neoplasms.

Nephron 1983;33(4):253-6. Influence of inhibitor of glucose utilization on the blood platelet function. Tison P, Kubisz P, Cernacek P, Dzurik R. The inhibition of glycolysis by an inhibitor of glucose utilization isolated from urine of the uremic subjects reflects in: (1) decreased platelet aggregation induced by adenosine diphosphate, adrenaline, or collagen, respectively; (2) decreased platelet factor 4 release induced by the same inductors; (3) decreased availability of platelet factor 3, and (4) inhibition of retraction of reptilase clot. It is concluded that the inhibition of glycolysis by 'inhibitor of glucose utilization' contributes to the functional changes of platelets and thus to the alteration of hemostasis in uremic patients.

Energy: vasodilate, bronchoconstrict, secrete/leak, swell, grow, tumefy. Invasion by sympathetic balances the chronic stimulation by mast cells, platelets, pituitary hormones, locally formed estrogen, and the other mediators of stress.

Res Exp Med (Berl) 1987;187(5):385-93. Possible interaction of platelets and adrenaline in the early phase of myocardial infarction. Seitz R, Leising H, Liebermann A, Rohner I, Gerdes H, Egbring R. It is known that in most cases of transmural acute myocardial infarction a platelet clot originates within a coronary artery. In acute myocardial infarction patients increased levels of the plasma catecholamines adrenaline and noradrenaline as well as the platelet release proteins platelet factor 4 and beta-thromboglobulin have been reported. In this study, significantly higher values were found of platelet factor 4 (P less than 0.0001) and beta-thromboglobulin (P less than 0.002) in 17 acute myocardial infarction patients as compared to 17 control patients (on intensive care due to non-cardiac disorders), while the plasma levels of adrenaline and noradrenaline were not different. Positive correlations were obtained between the two catecholamines and the platelet products in the control group and between adrenaline and both platelet factor 4 (r = 0.715, P less than 0.01) and beta-thromboglobulin (r = 0.547, P less than 0.05) in the acute myocardial infarction patients. The data suggest that a stimulation of the platelets by adrenaline may facilitate in vitro activation during sampling in patients with high catecholamine load. On the other hand, a "preactivation" of the platelets by an increase of adrenaline might be of significance for thrombus formation in acute myocardial infarction.

Anesthesiology 1991 Jun;74(6):973-9. Comment in: Anesthesiology. 1992 Mar;76(3):475. Magnesium inhibits the hypertensive but not the cardiotonic actions of low-dose epinephrine. Prielipp RC, Zaloga GP, Butterworth JF 4th, Robertie PG, Dudas LM, Black KW, Royster RL. Intravenous magnesium supplementation is often used to control cardiac arrhythmias and coronary artery vasospasm resulting from disturbances of magnesium homeostasis after coronary artery bypass surgery. Many such patients also require inotropic drug support of depressed myocardial function. However, increased serum magnesium concentrations directly depress cardiac contractility in animals and may interfere with catecholamine actions. To determine whether small intravenous doses of magnesium sulfate (MgSO4) interfere with the cardiotonic actions of epinephrine, we examined the hemodynamic effects of MgSO4 and epinephrine infusion in 17 cardiac surgical patients on their 1st postoperative day in a prospective, controlled study. In 11 patients, infusion of MgSO4 (7-mg.kg-1 bolus followed by 10 mg.kg-1.h-1 as a continuous infusion) increased serum magnesium concentrations by 44% (mean +/- standard error of the mean [SEM] of 0.8 +/- 0.1 to 1.2 +/- 0.1 mM; P less than 0.01) but had no significant effect on heart rate; mean arterial, central venous, or pulmonary arterial occlusion pressures; or cardiac output. Epinephrine infusion (30 ng.kg-1.min-1) significantly increased cardiac index (2.7 +/- 0.1 to 3.1 +/- 0.21.min-1.m-2; P less than 0.05); this effect was not altered by MgSO4 administration (n = 11). However, MgSO4 significantly blunted epinephrine's hypertensive action and prevented a significant increase in mean arterial pressure during concurrent MgSO4-epinephrine administration. Six placebo control patients were given two sequential infusions of epinephrine separated by a placebo infusion to rule out an effect of time on the hemodynamic response to epinephrine. Mean arterial pressure and cardiac index responses to epinephrine were identical before and after placebo infusion.(

Jpn Heart J 1979 Jan;20(1):75-82. Inhibition of constrictor responses of dog coronary artery by atropine. A possible effectiveness of atropine on variant form of angina pectoris. Sakanashi M, Furukawa T, Horio Y. A possible effectiveness of atropine on variant form of angina pectoris was investigated using the left circumflex coronary arterial strips of dogs. Acetylcholine 10(-5)--10(-3) Gm/ml dose-dependently constricted the isolated arterial strips during potassium-contracture in 6 cases, and repetitive applications of acetylcholine could produce the similar contractions to the control. In 18 strips atropine 10(-6) Gm/ml significantly depressed the contractions of coronary arteries induced by acetylcholine 10(-5)--10(-3) Gm/ml. In 5 arterial strips atropine 10(-6) Gm/ml significantly inhibited norepinephrine-induced responses of these arteries, and by 10(-5) Gm/ml further suppression of the responses was obtained. The results suggest that atropine may suppress the contractile responses of the coronary artery induce by acetylcholine and nonrepinephrine through a muscarinic-receptor blocking action and simultaneously partly through an adrenergic alpha-receptor blocking action.

Eur J Clin Pharmacol 1981;20(4):245-50. Effect of long-term beta-blockade with alprenolol on platelet function and fibrinolytic activity in patients with coronary heart disease. Jurgensen HJ, Dalsgaard-Nielsen J, Kjoller E, Gormsen J. In 14 patients with coronary heart disease the effect of long-term treatment (mean 16 months, range 12-33) with alprenolol on platelet function and fibrinolytic activity was studied. While on the beta-blocker and two weeks after gradual withdrawal of it, the patients performed a bicycle-ergometer test and blood samples were obtained before and following exercise. Pre-exercise fibrinolytic activity, assessed by the euglobulin clot lysis time, was 183 +/- 27 min (mean +/- SEM) while on alprenolol as compared to 111 +/- 18 min (p less than 0.01) after its withdrawal. Activation of fibrinolysis following exercise was not significantly influenced by alprenolol. In patients treated with alprenolol, the pre-exercise threshold level of ADP, producing platelet aggregation was 3.3 muM (geometric mean) and 5.1 muM after stopping treatment (p less than or equal to 0.05). In patients receiving the beta-blocker, the ADP- threshold value dropped from 3.3 muM before exercise to 2.3 muM immediately after exercise (not significant). The corresponding values after withdrawal of alprenolol were 5.1 muM and 2.7 muM (p less than or equal to 0.02). Adrenaline - stimulated aggregation was not significantly influenced by alprenolol. Serotonin release from platelets following maximal ADP- and adrenaline stimuli was not significantly changed by exercise in patients on beta-blockade. After stopping treatment, ADP-induced serotonin release was 22 +/- 4.1% before and 15 +/- 4.7% after exercise (p less than 0.02). the corresponding values using the adrenaline stimulus were 29 +/- 5.7% and 17 +/- 4.7% (p less than 0.05). It is suggested that during physical stress alprenolol may protect platelets against aggregatory stimuli.

C R Seances Soc Biol Fil 1987;181(3):242-8. [Adrenaline activates oxidative phosphorylation of rat liver mitochondria through alpha 1-receptors]. Breton L, Clot JP, Bouriannes J, Baudry M. We studied the effects and mode of action of epinephrine on the oxidative phosphorylation of rat liver mitochondria. With either succinate or beta-hydroxybutyrate as substrate, i.v. injection of 1.5 microgram/100 g epinephrine increased the respiratory rates by 30-40% in state 3 (with ADP), and by 20-30% in state 4 (after ADP phosphorylation), so that the respiratory control ratio (state 3/state 4) changed little. The respiratory stimulation by epinephrine was maximal 20 minutes after its injection. The action of epinephrine on mitochondria was blocked by pretreatment of the animals with the alpha 1-antagonist prazosin but not by treatment with the beta-antagonist propranolol. I. v. injection of 10 micrograms/100 g phenylephrine evoked the same mitochondrial response as epinephrine. I. v. administration of 50 micrograms/100 g dibutyryl cyclic AMP enhanced glycaemia but did not affect mitochondrial respiration. Epinephrine therefore has an alpha 1-type of action on mitochondrial oxidative phosphorylation.

Biochimie 1975;57(6-7):797-802. Effects of catecholamines on rat myocardial metabolism. I. Influence of catecholamines on energy-rich nucleotides and phosphorylated fraction contents. Merouze P, Gaudemer Y. 1. The influence of catecholamines (adrenaline and noradrenaline) on energy metabolism of the rat myocardium has been studied by incubating slices of this tissue with these hormones and by following the levels of the different phosphorylated fractions and adenylic nucleotides. 2. Similar effects are obtained with both hormones, adrenaline being more effective. 3. Catecholamines decrease significantly the total amount of phosphate while Pi content increases during the first 10 minutes of incubation; labile and residual phosphate contents increase at the beginning of incubation and decrease to the initial values afterwards. 4. ATP and ADP levels decrease significantly with both hormones; however, the effect of noradrenalin on the ATP level needs a longer time of incubation. The ATP/ADP ratios decrease after 5 minutes incubation and the total adenylic nucleotide content is severely decreased (35 per cent with adrenalin, after 20 minutes incubation). 5. Similar results have been obtained with other tissues; these results can explain the decrease of aerobic metabolism we observed under the same conditions.

Eur J Pharmacol 1982 Jul 30;81(4):569-76. Actions of serotonin antagonists on dog coronary artery. Brazenor RM, Angus JA. Serotonin released from platelets may initiate coronary vasospasm in patients with variant angina. If this hypothesis is correct, serotonin antagonists without constrictor activity may be useful in this form of angina. We have investigated drugs classified as serotonin antagonists on dog circumflex coronary artery ring segments in vitro. Ergotamine, dihydroergotamine, bromocriptine, lisuride, ergometrine, ketanserin, trazodone, cyproheptadine and pizotifen caused non-competitive antagonism of serotonin concentration-response curves. In addition, ketanserin, trazodone, bromocriptine and pizotifen inhibited noradrenaline responses in concentrations similar to those required for serotonin antagonism. All drugs with the exception of ketanserin, cyproheptadine and pizotifen showed some degree of intrinsic constrictor activity. Methysergide antagonized responses to serotonin competitively but also constricted the coronary artery. The lack of a silent competitive serotonin antagonist precludes a definite characterization of coronary serotonin receptors at this time. However, the profile of activity observed for the antagonist drugs in the coronary artery differs from that seen in other vascular tissues. Of the drugs tested, ketanserin may be the most useful in variant angina since it is a potent 5HT antagonist, lacks agonist activity and has alpha-adrenoceptor blocking activity.

Arch Mal Coeur Vaiss 1983 Feb;76 Spec No:3-6. Role of autonomic nervous system in the pathogenesis of angina pectoris. Yasue H. The attacks of vasospastic angina or coronary spasm can be induced by injection of epinephrine, cold pressor test, Valsalva maneuver, and exercise. The attacks induced by these procedures can be suppressed by injection of phentolamine, an alpha adrenergic blocking agent in 80 per cent of the patients. On the other hand, propranolol, a beta adrenergic blocking agent, is not only ineffective in suppressing the attacks but aggravates the attacks in 50 per cent of the patients. Thus, alpha adrenergic receptors seem to play an important role in the production of vasospastic angina. The attacks of vasospastic angina can also be induced by injection of methacholine, a parasympathomimetic agent, and this reaction is suppressed by atropine, a parasympathetic blocking agent. Thus, parasympathetic nervous system also seems to play a role in the production of vasospastic angina. The attacks of vasospastic angina can be easily induced by adrenergic or parasympathetic stimuli from midnight to early morning but is usually not provoked by these stimuli in the daytime. Thus, there is circadian variation in the reactivity of coronary arteries to adrenergic or parasympathetic stimuli. There are also weekly, monthly and yearly variations of the reactivity of coronary arteries to these stimuli. Thus, alpha adrenergic or parasympathetic activity is not the sole factor in the production of vasospastic angina. Angina pectoris caused by increased myocardial oxygen demand is induced by infusion of isoproterenol, a beta adrenergic stimulant, and is suppressed by propranolol but not by phentolamine. So, beta adrenergic receptors play an important role in the production of angina pectoris caused by increased myocardial oxygen demand or organic angina pectoris.

Nippon Yakurigaku Zasshi 1986 Mar;87(3):281-90. [Vasoconstrictor responses of isolated pig coronary arteries]. [Article in Japanese] Ikenoue K, Kawakita S, Toda N. In helical strips of pig coronary arteries, histamine, serotonin, acetylcholine and a stable analogue of thromboxane A2 (9, 11-epithio-11, 12-methano TXA2: s-TXA2) produced a dose-dependent contraction. The histamine-induced contraction was suppressed by treatment with chlorpheniramine, suggesting an involvement of H1 receptors. Contractile responses to serotonin were attenuated by not only ketanserin, an S2 antagonist, but also by cinanserin and methysergide. Relaxation induced by serotonin in preparations treated with high concentrations of ketanserin were inhibited by cinanserin and methysergide. Norepinephrine contracted coronary arteries treated with propranolol. Contractile responses to norepinephrine were reversed to relaxations by prazosin, which were abolished by treatment with yohimbine. Contractile responses to histamine were potentiated by treatment with low concentrations of serotonin or s-TXA2. Contractile responses to serotonin were also potentiated by low concentrations of histamine or s-TXA2. Removal of the endothelium from pig coronary arterial strips potentiated contractions induced by serotonin, histamine and norepinephrine. These results suggest that, in addition to damaged endothelium, integrating action of endogenous vasoconstrictors, including histamine, serotonin, TXA2 and norepinephrine, may play an important role in producing coronary vasospasm.

Jpn Heart J 1987 Sep;28(5):649-61. The role of parasympathetic nerve activity in the pathogenesis of coronary vasospasm. Suematsu M, Ito Y, Fukuzaki H. To evaluate the role of the autonomic nervous system, especially the parasympathetic nervous system, in the initiation mechanism of vasospastic angina pectoris (AP), the coefficient of R-R interval variation (CV) on the electrocardiogram (ECG) and plasma catecholamine concentration were measured in 25 patients with vasospastic AP, 10 patients with effort AP and 12 control subjects. CV which has been recognized as reflecting parasympathetic nervous system activity was calculated from 100 consecutive heart beats on the ECG and represented as the percentage of standard deviation of the R-R interval per mean R-R interval. Repeated measurements of plasma catecholamine concentration revealed higher values at any sampling point throughout a day in patients with vasospastic AP than those in control subjects. A distinctly higher CV was observed at night in the vasospastic AP group. This elevated CV was abolished by atropine sulfate (1.5 mg/day per os). Pilocarpine injection (1.3 mg/10 kg B.W. subcutaneously) induced a marked increase in CV that preceded the occurrence of chest pain and/or ischemic ECG changes in 5 patients with vasospastic AP. The increment in CV at 10 min after pilocarpine administration was greater in vasospastic AP than in control subjects (p less than 0.05). It is concluded that enhanced parasympathetic activity may play a role in the initiation of coronary vasospasm associated with sympathetic hyperactivity.

Science 1984 Mar 30;223(4643):1435-7. Coronary arteries of cardiac patients are hyperreactive and contain stores of amines: a mechanism for coronary spasm. Kalsner S, Richards R. Coronary arteries from hearts of cardiac patients contain significantly higher concentrations of histamine than do those from noncardiac patients. The coronary vessels of cardiac patients are also hyperresponsive to histamine and serotonin. These differences between groups of patients suggest an explanation for coronary artery spasm in heart disease.

Fed Proc 1985 Feb;44(2):321-5. Coronary artery reactivity in human vessels: some questions and some answers. Kalsner S. Spasm of a conduit coronary artery, converting it into a major resistance vessel impeding myocardial blood flow, may have severe short- or long-term effects on cardiac rhythm and systolic ejection of blood. It is now clear that human coronary arteries in vitro contract to acetylcholine but that relaxation is the only response observed in dog coronary vessels. Acetylcholine is as powerful a constrictor of human coronary arteries, in terms of tension induced, as 5-hydroxytryptamine (5-HT) or histamine and is a substantially more powerful constrictor than norepinephrine. Field stimulation of coronary artery strips caused a vasoconstriction that was partially antagonized by atropine (3.45 X 10(-6) M). An enhanced reactivity of the epicardial arteries of cardiac and older patients to several agonists was also observed and appears to provide a background against which a number of vasoactive agents might induce spasm. Coronary tissue from cardiac patients also contains stores of 5-HT and histamine, and the histamine levels are substantially increased above the values in vessels from noncardiac patients. Coronary artery spasm or contraction probably can be initiated by diverse intrinsic and extrinsic influences, including autonomic discharge from either the parasympathetic or sympathetic nervous system or from histamine or 5-HT, and probably no one agent or entity is causative in all cases.

Ann N Y Acad Sci 1969 Oct 14;164(2):517-9. Induced carcinogenesis under various influences on the hypothalamus. Kavetsky RE, Turkevich NM, Akimova RN, Khayetsky IK, Matveichuck YD.

Ann N Y Acad Sci 1966 Jan 21;125(3):933-45. On the psychophysiological mechanism of the organism's resistance to tumor growth. Kavetsky RE, Turkevich NM, Balitsky KP.

Patol Fiziol Eksp Ter 1971 Sep-Oct;15(5):3-10. [Role of disorders in intra-cellular and neuro-humoral regulation in the development of the tumor process]. [Article in Russian] Kavetskii RE, Balitskii KP.

Obstet Gynecol Surv 1977 May;32(5):267-81. Estrogen and endometrial carcinoma. Knab DR. 1. It has become evident that the estrogen secreting tumors of the ovary are associated with endometrial carcinoma, but this association is most easily observed in the postmenopausal patient where the incidence of carcinoma has been reported at 10.3% (1. 02) to 24% (83). 2. The most consistent association of endometrial carcinoma is with polycystic ovarian disease, where 19 (34), 21 (152), and 25% (150) of young women with endometrial carcinoma had Stein-Leventhal syndrome (67). 3. A very significant discovery became known in 1967 when the peripheral aromatization of delta4 androstenedione to estrone was reported by Kase (94) and MacDonald (111,112). Since that time we have learned that endometrial carcinoma patients have an increased peripheral conversion (139) (0.1% compared to 0.027%), which is similar to that found in obese and aging patients, by Hemsell, et al (77). This can be 2 to 4 times greater than the young adult or the patient without cancer. Estrone produced peripherally in normal postmenopausal women can amount to 40-60 microng/day and rise as high as 120-180 microng/day in the endometrial neoplasia group (39). Similarly patients with polycystic ovary disease, hyperthecosis and lipoid cell tumors of the ovary demonstrate androgen excess with extraglandular conversion to estrone (2). 4. It has become apparent that the principal estrogen in the postmenopausal patient is estrone and that the estrone-estradiol ratio in the serum is higher in postmenopausal women with corpus cancer than similar patients without cancer (135). Clearly, we must find the effect of this estrone excess at the nuclear "acceptor" level; and does this imbalance create a hormonal environment conducive to the development of endometrial carcinoma when age (an extremely important factor) and an oncogenic agent are added? 5. With the lack of ovarian estrogen there is a relative excess of adrenal testosterone, dihydrotestosterone and delta4 androstenedione, the available precursors of extraglandular estrone (1). 6. With the passage of time it appears that endometrial carcinoma is associated with hypothalamic "hyperactivity" (31) which exhibits immunologic-biologic dissociation of LH as previously observed in persistent trophoblastic disease when measuring hCG. The significance of this is still unknown. In a like fashion a significant number of the at risk polycystic ovary disease patients have an increased LH secretion. 7. Patient susceptibility is required as seen in animal experiments where prolonged administration of stilbestrol is used and still only rabbits and mice developed a malignant change. 8. Long term exogenous estrogen appears to have caused malignant changes in the endometrium, but it was universally given over a prolonged period (4 or more years). The recent retrospective studies demonstrate an association of oral estrogen therapy with endometrial cancer, but prospective studies investigating dose and duration of all estrogen preparations need to be undertaken. 9...

Endocrinology 2000 Mar;141(3):1059-72. An increased intraovarian synthesis of nerve growth factor and its low affinity receptor is a principal component of steroid-induced polycystic ovary in the rat. Lara HE, Dissen GA, Leyton V, Paredes A, Fuenzalida H, Fiedler JL, Ojeda SR. A form of polycystic ovary (PCO) resembling some aspects of the human PCO syndrome can be induced in rats by a single injection of estradiol valerate (EV). An increase in sympathetic outflow to the ovary precedes, by several weeks, the appearance of cysts, suggesting the involvement of a neurogenic component in the pathology of this ovarian dysfunction. The present study was carried out to test the hypotheses that this change in sympathetic tone is related to an augmented production of ovarian nerve growth factor (NGF), and that this abnormally elevated production of NGF contributes to the formation of ovarian cysts induced by EV. Injection of the steroid resulted in increased intraovarian synthesis of NGF and its low affinity receptor, p75 NGFR. The increase was maximal 30 days after EV, coinciding with the elevation in sympathetic tone to the ovary and preceding the appearance of follicular cysts. Intraovarian injections of the retrograde tracer fluorogold combined with in situ hybridization to detect tyrosine hydroxylase (TH) messenger RNA-containing neurons in the celiac ganglion revealed that these changes in NGF/p75 NGFR synthesis are accompanied by selective activation of noradrenergic neurons projecting to the ovary. The levels of RBT2 messenger RNA, which encodes a beta-tubulin presumably involved in slow axonal transport, were markedly elevated, indicating that EV-induced formation of ovarian cysts is preceded by functional activation ofceliac ganglion neurons, including those innervating the ovary. Intraovarian administration of a neutralizing antiserum to NGF in conjunction with an antisense oligodeoxynucleotide to p75 NGFR, via Alzet osmotic minipumps, restored estrous cyclicity and ovulatory capacity in a majority of EV-treated rats. These functional changes were accompanied by restoration of the number of antral follicles per ovary that had been depleted by EV and a significant reduction in the number of both precystic follicles and follicular cysts. The results indicate that the hyperactivation of ovarian sympathetic nerves seen in EV-induced PCO is related to an overproduction of NGF and its low affinity receptor in the gland. They also suggest that activation of this neurotrophic-neurogenic regulatory loop is a component of the pathological process by which EV induces cyst formation and anovulation in rodents. The possibility exists that a similar alteration in neurotrophic input to the ovary contributes to the etiology and/or maintenance of the PCO syndrome in humans.

Acta Physiol Hung 1996;84(2):183-90. Effects of hormones on the number, distribution and degranulation of mast cells in the ovarian complex of mice. Jaiswal K, Krishna A. The changes in the number and degranulation pattern of mast cells varied with the types of hormonal treatment and ovarian compartment. Luteinizing hormone (LH), follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH) and 17-beta estradiol (E2) treatment caused increase (P < 0.05) in the number of mast cells in the hilum as compared with the controls. Increase (P < 0.05) in the number of mast cells in the whole ovarian complex was observed only following FSH and E2 treatment. All the hormones used in the present study increased the percentage degranulation of mast cells in the hilum. However, only LH, FSH and E2 increased the percentage degranulation of mast cells in other compartments of the ovary (medulla, bursa and cortex). TSH and ACTH failed to cause any increase in the percentage degranulation of mast cells in these compartments. The present findings indicate E2 to be the most potent among the hormones tested in causing degranulation of mast cells in all ovarian compartments.

Fertil Steril 2001 Jun;75(6):1141-7. Increase in nerve fibers and loss of mast cells in polycystic and postmenopausal ovaries. Heider U, Pedal I, Spanel-Borowski K. OBJECTIVE: To quantify nerve fibers and mast cells in human ovaries at different functional stages. DESIGN: Retrospective study. SETTING: Research laboratory of the university. SPECIMEN(S): 8 human ovaries in the follicular (cyclic) phase, 7 polycystic ovaries, and postmenopausal ovaries with (n=5) or without (n=7) hyperthecosis. MAIN OUTCOME MEASURE(S): Single- and double immunohistology for the S100 antigen in glial cells of autonomic nerve fibers, for chymase and tryptase in mast cells, and for the common leukocyte antigen on leukocytes. Histometric evaluation was also performed. INTERVENTION(S): None. RESULT(S): Polycystic ovaries contained significantly more S100-positive nerve fibers in the corticomedullary region than did cyclic ovaries (mean +/- SD per 2-mm(2) area, 476 +/- 136 and 224 +/- 133; P<.01). Postmenopausal ovaries with or without hyperthecosis had the highest density of nerve fibers. In cyclic and polycystic ovaries, more tryptase-positive mast cells than chymase-positive mast cells were found in the interstitial cortex and the medulla. In cyclic ovaries, areas with a moderate density of nerve fibers contained many mast cells. Hence, with increasing nerve fiber density in polycystic ovaries, the number of mast cells decreased strikingly compared with cyclic ovaries (p<.001). Almost no mast cells were seen in postmenopausal ovaries with and without hyperthecosis. The number of leukocyte antigen-positive leukocytes was similar in all groups. CONCLUSION(S): The high density of nerve fibers in polycystic and postmenopausal ovaries, together with a conspicuous decrease in mast cells, indicates altered neuroimmune communication.

Endocrinology 1993 Dec;133(6):2696-703. Ovarian steroidal response to gonadotropins and beta-adrenergic stimulation is enhanced in polycystic ovary syndrome: role of sympathetic innervation. Barria A, Leyton V, Ojeda SR, Lara HE. Experimental induction of a polycystic ovarian syndrome (PCOS) in rodents by the administration of a single dose of estradiol valerate (EV) results in activation of the peripheral sympathetic neurons that innervate the ovary. This activation is evidenced by an increased capacity of ovarian nerve terminals to incorporate and release norepinephrine (NE), an increase in ovarian NE content, and a decrease in ovarian beta-adrenergic receptor number in the ovarian compartments receiving catecholaminergic innervation. The present experiments were undertaken to examine the functional consequences of this enhanced sympathetic outflow to the ovary. The steroidal responses of the gland to beta-adrenergic receptor stimulation and hCG were examined in vitro 60 days after EV administration, i.e. at the time when follicular cysts are well established. EV-treated rats exhibited a remarkable increase in ovarian progesterone and androgen responses to isoproterenol, a beta-adrenergic receptor agonist, with no changes in estradiol responsiveness. Basal estradiol release was, however, 50-fold higher than the highest levels released from normal ovaries at any phase of the estrous cycle. The ovarian progesterone and androgen responses to hCG were enhanced in EV-treated rats, as were the responses to a combination of isoproterenol and hCG. Transection of the superior ovarian nerve (SON), which carries most of the catecholaminergic fibers innervating endocrine ovarian cells, dramatically reduced the exaggerated responses of all three steroids to both beta-adrenergic and gonadotropin stimulation. SON transection also reduced the elevated levels of ovarian NE resulting from EV treatment and caused up-regulation of beta-adrenoreceptors. Most importantly, SON transection restored estrous cyclicity and ovulatory capacity. The results indicate that the increased output of ovarian steroids in PCOS is at least in part due to an enhanced responsiveness of the gland to both catecholaminergic and gonadotropin stimulation. The ability of SON transection to restore a normal response indicates that the alteration in steroid output results from a deranged activation of selective components of the noradrenergic innervation to the ovary. These findings support the concept that an alteration in the neurogenic control of the ovary contributes to the etiology of PCOS.

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<span class="koboSpan" id="kobo.1.1">Bleeding, clotting, cancer</span> A R T I C L E

Bleeding, clotting, cancer

The balance between bleeding and clotting is easily disturbed. The condensation and dissolution of the clotting protein, fibrinogen/fibrin, is a continuous process, sensitive to changes in stress, nutrition, and hormones. Clots form, locally or systemically, when fibrin is formed faster than it is dissolved. When fibrin is destroyed faster than it can be replaced, blood vessels become too permeable, and bleeding can occur more easily.

Mental stress, exercise, estrogen, and serotonin activate both the formation and dissolution of clots.

Bleeding and clotting are not only very closely related with each other, such that a given stress can induce either or both, but the condensation and dissolution of the clotting protein are involved in edema, multiple organ failure, and the growth of cancers. The growth of tumors is as directly related to the clotting system as are thromboses and hemorrhages.

Disordered clotting contributes to maladaptive inflammation and to the "diseases" of aging and degeneration.

Metabolic energy is the basic defense against the stress reactions that disrupt circulation, healing, and growth.

"It is commonly known that the ESR (red cell sedimentation rate) of cancer patients is always high."

"Thus far, completely unagglutinated blood has been found only in strictly healthy animals and men. No severely ill person has yet been seen who did not have intravascular agglutination of the blood and visibly pathologic vessel walls." Melvin H. Knisely, et al., 1947)

When science became a sort of profession, in the 19th century, the old natural philosophy of Newtons time began to subdivide into many specialties. At that time, medicine had some general theories to account for deviations from good health, such as the theory of the four humors and their balance, but as those general theories disappeared, they werent replaced by any single scientific understanding of the nature of good health and disease. Medical education has convinced doctors and the public that the reasons for suffering, disability and death are mostly known, and that when medical experts agree to give a condition a name, there must be some clear scientific evidence behind that disease name.

That mystique of diagnosing disease (specific, concrete, reified disease) was so strong that when Hans Selye noticed (in the 1930s) something that underlies all sickness (he first called it the syndrome of being sick), he was disregarded and disrespected, at least until his dangerous perceptions could be trimmed, distorted, and subsumed under some proper medical categories. Selye observed that stress causes internal bleeding (in lungs, adrenals, thymus, intestine, salivary and tear glands, etc.), but instead of trying to understand what that means for the control of sickness, the medical schools and journals have offered concrete, fragmentary, and false explanations for his observations. Stomach acid causes bleeding in the stomach and duodenum; stuff leaking out of the brain gets the blame for some cases of systemic bleeding, stuff leaking out of the uterus, for other cases, and so on. Selyes observations have been rendered harmless (to medicine) by these falsely concrete explanations. While conventional medicine propagated its medical fantasies, it characterized Selyes work as controversial.

In many cases, diagnosis consists of what could, at best, be called an educated guess, with no attempt to find evidence to support it. Obviously, if every doctor in the country is guessing wrong about certain deadly conditions, lots of people will die, and no one will see the need to even study the subject, since it has a definite name and an explanation that seems to satisfy.

Instead of finding pseudo-reasons for the bleeding abnormalities caused by stress, it would be good to look freshly at the nature of blood and its circulation. It might turn out that its a way to expand our understanding of the stress reaction.

Most people are aware of some of the variations of bleeding and clotting that occur commonly. Bleeding gums, nose-bleeds, menstruation and its variations, and the spontaneous bruising (especially on the thighs) that many women have premenstrually, are familiar events that dont seem to mean much to the medical world. Sometimes nose-bleeds are clearly stress-related, but the usual explanation for that association is that high blood pressure simply blows out weak blood vessels. Bleeding gums are sometimes stress related, but high blood pressure is seldom invoked to explain that problem.

The whole issue of blood vessel fragility is usually disposed of as a genetic trait, or a result of old age. This is part of a general tendency to think of the blood vessels as an anatomically fixed, congenital, and genetically determined system. At least until recently, nearly all physicians have called aneurysms congenital defects. But varicose veins are merely low-pressure analogs of arterial aneurysms, and they obviously develop under specific conditions, such as pregnancy and malnutrition. Spider veins are another anatomical variation that commonly appears under the influence of estrogen. Subarachnoid hemorrhages, which can put pressure on the brain, are usually considered to result from a ruptured aneurysm, and these hemorrages are twice as common in women as in men, and probably result from a hormone imbalance.

Menstrual bleeding is a good place to start the investigation of bleeding problems, since its relatively harmless abnormalities are physiologically related to some very serious health problems, such as pregnancy bleeding, abruptio placentae, and eclampsia. Women who die from eclampsia have been found to have massively clotted blood vessels in their brains, but the variety of names for the pregnancy disorders have prevented most people from thinking of pregnancy as a time when there is a high risk of the thrombohemorrhagic disorders, a time when the clotting system is under stress. (For about fifteen years after Selye coined the term, only he and some Russians were publishing research on it, and Americans still dont show much interest in the subject.)

Women with a chronic menstrual problem resulting from progesterone deficiency often continue to bleed each month even when they are pregnant, and these women tend to develop toxemia, and to have a high incidence of pregnancy complications, and to deliver premature, poorly developed babies.

In 1933 James Shute was recommending the use of vitamin E for preventing the clotting problems associated with pregnancy, that often lead to miscarriage. He based his work on animal studies, that led to vitamin Es being known as the fertility vitamin. Later, his sons Wilfred and Evan reported that vitamin E could prevent heart attacks, birth defects, complications of diabetes, phlebitis, hypertension, and some neurological problems.

Later, referring to the decades of hostility of the medical establishment to vitamin E, Dr. Shute said ...an obstetrician was unduly hardy and audacious to try it. The spectrum of vitamin Es protective effects (like those of aspirin) has been consistently misrepresented in the medical literature.

Hematomas in many organs (pituitary, kidney, pancreas, liver, even around the abdominal muscles) can occur because of hormone imbalances in these difficult pregnancies. Tom Brewers demonstration that a good diet, with abundant protein, can prevent and cure pregnancy toxemia, is practically unknown in the medical world, though a protein deficiency has been shown to increase the risk of blood clots under many other circumstances besides pregnancy.

Abruptio placentae (premature detachment of the placenta) has often been blamed on the use of vitamin E, because of vitamin Es reputation for preventing abnormal clotting, though the evidence tends to suggest instead that vitamin E (like aspirin) reduces the risk of pregnancy-related hemorrhaging.

One of the deadly clotting conditions related to childbirth has been called pregnancy anaphylaxis, but it is more often called amniotic fluid embolism, despite the fact that amniotic fluid injected intravenously is harmless (Petroianu, et al.), and only by grinding up and injecting massive amounts of the pregnancy membranes can the clotting system be disturbed. The term is really a criminal misnomer, serving to blame a preventable clotting/shock disorder on the patient.

Consumption coagulopathy refers to the bleeding that follows excessive activation of the clotting system, combined with a defensive dissolving of the clots, when finally the fibrinogen or other elements of the clotting system have been depleted, consumed. A blood test can show when clot degradation products are being produced too rapidly, even while a person has no symptoms, so there should be time for the accelerated clotting to be controlled, before major thromboses and bleeding and shock have developed.

In 1936 Albert Szent-Gyorgyi reported that some chemicals in lemon juice, which he called vitamin P (or citrin), would prevent purpura, subcutaneous capillary bleeding. By 1938, he had decided that citrin, (which he now called bioflavonoid) probably wasnt a vitamin, and that its action was more like that of a drug, substituting for a natural regulatory factor that was missing. Later research has confirmed that view, showing that the bioflavonoids inhibit the enzyme hyaluronidase, which degrades the ground substance of connective tissues. At least one natural endogenous inhibitor of hyaluronidase has now been identified. The basement membrane that surrounds and unites the endothelial cells of capillaries is largely hyaluronic acid and collagen. It isnt thrombogenic (Buchanan, et al.), despite the common belief that collagen is intrinsically a clot instigator. The breakdown of this ground substance is involved in growth and reproduction, so an excess of bioflavonoids in the diet could conceivably interfere with fertility and fetal development. Some bioflavonoids have been prescribed for menstrual problems, and are probably useful when the physiological inhibitor isnt adequate.

Hyaluronidase is activated by shock, and also by estrogen. Both hyaluronidase and estrogen have been used in plastic surgery to expand tissue, weakening it and allowing it to be enlarged. During aging, hyaluronic acid (the major water-retaining component of connective tissue thats broken down by hyaluronidase) decreases in the connective tissues, but increases in the blood stream. Shock allows hyaluronic acid to increase in the serum. Fragments of degraded hyaluronic acid are pro-inflammatory.

In the 1940s Hans Selye studied the steroid hormones in a comprehensive way, defining their actions and interactions. At that time he found that progesterone protected broadly against stress, and that a large dose of estrogen created a condition that duplicated the initial shock phase of the stress reaction. Later animal studies showed that estrogen quickly causes enlargement of the adrenal glands, followed by bleeding, and, with large and continuous doses, death of the adrenal cells.

Estrogen promotes vascular permeability by a variety of mechanisms. Serotonin, histamine, lactic acid, and various cytokines and prostaglandins contribute to the leakage stimulated by estrogen, trauma, irradiation, poisoning, oxygen deprivation, and other factors that can induce shock. Even exercise, mental stress, and aging can increase the tendency of capillaries to leak.

Progesterone and cortisol protect against shock and stress partly by maintaining the resistance and integrity of the capillaries, preventing leakage of blood materials into the tissues. The maintenance of the capillary barrier probably also prevents substances from the extracellular matrix from triggering the clotting systems.

Clots are formed when soluble fibrinogen polymerizes, condenses, and becomes insoluble. Even before the particles of fibrin become insoluble, a clot-dissolving system is continuously breaking it down into small peptides. These peptides tend to cause capillaries to leak. If a massive amount of fibrinogen and fibrin leak out of capillaries, clots are formed outside capillaries, and the peptides released in the process of cleaning up this debris contribute to further leakage, and to inflammation. The inflammation stimulates the production of collagen-rich connective tissue, and a fibrotic tissue replaces the functional tissues. Many of Hans Selyes experiments explored the conditions in which inflammation, exudation, and fibrosis developed, sometimes ending with calcification of the region.

The presence of fibrin in the extracellular matrix interferes with the differentiated functioning of cells, which depend on their contact with a normal matrix. When healing and regeneration occur in the normal matrix, the remodeling of the tissue involves the breakdown of collagen, which releases peptides with antiinflammatory, antiangiogenic and antiinvasive actions. When fibrin is present, the remodeling process releases peptides that increase cell growth, invasiveness, inflammation, and the production of new blood vessels, which in turn become leaky.

Leakage of fluid out of the blood is one of the main features of shock, and at first it is mainly the loss of water and volume that creates a problem, by reducing the oxygenation of tissue and increasing the viscosity of the remaining blood. Blood becomes more concentrated during strenuous exercise, during the night, and in the winter, increasing the viscosity, and increasing the risk of strokes and other thrombotic problems. The absence of light causes the metabolic and hormonal changes typical of stress.

Tom Brewer and his associates showed that pregnancy toxemia involves inadequate blood volume, and that using extra sodium can alleviate the symptoms, including preventing albuminuria, one of the most characteristic signs of toxemia/preeclampsia. (Besides causing loss of albumin through leaky capillaries, estrogen also inhibits its synthesis by the liver; the loss of colloid osmotic pressure in hypoalbuminemia has many consequences, including disturbances of blood lipids.) Estrogens action in toxemia of pregnancy is paralleled by the fact that blood viscosity is highest at the time of ovulation during the normal monthly cycle.

In the healthy person, some of the fibrin that is constantly being formed is deposited on the inside of blood vessels (and on the surfaces of blood cells), and this layer forms an important part of the capillarys resistance to leaking. A.L. Copley, who pioneered the study of hemorrheology, called this the endoendothelial layer. This layer probably contains albumin, too, in close association with the (carbohydrate) glycocalyx of the endothelial cell surface. Disturbances that accelerate the formation and dissolution of the fibrin layer can be detected by an increase in the concentration of the fibrin degradation products (FDP, or D-dimers) in the blood, even before any symptoms have appeared.

Although Selye described shock as the first (potentially lethal) phase of stress, usually followed by the corrective adaptive processes, its useful to think of aging in terms of a lingering partial state of shock, in which adaptation is less than perfect.

The loss of blood volume through leaky capillaries tends to be self-aggravating. The concentrated and viscous blood doesnt flow as well through the capillaries, and this energy deprivation leads to increased leakiness of the cells, and to swelling of the endothelial cells, decreasing the internal diameter of the small blood vessels. The energy-deprived state increases lactic acid, adrenaline, and free fatty acids, all of which contribute to increased leakiness and impaired circulation.

In the bowel, the capillary malfunction increases the absorption of endotoxin, which intensifies the systemic energy problem. (Polyunsaturated oils, especially fish oil, damage the bowel capillaries, allowing more endotoxin to be absorbed.)

In the uterus, increased viscosity of the blood impairs the delivery of oxygen and nutrients to the fetus, retarding its development. Dilution of the blood under the influence of progesterone reduces the hematocrit, helping to compensate for the viscosity; in toxemic pregnancies this isnt sufficient to maintain normal viscosity and perfusion.

In the brain, hyperviscosity contributes to dementia. In the lung, to edema and reduced oxygenation (shock lung, wet lung, respiratory distress; this lung edema is a major cause of mortality in pregnancy). In the pancreas, to inflammation, and to the release of proteolytic enzymes, impairing the clotting system even more.

During the development of cancer, hyperviscosity (and the associated hypoxia) contributes to the tumors deranged metabolism, tending to increase its production of ammonia, clotting factors, and other stress-inducing toxins.

Factors that increase the fluidity of the blood protect against all of the thrombohemorrhagic conditions, and are especially protective against the estrogen-promoted cancers. Progesterone decreases the production of fibrinogen, and increases the volume of the blood and the flexibility of the red blood cells, increasing the ability of blood to flow freely, and it also decreases the leakiness of capillaries. Hypothyroid people (who tend to have low progesterone and high estrogen) are highly susceptible to heart disease and cancer, and have abnormally viscous blood. Hyperthyroid people have unusually fluid blood. Hypothyroidism increases the leakiness of capillaries, and decreases the amount of albumin in the blood. Albumin itself decreases the permeability of blood vessels.

In hypothyroidism and under the influence of estrogen, there is a chronic increase of free fatty acids, and the free fatty acids are an important factor in increasing the production of fibrinogen (Pickart), and in blocking fibrinolysis (Lindquist, et al.). If the bodys stores of fat are largely polyunsaturated fats, the free fatty acids will combine with the fibrin as it polymerizes, making the clots especially resistant to dissolution.

In the 1940s, Melvin Knisely noticed that all seriously sick people had sludged blood, that can be observed microscopically in the small blood vessels on the surface of the persons eye. The cells tend to stick together, producing a sludgy appearance and slow flow. This probably corresponds to increased viscosity of the plasma, increased red cell sedimentation rate, increased fibrinogen, decreased albumin, and decreased thyroid and progesterone. Clumped red cells, when separated under the microscope, appear to be bound together by fine filaments, possibly of fibrin.

Aspirin is known to have a variety of anticancer activities, including the prevention of metastasis, and some people have reasoned that the clotting process simply helps migrating cancer cells to become anchored. However, the clotting process is normally part of the healing and repair processes, and I think the role of the fibrin clotting system in cancer is that the breakdown products of fibrin are growth-promoters, and that their presence in the extracellular matrix in large quantity, distorting the normal composition of the matrix, is what causes the formation of a tumor. Its the leakage of the fibrin into the extracellular matrix that leads to the development of tumors.

Heparin, a natural anticoagulant, is currently being tested as an anticancer agent.

All of the factors that promote stable oxidative energy production protect against the coagulative derangements, largely by preventing capillary leakage, and it now seems that these processes protect against cancer as well as protecting against all of the stress-related degenerative and inflammatory diseases.

Since hyperventilation can increase capillary leakage and cause the blood to become more concentrated, breathing carbon dioxide (breathing in a bag) should help to restore capillary function.

Since the blood becomes more concentrated, viscous, and clottable during the night (especially during long winter nights), the risk of a heart attack or stroke would probably be reduced by drinking orange juice before getting out of bed (and at bed-time), to dilute the blood and decrease adrenaline and the free fatty acids, which contribute to the increased tendency to form clots in the morning. (Assanelli, et al., discuss the importance of adrenaline in morning/winter sudden death; Antoniades and Westmoreland show that the availability of glucose can override major promoters of clotting and bleeding.)

Things to reduce the stress-related coagulopathies: Sugar and niacin to minimize the liberation of fatty acids, progesterone and thyroid to protect against estrogen and to avoid hypoglycemia (which increases adrenaline and free fatty acids and accelerates clotting), magnesium and gelatin (or glycine), to protect against intracellular calcium overload and hypoxia, and vitamin E and salicylic acid for antiinflammatory effects, are major nutrients that protect the circulatory system against clotting, bleeding, edema, and tumefaction.

Even on the mornings that you dont drop dead, there is reduced adaptive capacity and functional impairment before eating breakfast. For example, men who went for a run before breakfast were found to have broken chromosomes in their blood cells, but if they ate breakfast before running, their chromosomes werent damaged.

REFERENCES

Vet Rec. 1988 Apr 2;122(14):329-32. Relationships between the erythrocyte sedimentation rate, plasma proteins and viscosity, and leucocyte counts in thoroughbred racehorses. Allen BV. The influence of plasma proteins on erythrocyte aggregation was studied in a population of young thoroughbred racehorses, using the 60 minute erythrocyte sedimentation rate (ESR) with and without haematocrit standardisation. The ESR was correlated inversely with the haematocrit, but directly with fibrinogen, plasma viscosity and serum total globulins. When ESR values were standardised to a common haematocrit the correlation coefficients for the same plasma protein factors were increased. Albumin levels showed a strong direct relationship with haematocrit which accounted for the inverse correlation found between albumin and ESR. The haematocrit standardised ESR showed no significant correlation with albumin levels. The high correlation (r = 0.75) found between fibrinogen levels and haematocrit standardised ESR suggests that differences in this acute phase protein influence the degree of red cell aggregation and rouleaux formation in the horse.

Ann N Y Acad Sci. 1976;275:28-46. Metabolic influences in experimental thrombosis. Antoniades HN, Westmoreland N. Studies presented in this report demonstrate that intravascular coagulation and thrombosis in the whole animal can be greatly influenced by noncoagulation factors, such as metabolic, endocrinologic, and nutritional states. Injection of a partially purified human serum procoagulant fraction produced no significant clotting abnormalities in normal fed rats; however, injection of an identical preparation in fasted, diabetic, and obese rats produced hypercoagulability of blood, thrombosis, and hemorrhage. Glucose injection in fasted rats and insulin injection in diabetic rats reversed their susceptibility to thrombosis. The concentrations of serum free fatty acids were shown to be elevated in the susceptible animals; however, they returned to normal in fasted and diabetic rats after injections of glucose and insulin, respectively. Infusion of free fatty acid-albumin preparations in normal fed rats rendered the animals susceptible to thrombosis when challenged with the serum procoagulant fraction.

Cardiologia. 1997 Jul;42(7):729-35. [Circadian variation of sudden cardiac death in young people with and without coronary disease] Assanelli D, Bersatti F, Turla C, Restori M, Amariti ML, Romano A, Ferrari M. To clarify whether sudden cardiac death has a circadian rhythm in young people we have studied 40 patients < 45 years who died in Brescia between 1984 and 1993 of sudden cardiac death showing at autopsy features of coronary artery disease (CAD) and 12 patients aged < 30 years who died of sudden cardiac death without autoptic features of CAD. We observed a circadian rhythm in the hours of the morning in the two groups, more evident in patients without CAD. In patients with autoptic features of CAD, we also observed a higher rate of events during the winter months. We would like to stress the importance of the adrenergic system as a trigger able to produce the event.

An R Acad Nac Med (Madr). 2002;119(1):163-73; discussion 173-4. [HELLP syndrome and hemorrhagic gestosis] Botella Llusia J. In the year 1817, Charlotte daughter of Georges IV and princess of Wales, died on an unknown condition with uteroplacental hemorrhage and fetal death called at the time "Uteroplacental Apoplexy" and later "Abruptio Placentae". This affection was described in the classical books as an hemorrhagic complication of labor. In 1961 we have at first related the Abruptio with acute toxemia (preeclampsia) and have proposed the term "Gestosis hemorragica" to design it. In 1982 Weinstein has described the called HELLP syndrome (Hemolysis, Elevated liver Enzymes, at Low Platelets) which basically is the same pathological picture as the described by us as "hemorrhagic toxemia". The aim of the paper is to demonstrate the identity of both syndromes and to claim for the priority of our definition.

Thromb Haemost. 1987 Aug 4;58(2):698-704. The basement membrane underlying the vascular endothelium is not thrombogenic: in vivo and in vitro studies with rabbit and human tissue. Buchanan MR, Richardson M, Haas TA, Hirsh J, Madri JA.

Am J Physiol Heart Circ Physiol. 2003 Mar;284(3):H1028-34. Epub 2002 Nov 21. Endotoxemia stimulates skeletal muscle Na+-K+-ATPase and raises blood lactate under aerobic conditions in humans. Bundgaard H, Kjeldsen K, Suarez Krabbe K, van Hall G, Simonsen L, Qvist J, Hansen CM, Moller K, Fonsmark L, Lav Madsen P, Klarlund Pedersen B.

Thromb Haemost. 2001 Jul;86(1):334-45. Tissue factor--a receptor involved in the control of cellular properties, including angiogenesis. Chen J, Bierhaus A, Schiekofer S, Andrassy M, Chen B, Stern DM, Nawroth PP. Tissue factor (TF), the major initiator of blood coagulation, serves as a regulator of angiogenesis, tumor growth and metastasis.

Thromb Res Suppl. 1983;5:105-45. The physiological significance of the endoendothelial fibrin lining (EEFL) as the critical interface in the 'vessel-blood organ' and the importance of in vivo 'fibrinogenin formation' in health and disease. Copley AL. The author's theory of the endoendothelial fibrin lining (EEFL) . . . localizes the homeostasis between steady fibrin formation and deposition, or 'fibrination', and continuous fibrinolysis in the more or less immobile portion of the plasmatic zone next to the vessel wall. In 1971, the author advanced, in relation to the EEFL, the theory of fibrinogen gel clotting without thrombin action or 'fibrinogenin' formation in vivo. The EEFL of the vessel-blood organ is considered by the author as the crucial critical interface between the blood and the vessel wall. It is the primary barrier, followed by the endothelium (comprising the endothelial cells and the interendothelial cement substance which contains or is identical with 'cement fibrin') and the basement membrane for the exchanges between the blood, the vessel wall and its surrounding tissues and spaces. The EEFL acts as anticoagulant, is antithrombogenic, maintains vascular patency and aids cardiac action by decreasing significantly the apparent viscosity of blood, referred to in the literature as the 'Copley-Scott Blair phenomenon'. A new concept of leukocyte emigration traversing the capillary wall is presented, affecting focal fibrinolysis of the EEFL and of fibrin contained in the interendothelial cement substance and in the basement membrane. The physical property of capillary (or vascular) permeability is related to the existence of the EEFL, since, as found by Copley et al, both fibrinopeptides, liberated in the transition of fibrinogen to fibrin, and plasminopeptides, freed in the conversion of plasminogen to plasmin, enhance capillary permeability. Capillary fragility, which is antagonistic to capillary permeability, is in great part due to fibrinolytic action on fibrin as a constituent of the basement membrane.

Am J Obstet Gynecol. 1995 Apr;172(4 Pt 1):1291-8. Blindness associated with preeclampsia and eclampsia. Cunningham FG, Fernandez CO, Hernandez C.

East Afr Med J. 2002 Apr;79(4):181-3. Haemorheological changes during the menstrual cycle. Dapper DV, Didia BC.

Cancer Res. 2001 Feb 1;61(3):795-8. Tumor hypoxia, the physiological link between Trousseau's syndrome (carcinoma-induced coagulopathy) and metastasis. Denko NC, Giaccia AJ.

Lab Invest 1998 Jun;78(6):657-68. Development of porous defects in plasma membranes of adenosine triphosphate-depleted Madin-Darby canine kidney cells and its inhibition by glycine. Dong Z, Patel Y, Saikumar P, Weinberg JM, Venkatachalam MA

Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):2692-7. Seasonal variations of rheological and hemostatic parameters and acute-phase reactants in young, healthy subjects. Frohlich M, Sund M, Russ S, Hoffmeister A, Fischer HG, Hombach V, Koenig W.

Respir Physiol Neurobiol. 2003 Oct 16;138(1):37-44. Lactate as a modulator of hypoxia-induced hyperventilation.Gargaglioni LH, Bicego KC, Steiner AA, Branco LG.

Am J Vet Res. 1994 Jun;55(6):854-61. Hemorheologic alterations induced by incremental treadmill exercise in Thoroughbreds. Geor RJ, Weiss DJ, Smith CM.

Vopr Pitan. 1995;(1):7-11. [Effects of dietary fat on permeability of the protective intestinal barrier to

macromolecules in experimental anaphylaxis][Article in Russian]

Gmoshinskii IV, Ermekpaeva RA, Lysikov IuA, Kulakova SN, Mazo VK, Morozov IA.

Am J Physiol Cell Physiol 2000 Nov;279(5):C1495-505. Calcium regulates estrogen increase in permeability of cultured CaSki epithelium by eNOS-dependent mechanism. Gorodeski GI.

J Reprod Med. 2002 Dec;47(12):1021-4. Documentation of amniotic fluid embolism via lung histopathology. Fact or Fiction? Hankins GD, Snyder R, Dinh T, Van Hook J, Clark S, Vandelan A.

Klin Wochenschr. 1990 Jun 5;68(11):559-64. [Hemodynamic and hemorheologic findings in patients with pregnancy-induced hypertension: comparison of pre-eclampsia and chronic hypertension] Heilmann L, Schmid-Schonbein H.

Zentralbl Gynakol. 1986;108(7):393-402. [Changes in flow properties of the blood in pregnancy] Heilmann L.

Eur J Vasc Surg. 1992 Jan;6(1):36-40. Claudication induces systemic capillary endothelial swelling. Hickey NC, Hudlicka O, Simms MH.

Blood. 2001 Mar 15;97(6):1697-702. Serotonin induces the expression of tissue factor and plasminogen activator inhibitor-1 in cultured rat aortic endothelial cells. Kawano H, Tsuji H, Nishimura H, Kimura S, Yano S, Ukimura N, Kunieda Y, Yoshizumi M, Sugano T, Nakagawa K, Masuda H, Sawada S, Nakagawa M.

Br Med J (Clin Res Ed). 1984 Nov 24;289(6456):1405-8. Increases in platelet and red cell counts, blood viscosity, and arterial pressure during mild surface cooling: factors in mortality from coronary and cerebral thrombosis in winter. Keatinge WR, Coleshaw SR, Cotter F, Mattock M, Murphy M, Chelliah R. Six hours of mild surface cooling in moving air at 24 degrees C with little fall in core temperature (0.4 degree C) increased the packed cell volume by 7% and increased the platelet count and usually the mean platelet volume to produce a 15% increase in the fraction of plasma volume occupied by platelets. Little of these increases occurred in the first hour. Whole blood viscosity increased by 21%; plasma viscosity usually increased, and arterial pressure rose on average from 126/69 to 138/87 mm Hg.

Acta Chir Scand. 1976;142(1):20-5. Induction of endogenous fibrinolysis inhibition in the dog. Effect of intravascular coagulation and release of free fatty acids. Lindquist O, Bagge L, Saldeen T. In all groups subjected to infusion of thrombin an increase in plasma free fatty acids (FFA) was observed. The role of this increase for the development of fibrinolysis inhibition was tested by infusion of norepinephrine alone and in combination with nicotinic acid. Norepinephrine caused an increase of FFA after 2 hours and in urokinase inhibitor activity after 24-48 hours. Both of these were diminished by high doses of nicotinic acid, indicating that the release of FFA rather than intravascular coagulation might be the principal mechanism underlying the occurrence of fibrinolysis inhibition following trauma.

Matrix Biol. 2002 Jan;21(1):31-7. Inhibitors of the hyaluronidases. Mio K, Stern R. Because of increased interest in hyaluronidases and their hyaluronan substrate, a study of these inhibitors was undertaken recently. The predominant serum inhibitor is magnesium-dependent....

Vopr Onkol. 1991;37(9-10):992-7. [Blood coagulation disorders and tumor growth][Article in Russian] Mkrtchian LN, Shukurian SG, Sarkisian OM, Magakian AG, Khachaturova TS, Ambartsumian AM.

Usp Fiziol Nauk. 1989 Oct-Dec;20(4):94-109. [The physiologic coagulation fibrinolytic system of the body and thrombohemorrhagic theory in oncology] [Article in Russian] Nadiradze ISh, Machabeli MS.

Arch Gynecol Obstet. 2002 Nov;267(1):7-10. Sex hormones, hemostasis and early pregnancy loss. Nelson DB, Ness RB, Grisso JA, Cushman M. This study was designed to determine the association between coagulation factors and spontaneous abortion adjusting for sex steroids and to examine the influence of sex hormones on coagulation factors early in pregnancy. The relationship between coagulation factors and spontaneous abortion was reduced after adjustment for progesterone suggesting that progesterone mediates the relationship between low levels of coagulation factors and spontaneous abortion. Progesterone seems to be the primary marker for a spontaneous abortion among women seeking emergent care.

Toxicol Pathol. 1992;20(1):71-80. Pathogenesis of blood-filled cavities in estrogen-induced anterior pituitary tumors in male Sprague-Dawley rats. van Nesselrooij JH, Hendriksen GJ, Feron VJ, Bosland MC.

Arch Int Physiol Biochim. 1983 Jul;91(2):81-5. Effects of the administration of progesterone and adrenal medullectomy on the plasma fibrinogen levels in rats with surgical injury (laparotomy). Palma JA, Gavotto AC, Villagra SB.

Pediatr Crit Care Med. 2000 Jul;1(1):65-71. Administration of autologous fetal membranes: Effects on the coagulation in pregnant mini-pigs. Petroianu GA, Toomes LM, Maleck WM, Friedberg C, Bergler WF, Rufer R. A hallmark of the so-called amniotic fluid embolism is the induction of coagulation defects. Entry of meconium-free autologous amniotic fluid into the circulation, however, is innocuous. Animals received 2 g FM [fetal membranes] (shredded and suspended in lactated Ringer's solution) via an ear vein. However, the full clinical picture of amniotic fluid embolism and disseminated intravascular coagulation could not be elicited despite the high dose of FM used.

Am J Physiol. 1976 Apr;230(4):996-1002. Free fatty acids and albumin as mediators of thrombin-stimulated fibrinogen synthesis. Pickart LR, Thaler MM. Mobilization of FFA in mice, triggered with an injection of thrombin, was followed within 24 h by a 2.5-fold increase in fibrinogen synthesis and a 30% increase in plasma fibrinogen concentration. Injection of exogenous defatted albumin into mice before thrombin injection prevented the FFA-associated rise in fibrinogen synthesis and plasma concentration. These studies indicate that the FFA/ALBUMIN RATIO MAY PLAY A MAJOR ROLE IN THE REPLENISHMENT OF FIBRINOGEN AFTER PERIODS OF RAPID DEFIBRINOGENATION.

Thromb Haemost. 1995 Jul;74(1):391-5. Tissue factor expression in human leukocytes and tumor cells. Rickles FR, Hair GA, Zeff RA, Lee E, Bona RD. Tissue factor (TF) exists in a cryptic form [i.e. without procoagulant activity (PCA)] in peripheral blood monocytes and quiescent tissue macrophages but is expressed constitutively in most human tumor cells. The regulation of TF synthesis in cells is complex and new information from transfection studies suggests that changes in cellular glycosylation pathways impair cell surface expression of functional TF. The importance of carbohydrate modification of TF is reviewed.

Nature 138: 32 (1936). Selye, H. A Syndrome produced by diverse nocuous agents.

Int J Microcirc Clin Exp. 1996 Sep-Oct;16(5):266-70. Hyperventilation enhances transcapillary diffusion of sodium fluorescein. Steurer J, Schiesser D, Stey C, Vetter W, Elzi MV, Barras JP, Franzeck UK.

Lancet. 1991 Jul 6;338(8758):9-13. Seasonal variations in fibrinogen concentrations among elderly people. Stout RW, Crawford V. Mortality and morbidity in elderly people are higher in winter than in summer months, with seasonal variations in rates of both fatal and non-fatal myocardial infarction and stroke. Significant seasonal effects were found for fibrinogen, plasma viscosity, and HDL cholesterol (p less than 0.003, Bonferroni adjustment). Plasma fibrinogen concentrations showed the greatest seasonal change and were 23% higher in the coldest six months compared with summer months. Fibrinogen was significantly (p less than 0.05) and negatively related to core body temperature and all measures of environmental temperature. Those living in institutions had greater changes in plasma fibrinogen than those living in the community. The seasonal variation in plasma fibrinogen concentration is large enough to increase the risk of both myocardial infarction and stroke in winter.

Akush Ginekol (Mosk). 1989 Jan;(1):43-6. [Coagulative activity of the amniotic fluid] [Article in Russian] Tersenov OA, Mikhaleva IV, Usol'tseva VA, Byshevskii Ash. An ultracentrifugation study has shown thromboplastin to be the only blood coagulating agent, present in the amniotic fluid (AF). Its AF level shows no correlation to the rate of intrapartum or early postpartum thrombohemorrhagic complications....

Metabolism. 1989 May;38(5):471-8. Effects of hypothyroidism on vascular 125I-albumin permeation and blood flow in Rats. Tilton RG, Pugliese G, Chang K, Speedy A, Province MA, Kilo C, Williamson JR. Effects of hypothyroidism on vascular 125I-albumin permeation and on blood flow were assessed in multiple tissues of male Sprague-Dawley rats rendered hypothyroid by dietary supplementation with 0.5% (wt/wt) 2-thiouracil or by thyroidectomy. After 10 to 12 weeks of thiouracil treatment, 125I-albumin permeation was increased significantly in the kidney, aorta, eye (anterior uvea, choroid, retina), skin, and new granulation tissue....

Clin Nutr. 2001 Aug;20(4):351-9. Effect of eicosapentaenoic acid (EPA) on tight junction permeability in intestinal monolayer cells. Usami M, Muraki K, Iwamoto M, Ohata A, Matsushita E, Miki A.

Carcinogenesis. 2003 Jun;24(6):1009-13. Epub 2003 Mar 28. Tissue factor signal transduction in angiogenesis. Versteeg HH, Peppelenbosch MP, Spek CA. Tissue factor (TF), a 47-kDa transmembrane glycoprotein, is a principal regulator of oncogenic neoangiogenesis and controls therefore the cancerous process. Although originally identified as a component of the coagulation cascade, it has become clear that TF functions as a cytokine-like receptor and this notion was confirmed by the discovery of coagulation-independent actions of TF (which include regulation of tumour growth, embryonic and oncogenic blood vessel formation as well as regulation of inflammation and sepsis). In accordance, TF-mediated signal transduction events are readily detected and the elucidation of the underlying molecular mechanisms has recently seen spectacular progress and it is now understood that the role of TF in angiogenesis is both coagulation-dependent and independent. The recent evidence for this emerging insight will be the subject of this review.

Semin Thromb Hemost. 2003 Jun;29(3):317-20. Occurrence of components of fibrinolytic pathways in situ in laryngeal cancer. Wojtukiewicz MZ, Sierko E, Zacharski LR, Rozanska-Kudelska M, Zimnoch L.

Semin Thromb Hemost. 2003 Jun;29(3):239-46. Malignancy as a solid-phase coagulopathy: implications for the etiology, pathogenesis, and treatment of cancer. Zacharski LR.

Thromb Res. 2003 Jun 1;110(4):213-4. Heparin treatment of malignancy: the case for clinical trials in colon cancer. Zacharski LR.

Anticancer Res. 2003 May-Jun;23(3C):2789-93. Low-molecular-weight heparin in oncology. Zacharski LR, Loynes JT.

Cancer Lett. 2002 Dec 1;186(1):1-9. Anticoagulants in cancer treatment: malignancy as a solid phase coagulopathy. Zacharski LR.

© Ray Peat 2006. All Rights Reserved. www.RayPeat.com

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<span class="koboSpan" id="kobo.1.1">Blocking Tissue Destruction</span> A R T I C L E

Blocking Tissue Destruction

There always seems to be a rough balance between tissue regeneration and tissue degeneration, with growth and repair occurring when the equilibrium shifts in one direction,and with atrophy or degeneration occurring when the balance shifts in the other direction. If we can understand the mechanisms of atrophy, and how to retard or to block tissue destruction, then we can restore the balance to a degree which might allow regeneration to occur, even if we don't clearly understand the mechanisms of growth.

Skin and bones are such different types of tissue that it will be useful to start with them, because if we can see similar processes of degeneration or regeneration in them, then the chances are good that the same processes will occur in other tissues too. Bone is a relatively stable tissue, while skin is a tissue whose cells divide rapidly.

It is common medical knowledge that cortisone and realted glucocorticioid-type hormones cause skin to atrophy, becoming thinner. Using topical applications of a synthetic derivative of cortisione,CM Papa and A M. Kligman showed that the atrophy extended to the pigment cells,reducing theirr size and eliminating most of their dendritic branches. Some animal studies have found that estrogen caused the skin to become thinner. The other steroids they tested,progesterone, testosterone,and pregnenolone, acted in the opposite direction, making aged and atrophied skin thicker and more regular. They also made the pigment cells larger, and increased their branchinhg.l Since these hormones were already known to have protective actions against cortisone and estrogen, these results were not too surprising, though they did directly contradict the claims of people who made estrogen-containing cosmetics.

Since progesterone and pregnenolone do not cause healthy, young skin to thicken, their effect in damaged skin is probably partly to replace the deficiency of that type of steroid which occurs with aging, and to offset the damaging effects of the catabolic hormones, whose influence does not decrease with age.

Many years ago it was found that in old age a woman's estrogens were increasedd relative to the 17-keto steroids adrenal androgens. Later, it was found that the conversion of androgen to estrogen increases with age in both men and women, and that this occurs largely in fat cells. Several years ago, P. K. Siiteri found that low thyroid modified the enzymes of fat cells in a way that would tend to increase the conversion of androgen to estrogen. More recently, it was found that adding progesterone to the enzymes had the opposite effect of aging and hypothyroidism, protecting the androgen from conversion to estrogen. These researchers (C. J. Newton and colleagues, of London) concluded that the decreased output of progesterone after the menopause might account for the increased production of estrogen.3 Since progesterone declines in aging men, too, this could account for the same process in men.

Vitamin A's effect on the skin opposes that of estrogen.4 There are several mechanisms that could account for this. Vitamin A is used in the formation of steroids, and since the skin is a major site of steroid metabolism, vitamin A might help to maintain the level of the anti-catabolic steroids. A deficiency of vitamin A causes excessive release of the lysosomal enzymes, acid hydrolases, resulting in tissue catabolism.5 Also, vitamin A is necessary for the proper differentiation of cells in skin and other membranes. A deficiency tends to cause an increased rate of cell division, with the production of abnormal cells, and a substitution of keratinized cells for other types. Estrogen also promotes keratinization and speeds cell division. A deficiency of vitamin A can cause leukoplakia in the mouth and on the cervix of the uterus; although this is considered "pre-cancerous," I have found it to be very easily reversible, as I have discussed elsewhere.6 I suspect that the intracellular fiber, keratin, is produced when a cell can't afford to do anything more complex. Adequate vitamin A speeds protein synthesis,7 and allows it to be used more efficiently.

Prolactin (which is promoted by estrogen, and inhibited by progesterone) increases with stress and with age. It probably affects every tissue, but it seems to have its greatest efects on the secretory membranes. It is known to have strong effects on the kidney, gut and skin (sweat and oil glands, hair follicles, and feathers inbirds), and on the gills of fish. Its involvement with milk production suggests that it might mobilize calcium from bones, and inf fact it does contribute to osteoporosis. This was foreseen by G. Bourne, in his book on the metabolism of hard tissues, when he suggested that estrogen, acting through the pituitary, might be expected to promote osteoporosis.

Since reading Bourne's book, I have doubted that it was rational to use estrogen to prevent osteoporosis, especially when it is known to be carcinogenic and when the ratio of estrogen to and

androgens and progesterone increases after menopause. Now that several publications have appeared clearly showing that estrogen increases prolactin, that prolactin increases with

cancellous bone; adrenal androgens. Thyroid. Rate of formation, overall metabolic rate.

ARTHRITIS AND NATURAL HORMONES

A very healthy 71 year-old man was under his house repairing the foundation, when a support slipped and let the house fall far enough to break some facial bones. During his recovery, he developed arthritis in his hands. It is fairly common for arthritis to appear shortly after an accident, a shock, or surgery, and Han Selye's famous work with rats shows that when stress exhausts the adrenal glands (so they are unable to produce normal amounts of cortisone and related steroid hormones), arthritis and other "degenerative" diseases are likely to develop.

But when this man went to his doctor to "get something for his arthritis," he was annoyed that the doctor insisted on giving him a complete physical exam, and wouldn't give him a shot of cortisone. The examination showed low thyroid function, and the doctor prescribed a supplement of thyroid extract, explaining that arthritis is one of the many symptoms of hypothyroidism. The patient agreed to take the thyroid, but for several days he grumbled about the doctor 'fixing something that wasn't wrong' with him, and ignoring his arthritis. But in less than two weeks, the arthritis had entirely disappeared. He lived to be 89, without a recurrence of arthritis. (He died iatrogenically, while in good health.)

Selye's work with the diseases of stress, and the anti-stress hormones of the adrenal cortex, helped many scientists to think more clearly about the interaction of the organism with its environment, but it has led others to focus too narrowly on hormones of the adrenal cortex (such as cortisol and cortisone), and to forget the older knowledge about natural resistance. There are probably only a few physicians now practicing who would remember to check for hypothyroidism in an arthritis patient, or in other stress-related conditions. Hypothyroidism is a common cause of adrenal insufficiency, but it also has some direct effects on joint tissues. In chronic hypothyroidism (myxedema and cretinism), knees and elbows are often bent abnormally.

By the 1930's, it was well established that the resistance of the organism depended on the energy produced by respiration under the influence of the thyroid gland, as well as on the adrenal hormones, and that the hormones of pregnancy (especially progesterone) could substitute for the adrenal hormones. In a sense, the thyroid hormone is the basic anti-stress hormone, since it is required for the production of the adrenal and pregnancy hormones.

A contemporary researcher, F. Z. Meerson, is putting together a picture of the biological processes involved in adapting to stress, including energy production, nutrition, hormones, and changes in cell structure.

While one of Selye's earliest observations related gastrointestinal bleeding to stress, Meerson's work has revealed in a detailed way how the usually beneficial hormone of adaptation, cortisone, can cause so many other harmful effects when its action is too prolonged or too intense.

Some of the harmful effects of the cortisone class of drugs (other than gastro-intestinal bleeding) are: Hypertension, osteoporosis, delayed healing, atrophy of the skin, convulsions, cataracts, glaucoma, protruding eyes, psychic derangements, menstrual irregularities, and loss of immunity allowing infections (or cancer) to spread.

While normal thyroid function is required for the secretion of the adrenal hormones, the basic signal which causes cortisone to be formed is a drop in the blood glucose level. The increased energy requirement of any stress tends to cause the blood sugar to fall slightly, but hypothyroidism itself tends to depress blood sugar.

The person with low thyroid function is more likely than a normal person to require cortisone to cope with a certain amount of stress. However, if large amounts of cortisone are produced for a long time, the toxic effects of the hormone begin to appear. According to Meerson, heart attacks are provoked and aggravated by the cortisone produced during stress. (Meerson and his colleagues have demonstrated that the progress of a heart attack can be halted by a treatment including natural substances such as vitamin E and magnesium.)

While hypothyroidism makes the body require more cortisone to sustain blood sugar and energy production, it also limits the ability to produce cortisone, so in some cases stress produces symptoms resulting from a deficiency of cortisone, including various forms of arthritis and more generalized types of chronic inflammation.

Often, a small physiological dose of natural hydrocortisone can help the patient meet the stress, without causing harmful side-effects. While treating the symptoms with cortisone for a short time, it is important to try to learn the basic cause of the problem, by checking for hypothyroidism, vitamin A deficiency, protein deficiency, a lack of sunlight, etc. (I suspect that light on the skin directly increases the skin's production of steroids, without depending on other organs. Different steroids probably involve different frequencies of light, but orange and red light seem to be important frequencies.) Using cortisone in this way, physiologically rather than pharmacologically, it is not likely to cause the serious problems mentioned above.

Stress-induced cortisone deficiency is thought to be a factor in a great variety of unpleasant conditions, from allergies to ulcerative colitis, and in many forms of arthritis. The stress which can cause a cortisone deficiency is even more likely to disturb formation of progesterone and thyroid hormone, so the fact that cortisone can relieve symptoms does not mean that it has corrected the problem.

According to the Physicians' Desk Referenc, hormones similar to cortisone are useful for treating rheumatoid arthritis, post-traumatic osteoarthritis, synovitis of osteoarthritis, acute gouty arthritis, acute nonspecific tenosynovitis, psoriatic arthritis, ankylosing spondylitis, acute and subacute bursitis, and epicondylitis.

Although cortisone supplementation can help in a great variety of stress-related diseases, no curewill take place unless the basic cause is discovered. Besides the thyroid, the other class of adaptive hormones which are often out of balance in the diseases of stress, is the group of hormones produced mainly by the gonads: the "reproductive hormones." During pregnancy these hormones serve to protect the developing baby from the stresses suffered by the mother, but the same hormones function as part to the protective anti-stress system in the non-pregnant individual, though at a lower level.

Some forms of arthritis are known to improve or even to disappear during pregnancy. As mentioned above, the hormones of pregnancy can make up for a lack of adrenal cortex hormones. During a healthy pregnancy, many hormones are present in increased amounts, including the thyroid hormones. Progesterone, which is the most abundant hormone of pregnancy, has both anti-inflammatory and anesthetic actions, which would be of obvious benefit in arthritis.

There are other naturally anesthetic hormones which are increased during pregnancy, including DHEA, which is being studied for its anti-aging, anti-cancer, and anti-obesity effects. (One of the reasons that is frequently given for the fact that this hormone hasn't been studied more widely is that, as a natural substance, it has not been monopolized by a drug patent, and so no drug company has been willing to invest money in studying its medical uses.) These hormones also have the ability to control cell division, which would be important in forms of arthritis that involve invasive tissue growth.

While these substances, so abundant in pregnancy, have the ability to substitute for cortisone, they can also be used by the adrenal glands to produce cortisol and related hormones. But probably the most surprising property of these natural steroids is that they protect against the toxic side-effects of excessive adrenal hormones. And they seem to have no side-effects of their own; after about fifty years of medical use, no toxic side effects have been found for progesterone or pregnenolone.

Pregnenolone is the material the body uses to form either progesterone or DHEA. Others, including DHEA, haven't been studied for so long, but the high levels which are normally present in healthy people would suggest that replacement doses, to restore those normal levels, would not be likely to produce toxic side effects. And, considering the terrible side effects of the drugs that are now widely used, these drugs would be justifiable simply to prevent some of the toxic effects of conventional treatment.

It takes a new way of thinking to understand that these protective substances protect against an excess of the adrenal steroids, as well as making up for a deficiency. Several of these natural hormones also have a protective action against various poisons; Selye called this their "catatoxic" effect.

Besides many people whose arthritis improved with only thyroid supplementation, I have seen 30 people use one or more of these other natural hormones for various types of arthritis, usually with a topical application. Often the pain is relieved within a few minutes. I know of several other people who used progesterone topically for inflamed tendons, damaged cartilage, or other inflammations. Only one of these, a woman with rheumatoid arthritis in many joints, had no significant improvement. An hour after she had applied it to her hands and feet, she enthusiastically reported that her ankle had stopped hurting, but after this she said she had no noticeable improvement.

We often hear that "there is no cure for arthritis, because the causes are not known." If the cause is an imbalance in the normal hormones of adaptation and resistance, then eliminating the cause by restoring balance will produce a true cure. But if it is more profitable to sell powerful drugs than to sell the nutrients needed to form natural hormones (or to supplement those natural hormones) we can't expect the drug companies to spend any money investigating that sort of cure. And at present the arthritis market amounts to billions of dollars in drug sales each year.

© Ray Peat 2006. All Rights Reserved. www.RayPeat.com

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A R T I C L E

Bone Density: First Do No Harm

No topic can be understood in isolation. People frequently ask me what they should do about their diagnosed osteoporosis/osteopenia, and when they mention “computer controlled” and “dual photon x-ray” bone density tests, my attention tends to jump past their bones, their diet, and their hormones, to the way they must perceive themselves and their place in the world. Are they aware that this is an x-ray that’s powerful enough to differentiate very opaque bones from less opaque bones? The soft tissues aren’t being studied, so they are allowed to be “overexposed” until they appear black on the film. If a thick area like the thigh or hip is to be measured, are they aware that the x-ray dose received at the surface where the radiation enters might be 20 times more intense than the radiation that reaches the film, and that the 90 or 95% of the missing energy has been absorbed by the person’s cells? If I limited my response to answering the question they thought they had asked me, I would feel that I had joined a conspiracy against them. My answer has to assume that they are really asking about their health, rather than about a particular medical diagnosis.

Neurologists are famous for making exquisitely erudite diagnoses of problems that they can’t do anything to remedy. The owners of expensive dual photon x-ray absorptiometer diagnostic machines are in a very different position. The remedies for osteoporosis are things that everyone should be doing, anyway, so diagnosis makes no difference in what the physician should recommend to the patient.

Most often, estrogen is prescribed for osteoporosis, and if the doctors didn’t have their bone density tests, they would probably prescribe estrogen anyway, “to protect the heart,” or “to prevent Alzheimer’s disease.” Since I have already written about estrogen and those problems, there’s no need to say more about it here, except that estrogen is the cause of a variety of tissue atrophies, including the suppression of bone formation.[1]

General Electric, a major advocate of x-ray screening for osteoporosis and breast cancer, has advertised that 91% of breast cancers could be cured if everyone used their technology. Breast cancer has not decreased despite the massive application of the technology, though the US government and others (using crudely deceptive statistis) claim that the War on Cancer is being won. Similarly, during the last decades when the “high technology” x-ray machines have been more widely used, the age-specific incidence of osteoporosis has increased tremendously. This apparently includes a higher rate of shortening of stature with aging than in earlier generations.[2]

I think there are several reasons for avoiding x-ray tests of bone density, besides the simple one that everyone should eat a bone-protective diet, regardless of the present density of their bones.

Even seemingly identical x-ray machines, or the same machine at a different time, can give very different estimates of bone density.[3-10] Radiologists evaluating the same images often reach very different conclusions.[11] Changes in the tissue water and fat content can make large differences in apparent bone density,[12] and estrogen, which affects those, could appear to cause improved bone density, when it is merely causing a generalized inflammatory condition, with edema. A machine that is accurate when measuring an aluminum model, won’t necessarily give meaningful results when the composition of the tissue, including the bone marrow, has changed. Calcification of soft tissues can create the impression of increased bone density.[13] Studies of large groups of people show such small annual losses of bone density (around 1%), especially in the neck of the femur (which is important in hip fractures) that the common technical errors of measurement in an individual seem very large.

Ultrasound devices can do an extremely good job of evaluating both bone density and strength [14-16], rather than just density.

Ultrasound stimulates bone repair.

X-rays accelerate the rate of bone loss.

X-rays do their harm at any dose; there is no threshold at which the harm begins.

X-ray damage is not limited to the area being investigated. Deflected x-rays affect adjacent areas, and toxins produced by irradiated cells travel in the bloodstream, causing systemic effects. Dental x-rays cause thyroid cancer and eye cancer. Recent experiments have shown that low doses of radiation cause delayed death of brain cells. The action of x-rays produces tissue inflammation, and diseases as different as Alzheimer’s disease and heart disease result from prolonged inflammatory processes.

I have never known a physician who knew, or cared, what dose of radiation his patients were receiving. I have never known a patient who could get that information from their doctors.

The radiation exposure used to measure bone density may be higher (especially when the thigh and hip are x-rayed) than the exposure in dental x-rays, but dental x-rays are known to increase the incidence of cancer. Often, dentists have their receptionists do the x-rays, which probably doesn’t matter, since the dentist is usually no more concerned than the receptionist about understanding, and minimizing, the dose. Even radiological specialists seldom are interested in the doses they use diagnostically.

It was only after a multitude of dentists had a finger amputated that it became standard practice to ask the patient to hold the film, while the dentist stood safely back away from the rays.

Just after the beginning of the century, Thomas Edison was helping to popularize x-rays, but the horrible death of his chief technician turned Edison into an enemy of the technology. By the 1940s, the dangers of radiation were coming to be understood by the general public, and it was only the intervention of the US government, to popularize atomic bombs and nuclear power, that was able to reverse the trend.

In 1956 and 1957, Linus Pauling was the only well known scientist who opposed the government’s policies. The government took away his passport, and his opportunities to write and speak were limited by a boycott imposed by a variety of institutions, but instigated by the nuclear industry and its agent, the Atomic Energy Commission. The government which considered Pauling a threat to national security, had placed thousands of German and Hungarian “ex”-Nazis in high positions in industry and government agencies, after protecting them from prosecution as war criminals. The official government policy, directed by the financier Admiral Strauss who controlled the Atomic Energy Commision, was to tell the public that radiation was good. Their extreme secrecy regarding their radiation experiments on Americans, however, indicated that they were aware of the malignant nature of their activities; many of the records were simply destroyed, so that no one could ever know what had been done. Scientists who worked for the government, Willard Libby, John Goffman, and many others, were working to convince the public that they shouldn’t worry. Of the multitude of scientists who served the government during that time, only a few ever came to oppose those policies, and those who did were unable to keep their jobs or research grants. Gofman has become the leader in the movement to protect the public against radiation, especially, since 1971, through the Committee for Nuclear Responsibility, PO Box 421993, San Francisco, CA 94132..

Gofman has said: "I was stupid in those days. In 1955, '56, people like Linus Pauling were saying that the bomb fallout would cause all this trouble. I thought, 'We're not sure. If you're not sure, don't stand in the way of progress.' I could not have thought anything more stupid in my life.

"The big moment in my life happened while I was giving a health lecture to nuclear engineers. In the middle of my talk it hit me! What the hell am I saying? If you don't know whether low doses are safe or not, going ahead is exactly wrong. At that moment, I changed my position entirely."[17]

In 1979, Gofman said: "There is no way I can justify my failure to help sound an alarm over these activities many years sooner than I did. I feel that at least several hundred scientists trained in the biomedical aspect of atomic energy - myself definitely included - are candidates for Nuremburg-type trials for crimes against humanity for our gross negligence and irresponsibility. Now that we know the hazard of low-dose radiation, the crime is not experimentation - it's murder." [18]

Many ordinary people were making exactly that argument in the 1950s, but government censorship kept the most incriminating evidence from the public. The climate of intimidation spread throughout the culture, so that teachers who spoke about the dangers of radiation were called disloyal, and were fired. Now, people who don’t want x-rays are treated as crackpots. Probably because of this cultural situation, Gofman’s recommendations are very mild--simply for doctors to use good technology and to know what they are doing, which could lead to ten-fold or even hundred-fold dose reduction. Even with such mild restraint in the use of diagnostic x-rays, Gofman’s well founded estimate is that 250,000 deaths caused by radiation could be prevented annually. I believe many more deaths would be prevented if ultrasound and MRI were used consistently instead of x-rays. Using Gofman’s estimate, I think we can blame at least ten million deaths on just the medical x-rays that have been used inappropriately because of the policies of the U.S. government in the last half century. That wouldn’t include the deaths caused by radioactive fallout from bomb tests and leaks from nuclear power plants, or the vast numbers of people mentally impaired by all sorts of toxic radiation.

Although nearly all the people who committed the radiation crimes of the 1950s and 1960s have died or retired, the culture they created remains in the mass media and scientific journals, and in the medical and academic professions.

Medical journals describe ways to minimize diagnostic x-ray exposure, and they advocate many seemingly effective treatments for osteoporosis, giving an impression that progress is being made in “managing” osteoporosis, but the real situation is very different. Fractures resulting from osteoporosis are increasing, and osteoporosis is affecting younger and younger people. I think it would be reasonable to say that a woman with osteoporosis is usually better off when it’s not diagnosed, because of the dangerous things prescribed for it. Estrogen has become the main “treatment” for osteoporosis, but many of the other ways of “managing” osteoporosis are both ineffective and unsafe.

Many women are told to stop taking a thyroid supplement when osteoporosis is diagnosed, but hypothyroidism often leads to hyperprolactinema and hypercortisolemia, which are two of the most clearly established causes of osteoporosis. Calcitonin, vitamin D-active metabolite, and estrogen-”HRT” treaments can cause respiratory alkalosis (relative hyperventilation),[19-24] and hypothyroidism produces a predisposition to hyperventilation.[25] Hyperventilation tends to cause calcium loss. In respiratory alkalolis, CO2 (and sometimes bicarbonate) are decreased, impairing calcium retention, and in “metabolic alkalosis,” with increased bicarbonate, calcium is retained more efficiently and bone formation is stimulated, and its dissolution is suppressed.

Other women are told to reduce their protein consumption, or to take fluoride or whatever drug has been most recently promoted. A protein deficiency is a clear cause of osteoporosis, and bone density corresponds to the amount of protein consumed. Milk protein, especially, protects against osteoporosis, independently of milk’s other important nutrients. Too much fluoride clearly increases the risk of bone fractures,[26] and the side effects of other drugs haven’t been properly studied in humans, while they often have dangerous effects in animals.

Calcium, magnesium, vitamin A, vitamin B6- , vitamin K, and vitamin D are important for the development and maintenance of bones. For example, a vitamin A deficiency limits the synthesis of progesterone and proteins. In calcium deficiency, parathyroid hormone is increased, and tends to cause the typical changes of aging, shifting calcium from hard tissues to soft, and decreasing the ratio of extracellular to intracellular (excitatory) calcium.

Polyunsaturated fats are converted to prostaglandins (especially under the influence of estrogen), and several prostaglandins have toxic effects on bone. Those fats also suppress the formation of thyroid hormone and progesterone. The increased use of the unsaturated oils has coincided with the increase of osteoporosis.

The oxidation of proteins caused by free radicals is increased with aging and by the use of unsaturated fats, and it contributes to tissue atrophy, including the age-related shrinkage of the bones. In animal studies, “adequate” dietary protein, 13.8% of the diet (equivalent to about 80 grams per day for a person) is associated with more oxidative damage to tissue proteins than the very high protein diets, 25.7% or 51.3%, that would be equivalent to about 150 or 300 grams of protein daily for a person.[27] Yet, many physicians recommend a low protein diet to protect against osteoporosis.

Avoiding fluoridated water and the polyunsaturated oils, and drinking two quarts of milk daily (which will provide only 66 grams of protein), and using some other nutrient-rich foods such as eggs and fruits, are probably the basic things to protect the bones. For vitamins, especially K, occasional liver can be helpful. Meats, fruits, leaves, and coffee are rich in magnesium.

Some people have argued that the acidity of urine produced by eating meat causes calcium loss. However, a high protein diet also improves the absorption of calcium by the intestine. Another overlooked function of dietary protein is that it stimulates insulin secretion, and insulin is anabolic for bone.[28]

The same diet that protects against osteoporosis, i.e., plenty of protein and calcium, etc., also protects against kidney stones and other abnormal calcificatons.

REFERENCES

1. Proc Assoc Am Physicians 1996 Mar;108(2):155-64 Potential mechanism of estrogen-mediated decrease in bone formation: estrogen increases production of inhibitory insulin-like growth factor-binding protein-4. Kassem M, Okazaki R, De Leon D, Harris SA, Robinson JA, Spelsberg TC, Conover CA, Riggs BL.

2. Am J Phys Anthropol 1990 Dec;83(4):467-76. Stature loss among an older United States population and its relation to bone mineral status. Galloway A, Stini WA, Fox SC, Stein P. “With advancing age there is a gradual decrease in height apparently beginning in the mid-40s. Thereafter, there is a relatively rapid decrease in measured height. This contrasts to the much slower rates predicted from earlier populations (Trotter and Gleser: American Journal of Physical Anthropology 9:311-324, 1951). The rate of stature loss is associated with diminution of bone mineral density as well as with maximum height. Since there are suggestions of a secular trend toward greater reductions in bone mineral density, this study suggests there may be a secular trend toward an increase in statural loss with age.”

3. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 1994 Mar;160(3):260-5. [The quantitative determination of bone mineral content--a system comparison of similarly built computed tomographs]. [Article in German] Andresen R, Radmer S, Banzer D, Felsenberg D, Wolf KJ Klinik fur Radiologie, Universitatsklinikum Steglitz der FU Berlin. An intercomparison of 4 CT scanners of the same manufacturer was performed. The bone mineral content of 11 lumbar vertebral columns removed directly post mortem was determined in a specially constructed lucite-water phantom. Even devices of the same construction were shown to yield a variation in the quantitative evaluation markedly exceeding the annual physiological mineral loss. As long as scanner adjustment by physical calibration phantoms has not yet been established, a course assessment and therapy control of bone mineral content should always be carried out on the same QCT scanner.

4. Osteoporos Int 1990 Oct;1(1):23-9. Vertebral bone mineral density measured laterally by dual-energy X-ray absorptiometry. Slosman DO, Rizzoli R, Donath A, Bonjour JP. “The bone mineral density (BMD) of lumbar vertebrae in the anteroposterior (AP) view may be overestimated in osteoarthritis or with aortic calcification, which are common in elderly.” “Then, we compared the capability of BMD LAT and BMD AP scans for monitoring bone loss related to age and for discriminating the BMD of postmenopausal women with nontraumatic vertebral fractures from that of young subjects. In vitro, when a spine phantom was placed in lateral position in the middle of 26 cm of water in order to simulate both soft-tissue thickness and X-ray source remoteness, the coefficient of variation (CV) of six repeated determinations of BMD was 1.0%. In vivo, the CV of paired BMD LAT measurements obtained in 20 healthy volunteers after repositioning was 2.8%.”

5. Eur J Nucl Med 1990;17(1-2):3-9. Comparative study of the performances of X-ray and gadolinium 153 bone densitometers at the level of the spine, femoral neck and femoral shaft. Slosman DO, Rizzoli R, Buchs B, Piana F, Donath A, Bonjour JP. “In vivo, at the spine level, with DPA, mean CV of BMD measured 6 times after repositioning in 6 healthy volunteers was 3.8% +/- 1.9% and 2.1% +/- 0.7% . . . .”

6. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 1995 Apr;162(4):269-73. [Experimental studies of the visualization of the vertebral body spongiosa by high-resolution computed tomography]. Henschel MG, Freyschmidt J, Holland BR. “The measured lower limit of visualisation of cancellous bone structures is clearly worse than expected from the measurements of spatial resolution with standard phantoms used for HR-CT (0.6 versus 0.4 mm). True and exact imaging of normal cancellous bone cannot be achieved even by modern HR-CT. Noise creates structures mimicking cancellous bone.”

7. J Comput Tomogr 1984 Apr;8(2):91-7. Quantitative computed tomography assessment of spinal trabecular bone. I. Age-related regression in normal men and women. Firooznia H, Golimbu C, Rafii M, Schwartz MS, Alterman ER. “Computed tomography, utilized in conjunction with a calibrated phantom containing a set of reference densities (K2HPO4 and water), is capable of determining the mineral content of the trabecular bone of the spine with an accuracy of about 6% of the ash weight of the vertebrae scanned (specimen studies).”

8. Calcif Tissue Int 1991 Sep;49(3):174-8. Precision and stability of dual-energy X-ray absorptiometry measurements. Johnson J, Dawson-Hughes B. “The phantom was scanned repeatedly in 15.2, 20.3, and 27.9 cm of water over a 9 month period. In 15.2 and 20.3 cm of water, phantom BMD did not vary significantly whereas in 27.9 cm of water (equivalent to a human over 30 cm thick), phantom BMD increased 2.3% (P = 0.01) over the 9 months.”

9. J Comput Assist Tomogr 1993 Nov-Dec;17(6):945-51. Influence of temperature on QCT: implications for mineral densitometry. Whitehouse RW, Economou G, Adams JE. “Inaccuracies in quantitative CT (QCT) for vertebral bone mineral measurements may result from differences between the temperature of the vertebrae and the calibration standards.” “In the computer simulation, the fat error associated with single energy QCT for trabecular bone mineral densitometry was 20% less for specimens at room temperature than at body temperature.” “The fat error of single energy QCT for mineral densitometry may have been underestimated in previous in vitro studies using vertebral specimens scanned at room temperature.”

10. Phys Med Biol 1986 Jan;31(1):55-63. Quantitative CT measurements: the effect of scatter acceptance and filter characteristics on the EMI 7070. Merritt RB, Chenery SG “Non-linearities in projection values on computed tomography (CT) scanners cause corresponding errors in derived Hounsfield unit attenuation measurements. Existing commercial machines have been refined for clinical usefulness but not necessarily for quantitative accuracy.”“It is concluded that, irrespective of any quality assurance protocol, interpatient and interslice errors can be expected to range from 3 to 10% for water-equivalent materials and the intraslice positional dependence of the CT number can vary up to 5% for dense bone-like materials in a uniform phantom.”

11. Skeletal Radiol 1986;15(5):347-9. Observer variation in the detection of osteopenia. Epstein DM, Dalinka MK, Kaplan FS, Aronchick JM, Marinelli DL, Kundel HL. In order to determine observer variation in the detection of osteopenia, 15 pairs of lateral chest radiographs obtained within two weeks of each other were reviewed separately by two radiologists and one orthopedist on three separate occasions. Intra- and interobserver variations were calculated for each individual film and film pairs using Kappa values. The individual observers were not able to give consistent readings on the same film on different days (average Kappa = 0.54). When the additional factors of repeat films (average kappa = 0.47), or separate observers (average Kappa = 0.38) were analyzed, agreement was even worse.The identification of osteopenia from the lateral view of the thoracic spine is highly subjective and variable from film to film and observer to observer.

12. P. Schneider and C. Reiners, Letter, JAMA 277(1), 23, Jan. 1, 1997. "The influence of fat distribution on bone mass measurements with DEXA can be of considerable magnitude and ranges up to 10% error per 2 cm of fat."

13. Calcif Tissue Int 1990 Apr;46(4):280-1. Effect of radiographic abnormalities on rate of bone loss from the spine. Dawson-Hughes B, Dallal GE. “Spurious rates of loss of spine BMD are likely to be found in subjects with calcification of the aorta, osteophytes or other abnormalities in the spine scan field. This should be kept in mind when serial spine scans are being considered in these subjects.”

14. Przegl Lek 2000;57(2):93-9. [No title available]. Jaworski M, Lorenc RS. “. . .Dual Energy X-ray Absorptiometry (DEXA) method is a reference method to diagnose osteoporosis. This method allows to measure bone density and bone mass, however bone quality can not be estimated. Quantitative ultrasound (QUS)method provides information about bone structure.”

15. Osteoporos Int 2000;11(4):354-60. Assessment of a new quantitative ultrasound calcaneus measurement: precision and discrimination of hip fractures in elderly women compared with dual X-ray absorptiometry. He YQ, Fan B, Hans D, Li J, Wu CY, Njeh CF, Zhao S, Lu Y, Tsuda-Futami E, Fuerst T, Genant HK.

16. Cas Lek Cesk 2000 Apr 26;139(8):231-6 [X-ray densitometry and ultrasonography of the heel bone--sensitivity and comparison with densitometry of the axial skeleton]. [Article in Czech] Michalska D, Zikan V, Stepan J, Weichetova M, Kubova V, Krenkova J, Masatova A. “The DXA of the heel underestimates the prevalence of osteoporosis. The results of the heel QUS (Stiffness) appear to be better correlated to femoral BMD than heel BMD.”

17. John Gofman, M.D. (biographical chapter. pages 401-412.) In Studs Terkel's book Coming of Age. The Story of our Century by Those Who Lived It. The New Press. NY. 1995.

18. Gofman, J.W. An irreverent, illustrated view of nuclear power. Committee for Nuclear Responsibility. San Francisco, CA. pp. 227-228, 1979.

19. Kidney Int 1992 Sep;42(3):727-34. Chronic respiratory alkalosis induces renal PTH-resistance, hyperphosphatemia and hypocalcemia in humans. Krapf R, Jaeger P, Hulter HN Department of Medicine, Insel University Hospital, Berne, Switzerland. “The effects of chronic respiratory alkalosis on divalent ion homeostasis have not been reported in any species.” “Chronic respiratory alkalosis (delta PaCO2, -8.4 mm Hg, delta[H+] -3.2 nmol/liter) resulted in a sustained decrement in plasma ionized calcium concentration (delta[IoCa++]p, -0.10 mmol/liter, P less than 0.05) and a sustained increment in plasma phosphate concentration (delta[PO4]p, +0.14 mmol/liter, P less than 0.005) associated with increased fractional excretion of Ca++ . . .”

20. J Clin Endocrinol Metab 1999 Jun;84(6):1997-2001 Hormone replacement therapy causes a respiratory alkalosis in normal postmenopausal women. Orr-Walker BJ, Horne AM, Evans MC, Grey AB, Murray MA, McNeil AR, Reid IR. “Serum bicarbonate concentrations decreased significantly in the groups receiving either MPA or estrogen plus MPA (P = 0.008). This trend was apparent as early as 2 days and reached 2.7 and 2.3 mmol/L in the respective groups by 3 months. Similar changes were seen with partial pressure of carbon dioxide. . . .”“Accompanying changes in blood pH were apparent in the estrogen plus MPA group, where there was an upward trend at 1 week (P = 0.056) and a significant change from baseline (+0.013) at 3 months (P = 0.03).”

21. Wien Klin Wochenschr 1979 Apr 27;91(9):304-7 [Investigations on the pathogenesis of distal renal tubular acidosis]. Schabel F, Zieglauer H. “Bicarbonate loading is followed by a lowering of calcium excretion to within the normal range and a decrease in the uncharacteristic renal hyperaminoaciduria.”

22. Calcif Tissue Int 1984 Sep;36(5):604-7. Respiratory alkalosis and reduced plasmatic concentration of ionized calcium in rats treated with 1,25 dihydroxycholecalciferol. Locatto ME, Fernandez MC, Caferra DA, Gimenez MC, Vidal MC, Puche RC. “The daily administration of supraphysiological doses of 1,25 dihydroxycholecalciferol (0.1-2.5 micrograms/d/100 g body weight) to rats, produced respiratory alkalosis. With the doses of 0.1-0.2 micrograms/d/100 g and feeding a diet with 0.7% of calcium, calcemias did not exceed 2.75 mM, and significantly reduced plasma ionized calcium levels were measured. The latter phenomenon was found associated with increased urinary excretion of cAMP, soft tissue calcium content, and polyuria with hypostenuria, all known effects of parathyroid hormone.”

23. Am J Physiol 1996 Jul;271(1 Pt 2):F216-22. Metabolic alkalosis decreases bone calcium efflux by suppressing osteoclasts and stimulating osteoblasts. Bushinsky DA. “In vivo and in vitro evidence indicates that metabolic acidosis, which may occur prior to complete excretion of end products of metabolism, increases urinary calcium excretion.The additional urinary calcium is almost certainly derived from bone mineral.” “To determine whether metabolic alkalosis alters net calcium efflux (JCa+) from bone and bone cell function, we cultured neonatal mouse calvariae for 48 h in either control medium (pH approximately equal to 7.4, [HCO3-] approximately equal to 24), medium simulating mild alkalosis (pH approximately equal to 7.5, [HCO3-] approximately equal to 31), or severe alkalosis (pH approximately equal to 7.6, [HCO3-] approximately equal to 39) and measured JCa+ and the release of osteoclastic beta-glucuronidase and osteoblastic collagen synthesis. Compared with control, metabolic alkalosis caused a progressive decrease in JCa+, which was correlated inversely with initial medium pH (pHi). Alkalosis caused a decrease in osteoclastic beta-glucuronidase release, which was correlated inversely with pHi and directly with JCa+. Alkalosis also caused an increase in osteoblastic collagen synthesis, which was correlated directly with pHi and inversely with JCa+. There was a strong inverse correlation between the effects alkalosis on osteoclastic beta-glucuronidase release and osteoblastic collagen synthesis. Thus metabolic alkalosis decreases JCa+ from bone, at least in part, by decreasing osteoclastic resorption and increasing osteoblastic formation. These results suggest that the provision of base to neutralize endogenous acid production may improve bone mineral accretion.”

24. Am J Physiol 1997 Nov;273(5 Pt 2):F698-705 The effects of respiratory alkalosis and acidosis on net bicarbonate flux along the rat loop of Henle in vivo. Unwin R, Stidwell R, Taylor S, Capasso G.

25. Can J Anaesth 1999 Feb;46(2):185-9. Acute respiratory alkalosis associated with low minute ventilation in a patient with severe hypothyroidism. Lee HT, Levine M. “His profoundly lowered basal metabolic rate and decreased CO2 production, resulting probably from severe hypothyroidism, may have resulted in development of acute respiratory alkalosis in spite of concurrently diminished minute ventilation.”

26. Am J Epidemiol 1991 Apr 1;133(7):649-60. A prospective study of bone mineral content and fracture in communities with differential fluoride exposure. Sowers MF, Clark MK, Jannausch ML, Wallace RB. “Residence in the higher-fluoride community was associated with a significantly lower radial bone mass in premenopausal and postmenopausal women, an increased rate of radial bone mass loss in premenopausal women, and significantly more fractures among postmenopausal women. There was no difference in the 5-year relative risk of any fracture in the higher-calcium community versus the control community; however, the relative risk was 2.1 (95% confidence interval (CI) 1.0-4.4) in women in the higher-fluoride community compared with women in the control community.There was no difference in the 5-year risk of wrist, spine, or hip fracture in the higher-calcium community versus the control community; however, the 5-year relative risk for women in the higher-fluoride community, compared with women in the control community, was 2.2 (95% CI 1.1-4.7). Estimates of risk were adjusted for age and body size.”

27. J Nutr 2000 Dec;130(12):2889-96. Long-term high protein intake does not increase oxidative stress in rats. Petzke KJ, Elsner A, Proll J, Thielecke F, Metges CC.

28. Med Hypotheses 1995 Sep;45(3):241-6. Anabolic effects of insulin on bone suggest a role for chromium picolinate in preservation of bone density. McCarty MF. “Physiological levels of insulin reduce the ability of PTH to activate protein kinase C in osteoblasts, suggesting that insulin may be a physiological antagonist of bone resorption. In addition, insulin is known to promote collagen production by osteoblasts.” [I think chromium is too toxic to use as a supplement.]

29: Anesthesiology 1998 Dec;89(6):1389-400. Effects of hyperventilation and hypocapnic/normocapnic hypoxemia on renal function and lithium clearance in humans. Vidiendal Olsen N, Christensen H, Klausen T, Fogh-Andersen N, Plum I, Kanstrup IL, Hansen JM Department of Neuroanaesthesia, Copenhagen University Hospital, Denmark. NVO@DADLNET.DK BACKGROUND: Using the renal clearance of lithium as an index of proximal tubular outflow, this study tested the hypothesis that acute hypocapnic hypoxemia decreases proximal tubular reabsorption to the same extent as hypocapnic normoxemia (hyperventilation) and that this response is blunted during normocapnic hypoxemia. METHODS: Eight persons were studied on five occasions: (1) during inhalation of 10% oxygen (hypocapnic hypoxemia), (2) during hyperventilation of room air leading to carbon dioxide values similar to those with hypocapnic hypoxemia, (3) during inhalation of 10% oxygen with the addition of carbon dioxide to produce normocapnia, (4) during normal breathing of room air through the same tight-fitting face mask as used on the other study days, and (5) during breathing of room air without the face mask. RESULTS: Hypocapnic and normocapnic hypoxemia and hyperventilation increased cardiac output, respiratory minute volume, and effective renal plasma flow. Glomerular filtration rate remained unchanged on all study days. Calculated proximal tubular reabsorption decreased during hypocapnic hypoxemia and hyperventilation but remained unchanged with normocapnic hypoxemia. Sodium clearance increasedslightly during hypocapnic and normocapnic hypoxemia, hyperventilation, and normocapnic normoxemia with but not without the face mask. CONCLUSIONS:The results indicate that (1) respiratory alkalosis with or without hypoxemia decreases proximal tubular reabsorption and that this effect, but not renal vasodilation or natriuresis, can be abolished by adding carbon dioxide to the hypoxic gas; (2) the increases in the effective renal plasma flow were caused by increased ventilation rather than by changes in arterial oxygen and carbon dioxide levels; and (3) the natriuresis may be secondary to increased renal perfusion, but application of a face mask also may increase sodium excretion.

31: Wien Klin Wochenschr 1979 Apr 27;91(9):304-7. [Investigations on the pathogenesis of distal renal tubular acidosis]. [Article in German] Schabel F, Zieglauer H In distal (type 1) RTA, renal acid excretion is impaired by the inability to establish adequate pH gradients between plasma and distal tubular fluid at any level of acidosis. Main clinical signs in infancy are anorexia, vomiting and failure to thrive. Despite low serum bicarbonate levels the renal threshold of bicarbonate is normal, while urinary pH levels are high even with values below the threshold. Under conditions of bicarbonate-induced systemic alkalosis urinary the pCO2 exceeds blood pCO2 in normal subjects. by contrast, the urinary pCO2 tension is not significantly greater in distal RTA, indicating a failure of the cells of the distal nephron to secrete hydrogen ions even without a gradient. Red cell carbonic anhydrase is within the normal range, whilst the inhibition of carbonic anhydrase activity has no effect on distal tubular function. Until now no histological or enzymatic defect could be detected to explain the ineffective acidification. Bicarbonate loading is followed by a lowering of calcium excretion to within the normal range and a decrease in the uncharacteristic renal hyperaminoaciduria.

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A R T I C L E

Breast Cancer

It’s important to know the realities of cancer in the population, the death rate from cancer, and the effects of its aggressive diagnosis and treatment. Appreciating those, I think the need for a new attitude toward cancer can be seen.

Official US data for the years 1990 to 1993 showed 505,300 cancer deaths in 1990, and 529,900 cancer deaths in 1993. This was an increase of roughly 1.3% per year (which was faster than the population growth) during the time in which Rodu and Cole (1996) and agencies of the U.S. government claimed the death rate was decreasing one half percent (0.5%) per year.

This increase happened despite the abnormal population bulge in the number of people between the ages of 35 and 50, resulting from the postwar baby boom. Cancer incidence is about ten times higher among the older population than in this younger age range, so in this abnormally structured population, the death rate from cancer is much lower than it would be if the population composition were the same as before the war, and it is lower than it will be in ten or twenty years, when the population bulge reaches the prime cancer years.

In 1994, total cancer deaths increased to 536,900 (an increase of 1.32% over 1993). The crude death rate per 100,000 population was 203.2 in 1990, in 1993 it was 205.6, in 1994 it had increased to 206. This, despite the population distortion caused by the baby boom, causing a scarcity of people in the age groups with the highest rates of cancer mortality.

In the U.S. in 1994 there were altogether 2,286,000 deaths. In a population of about 260 million, this was a death rate of less than 1% per year (about 0.88%). The chance of dying that year for any person was less than one in a hundred. That doesn’t mean that life expectancy is over 100 years, but that would be implied if we ignored the population bulge of the baby boomers, as the cancer statisticians are doing.

When the U.S. Department of Health and Human Services, and every major medical journal in the United States lies about the simple statistics of cancer death rates, it’s clear that very powerful and dangerous social forces are operating.

Anyone who knows about the baby boom that started right after the second world war must also realize that in 1940, at the end of the great depression, when infant and childhood mortality was very high and people postponed having children, the population had a disproportionate number of old people, and that it would be outrageous to use the rate of cancer in the pre-war population to evaluate the rate of cancer in the post-war population. But that is what is being done, and the mass media are helping to prevent the public from questioning the official story about cancer.

If the health of the population in 1940 is to be compared to that of a very differently constituted later population, the appropriate method is to compare the rate of death among people of a certain age. The death rate from leukemia, especially among children, was greatly increased in the post-war years, when people were being exposed to radiation from atomic bomb tests. The death rates among adults of various ages, from breast cancer, prostate cancer, and melanoma have steadily increased. Rodu and Cole, who declared victory in the war against cancer, said the decline in total cancer mortality began in 1991. (Cole and Rodu, 1996) If lung cancer is excluded, they say mortality from other cancers has been declining since 1950! (“The fifty-year decline of cancer in America,” Rodu and Cole, 2001.) The first time I saw this bizarre use of “age restandardization” was when Professor Bruce Ames was on a lecture tour for the American Cancer Society, and was speaking to the biology department at the University of Oregon. He showed a graph indicating that the mortality curves for most types of cancer in the U.S. had begun their downward curve in the late 1940s just after the A.C.S. came onto the scene. Even though I think the A.C.S. probably initiated the practice of age-standardizing with reference to the 1940 population, they don’t always find that date suitable for their purposes. In fund-raising literature showing their past success in curing childhood leukemia, they restandardized mortality with reference to the postwar year when the leukemia death rate was at its highest, with the result that their cures appeared to be steadily lowering the death rate. But the incidence rate varied according to the intensity of the radioactive intensity that pregnant women were exposed to, and so both the incidence and the mortality fell after atmospheric testing was stopped.

Government officials, editors of the big medical journals, professors and broadcasters, have been able to get away with this huge statistical fraud. I suspect that they will soon feel encouraged to simply make up the data that they want, because eventually “age standardization” isn’t going to work to hide the actual increases in mortality. Since people with cancer usually die of something else, such as a stroke or heart failure, it will be no trick at all to make cancer mortality decline to be replaced by other causes of death. The precedent for such fabulizing of data exists in the FDA’s approval of AZT, and other less notorious drugs.

Radiation, estrogen, and a variety of chemical pollutants are known to be the major causes of breast cancer, but the efforts of the cancer establishment have been directed toward denying that these avoidable agents are the cause of the great increase in breast cancer during the last several decades. The cancer industry, including major producers of chemotherapy drugs, subsidizes the American Cancer Society and “Breast Cancer Awareness Week,” and it is in their interest to convince the public that early detection and conventional treatment with surgery, chemotherapy, and radiation are winning the war against cancer. There is always light at the end of the tunnel, in the war against cancer, just as there was in the Vietnam war. Their consistent effort to dissuade the government from acting to reduce the public’s exposure to the known causes of cancer should make it clear that they are in the business of treating cancer, not eliminating it.

In the 1960s I read some articles in a small town newspaper about Leonell Strong’s cancer research, and his treatment by the American Cancer Society and the Salk Institute. Leonell Strong had developed strains of mice for use in cancer research. In some of the strains, 100% of the females developed mammary cancer. Strong had demonstrated that these strains had very high levels of estrogen. He showed me mice that he had treated with simple extracts of liver, that were free of cancer, and whose descendants remained free of cancer for several generations.

Strong had received his PhD in genetics under T. H. Morgan. For a person trained in classical genetics, and who had spent his career developing the supposedly genetically determined cancer trait, the elimination of the trait by a few injections must have been hard to understand, but at least he tried to understand it.

When he had earlier demonstrated the presence of a virus in the milk of cancer-prone mice, and when he showed the role of heredity in cancer, he was popular with the cancer business, but when he showed that “genetic” cancer could be eradicated with a simple treatment, he became the object of official abuse. He said that the Salk institute had offered him a position to induce him to move with his large colony of mice from New York to San Diego, but when he arrived he found that he had no job, and his records of decades of research had been lost. He said that a memo which was discovered in a lawsuit revealed that the institute had just wanted his mice, and never intended to give him the promised job. For the cancer establishment, his discovery of a way to prevent cancer was not welcome.

In 1969, two years before the war against cancer had begun pouring public money into the pockets of the cancer establishment, Harry Rubin gave a lecture that criticized the cancer establishment’s claim that it was curing cancer. He cited a study by a pathologist who had looked for cancer in the tissues of people who had been killed in accidents. He found identifiable cancers in the tissues of everyone over the age of fifty that he examined. If everyone over 50 has histologically detectable cancer, then the use of biopsy specimens as the basis for determining whether a person needs treatment has no scientific basis.

The definition of a disease, and the recognition of its presence, has an important place in medicine, but understanding its cause or causes is essential for both treatment and prevention. The dominant belief in medicine is that diseases are significantly caused by “genes,” including diseases such as cancer, diabetes, psychoses, and neurological diseases. In Israel, ethnic groups that had never had much diabetes before immigrating, within a single generation had diabetes as often as other Israelis. Shortly after insulin became available for the treatment of diabetes, the incidence of the disease in the U.S. began to increase. The simple death rate from diabetes per 100,000 population is now higher than it was in 1920, before insulin treatment became available. Neurological diseases and autoimmune diseases, along with diabetes and cancer, have increased greatly in recent generations. These simply aren’t genetic diseases, and there should be a shift of resources away from useless or harmful treatments toward their prevention.

Even when a disease’s cause isn’t clearly understood, it is essential to use logical thinking in diagnosing its presence. The presence of a certain gene or “genetic marker” is often thought to have great diagnostic significance, which it rarely has. But even gross “signs” of a disease can be used diagnostically only if we know that similar signs aren’t present in perfectly healthy people. When pains are thought to be the result of a herniated intervertebral disk, x-ray pictures may be produced as confirmation of the diagnosis. But when people without pains are just as likely to have herniated disks (about 2/3 of normal people have them), the diagnosis fails to be convincing. When x-rays or MRIs show “plaques” in the head, multiple sclerosis is often “confirmed,” but when normal medical students show just as many brain plaques, the diagnosis must be questioned. Similarly, when mature people who were perfectly healthy until they were killed by an accident are found to always have identifiable cancers, any diagnosis of cancer that is based on a similar histological specimen must be reconsidered.

By diagnosing something that is as common and trivial as dandruff as “cancer,” physicians can get a very high rate of cures, whether they use surgery, radiation, or chemotherapy. Abnormal cellular proliferation is usually harmless, but it has become an important part of a business that makes several billion dollars per year, with no definite benefits except the financial benefits for those in the business.

Before cancer treatment became culturally practically obligatory, and when fewer people died of cancer, some people lived into old age with clearly “malignant” cancers, and died of some other cause. The policy of leaving a cancer alone is now established for prostate cancer in old men. Until there is clear evidence to the contrary, a similar policy might be appropriate for many kinds of cancer.

If every year more people are treated for cancer, and every year more people die of cancer, one simply wonders whether fewer people would die if few were treated.

If the first rule of medicine is to do no harm, then the second rule, growing out of the first, would have to be to give no treatment without knowing what is being treated, and to have a valid basis for believing that the damage done by the treatment is not worse than the damage that the disease would cause. If cancer specialists haven’t demonstrated that their treatments improve their patients’ situation, then their professional activities aren’t justified; the statistics suggest that they aren’t.

There simply isn’t a valid base of knowledge about the natural history of cancer development in humans to permit a valid judgment to be made about the meaning of particular signs or indicators or histological structures. The extensive use of mammograms has increased the diagnosis of “ductal carcinoma in situ” by more than 1000% (a 16- or 18-fold increase in some hospitals, and expected to double in the next decade), increasing the number of mastectomies and other treatments, but the increased treatments and early diagnosis haven’t produced any visible change in the death rate.

The pathologists talk knowingly of “pre-neoplastic” conditions that indicate an increased risk of malignancy, but instead of data, what they have is an ideology about the nature of cancer. When they say that a growth pattern is premalignant or that a cell has a malignant structure, they might as well be talking about goblins, because the scientific basis for what they are saying is nothing but a belief in the ideology that cancer is “clonal,” that a particular cancer derives from a single defective cell. They are so self-assured, and have so many sources to cite about the “clonal nature of cancer,” that it seems impolite to suggest that they might simply be misusing language and logic.

Isn’t a person derived from a single cell, and so, in that sense, “clonal”? As organs differentiate in the development of the organism, can’t organs be traced back to the cells from which they developed? Isn’t every tissue “a clone” in that sense? What is it that makes the “clonal” nature of cancer tissue so special? Isn’t it just that a nasty, mean, malignant tissue is, mentally, traced back to a “malignant” cell, by analogy with the way good tissues are traced back to good cells? If the tumor is odious, it must derive from an odious cell, and what could make that cell so hateful if it is genetically identical to the good cells? Therefore, the goblin reasoning goes, a genetic mutation must have produced the evil cell.

The actual evidence is that there are broad changes in tissues preceding the appearance of cancer. The goblin theory explains this by saying that a multitude of “precancerous” mutations occurred before the mutant cancer cell appeared. Harry Rubin has carefully shown experimentally and logically that cancer precedes the genetic changes that occur in tumors. But the ideology that cancer is the result of a genetic mutation forces its devotees to say that the genetic changes that can be found in a mature tumor must have occurred in one cell that was previously not malignant. An effect is identified as a cause.

The clonal-goblin theory of cancer leads logically to the conclusion that the cancer clone must be exorcised by surgery, chemotherapy, and/or radiation.

The biological theory of cancer, on the other hand, is inclined to view the normal and abnormal development of cells in terms of the cells’ responses to conditions.

Estrogen and ionizing radiation are the most clearly documented causes of breast cancer. Their excitatory effects lead to inflammation, edema, fibrosis, and interruption of intercellular regulatory processes. Radiation is estrogenic, and increased estrogenic stimulation produces growth and temporary loss of differentiated functions. Estrogen and radiation aren’t the only things that can cause these systematic changes in the structure of tissues--for example, vitamin A deficiencies, hypothyroidism, chlorinated hydrocarbons, irritation, and lack of oxygen can cause similar changes--but estrogen and irradiation have been studied enough to give us a fairly distinct picture of the real processes involved in the development of cancer.

Polyunsaturated fats are another clearly identified cause of cancer, especially breast cancer. These fats synergize with estrogen, and sensitize to radiation. Their effects on the mother can be seen in the offspring, as an increased tendency to develop breast or prostate cancer.

An individual’s hormone balance can be disrupted by exposure to radiation, estrogens, or unsaturated fats. The hormonal balance of the parent is imprinted upon the offspring, acting on the chromosomes, the liver, brain, genitals, pituitary, bones--in fact, the prenatal imprint can probably be found everywhere in the offspring.

It’s easy to reduce our exposure to radiation, by avoiding mammograms, bone density scans, and other x-rays of all sorts. Ultrasound and MRI can produce good images of any tissue without the deadly effects of ionizing radiation.

Polyunsaturated fats can be reduced by careful selection of foods, but the food industry is finding ways to contaminate traditionally safe foods, such as beef and milk, by using new kinds of animal feed. Still, milk, cheese, beef, and lamb are safe, considering their high nutritional content, and the remarkable purification that occurs in the rumen of cows, sheep, and goats. Some studies suggest a protective effect from saturated fat (Chajes, et al., 1999.)

Estrogenic influences can be significantly reduced by avoiding foods such as soy products and unsaturated fats, by eating enough protein to optimize the liver’s elimination of estrogen, and by using things such as bulk-forming foods (raw carrots, potatoes, and milk, for example) that stimulate bowel action and prevent reabsorption of estrogens from the intestine. Avoiding hypothyroidism is essential for preventing chronic retention or formation of too much estrogen.

Some studies show that dietary starch, rather than fat, is associated with breast cancer. Starch strongly stimulates insulin secretion, and insulin stimulates the formation of estrogen.

Estrogen is formed in fat cells under the influence of cortisol, and this formation is suppressed by progesterone and thyroid. Postmenopausal obesity is associated with increased estrogen and breast cancer. The prevention of weight gain, and supplementation with thyroid and progesterone if necessary, should be protective against many types of cancer, especially breast, kidney, and uterine cancer.

Prenatal or early life exposure to estrogens, including phytoestrogens, or to irradiation, or to polyunsaturated oils, increases the incidence of mammary cancers in adulthood.

Protein deficiency prenatally or early in life causes a life-long excess of serotonin. Feeding an excess of tryptophan, the precursor of serotonin, during pregnancy produces pituitary and mammary tumors in the offspring. Serotonin, besides being closely associated with the effects of estrogen (e.g., mediating its stimulation of prolactin secretion) and polyunsaturated fats, can be metabolized into carcinogens.

Prenatal protein deficiency and excess unsaturated oils predispose to a developmental pattern involving hypothyroidism and hyperestrogenism; puberty occurs at an earlier age, along with a tendency to gain weight. Inflammatory processes (e.g., “autoimmune diseases”) are usually intensified under those conditions. Inflammation itself increases the effects of estrogen and serotonin.

Both preventively and therapeutically, the use of the antiinflammatory and antioxidative substances such as aspirin, caffeine, progesterone, and thyroid hormone would seem appropriate. Aspirin is coming to be widely accepted as an anticancer agent, and at moderate doses can cause cancer cells to die. It, like progesterone and thyroid, has a wide variety of anti-estrogenic effects. Especially when a tumor is painfully inflamed, aspirin’s effects can be quick and dramatic. However, people aren’t likely to be pleased if their cancer doctor tells them to “take aspirin and call me in six months.” Aspirin’s reputation for causing stomach bleeding causes people to avoid it, even when the alternative is something that’s seriously toxic to other organs, and it might just seem too ordinary to be considered as a powerful anticancer drug.

Because of the toxic (carcinogenic, and anti-respiratory) effects of the “essential fatty acids,” which are usually stored in the tissues in very large quantities, it’s important to avoid the stresses or hunger that would release the fats into the blood stream. Estrogens and adrenalin and serotonin and growth hormone, and prolonged darkness, increase the release of the free fatty acids. Frequent meals, including some saturated fats such as coconut oil, and a balance of protein, sugars, and salts, will minimize the release of stored fats.

The population trends toward greater obesity and earlier puberty, both of which are associated with a higher risk of breast cancer, suggest that the war against cancer is far from over. In the 19th century when the incidence of breast cancer was much lower than it is now, puberty usually occurred around the age of 17. In countries with a low incidence of breast cancer, puberty still occurs in the middle to late teens. People who are now 100 generally had puberty years later than girls do now. The biological changes now seen in children in the U.S. suggest that the incidence of degenerative diseases of all sorts is likely to increase as these children grow up.

A metabolic approach to the prevention and treatment of cancer would have many beneficial side effects, such as producing generally healthier, happier and brighter babies.

REFERENCES

Radiat Res 1998 Sep;150(3):330-48 Mortality in beagles irradiated during prenatal and postnatal development. II. Contribution of benign and malignant neoplasia. Benjamin SA, Lee AC, Angleton GM, Saunders WJ, Keefe TJ, Mallinckrodt CH. To evaluate the lifetime carcinogenic hazards of exposure to ionizing radiation during development, 1,680 beagles received whole-body exposures to 60Co gamma rays or sham exposures. Eight groups of 120 dogs each received mean doses of 15.6-17.5 or 80.8-88.3 cGy in early, mid- or late gestation, at 8, 28 or 55 days postcoitus or at 2 days after birth. Another group of 120 dogs received a mean dose of 82.6 cGy as 70-day-old juveniles and one group of 240 dogs received a mean dose of 81.2 cGy as 365-day-old young adults. Sham irradiations were given to 360 controls. Sexes were equally represented. In 1,343 dogs allowed to live out their life span, neoplasia was a major disease, contributing to mortality in 40% of the dogs. There was a significant increase in benign and malignant neoplasms occurring in young dogs (<4 years old), including fatal malignancies, after irradiation in the perinatal (late fetal and neonatal) periods. The lifetime incidence of fatal neoplasms was also increased in dogs irradiated perinatally. Three malignancies-lymphomas, hemangiosarcomas and mammary carcinomas-accounted for 51% of all fatal tumors. There was an apparent lifetime increase and earlier onset of lymphomas in dogs exposed as fetuses. Fatal hemangiosarcomas were increased in dogs irradiated early and late in gestation. Fatal mammary carcinomas were not increased by irradiation, although non-fatal carcinomas were increased after perinatal exposure. Myeloproliferative disorders and central nervous system astrocytomas appeared to be increased in perinatally irradiated dogs. These data suggest that irradiation in both the fetal and neonatal periods is associated with increased early onset and lifetime cancer risk.

Int J Cancer 1999 Nov 26;83(5):585-90. Fatty-acid composition in serum phospholipids and risk of breast cancer: an incident case-control study in Sweden. Chajes V, Hulten K, Van Kappel AL, Winkvist A, Kaaks R, Hallmans G, Lenner P, Riboli E. “. . . women in the highest quartile of stearic acid had a relative risk of 0.49 (95% confidence interval, 0.22-1.08) compared with women in the lowest quartile (trend p = 0.047), suggesting a protective role of stearic acid in breast-cancer risk.”

Tumori 2000 Jan-Feb;86(1):12-6 Factors of risk for breast cancer influencing post-menopausal long-term hormone replacement therapy. Chiechi LM, Secreto G. “. . . growing evidence points to increased breast cancer risk in HRT long-term users, and the adverse effect would, obviously, overwhelm any other benefit. At present, the risk/benefit ratio of HRT is an object of hot debate . . . .” “We conclude that some biologic and clinical markers, namely android obesity, bone density, mammographic density, androgen and estrogen circulating levels, alcohol consumption, benign breast disease, and familiarity, should be carefully considered before prescribing long-term HRT. Our analysis suggests that HRT could increase the risk of breast cancer and useless in preventing coronary heart disease and osteoporotic fractures when administered in women with positivity for one or more of these markers.”

Cancer 1996 Nov 15;78(10):2045-8. Declining cancer mortality in the United States. Cole P, Rodu B.

Preventing Breast Cancer:The story of a Major, Proven, Preventable Cause of This Disease. John W. Gofman, M.D., Ph.D. 1996. “This book uncovers the major cause of the recent breast-cancer incidence in the USA. The author shows that past exposure to ionizing radiation --- primarily medical x-rays --- is responsible for about 75 percent of the breast-cancer problem in the United States. The good news: Since the radiation dosage given today by medical procedures can be significantly reduced without interfering with a single useful procedure, numerous future cases of breast-cancer can be prevented. The author recommends specific actions to start breast-cancer prevention now, not ten years from now.”

Am J Public Health 1998 Mar;88(3):458-60. Geographic variations in breast cancer mortality: do higher rates imply elevated incidence or poorer survival? Goodwin JS, Freeman JL, Freeman D, Nattinger AB. “Mortality rates from breast cancer are approximately 25% higher for women in the northeastern United States than for women in the South or West. This study examined the hypothesis that the elevation is due to decreased survival rather than increased incidence.” “The elevated mortality in the Northeast is apparent only in older women. For women aged 65 years and older, breast cancer mortality is 26% higher in New England than in the South, while incidence is only 3% higher. Breast cancer mortality for older women by state correlates poorly with incidence (r = 0.28). CONCLUSIONS: Those seeking to explain the excess breast cancer mortality in the Northeast should assess survival and should examine differences in cancer control practices that affect survival.”

Nutrition 1999 May;15(5):392-401 The influence of maternal diet on breast cancer risk among female offspring. Hilakivi-Clarke L, Clarke R, Lippman M. The induction of breast cancer is a long process, containing a series of biological events that drive a normal mammary cell towards malignant growth. However, it is not known when the initiation of breast cancer occurs. One hypothesis is that a high estrogenic environment during the perinatal period increases subsequent breast cancer risk. There are many sources of extragonadal estrogens, particularly in the diet. The purpose of this paper is to review the evidence that a high maternal intake of dietary fats increases serum estrogens during pregnancy and increases breast cancer risk in daughters. Our animal studies show that a high maternal consumption of corn oil consisting mainly of linoleic acid (omega-6 polyunsaturated fatty acid, PUFA), increases both circulating estradiol (E2) levels during pregnancy and the risk of developing carcinogen-induced mammary tumors among the female rat offspring. A similar increase in breast cancer risk occurs in female offspring exposed to injections of E2 through their pregnant mother. Our data suggest that the mechanisms by which an early exposure to dietary fat and/or estrogens increases breast cancer risk is related to reduced differentiation of the mammary epithelial tree and increased number of mammary epithelial cell structures that are known to the sites of neoplastic transformation. These findings may reflect our data of the reduced estrogen receptor protein levels and protein kinase C activity in the developing mammary glands of female rats exposed to a high-fat diet in utero. In summary, a high dietary linoleic acid intake can elevate pregnancy estrogen levels and this, possibly by altering mammary gland morphology and expression of fat- and/or estrogen-regulated genes, can increase breast cancer risk in the offspring. If true for women, breast cancer prevention in daughters may include modulating the mother's pregnancy intake of some dietary fats.

Mol Cell Biochem 1998 Nov;188(1-2):5-12 Timing of dietary fat exposure and mammary tumorigenesis: role of estrogen receptor and protein kinase C activity. Hilakivi-Clarke L, Clarke R. The possible association between a high fat diet and increased breast cancer risk has remained controversial. This largely reflects the conflicting data obtained from migrant, case control and animal studies, which generally support this association, and cohort studies which often fail to show a link between fat and breast cancer. The mammary gland is particularly sensitive to estrogens during fetal development, leading us to hypothesize that dietary fat levels during this period may significantly influence breast cancer risk. Using chemically-induced mammary tumors in rats as our experimental model, we have demonstrated the ability of a maternal diet, high in the polyunsaturated fatty acid (PUFA) linoleic acid, to alter mammary gland differentiation, accelerate the onset of sexual maturation, and increase breast cancer risk. The mammary glands of female rats exposed to a high-fat diet in utero have more of the undifferentiated structures (terminal end buds) and fewer of the differentiated structures (alveolar buds) than the glands of rats exposed to a low-fat diet in utero. Furthermore, these mammary glands contain lower levels of total estrogen receptors and have reduced total protein kinase C activity. These effects appear to be mediated by an increase in the serum estradiol levels of pregnancy, which are elevated at least 30% in pregnant dams fed a high-fat diet. Furthermore, the administration of estradiol to pregnant dams produces effects on mammary gland development, onset of puberty and sensitivity to chemical carcinogenesis comparable to those seen in the offspring of rats fed a high fat diet during pregnancy. Our results, thus, support the hypothesis based on epidemiological data that high maternal estrogen levels increase daughters' breast cancer risk. The results also suggest that a high-fat diet may be an important factor in increasing pregnancy estrogenic activity.

Proc Natl Acad Sci U S A 1997 Aug 19;94(17):9372-7. A maternal diet high in n - 6 polyunsaturated fats alters mammary gland development, puberty onset, and breast cancer risk among female rat offspring. Hilakivi-Clarke L, Clarke R, Onojafe I, Raygada M, Cho E, Lippman M. We hypothesized that feeding pregnant rats with a high-fat diet would increase both circulating 17beta-estradiol (E2) levels in the dams and the risk of developing carcinogen-induced mammary tumors among their female offspring. Pregnant rats were fed isocaloric diets containing 12% or 16% (low fat) or 43% or 46% (high fat) of calories from corn oil, which primarily contains the n - 6 polyunsaturated fatty acid (PUFA) linoleic acid, throughout pregnancy. The plasma concentrations of E2 were significantly higher in pregnant females fed a high n - 6 PUFA diet. The female offspring of these rats were fed with a laboratory chow from birth onward, and when exposed to7,12-dimethylbenz(a)anthracene had a significantly higher mammary tumor incidence (60% vs. 30%) and shorter latency for tumor appearance (11.4 +/- 0.5 weeks vs. 14.2 +/- 0.6 weeks) than the offspring of the low-fat mothers. The high-fat offspring also had puberty onset at a younger age, and their mammary glands contained significantly higher numbers of the epithelial structures that are the targets for malignant transformation. Comparable changes in puberty onset, mammary gland morphology, and tumor incidence were observed in the offspring of rats treated daily with 20 ng of E2 during pregnancy. These data, if extrapolated to humans, may explain the link among diet, early puberty onset, mammary parenchymal patterns, and breast cancer risk, and indicate that an in utero exposure to a diet high in n - 6 PUFA and/or estrogenic stimuli may be critical for affecting breast cancer risk.

Oncol Rep 1998 May-Jun;5(3):609-16 Maternal genistein exposure mimics the effects of estrogen on mammary gland development in female mouse offspring. Hilakivi-Clarke L, Cho E, Clarke R. Human and animal data indicate that a high maternal estrogen exposure during pregnancy increases breast cancer risk among daughters. This may reflect an increase in the epithelial structures that are the sites for malignant transformation, i.e., terminal end buds (TEBs), and a reduction in epithelial differentiation in the mammary gland. Some phytoestrogens, such as genistein which is a major component in soy-based foods, and zearalenone, a mycotoxin found in agricultural products, have estrogenic effects on the reproductive system, breast and brain. The present study examined whether in utero exposure to genistein or zearalenone influences mammary gland development. Pregnant mice were injected daily with i) 20 ng estradiol (E2); ii) 20 microg genistein; iii) 2 microg zearalenone; iv) 2 microg tamoxifen (TAM), a partial estrogen receptor agonist; or v) oil-vehicle between days 15 and 20 of gestation. E2, genistein, zearalenone, and tamoxifen all increased the density of TEBs in the mammary glands. Genistein reduced, and zearalenone increased, epithelial differentiation. Zearalenone also increased epithelial density, when compared with the vehicle-controls. None of the treatments had permanent effects on circulating E2 levels. Maternal exposure to E2 accelerated body weight gain, physical maturation (eyelid opening), and puberty onset (vaginal opening) in the female offspring. Genistein and tamoxifen had similar effects on puberty onset than E2. Zearalenone caused persistent cornification of the estrus smears. These findings indicate that maternal exposure to physiological doses of genistein mimics the effects of E2 on the mammary gland and reproductive systems in the offspring. Thus, our results suggest that genistein acts as an estrogen in utero, and may increase the incidence of mammary tumors if given through a pregnant mother. The estrogenic effects of zearalenone on the mammary gland, in contrast, are probably counteracted by the permanent changes in estrus cycling.

Am J Public Health 1991 Apr;81(4):462-5 Does increased detection account for the rising incidence of breast cancer? Liff JM, Sung JF, Chow WH, Greenberg RS, Flanders WD. “The incidence of breast cancer has been increasing over time in the United States.” “To determine the role of screening in this increase, trends in the incidence of in situ and invasive carcinoma of the breast were evaluated using records of the metropolitan Atlanta SEER program between 1979 and 1986.” “The average annual age-adjusted incidence of invasive disease rose 29 percent among Whites and 41 percent among Blacks. Incidence increased in all age groups.” “Asymptomatic tumors accounted for only 40 percent of the increased incidence among whites and 25 percent of the increased incidence among blacks, with mammography as the principal contributing procedure.” “These data suggest that increased detection accounts for some but not all of the rising incidence of breast cancer in the United States.”

J Clin Oncol 2001 Jan 1;19(1):239-41. The fifty-year decline of cancer in america. Rodu B, Cole P. Department of Pathology, School of Medicine, and the Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL. PURPOSE: From 1950 to 1990, the overall cancer mortality rate increased steadily in the United States, a trend which ran counter to declining mortality from other major diseases. The purpose of this study was to assess the impact of lung cancer on all-cancer mortality over the past 50 years. METHODS: Data from the National Centers for Health Statistics were used to develop mortality rates for all forms of cancer combined, lung cancer, and other-cancer (all-cancer minus lung cancer) from 1950 to 1998. RESULTS: When lung cancer is excluded, mortality from all other forms of cancer combined declined continuously from 1950 to 1998, dropping 25% during this period. The decline in other-cancer mortality was approximately 0.4% annually from 1950 to 1990 but accelerated to 0.9% per year from 1990 to 1996 and to 2.2% per year from 1996 to 1998.CONCLUSION: The long-term decline is likely due primarily to improvements in medical care, including screening, diagnosis, and treatment.

J Mammary Gland Biol Neoplasia 1998 Jan;3(1):49-61 Role of hormones in mammary cancer initiation and progression. Russo IH, Russo J. “Administration of carcinogen to pregnant, parous or hormonally treated virgin rats, on the other hand, fails to elicit a tumorigenic response, a phenomenon attributed to the higher degree of differentiation of the mammary gland induced by the hormonal stimulation of pregnancy. In women a majority of breast cancers that are initially hormone dependent are manifested during the postmenopausal period. Estradiol plays a crucial role in their development and evolution.”

Hum Reprod 1999 Aug;14(8):2155-61 Tryptophan ingestion by pregnant rats induces pituitary and mammary tumours in the adult female offspring. Santana C, Martin L, Valladares F, Diaz-Flores L, Santana-Herrera C, Milena A, Rodriguez Diaz M “. . . maternal ingestion of tryptophan induced a marked rise in 665-day-old offspring in the incidence of both pituitary prolactinomas (62%) and mammary adenomas (49%). Present data suggest that tryptophan regulates serotonergic differentiation during early development. A transitory modification of the tryptophan concentration in the fetal brain induces a permanent increase in hypothalamic serotonin level and, in addition to modifying the release of prolactin, increases the incidence of tumours in the hypophysis and mammary gland.”

JAMA 1977 Feb 21;237(8):789-90. Breast cancer induced by radiation. Relation to mammography and treatment of acne. Simon N.This communication reports cases of 16 women in whom cancer of the breast developed after radiation therapy for acne or hirsutism, suggesting another group at higher risk than is generally expected for cancer of the breast. It is prudent to regard the carcinogenic effect of radiation on the breast as proportional to dose without a threshold. Mammography in young women should be ordered only selectively, not for screening.

Rev Interam Radiol 1977 Oct;2(4):199-203. Cancer of the breast--induction by radiation and role of mammography. Simon N.

Eur J Clin Nutr 1999 Feb;53(2):83-7. Western nutrition and the insulin resistance syndrome: a link to breast cancer. Stoll BA. “The incidence of breast cancer in the Western world runs parallel to that of the major components of the insulin resistance syndrome--hyperinsulinaemia, dyslipidaemia, hypertension and atherosclerosis. Evidence is reviewed that the growth of breast cancer is favoured by specific dietary fatty acids, visceral fat accumulation and inadequate physical exercise, all of which are thought to interact in favouring the development of the insulin resistance syndrome.” “Experimental evidence suggests that hyperinsulinaemia and its concomitants can increase the promotion of mammary carcinogenesis and the mechanism is likely to involve increased bioactivity of insulin-like growth factor 1 (IGF-1). Case-control and cohort studies have shown that higher serum levels of IGF-1 are associated with increased breast cancer risk.” “Nutritional and lifestyle modifications that improve insulin sensitivity may not only decrease a tendency to atherosclerosis but also reduce breast cancer risk in women.”

Strong, Leonell C, Biological Aspects of Cancer and Aging, Oxford, Pergamon Press, 1968.

Ethn Dis 1999 Spring-Summer;9(2):181-9. Secular trend of earlier onset of menarche with increasing obesity in black and white girls: the Bogalusa Heart Study. Wattigney WA, Srinivasan SR, Chen W, Greenlund KJ, Berenson GS. “Secular trends in onset of menarche and obesity were examined 14 years apart in two biracial (black-white) cohorts of girls aged 8 to 17 under study for cardiovascular risk. The first cohort (N=1,190, 64% white) was examined in 1978-1979, the second (N=1,164, 57% white) in 1992-1994.” “The onset of menarche occurred at an earlier age in the second cohort compared with the first cohort (P<0.0001), both in black girls (11.4+/-1.3 vs 12.3+/-1.4 years) and white girls (11.5+/-1.3 vs 12.3+/-1.3 years). Furthermore, twice as many girls in the second cohort had reached menarche by ages younger than 12 years (P<0.001).” “Since increases in body fatness and related early onset of menarche are risk factors for disorders in adult life including cardiovascular disease and breast cancer, the secular trend in the increasing incidence of obesity throughout the United States is becoming a major public health problem.”

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A R T I C L E

BSE - mad cow - scrapie, etc.: Stimulated amyloid degeneration and the toxic fats

I have written before about the protective effects of carbon dioxide and progesterone, especially for the brain, and how the structure of cell water is affected by adsorbed and dissolved materials, and by metabolic energy. In the high energy (rested) state, cell water behaves as if it were colder than its real temperature, and this affects the behavior of proteins and fats in the cell, allowing “oily” surfaces to remain in contact with the more orderly water. Carbon dioxide spontaneously combines with the amino groups in proteins, stabilizing the normal functional conformation. The loss of carbon dioxide affects the structure of all proteins in the body, and the loss of cellular energy affects the structure of the intracellular proteins and their associated molecules.

In scrapie and many other degenerative diseases (the amyloidoses), proteins condense into fibrils that tend to keep enlarging, with a variety of very harmful effects. The condensation of the “amyloid” proteins is sensitive to temperature, and a slight increase in the disorder of the water can induce functional proteins to change their conformation so that they spontaneously associate into fibrous masses. In the absence of sufficient carbon dioxide, all proteins are susceptible to structural alteration by the addition of sugars and fats and aldehydes, especially under conditions that favor lipid peroxidation.

The amyloidoses affect different tissues in different ways, but when they occur in the brain, they produce progressive loss of function, with the type of protein forming the fibrils determining the nature of the functional loss. The protein which carries thyroid hormone and vitamin A, transthyretin, can produce nerve and brain amyloid disease, but it can also protect against other amyloid brain diseases; in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and the “prion diseases” (scrapie, kuru, CJD, BSE, etc.) amyloid particles are formed by different proteins. The transthyretin protein which is binding small molecules resists condensation into the amyloid fibrils, but without its normal vitamin A and thyroid hormone, it can create toxic fibrils. (Raghu, et al., 2002.)

Around 1970 I read E. J. Field’s suggestion that aging tissues and tissues affected by viral diseases showed some similar structures (“inclusion bodies”) under the electron microscope. In following up those observations, it turned out that old tissues appeared to develop antigens “identical with, or similar to,” scrapie-infected young tissues. The premature aging caused by removal of the thymus gland in newborn animals produced similar results.

Field’s group and others (e.g., Alpers) were clearly showing that the scrapie infection involved proteins, but not viruses with nucleic acids. In one of Field’s last publications (1978), he even suggested that the infectious process might depend on a structural rearrangement of the host’s molecules, similar to the idea which is now known as the “prion hypothesis.” Field’s suggestion was an important advance in the theory of aging, and the evidence supporting it is now voluminous, but that work has been omitted from the official histories.

Although phenomena of “imprinting” and non-genetic inheritance had been established earlier, the dogmatism of genetics led the scientific establishment to reject everything that challenged the primacy of DNA. When I mentioned to my professors (in 1971) the evidence that scrapie was transmitted without nucleic acid, I could see from their reactions that it would be a very long time before much progress would be made in understanding the degenerative brain diseases. When the exact structure of the “infectious” protein was later worked out, and the 1997 Nobel Prize awarded (to Stanley Prusiner), I was surprised that no one from Field’s group was included. (In 1976, a nobel prize had been awarded to D.C. Gajdusek, for his promotion of the idea of “slow viruses” in general, and particularly for arguing that scrapie, CJD and kuru were caused by slow viruses.)

In reading Prusiner’s autobiographical statements, I was even more surprised to see that he claimed to have been puzzled to find out, around 1983, that the infectious agent was a protein. I had thought that my professors were lethargic authoritarians when they refused to look at the evidence in 1970-72, but Prusiner’s expression of puzzlement so many years later over the absence of nucleic acid in the infectious agent is hard to account for.

In my own research in 1971, I was interested in another kind of age-related “inclusion body,” which was variously called lipofuscin, age pigment, and ceroid pigment. This brown (yellow autofluorescent) pigment contained proteins and metals, as well as polyunsaturated lipids, and overlapped in many ways with the amyloid bodies. All of these inclusion bodies were known to be associated with radiation injury, aging, and hormonal-nutritional imbalances. Excess of estrogen, polyunsaturated fatty acids, and oxidative metals were major factors in the development of lipofuscin, and estrogen was also known to cause other types of “inclusion bodies” to develop in cells.

Although very little was known about the composition of the inclusion bodies (they were usually thought to be organelles damaged by free radical activity, or antibodies resulting from autoimmunity), their involvement in aging and degenerative disease was clear, and it was widely known that ionizing radiation accelerated their formation. But it was just at this time that the national research priorities of the U.S. were redirected toward genetic explanations for all major diseases, with for example the “war on cancer” centering on the concepts of the “oncogene” and the cancer virus. Since the “slow virus” of cancer, or the viral oncogene, requires activation by something in the environment, its function is to distract the public’s attention from those environmental causes of disease, viz., radiation and chemical pollution.

The U.S. Public Health Service has historically been one of the branches of the military, and currently has 6000 commissioned officers. It has been intimately involved in all aspects of chemical, biological, and nuclear warfare, and it has participated in many covert projects, including experimentation on people without their knowledge. For decades, information on radiation injury to the public was hidden, classified, altered, or destroyed by the PHS. During the radiation disaster at Three Mile Island, they calmly defended the interests of the nuclear industry.

After the April, 1986 catastrophe at the reactor in Chernobyl, some of the food being imported into the U.S. was so highly radioactive that the FDA secretly seized it, to prevent the public from being concerned. The first cow found to have BSE in England was in November, 1986, several months after England’s pastures had been heavily contaminated by rainfall carrying radioactive material from Chernobyl, which soaked into the soil and continued to contaminate crops for years (and will continue, for centuries). The number of sick cows increased rapidly to a peak in 1992. Human deaths from the similar disease (“variant CJD”) began a few years later.

In June, 2000, a wildfire burned across southern Washington, turning the radioactive vegetation on the Hanford Nuclear Site into radioactive smoke, contaminating a wide area, including farms, dairies, and orchards. In 2003, the first cow in the U.S. with BSE was reported, from a dairy a few miles from the Hanford Site.

Beginning in 1946, Bikini Island was used to test atomic bombs. In 1954, they began to test hydrogen bombs in the Pacific; some of the bombs were deliberately designed to vaporize whole islands, so that the effects of radioactive fallout could be studied. In 1954, the first child with kuru was reported in the rainy highlands of New Guinea.

Within two years, hundreds of people in that area (of the Fore tribe) were dying from kuru, with the mortality highest among the women; in some villages, the majority of the women died from the disease, but by 1957 the mortality was falling rapidly. Between 1957 and 1964, 5% of the population of the Fore tribe died of the disease, according to D.C. Gajdusek, who had been sent by the U.S. Army to investigate the disease. Although Gajdusek graduated in 1946 from Harvard medical school as a pediatrician, in his autobiography he said that when he was drafted in 1951, the army assigned him to work in virology. In 1958, Gajdusek became director of the NIH laboratories for neurological and virological research. This was a remarkable achievement for someone who had supposedly only done some scattered field-work in infectious diseases, and whose purpose in going to New Guinea had been to study ''child growth and development in primitive cultures.'' The only published reason I have found that might be a basis for making him head of neurology, was his sending a diseased Fore brain to Fort Detrick in 1957.

Gajdusek claimed to have seen the Fore people eating dead relatives, but his figures show that the disease was already in rapid decline when he arrived. He took photographs which were widely published in the US, supposedly showing cannibalism, but 30 years later, he said the photographs showed people eating pork, and that he had seen no cannibalism. (At the time Gajdusek was observing kuru in New Guinea, the influence of “cannibalism” on brain function was already in the news, because of the discovery by J.V. McConnell that the behavior of “trained” flatworms could be transmitted to other worms by chopping them up and feeding them to the naive worms.)

Harvard medical school, in association with the military program centered at Fort Detrick, Fredericksburg, Maryland, was active in biological warfare in the 1940s, and I think it’s more plausible to see Gajdusek as a trouble-shooter for the biological warfare establishment, than as a biological researcher. One of his biographers has written that the idea of associating kuru with scrapie was suggested to him by a veterinarian, and that Gajdusek had responded by claiming to have experiments in progress to test that theory, four years before the experiments were actually made.

In other words, the slow virus theory for which Gajdusek was given the Nobel Prize is scientific junk, which Gajdusek has repeatedly reinterpreted retrospectively, making it seem to have been anticipatory of the prion theory. Whatever actually caused kuru, I think the army was afraid that it was the result of radioactive fallout from one of its bomb tests, and that Gajdusek’s job was to explain it away.

I suspect that kuru was the result of an unusual combination of malnutrition (the women were vegetarian) and radiation. In the very short time that Gajdusek spent in New Guinea, he claimed to have done studies to eliminate all of the alternative causes, nutritional, toxic, anthropological, bacterial causes, studies that would normally have required several years of well organized work. I don’t think he mentioned the possibility of radiation poisoning.

In 1998 Congress commissioned a study of the health effects of radiation from bomb testing, and although the study examined the effects of only part of the bomb tests, it concluded that they had killed 15,000 Americans. No one has tried to accurately estimate the numbers killed in other countries.

Even very low doses of ionizing radiation create an inflammatory reaction (Vickers, et al., 1991), and there is evidence that the inflammatory state can persist as long as the individual lives; in Japan, the “acute phase” proteins are still elevated in the people who were exposed to radiation from the atomic bombs. The acute phase proteins that are increased by malnutrition and radiation increase the tendency to form amyloid deposits. Strong radiation can even cause, after a delay of more than a year, the development of vacuoles, which are the most obvious feature of the “prion” brain diseases. The persistent inflammatory reaction eventually produces cellular changes, but these were originally overlooked because of the theory that radiation is harmful only when it produces immediate changes in the DNA.

Radiation damage to the brain is most visible early in life, and in old age. In 1955, Alice Stewart showed that prenatal x-rays increase the incidence of brain cancer, leukemia, and other cancers. In 1967, a study in Japanese bomb survivors found that prenatal exposure to radiation had reduced their head size and brain size. In 1979, Sternglass and Bell showed extremely close correspondence between scores on the SAT and prenatal exposure to radiation.

Serum amyloid A, which can increase 1000-fold under the influence of proinflammatory cytokines, resulting from irradiation, stress, trauma, or infection, is an activator of phospholipase A2 (PLA2), which releases fatty acids. Some of the neurodegenerative states, including amyloid-prion diseases, involve activated PLA2, as well as increases in the toxic breakdown products of the polyunsaturated fatty acids, such as 4-hydroxynonenal. The quantity of PUFA in the tissues strongly determines the susceptibility of the tissue to injury by radiation and other stresses. But a diet rich in PUFA will produce brain damage even without exceptional stressors, when there aren’t enough antioxidants, such as vitamin E and selenium, in the diet.

Amyloidosis has traditionally been thought of as a condition involving deposits mainly in blood vessels, kidneys, joints and skin and in extracellular spaces in the brain, and the fact that the “amyloid” stained in a certain way led to the idea that it was a single protein. But as more proteins--currently about 20--were identified in amyloid deposits, it was gradually realized that the deposits can be identified inside cells of many different tissues, before the larger, very visible, extracellular deposits are formed.

There is evidence of a steady increase in the death rate from amyloidosis. It kills women at a younger age than men, often at the age of 50 or 60.

Serum amyloid P is called “the female protein” in hamsters, because of its association with estrogen; castrated (or estrogen treated) males also produce large amounts of it, and its excess is associated with the deposition of amyloid (Coe and Ross, 1985). It can bind other amyloid proteins together, accelerating the formation of fibrils, but this function is probably just a variation of a normal function in immunity, tissue repair, and development.

Estrogen increases the inflammation-associated substances such as IL-6, C-reactive protein, and amyloid, and liberates fatty acids, especially the unstable polyunsaturated fatty acids. It also increases fibrinogen and decreases albumin, increasing the leakiness of capillaries. The decrease of albumin increases the concentration of free fatty acids and tryptophan, which would normally be bound to albumin.

In the U.S. and Europe, livestock are fed large amounts of high-protein feeds, and currently these typically contain fish meal and soybeans. The estrogenic materials in soybeans increase the animals’ tendency toward inflammation (with increased serum amyloid).

Officially, BSE appeared because cows were fed slaughter-house waste containing tissues of sheep that had died of scrapie. Scrapie was a nerve disease of sheep, first reported in Iceland in the 18th century. When I was studying the digestive system and nutrition of horses, I learned that it was common for horses in Norway to be fed dried fish during the winter. This abundant food was probably used for sheep, as well as for horses. The extra protein provided by fish meal is still important for sheep in areas where pastures are limited, but it has now become common to use it to increase productivity and growth throughout the lamb, beef, and dairy industries, as well as in most lab chows fed to experimental animals, such as the hamsters used for testing the infectivity of the diseased tissues.

Increased dietary polyunsaturated fatty acids (PUFA) suppress the activity of the ruminal bacteria which are responsible for the hydrogenation-detoxication of PUFA in the animal’s diet. This allows the unstable fats, 98% of which are normally destroyed, to pass into the animals’ tissues and milk.

The polyunsaturated fats in fish are very unstable, and when they get past the bacterial saturases (biohydrogenases) in the rumen that normally protect ruminants from lipid peroxidation, they are likely to cause their toxic effects more quickly than in humans, whose antioxidant systems are highly developed. The toxic effects of polyunsaturated fats involve altered (immunogenic) protein structure, decreased energy metabolism, and many inflammatory effects produced by the prostaglandin-like substances. Marine fish are now so generally polluted with dioxin, that in Japan there is a clear association between the amount of fish in a person’s diet (their body content of EPA and DHA) and the amount of dioxin in their body.

Radiation and many kinds of poisoning cause early peroxidation of those highly unsaturated fats, and the breakdown products accelerate the changes in the folding and chelating behavior of proteins. The accumulation of altered proteins is associated with the degenerative diseases. The role of toxic metals in brain inflammation is well established (e.g., aluminum, lead, mercury: Campbell, et al., 2004; Dave, et al., 1994; Ronnback and Hansson, 1992).

The “prion hypothesis” has the value of weakening the fanaticism of the DNA-genetics doctrine, but it has some problems. There are now several examples in which other degenerative diseases have been transmitted by procedures similar to those used to test the scrapie agent. (e.g., Goudsmit, et al., 1980; Xing, et al., 2001; Cui, et al., 2002.) Experimental controls haven’t been adequate to distinguish between the pure prion and its associated impurities. Gajdusek burned a sample of the infective hamster brain to ash, and found that it still retained “infectivity.” He argued that there was a mineral template that transmitted the toxic conformation to normal proteins. Others have demonstrated that the active structure of the infective agent is maintained by a carbohydrate scaffolding, or that the infectivity is destroyed by the frequency of ultraviolet light that destroys the active lipid of bacterial endotoxin, lipopolysaccharide.

But simply injuring the brain or other organ (by injecting anything) will sometimes activate a series of reactions similar to those seen in aging and the amyloidoses. When a slight trauma leads to a prolonged or expanding disturbance of structure and function, the process isn’t essentially different from transmitting a condition to another individual. The problem is being “transmitted” from the initial injury, recruiting new cells, and passing the disturbed state on to daughter cells in a disturbed form of regeneration. Keloids, hypertrophic scars, are analogous to the dementias in their overgrowth of connective tissue cells: In the aging or injured brain, the glial cells (mainly astrocytes) proliferate, in reparative processes that sometimes become exaggerated and harmful.

When tissue phospholipids contain large amounts of polyunsaturated fatty acids, large amounts of prostaglandins are immediately formed by any injury, including low doses of ionizing radiation. The liberated free fatty acids have many other effects, including the formation of highly reactive aldehydes, which modify DNA, proteins, and other cell components.

Animals which are “deficient” in the polyunsaturated fatty acids have a great resistance to a variety of inflammatory challenges. Their tissues appear to be poor allergens or antigens, since they can be easily grafted onto other animals without rejection. Something related to this can probably be seen in the data of human liver transplants. Women’s livers are subjected to more lipid peroxidation than men’s, because of the effects of estrogen (increasing growth hormone and free fatty acids, and selectively mobilizing the polyunsaturated fatty acids and increasing their oxidation). Liver transplants from middle-aged female donors fail much more often (40 to 45%) than livers from male donors (22 to 25%), and other organs show the same effect. The autoimmune diseases are several times as common in women as in men, suggesting that some tissues become relatively incompatible with their own body, after prolonged exposure to the unstable fatty acids. If we consider the healthy function of the immune system to be the removal or correction of injured tissue, it’s reasonable to view the random interactions of oxidized fats with proteins as exactly the sort of thing our immune system takes care of.

The serum amyloids A and P and the closely related lipoproteins are considered to be important parts of our “innate immunity,” operating in a more general way than the familiar system of specific acquired immunities.

The amyloids and lipoproteins are powerfully responsive to bacterial endotoxin, LPS, and their structural feature that binds it, the “pleated sheet” structure, appears to also be what allows the amyloids to form amorphous deposits and fibrils under some circumstances. Our innate immune system is perfectly competent for handling our normal stress-induced exposures to bacterial endotoxin, but as we accumulate the unstable fats, each exposure to endotoxin creates additional inflammatory stress by liberating stored fats. The brain has a very high concentration of complex fats, and is highly susceptible to the effects of lipid peroxidative stress, which become progressively worse as the unstable fats accumulate during aging.

More than 60 years ago, a vitamin E deficiency was known to cause a brain disease, sometimes associated with sterility and muscular dystrophy. The symptoms of the brain disease were similar to those of “mad cow disease,” and the condition is now usually called “crazy chick disease.” Veterinarians are usually taught that it is caused by a selenium deficiency, but it is actually the result of an excess of PUFA in the diet, and is exacerbated by increased iron or other oxidants, and prevented by increased vitamin E, selenium, or substitution of saturated fats for the unsaturated.

Terminology, established by tradition and thoughtless memorization, obscures many of the commonalities in the various brain diseases. Brain inflammation (Betmouni and Perry, 1999; Perry, et al., 1998), myelination disorders, edema, overgrowth of the astroglia, and circulatory changes are common occurrences in most of the degenerative encephalopathies, but traditional textbook descriptions have created the impression that each disease is pathologically very distinct from the others. The current classification of “the prion diseases” is reifying a group of symptoms that aren’t specific to any specific known cause. And standard laboratory procedures for preparing brain sections for microscopic examination may cause brain cells to shrink to 5% of their original volume (Hillman and Jarman, Atlas of the cellular structure of the human nervous system, 1991), so the objectivity of pathological studies shouldn’t be over-estimated.

According to a 1989 study (Laura Manuelidis, neuropathology department at Yale), 13% of the people who had died from “Alzheimer’s disease” actually had CJD. Between 1979 and 2000, the number of people dying annually from Alzheimer’s disease increased 50-fold. Very competent neuropathologists differ radically in their descriptions of the dementia epidemic.

By some tests, the “prion” resembles the LPS endotoxin. One of the interesting developments of the prion theory is that a particular structure that appears when the prion becomes toxic, the “beta pleated sheet,” is also a feature of most of the normal proteins that can form amyloid, and that this structure is directly related to binding and eliminating the bacterial LPS. If the prion theory is correct about the conversion of a normal protein into the pleated sheet, it isn’t necessarily correct about the incurability of the condition. The innate immune system should be able to inactivate the prion just as it does the bacterial endotoxin, if we remove the conditions that cause the innate immune reaction to amplify the inflammation beyond control.

In the prion diseases, the severely damaged brain appears to have a “pathological overactivity” of the serotonergic systems (Fraser, et al., 2003). This is an interesting parallel to Alzheimer’s disease, since it has been known for several years that the blood platelets have an increased tendency to release serotonin in that more common form of dementia. Serotonin itself is toxic to nerves, and is part of the adaptive system that gets out of control during prolonged inflammation. Serotonin is an important activator of the phospholipases.

The modification of proteins’ structure by glycosylation is involved in the development of the toxic form of the “prionic” protein, as well as in all the degenerative processes of aging. Until the ability to use sugar is impaired, cells produce enough carbon dioxide to protect proteins against random glycation, but with each exposure to free polyunsaturated fatty acids, the ability to use glucose is damaged. In the dementias, the brain has a greatly reduced ability to use glucose.

One of estrogen’s central effects is to shift metabolism away from the oxidation of glucose, decreasing carbon dioxide production. There is a much higher incidence of Alzheimer’s disease in women, and estrogen exposure exacerbates all of the changes that lead to it, such as shifts in nerve transmitters, increased vascular leakiness, and the increased production of the acute phase proteins.

Everything that is known about the “always fatal” prionic diseases, the diseases of disturbed protein folding, suggests that they can be avoided and even reversed by systematically reversing the processes that amplify inflammation.

People who take aspirin, drink coffee, and use tobacco, have a much lower incidence of Alzheimer’s disease than people who don’t use those things. Caffeine inhibits brain phospholipase, making it neuroprotective in a wide spectrum of conditions. In recent tests, aspirin has been found to prevent the misfolding of the prion protein, and even to reverse the misfolded beta sheet conformation, restoring it to the harmless normal conformation. Nicotine might have a similar effect, preventing deposition of amyloid fibrils and disrupting those already formed (Ono, et al., 2002). Vitamin E, aspirin, progesterone, and nicotine also inhibit phospholipase, which contributes to their antiinflammatory action. Each of the amyloid-forming proteins probably has molecules that interfere with its toxic accumulation.

Thyroid hormone, vitamins A and E, niacinamide (to inhibit systemic lipolysis), magnesium, calcium, progesterone, sugar, saturated fats, and gelatin all contribute in basic ways to prevention of the inflammatory states that eventually lead to the amyloid diseases. The scarcity of degenerative brain disease in high altitude populations is consistent with a protective role for carbon dioxide.

The relatively sudden acceptability of the idea of non-genetic transmission doesn't mean that Lamarck has been rehabilitated by the scientific establishment; it could just be that it's the most politically acceptable way to explain the outbreaks of deadly disease caused by the industrialization of foods and the exposure of the population to dangerous levels of radiation.

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Mol Biol Rep. 1996;23(3-4):253-60. The interaction of C-reactive protein and serum amyloid P component with nuclear antigens. Du Clos TW. “The pentraxins are a family of proteins characterized by cyclic pentameric structure, calcium-dependent ligand binding and sequence homology. The two main representatives of this family are the serum proteins, C-reactive protein (CRP) and serum amyloid P component (SAP). In man CRP is an acute phase reactant which increases up to 1,000 fold during the acute phaseresponse whereas SAP is a constitutive protein expressed at about 30 micrograms/ml. These proteins activate complement through the classical pathway and participate in opsonization of particulate antigensand bacteria. In the past several years it has been determined that both of these pentraxins interact with nuclear antigens including chromatin and small nuclear ribonucleoproteins (snRNPs). Both CRP and SAP have nuclear transport signals which facilitate their entry into the nuclei of intact cells. Furthermore, these pentraxins have been shown to affect the clearance of nuclear antigens in vivo.”

Am J Pathol. 1996 Oct;149(4):1313-20. Lipoproteins accumulate in immune deposits and are modified by lipid peroxidation in passive Heymann nephritis. Exner M, Susani M, Witztum JL, Hovorka A, Curtiss LK, Spitzauer S, Kerjaschki D.

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Acta Neurol Scand. 1975 Apr;51(4):299-309. Cellular sensitization in kuru, Jakob-Creutzfeldt disease and multiple sclerosis: with a note on the biohazards of slow infection work. Field EJ, Shenton BK.

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Arch Gesamte Virusforsch. 1970;30(2):224-37. The incorporation of (3H) thymidine and (14C) glucosamine into a DNA-polysaccharide complex in normal and scrapie-affected mouse brain. Adams DH, Caspary EA, Field EJ.

Biochem J. 1969 Sep;114(2):19P-20P. Structural changes in scrapie affected brain. Field EJ, Peat A.

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Nature. 1969 Apr 5;221(188):90-1. Susceptibility of scrapie agent to ionizing radiation. Field EJ, Farmer F, Caspary EA, Joyce G.

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Acta Neuropathol (Berl). 1967 Nov 29;9(4):305-15. Scrapie in the rat: an electron-microscopic study. II. Glial inclusions. Field EJ, Raine CS, Joyce G.

J Neurosci. 2001 Jan 1;21(1):136-42. Vaccination for neuroprotection in the mouse optic nerve: implications for optic Neuropathies. Fisher J, Levkovitch-Verbin H, Schori H, Yoles E, Butovsky O, Kaye JF, Ben-Nun A, Schwartz M. “T-cell autoimmunity to myelin basic protein was recently shown to be neuroprotective in injured rat optic nerves.” “The results of this study show that survival of RGCs after axonal injury can be enhanced by vaccination with an appropriate self-antigen. Furthermore, the use of nonencephalitogenic myelin peptides for immunization apparently allows neuroprotection without incurring the risk of an autoimmune disease.”

Neuropathol Appl Neurobiol. 2003 Oct;29(5):482-95. Neuronal and astrocytic responses involving the serotonergic system in human spongiform encephalopathies. Fraser E, McDonagh AM, Head M, Bishop M, Ironside JW, Mann DM.

J Neural Transm. 2001;108(2):221-30. Difference in toxicity of beta-amyloid peptide with aging in relation to nerve growth factor content in rat brain. Fukuta T, Nitta A, Itoh A, Furukawa S, Nabeshima T. “NGF levels in the hippocampus were increased only in adult rats. These results suggest that Abeta is toxic only in the matured adult brain, and that the mechanism of toxicity is related to NGF synthesis.”

Science 197: 943-960(1977). Unconventional viruses and the origin and disappearance of kuru. Gajdusek, D.C.

Trends Mol Med. 2001 Aug;7(8):336. Beneficial autoimmunity in traumatic brain injury. Gurwitz D.

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Arch Pathol. 1966 Oct; 82(4): 353-5. A lipofuscin-like pigment in the kidneys of estrogen-treated rats. Harris C.

Int J Radiat Biol. 2003 Feb; 79(2): 129-36. Radiation dose-dependent increases in inflammatory response markers in A-bomb Survivors. Hayashi T, Kusunoki Y, Hakoda M, Morishita Y, Kubo Y, Maki M, Kasagi F, Kodama K, Macphee DG, Kyoizumi S. “The well-documented increases in malignant tumours in the A-bomb survivors have recently been supplemented by reports that non-cancer diseases, including cardiovascular disease, may also have increased in incidence with increasing radiation dose. Given that low-level inflammatory responses are widely accepted as a significant risk factor for such diseases, we undertook a detailed investigation of the long-term effects of ionizing radiation on the levels of the inflammatory markers C-reactive protein (CRP) and interleukin 6 (IL-6) in A-bomb survivors.” “Blood samples were taken from 453 participants in a long-term epidemiological cohort of A-bomb survivors.” “CRP levels were significantly increased by about 31% Gy(-1) of estimated A-bomb radiation (p=0.0001). Higher CRP levels also correlated with age, male gender, body mass index and a history of myocardial infarction. After adjustments for these factors, CRP levels still appeared to have increased significantly with increasing radiation dose (about 28% increase at 1Gy, p=0.0002). IL-6 levels also appeared to have increased with radiation dose by 9.3% at 1Gy (p=0.0003) and after multiple adjustments by 9.8% at 1Gy (p=0.0007).” “Our results appear to indicate that exposure to A-bomb radiation has caused significant increases in inflammatory activity that are still demonstrable in the blood of A-bomb survivors and which may lead to increased risks of cardiovascular disease and other non-cancer diseases.”

Immunol Rev. 2000 Oct;177:52-67. Chemokines and chemokine receptors in inflammation of the nervous system: manifold roles and exquisite regulation. Huang D, Han Y, Rani MR, Glabinski A, Trebst C, Sorensen T, Tani M, Wang J, Chien P, O'Bryan S, Bielecki B, Zhou ZL, Majumder S, Ransohoff RM.

Am J Med Genet. 1989 Dec;34(4):562-8. Mortality rate of amyloidosis in Japan: secular trends and geographical Variations. Imaizumi Y. “The death rate in Japan from amyloidosis was analyzed using Japanese Vital Statistics for 1969-1985. The amyloidosis death rate has increased gradually year by year for both sexes.” “The mean age at death from amyloidosis gradually increased year by year for both sexes, although the age was 11-23 years shorter for males and 20-25 years shorter for females than that of the general population.”

Stroke. 1991 Nov;22(11):1448-51. Platelet secretory products may contribute to neuronal injury. Joseph R, Tsering C, Grunfeld S, Welch KM.

J Neurochem. 1997 Jul; 69(1): 266-72. Aggregation of beta-amyloid peptide is promoted by membrane phospholipid metabolites elevated in Alzheimer's disease brain. Klunk WE, Xu CJ, McClure RJ, Panchalingam K, Stanley JA, Pettegrew JW. “A beta peptides have been shown to be toxic to neurons in cell culture, and this toxicity is critically dependent on the aggregation of the peptide into cross-beta-pleated sheet fibrils. Also, in vivo and postmortem NMR studies have shown changes in certain brain membrane phospholipid metabolites in normal aging and more extensive alterations in patients with Alzheimer's disease. The finding that membrane phospholipids affect the aggregation of A beta suggests that the abnormalities in membrane metabolism found in Alzheimer's disease could affect the deposition of A beta in vivo.” “Certain metabolites (glycerophosphocholine, glycerophosphoethanolamine, and alpha-glycerophosphate) augment the aggregation of A beta. Other membrane phospholipid metabolites (phosphocholine, phosphoethanolamine, and inositol-1-phosphate) have no effect.We conclude that increased membrane phospholipid metabolite concentrations may play a role in the deposition of A beta seen in normal aging and the even greater deposition of A beta observed in Alzheimer's disease.”

J Pharm Sci. 1971 Feb; 60(2): 167-80. Experimental modification of the chemistry and biology of the aging process. Kormendy CG, Bender AD.

Radiobiologiia. 1990 May-Jun;30(3):317-20. [Cholesterol and fatty acids of the nuclei and chromatin of the rat thymus at long intervals following gamma irradiation] Kulagina TP. “The FFA content in the homogenate, nuclei and chromatin of rat thymus drastically increased 60 min after the last exposure. In a month, the FFA content of nuclei and chromatin dropped to control levels, whereas that of the homogenate remained high throughout the entire period of observation and sharply increased by the third month.”

J Neuropathol Exp Neurol. 1968 Jan; 27(1): 157-8. Amyloid in late postradiation necrosis of brain. Mandybur TJ, Gore y.

Hepatology. 1995 Dec;22(6):1754-62. Effect of donor age and sex on the outcome of liver transplantation. Marino IR, Doyle HR, Aldrighetti L, Doria C, McMichael J, Gayowski T, Fung JJ, Tzakis AG, Starzl TE.

Brain Res. 673(1), 149-152, 1995. "Glucose deprivation increases aspartic acid release from synaptosomes of aged mice,"M. Martinez, et al., "...in the absence of glucose in the medium of incubation aspartate and glutamate release was higher in old than in young animals." "...there is an age-dependent dysfunction in this process linked to energy metabolism disturbance."

Neurobiol Aging. 1995 Nov-Dec; 16(6): 977-81. Estrogen induction of glial heat shock proteins: implications for hypothalamic Aging. Mydlarski MB, Liberman A, Schipper HM. “In the aging mammalian hypothalamus, a unique subpopulation of glial cells accumulates peroxidase-positive cytoplasmic inclusions distinct from lipofuscin. In adult rodents, this senescence-dependent glial granulation is accelerated by administration of estradiol valerate.” “Our findings indicate that estrogen elicits a heat shock response and subsequent granulation in astrocytes residing in estradiol receptor-rich brain regions including the arcuate nucleus and the wall surrounding the third ventricle but not in estradiol receptor-deficient regions such as the striatum and corpus callosum. The heat shock proteins induced by estrogen, namely, the 27, 72, and 90 kDa stress proteins, are upregulated in astrocytes in response to oxidative challenge supporting our hypothesis that estrogen mediates senescent changes in the rodent hypothalamus through oxidative mechanisms.”

Proc. Natl. Acad. Sci. USA, vol. 44, pp. 712-717 (1958): "Epigenetic Control Systems". D. L. Nanney.

Journal of the Neurological Sciences 1995;134:61-6. Mortality from motor neuron disease in Japan, 1950-1990: association with radioactive fallout from atmospheric weapons testing. Neilson S, Robinson I, Rose FC.

Biol Psychiatry. 2002 Nov 1;52(9):880-6. Nicotine breaks down preformed Alzheimer's beta-amyloid fibrils in vitro. Ono K, Hasegawa K, Yamada M, Naiki H. “The antiamyloidogenic effect of nicotine may be exerted not only by the inhibition of fAbeta formation but also by the disruption of preformed fAbeta.”

Res Immunol. 1998 Sep-Oct; 149(7-8): 721-5. The contribution of inflammation to acute and chronic neurodegeneration. Perry VH, Bolton SJ, Anthony DC, Betmouni S.

Neurology. 1966 Oct;16(10):957-62. Myxedema and ataxia. Cerebellar alterations and "neural myxedema bodies". Price TR, Netsky MG.

Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1580-5. Epub 2003 Feb 03. Short-term administration of omega 3 fatty acids from fish oil results in increased transthyretin transcription in old rat hippocampus. Puskas LG, Kitajka K, Nyakas C, Barcelo-Coblijn G, Farkas T.

Arch Biochem Biophys. 2002 Apr 1;400(1):43-7. Inhibition of transthyretin amyloid fibril formation by 2,4-dinitrophenol through tetramer stabilization. Raghu P, Reddy GB, Sivakumar B.

Br J Ind Med. 1992 Apr;49(4):233-40. Chronic encephalopathies induced by mercury or lead: aspects of underlying cellular and molecular mechanisms. Ronnback L, Hansson E.

Radiat Res. 1967 Mar; 30(3): 640-53. Radiation studies on mice of an inbred tumor-resistant strain. The alteration of endogenous susceptibility to amyloidosis by x-irradiation. Rosenblum WI, Goldfeder A, Ghosh AK.

Neurotoxicology 15(3), 493-502, 1994."Phosphoinositide second messengers in cholinergic excitotoxicity," K. Savolainen, et al. "Acetylcholine is a powerful excitotoxic neurotransmitter in the brain. By stimulating calcium-mobilizing receptors, acetylcholine, through G-proteins, stimulates phospholipase C and cause the hydrolysis of a membrane phospholipid...."Female sex and senescence increase the sensitivity of rats to cholinergic excitotoxicity."

Int J Radiat Oncol Biol Phys. 1995 Jan 1;31(1):57-64. Radiation-induced changes in the profile of spinal cord serotonin, prostaglandin synthesis, and vascular permeability. Siegal T, Pfeffer MR. “Serotonin levels were unchanged at 2, 14,and 56 days after radiation but increased at 120 and 240 days in the irradiated cord segments when compared to both the nonirradiated thoracic and cervical segments (p < 0.01) and age-matched controls (p < 0.03).” “In the first 24 h after radiation, a 104% increase in microvessel permeability was observed which returned to normal by 3 days. Normal permeability was maintained at 14 and 28 days, but at 120 and 240 days a persistent and significant increase of 98% and 73% respectively above control level was noted.”

Annual Meeting of the American Psychological Association, New York, New York, September 3, 1979, "Fallout and the Decline of Scholastic Aptitude Scores," Ernest Sternglass and Stephen Bell.

Acta Neuropathol (Berl). 1995; 90(2): 135-41. Cerebral beta amyloid deposition in patients with malignant neoplasms: its prevalence with aging and effects of radiation therapy on vascular amyloid. Sugihara S, Ogawa A, Nakazato Y, Yamaguchi H. “The prevalence of cerebral A beta deposits was about two times higher in the patients who had received brain radiation therapy (27.8%) compared to non-radiated patients (14.8%). Amyloid angiopathy was much more prominent (P < 0.05) with radiation therapy (22.2%) than without (8.0%).”

Diabetes. 2003 Dec;52(12):2882-7. Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Tripathy D, Mohanty P, Dhindsa S, Syed T, Ghanim H, Aljada A, Dandona P.

Arterioscler Thromb Vasc Biol. 2003 Dec 29. Effect of Lower Dosage of Oral Conjugated Equine Estrogen on Inflammatory Markers and Endothelial Function in Healthy Postmenopausal Women. Wakatsuki A, Ikenoue N, Shinohara K, Watanabe K, Fukaya T. {Oral estrogen) “... increases plasma C-reactive protein (CRP) and interleukin-6 (IL-6) concentration. The proinflammatory effect of oral ERT may explain the increased risk of coronary heart disease (CHD) associated with this treatment.”

Am J Pathol. 1997 Jun; 150(6): 2181-95. Free fatty acids stimulate the polymerization of tau and amyloid beta peptides.In vitro evidence for a common effector of pathogenesis in Alzheimer's disease. Wilson DM, Binder LI. “We have discovered that free fatty acids (FFAs) stimulate the assembly of both amyloid and tau filaments in vitro.” “Utilizing fluorescence spectroscopy, unsaturated FFAs were also demonstrated to induce beta-amyloid assembly.” [These results] “...suggest that cortical elevations of FFAs may constitute a unifying stimulatory event driving the formation of two of the obvious pathogenetic lesions in Alzheimer's disease.”

Lab Invest. 2001 Apr; 81(4): 493-9. Transmission of mouse senile amyloidosis. Xing Y, Nakamura A, Chiba T, Kogishi K, Matsushita T, Li F, Guo Z, Hosokawa M, Mori M, Higuchi K. “In mouse senile amyloidosis, apolipoprotein A-II polymerizes into amyloid fibrils (AApoAII) and deposits systemically. Peripheral injection of AApoAII fibrils into young mice induces systemic amyloidosis....” “We isolated AApoAII amyloid fibrils from the livers of old R1.P1-Apoa2(c) mice and injected them with feeding needles into the stomachs of young R1.P1-Apoa2(c) mice for 5 consecutive days. After 2 months, all mice had AApoAII deposits in the lamina propria of the small intestine. Amyloid deposition extended to the tongue, stomach, heart, and liver at 3 and 4 months after feeding. AApoAII suspended in drinking water also induced amyloidosis.” “Amyloid deposition was induced in young mice reared in the same cage for 3 months with old mice who had severe amyloidosis. Detection of AApoAII in feces of old mice and induction of amyloidosis by the injection of an amyloid fraction of feces suggested the propagation of amyloidosis by eating feces. Here, we substantiate the transmissibility of AApoAII amyloidosis and present a possible pathogenesis of amyloidosis, ie, oral transmission of amyloid fibril conformation, where we assert that exogenous amyloid fibrils act as templates and change the conformation of endogenous amyloid protein to polymerize into amyloid fibrils.”

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<span class="koboSpan" id="kobo.1.1">Caffeine: A vitamin-like nutrient, or adaptogen. </span><span class="koboSpan" id="kobo.1.2">Questions about tea and coffee, cancer and other degenerative diseases, and the hormones.</span> A R T I C L E

Caffeine: A vitamin-like nutrient, or adaptogen

Questions about tea and coffee, cancer and other degenerative diseases, and the hormones.

There is a popular health-culture that circulates mistaken ideas about nutrition, and coffee drinking has been a perennial target of this culture. It is commonly said that coffee is a drug, not a food, and that its drug action is harmful, and that this harm is not compensated by any nutritional benefit. Most physicians subscribe to most of these common sense ideas about coffee, and form an authoritative barrier against the assimilation of scientific information about coffee.

I think it would be good to reconsider coffees place in the diet and in health care.

Coffee drinkers have a lower incidence of thyroid disease, including cancer, thannon-drinkers.

Caffeine protects the liver from alcohol and acetaminophen (Tylenol) and other toxins, and coffee drinkers are less likely than people who dont use coffee to have elevated serum enzymes and other indications of liver damage.

Caffeine protects against cancer caused by radiation, chemical carcinogens, viruses, and estrogens.

Caffeine synergizes with progesterone, and increases its concentration in blood and tissues.

Cystic breast disease is not caused by caffeine, in fact caffeines effects are likely to be protective; a variety of studies show that coffee, tea, and caffeine are protective against breast cancer.

Coffee provides very significant quantities of magnesium, as well as other nutrients including vitamin B1.

Caffeine improves efficiency of fuel use and performance: JC Wagner 1989.

Coffee drinkers have a low incidence of suicide.

Caffeine supports serotonin uptake in nerves, and inhibits blood platelet aggregation.

Coffee drinkers have been found to have lower cadmium in tissues; coffee making removes heavy metals from water.

Coffee inhibits iron absorption if taken with meals, helping to prevent iron overload.

Caffeine, like niacin, inhibits apoptosis, protecting against stress-induced cell death, without interfering with normal cell turnover.

Caffeine can prevent nerve cell death.

Coffee (or caffeine) prevents Parkinsons Disease (Ross, et al., 2000).

The prenatal growth retardation that can be caused by feeding large amounts of caffeine is prevented by supplementing the diet with sugar.

Caffeine stops production of free radicals by inhibiting xanthine oxidase, an important factor in tissue stress.

Caffeine lowers serum potassium following exercise; stabilizes platelets, reducing thromboxane production.

One definition of a vitamin is that it is an organic chemical found in foods, the lack of which causes a specific disease, or group of diseases. A variety of substances that have been proposed to be vitamins havent been recognized as being essential, and some substances that arent essential are sometimes called vitamins. Sometimes these issues havent had enough scientific investigation, but often nonscientific forces regulate nutritional ideas.

The definition of a disease isnt as clear as text-book writers have implied, and causality in biology is always more complex than we like to believe.

Nutrition is one of the most important sciences, and should certainly be as prestigious and well financed as astrophysics and nuclear physics, but while people say it doesnt take a brain surgeon to figure that out, no one says it doesnt take a nutritionist to understand that. Partly, thats because medicine treated scientific nutrition as an illegitimate step-child, and refused throughout the 20th century to recognize that it is a central part of scientific health care. In the 1970s, physicians and dietitians were still ridiculing the idea that vitamin E could prevent or cure diseases of the circulatory system, and babies as well as older people were given total intravenous nutrition which lacked nutrients that are essential to life, growth, immunity, and healing. Medicine and science are powerfully institutionalized, but no institution or profession has existed for the purpose of encouraging people to act reasonably.

In this environment, most people have felt that subtleties of definition, logic and evidence werent important for nutrition, and a great amount of energy has gone into deciding whether there were four food groups or seven food groups or a nutritional pyramid. The motives behind governmental and quasi-governmental nutrition policies usually represent something besides a simple scientific concern for good health, as when health care institutions say that Mexican babies should begin eating beans when they reach the age of six months, or that non-whites dont need milk after they are weaned. In a culture that discourages prolonged breast feeding, the effects of these doctrines can be serious.

After a century of scientific nutrition, public nutritional policies are doing approximately as much harm as good, and they are getting worse faster than they are getting better..

In this culture, what we desperately need is a recognition of the complexity of life, and of the political-ecological situation we find ourselves in. Any thinking which isnt system thinking should be treated with caution, and most contemporary thinking about health neglects to consider relevant parts of the problem-system. Official recommendations about salt, cholesterol, iron, unsaturated and saturated fats, and soybeans have generally been inappropriate, unscientific, and strongly motivated by business interests rather than by biological knowledge.

Definitions have rarely distinguished clearly between nutrients and drugs, and new commercial motives are helping to further blur the distinctions.

Essential nutrients, defensive (detoxifying, antistress) nutrients, hormone-modulating nutrients, self-actualization nutrients, growth regulating nutrients, structure modifiers, life extension agents, transgenerationally active (imprinting) nutrients--the line between nutrients and biological modifiers often depends on the situation. Vitamins D and A clearly have hormone-like properties, and vitamin Es effects, and those of many terpenoids and steroids and bioflavonoids found in foods, include hormone-like actions as well as antioxidant and pro-oxidant functions. The concept of adaptogen can include things that act like both drugs and nutrients.

Some studies have suggested that trace amounts of nutrients could be passed on for a few generations, but the evidence now indicates that these transgenerational effects are caused by phenomena such as imprinting. But the hereditary effects of nutrients are so complex that their recognition would force nutrition to be recognized as one of the most complex sciences, interwoven with the complexities of growth and development.

The idea that poor nutrition stunts growth has led to the idea that good nutrition can be defined in terms of the rate of growth and the size ultimately reached. In medicine, it is common to refer to an obese specimen as well nourished, as if quantity of food and quantity of tissue were necessarily good things. But poisons can stimulate growth (hormesis), and food restriction can extend longevity. We still have to determine basic things such as the optimal rate of growth, and the optimal size.

Nutrition textbooks flatly describe caffeine as a drug, not a nutrient, as if it were obvious that nutrients cant be drugs. Any of the essential nutrients, if used in isolation, can be used as a drug, for a specific effect on the organism that it wouldnt normally have when eaten as a component of ordinary food. And natural foods contain thousands of chemicals, other than the essential nutrients. Many of these are called nonessential nutrients, but their importance is being recognized increasingly. The truth is that we arent sure what they arent essential for. Until we have more definite knowledge about the organism I dont think we should categorize things so absolutely as drugs or nutrients.

The bad effects ascribed to coffee usually involve administering large doses in a short period of time. While caffeine is commonly said to raise blood pressure, this effect is slight, and may not occur during the normal use of coffee. Experimenters typically ignore essential factors. Drinking plain water can cause an extreme rise in blood pressure, especially in old people, and eating a meal (containing carbohydrate) lowers blood pressure. The increased metabolic rate caffeine produces increases the cellular consumption of glucose, so experiments that study the effects of coffee taken on an empty stomach are measuring the effects of increased temperature and metabolic rate, combined with increased adrenaline (resulting from the decrease of glucose), and so confuse the issue of caffeines intrinsic effects.

In one study (Krasilnikov, 1975), the drugs were introduced directly into the carotid artery to study the effects on the blood vessels in the brain. Caffeine increased the blood volume in the brain, while decreasing the resistance of the vessels, and this effect is what would be expected from its stimulation of brain metabolism and the consequent increase in carbon dioxide, which dilates blood vessels.

In the whole body, increased carbon dioxide also decreases vascular resistance, and this allows circulation to increase, while the hearts work is decreased, relative to the amount of blood pumped. But when the whole bodys metabolism is increased, adequate nutrition is crucial.

In animal experiments that have been used to argue that pregnant women shouldnt drink coffee, large doses of caffeine given to pregnant animals retarded the growth of the fetuses. But simply giving more sucrose prevented the growth retardation. Since caffeine tends to correct some of the metabolic problems that could interfere with pregnancy, it is possible that rationally constructed experiments could show benefits to the fetus from the mothers use of coffee, for example by lowering bilirubin and serotonin, preventing hypoglycemia, increasing uterine perfusion and progesterone synthesis, synergizing with thyroid and cortisol to promote lung maturation, and providing additional nutrients.

One of the most popular misconceptions about caffeine is that it causes fibrocystic breast disease. Several groups demonstrated pretty clearly that it doesnt, but there was no reason that they should have had to bother, except for an amazingly incompetent, but highly publicized, series of articles--classics of their kind--by J. P. Minton, of Ohio State University. Minton neglected to notice that the healthy breast contains a high percentage of fat, and that the inflamed and diseased breast has an increased proportion of glandular material Fat cells have a low level of cyclic AMP, a regulatory substance that is associated with normal cellular differentiation and function, and is involved in mediating caffeines ability to inhibit cancer cell multiplication. Minton argued that cAMP increases progressively with the degree of breast disease, up to cancer, and that cAMP is increased by caffeine. A variety of substances other than caffeine that inhibit the growth of cancer cells (as well as normal breast cells) act by increasing the amount of cyclic AMP, while estrogen lowers the amount of cAMP and increases cell growth. Mintons argument should have been to use more caffeine, in proportion to the degree of breast disease, if he were arguing logically from his evidence. Caffeines effect on the breast resembles that of progesterone, opposing estrogens effects.

Many studies over the last 30 years have shown caffeine to be highly protective against all kinds of carcinogenesis, including estrogens carcinogenic effects on the breast. Caffeine is now being used along with some of the standard cancer treatments, to improve their effects or to reduce their side effects. There are substances in the coffee berry besides caffeine that protect against mutations and cancer, and that have shown strong therapeutic effects against cancer. Although many plant substances are protective against mutations and cancer, I dont know of any that is as free of side effects as coffee.

To talk about caffeine, its necessary to talk about uric acid. Uric acid, synthesized in the body, is both a stimulant and a very important antioxidant, and its structure is very similar to that of caffeine. A deficiency of uric acid is a serious problem. Caffeine and uric acid are in the group of chemicals called purines.

Purines (along with pyrimidines) are components of the nucleic acids, DNA and RNA, but they have many other functions. In general, substances related to purines are stimulants, and substances related to pyrimidines are sedatives.

When the basic purine structure is oxidized, it becomes in turn hypoxanthine, xanthine, and uric acid, by the addition of oxygen atoms. When methyl groups (CH₃) are added to nitrogens in the purine ring, the molecule becomes less water soluble. Xanthine (an intermediate in purine metabolism) has two oxygen atoms, and when three methyl groups are added, it becomes trimethyl xanthine, or caffeine. With two methyl groups, it is theophylline, which is named for its presence in tea. We have enzyme systems which can add and subtract methyl groups; for example, when babies are given theophylline, they can convert it into caffeine.

We have enzymes that can modify all of the methyl groups and oxygen atoms of caffeine and the other purine derivatives. Caffeine is usually excreted in a modified form, for example as a methylated uric acid.

One of the ways in which uric acid functions as an antioxidant is by modifying the activity of the enzyme xanthine oxidase, which in stress can become a dangerous source of free radicals. Caffeine also restrains this enzyme. There are several other ways in which uric acid and caffeine (and a variety of intermediate xanthines) protect against oxidative damage. Coffee drinkers, for example, have been found to have lower levels of cadmium in their kidneys than people who dont use coffee, and coffee is known to inhibit the absorption of iron by the intestine, helping to prevent iron overload.

Toxins and stressors often kill cells, for example in the brain, liver, and immune system, by causing the cells to expend energy faster than it can be replaced. There is an enzyme system that repairs genetic damage, called PARP. The activation of this enzyme is a major energy drain, and substances that inhibit it can prevent the death of the cell. Niacin and caffeine can inhibit this enzyme sufficiently to prevent this characteristic kind of cell death, without preventing the normal cellular turnover; that is, they dont produce tumors by preventing the death of cells that arent needed.

The purines are important in a great variety of regulatory processes, and caffeine fits into this complex system in other ways that are often protective against stress. For example, it has been proposed that tea can protect against circulatory disease by preventing abnormal clotting, and the mechanism seems to be that caffeine (or theophylline) tends to restrain stress-induced platelet aggregaton.

When platelets clump, they release various factors that contribute to the development of a clot. Serotonin is one of these, and is released by other kinds of cell, including mast cells and basophils and nerve cells. Serotonin produces vascular spasms and increased blood pressure, blood vessel leakiness and inflammation, and the release of many other stress mediators. Caffeine, besides inhibiting the platelet aggregation, also tends to inhibit the release of serotonin, or to promote its uptake and binding.

J. W. Davis, et al., 1996, found that high uric acid levels seem to protect against the development of Parkinsons disease. They ascribed this effect to uric acids antioxidant function. Coffee drinking, which lowers uric acid levels, nevertheless appeared to be much more strongly protective against Parkinsons disease than uric acid.

Possibly more important than coffees ability to protect the health is the way it does it. The studies that have tried to gather evidence to show that coffee is harmful, and found the opposite, have provided insight into several diseases. For example, coffees effects on serotonin are very similar to carbon dioxides, and the thyroid hormones. Noticing that coffee drinking is associated with a low incidence of Parkinsons disease could focus attention on the ways that thyroid and carbon dioxide and serotonin, estrogen, mast cells, histamine and blood clotting interact to produce nerve cell death.

Thinking about how caffeine can be beneficial across such a broad spectrum of problems can give us a perspective on the similarities of their underlying physiology and biochemistry, expanding the implications of stress, biological energy, and adaptability.

The observation that coffee drinkers have a low incidence of suicide, for example, might be physiologically related to the large increase in suicide rate among people who use the newer antidepressants called serotonin reuptake inhibitors. Serotonin excess causes several of the features of depression, such as learned helplessness and reduced metabolic rate, while coffee stimulates the uptake (inactivation or storage) of serotonin, increases metabolic energy, and tends to improve mood. In animal studies, it reverses the state of helplessness or despair, often more effectively than so-called antidepressants.

The research on caffeines effects on blood pressure, and on the use of fuel by the more actively metabolizing cells, hasnt clarified its effects on respiration and nutrition, but some of these experiments confirm things that coffee drinkers usually learn for themselves.

Often, a woman who thinks that she has symptoms of hypoglycemia says that drinking even the smallest amount of coffee makes her anxious and shaky. Sometimes, I have suggested that they try drinking about two ounces of coffee with cream or milk along with a meal. Its common for them to find that this reduces their symptoms of hypoglycemia, and allows them to be symptom-free between meals. Although we dont know exactly why caffeine improves an athletes endurance, I think the same processes are involved when coffee increases a persons endurance in ordinary activities.

Caffeine has remarkable parallels to thyroid and progesterone, and the use of coffee or tea can help to maintain their production, or compensate for their deficiency. Women spontaneously drink more coffee premenstrually, and since caffeine is known to increase the concentration of progesterone in the blood and in the brain, this is obviously a spontaneous and rational form of self-medication, though medical editors like to see things causally reversed, and blame the coffee drinking for the symptoms it is actually alleviating. Some women have noticed that the effect of a progesterone supplement is stronger when they take it with coffee. This is similar to the synergy between thyroid and progesterone, which is probably involved, since caffeine tends to locally activate thyroid secretion by a variety of mechanisms, increasing cyclic AMP and decreasing serotonin in thyroid cells, for example, and also by lowering the systemic stress mediators.

Medical editors like to publish articles that reinforce important prejudices, even if, scientifically, they are trash. The momentum of a bad idea can probably be measured by the tons of glossy paper that have gone into its development. Just for the sake of the environment, it would be nice if editors would try to think in terms of evidence and biological mechanisms, rather than stereotypes.

REFERENCES

Fiziol Zh SSSR Im I M Sechenova 1975 Oct;61(10):1531-8. [Changes in the resistance and capacity of the cerebral vascular bed under the influence of vasoactive substances]. [Article in Russian] Krasil'nikov, V.G. Effects of intracarotid injections of vasoactive agents on cerebrovascular resistance (CVR) and cerebral blood volume (CBV) were studied in hemodynamically isolated brain of cats. Perfusion pressure shifts at a constant blood volume perfusion reflected CVR changes, and changes of venous outflow - CBV alterations. Administration of adrenaline, serotonin, and angiotensine was followed mainly by an increase of CVR and a decrease of CBV. The CVR could be reduced by isopropilnoradrenaline, acetylcholine, histamine, and caffeine. CBV was decreased after isopropilnoradrenaline, acetycholine, histamine injections and increased by caffeine. The possible role of the active changes of cerebral capacitance vessels in the transcapillary fluid exchange is discussed. Capacitance vessels active responses are supposed to entail wrong results when using certain techniques for measurement of cerebral blood flow and metabolism.

Proc Soc Exp Biol Med 1999 Apr;220(4):244-8. The prevention of lung cancer induced by a tobacco-specific carcinogen in rodents by green and black Tea. Chung FL The oxidation products found in black tea, thearubigins and theaflavins, also possess antioxidant activity, suggesting that black tea may also inhibit NNK-induced lung tumorigenesis. Indeed, bioassays in A/J mice have shown that black tea given as drinking water retarded the development of lung cancer caused by NNK. We conducted a 2-year lifetime bioassay in F344 rats to determine whether black tea and caffeine are protective against lung tumorigenesis induced by NNK. Our studies in both mice and rats have generated important new data that support green and black tea and caffeine as potential preventive agents against lung cancer, suggesting that a closer examination of the roles of tea and caffeine on lung cancer in smokers may be warranted.

Pharmacol Biochem Behav 2000 May;66(1):39-45. Caffeine-induced increases in the brain and plasma concentrations of neuroactive steroids in the rat. Concas A, Porcu P, Sogliano C, Serra M, Purdy RH, Biggio G. A single intraperitoneal injection of caffeine induced dose- and time-dependent increases in the concentrations of pregnenolone, progesterone, and 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) in the cerebral cortex. Caffeine also increased the plasma concentrations of pregnenolone and progesterone with a dose-response relation similar to that observed in the brain . . . Moreover, the brain and plasma concentrations of pregnenolone, progesterone, and allopregnanolone were not affected by caffeine in adrenalectomized-orchiectomized rats.

Cancer Res 1998 Sep 15;58(18):4096-101. Inhibition of lung carcinogenesis by black tea in Fischer rats treated with a tobacco-specific carcinogen: caffeine as an important constituent. Chung FL, Wang M, Rivenson A, Iatropoulos MJ, Reinhardt JC, Pittman B, Ho CT, Amin SG. The NNK-treated group, given 2% black tea, showed a significant reduction of the total lung tumor (adenomas, adenocarcinomas, and adenosquamous carcinomas) incidence from 47% to 19%, whereas the group given 1% and 0.5% black tea showed no change. The 2% tea also reduced liver tumor incidence induced by NNK from 34% in the group given only deionized water to 12%. The most unexpected finding was the remarkable reduction of the lung tumor incidence, from 47% to 10%, in the group treated with 680 ppm caffeine, a concentration equivalent to that found in the 2% tea. This incidence is comparable to background levels seen in the control group. This study demonstrated for the first time in a 2-year lifetime bioassay that black tea protects against lung tumorigenesis in F344 rats, and this effect appears to be attributed, to a significant extent, to caffeine as an active ingredient of tea.

Cancer Lett 1991 Mar;56(3):245-50. Inhibition by caffeine of ovarian hormone-induced mammary gland tumorigenesis in female GR mice. VanderPloeg LC, Welsch CW. Hormone treatment induced mammary tumors in 95-100% of the mice. Caffeine treatment significantly (P less than 0.05) reduced the mean number of mammary tumors per mouse and significantly (P less than 0.05) increased the mean latency period of mammary tumor appearance.

Breast Cancer Res Treat 1991 Nov;19(3):269-75. Caffeine inhibits development of benign mammary gland tumors in carcinogen-treated female Sprague-Dawley rats. Wolfrom DM, Rao AR, Welsch CW.

Cancer 1985 Oct 15;56(8):1977-81. The inhibitory effect of caffeine on hormone-induced rat breast cancer. Petrek JA, Sandberg WA, Cole MN, Silberman MS, Collins DC. The current investigation examines the effect of two caffeine doses in ACI rats with and without diethylstilbestrol (DES). Without DES, cancer did not develop in any of the rats receiving either of the two caffeine dosages. With DES, increasing caffeine dosage lengthened the time to first cancer, decreased the number of rats that developed cancers, and decreased the number of cancers overall. In conclusion, chronic caffeine ingestion inhibits rat breast cancer, neither by interfering with the high prolactin levels--a necessary step in murine tumor development--nor by causing hypocaloric intake.

Nutr Cancer 1998;30(1):21-4. Association of coffee, green tea, and caffeine intakes with serum concentrations of estradiol and sex hormone-binding globulin in premenopausal Japanese women. Nagata C, Kabuto M, Shimizu H. Although the effect of caffeine cannot be distinguished from effects of coffee and green tea, consumption of caffeine-containing beverages appeared to favorably alter hormone levels associated with the risk of developing breast cancer.

J Environ Pathol Toxicol Oncol 1992; 11(3):177-89. Caffeine, theophylline, theobromine, and developmental growth of the mouse mammary gland. VanderPloeg LC, Wolfrom DM, Rao AR, Braselton WE, Welsch CW. These data demonstrate that certain methylxanthines (e.g., caffeine and theophylline) but not others (e.g., theobromine) can significantly enhance mammotrophic hormone-induced mammary lobulo-alveolar differentiation in female Balb/c mice, an effect that appears not to be manifested via a direct action of the methylxanthines on the mammary gland.

J Environ Pathol Toxicol Oncol 1994;13(2):81-8. Enhancement by caffeine of mammary gland lobulo-alveolar development in mice: a function of increased corticosterone. Welsch CW, VanderPloeg LC. Previously we have reported that the stimulatory effect of caffeine on lobulo-alveolar development in the mammary glands of female Balb/c mice is not due to a direct action of the drug on the mammary gland but appears to be due to a caffeine-induced alteration of a yet to be defined systemic physiological process (VanderPloeg et al., J Environ Pathol Toxicol Oncol 11:177-189, 1992). In the present study, we administered caffeine (via the drinking water, 500 mg/L) to ovariectomized, estrogen- and progesterone-treated Balb/c mice. After 30 days of caffeine treatment, a significant (p < 0.001) enhancement of lobulo-alveolar development in the mammary glands of the hormone-treated mice, compared with hormone treated control mice, was observed.

Am J Clin Nutr 1997 Jun;65(6):1826-30. Dietary caffeine intake and bone status of postmenopausal women. Lloyd T, Rollings N, Eggli DF, Kieselhorst K, Chinchilli VM.

Eur J Epidemiol 1993 May;9(3):293-7. Unexpected effects of coffee consumption on liver enzymes. Casiglia E, Spolaore P, Ginocchio G, Ambrosio GB. Istituto di Medicina Clinica, Universita di Padova, Italy. The effects of regular daily coffee consumption on liver enzymes were studied in a large number of subjects from the general population. In coffee drinkers, liver enzymes (gamma-glutamyl transferase, alanine-amino transferase, and alkaline phosphatase) and serum bilirubin were lower than in non-coffee-drinking subjects or in those consuming less than 3 cups daily. The hypothesis proposed is that liver enzymes are a target for caffeine contained in coffee.

Anticancer Res 1996 Jan-Feb;16(1):151-3 Suppression by coffee cherry of the growth of spontaneous mammary tumours in SHN mice. Nagasawa H, Yasuda M, Sakamoto S, Inatomi H Experimental Animal Research Laboratory, Meiji University, Kanagawa, Japan. We previously found that coffee cherry (CC), residue after removal of coffee beans, significantly suppressed the development of spontaneous mammary tumours of mice. In this paper, the effects of CC on the growth of the palpable size of this type of tumour was examined. Free access as drinking water of 0.5% solution of the hot water extract of CC for 10 days resulted in a marked inhibition of the tumour growth: The percent changes of tumour sizes were 53.8 +/- 11.7% and 13.8 +/- 10.9% in the control and the experimental groups, respectively. Associated with this, thymidylate synthetase activity in the mammary tumours was significantly lower in the experimental group than in the control. Normal and preneoplastic mammary gland growth, body weight change and weights and structures of endocrine organs were only slightly affected by the treatment. The findings indicate that CC is promising as an antitumour agent.

Yakugaku Zasshi 1997 Jul;117(7):448-54. [Effect of tea extracts, catechin and caffeine against type-I allergic reaction]. [Article in Japanese] Shiozaki T, Sugiyama K, Nakazato K, Takeo T. Caffeine also showed a inhibitory effect on the PCA reaction. These results indicate that tea could provide a significant protection against the type-I allergic reaction. These findings also suggest that tea catechins and caffeine play an important role in having an inhibitory effect on the type-I allergic reaction.

Acta Chir Scand 1989 Jun-Jul;155(6-7):317-20. Does coffee consumption protect against thyroid disease? Linos A, Linos DA, Vgotza N, Souvatzoglou A, Koutras DA

Br J Nutr 1999 Aug;82(2):125-30. Inverse association between coffee drinking and serum uric acid concentrations in middle-aged Japanese males. Kiyohara C, Kono S, Honjo S, Todoroki I, Sakurai Y, Nishiwaki M, Hamada H, Nishikawa H, Koga H, Ogawa S, Nakagawa K

Cancer Res 1997 Jul 1;57(13):2623-9. Effects of tea, decaffeinated tea, and caffeine on UVB light-induced complete carcinogenesis in SKH-1 mice: demonstration of caffeine as a biologically important constituent of tea. Huang MT, Xie JG, Wang ZY, Ho CT, Lou YR, Wang CX, Hard GC, Conney A.H.

Mutat Res 1981 Jun;89(2):161-77. Non-mutagenicity of urine from coffee drinkers compared with that from cigarette smokers. Aeschbacher HU, Chappuis C.

Biol Neonate 1981;40(3-4):196-8. The effects of maternal carbohydrate (sucrose) supplementation on the growth of offspring of pregnancies with habitual caffeine consumption. Dunlop M, Court JM, Larkins RG. When maternal caffeine (10 mg/kg/day) was consumed together with supplementary sucrose (7 g/kg/day) the expected offspring growth reduction attributed to caffeine did not occur.

Biochim Biophys Acta 1992 Dec 15;1175(1):114-22. Caffeine promotes survival of cultured sympathetic neurons deprived of nerve growth factor through a cAMP-dependent mechanism. Tanaka S, Koike T.

JAMA 2000 May 24-31;283(20):2674-9. Association of coffee and caffeine intake with the risk of Parkinson disease. Ross GW, Abbott RD, Petrovitch H, Morens DM, Grandinetti A, Tung KH, Tanner CM, Masaki KH, Blanchette PL, Curb JD, Popper JS, White LR.

Farmakol Toksikol 1983 Sep-Oct;46(5):107-11 [Use of the swimming test for demonstrating antidepressive activity of drugs during single and repeated administration]. [Article in Russian] Rusakov DIu, Val'dman AV. The use of the "swimming test" made it possible to identify the activity of tricyclic (desipramine, chlorimipramine, amitryptyline) and atypical antidepressants (befuralin, zimelidine, trazodon), that of pyrazidol (type A MAO inhibitor) and of a number of new compounds--derivatives of benzofuran and morpholine upon single and chronic administration. To define the method specificity, use was made of the neuroleptic haloperidol, the tranquilizer diazepam, and of nembutal, which did not exhibit any activity in the test in question. Psychostimulants (amphetamine, caffeine) dramatically increased the time of active swimming. The effect lasted throughout all the 30 minutes of testing, which is not characteristic for antidepressants.

Gen Pharmacol 1996 Jan;27(1):167-70 The influence of antagonists of poly(ADP-ribose) metabolism on acetaminophen hepatotoxicity. Kroger H, Ehrlich W, Klewer M, Gratz R, Dietrich A, Miesel R.

Ann Clin Lab Sci 1977 Jan-Feb;7(1):68-72. Effects of drugs on platelet function. Morse EE.

Thromb Haemost 1982 Apr 30;47(2):90-5. Effect of cAMP phosphodiesterase inhibitors on ADP-induced shape change, cAMP and nucleoside diphosphokinase activity of rabbit platelets. Lam SC, Guccione MA, Packham MA, Mustard JF.

Carcinogenesis 1998 Aug;19(8):1369-75. The coffee-specific diterpenes cafestol and kahweol protect against aflatoxin B1-induced genotoxicity through a dual mechanism. Cavin C, Holzhauser D, Constable A, Huggett AC, Schilter B.

Am J Epidemiol 1994 Apr 1;139(7):723-7. Coffee and serum gamma-glutamyltransferase: a study of self-defense officials in Japan. Kono S, Shinchi K, Imanishi K, Todoroki I, Hatsuse K.

Carcinogenesis 1996 Nov;17(11):2377-84 Placental glutathione S-transferase (GST-P) induction as a potential mechanism for the anti-carcinogenic effect of the coffee-specific components cafestol and kahweol. Schilter B, Perrin I, Cavin C, Huggett AC

J Nutr 1999 Jul;129(7):1361-7. Teas and other beverages suppress D-galactosamine-induced liver injury in rats. Sugiyama K, He P, Wada S, Saeki S

Nutr Cancer 1999;33(2):146-53. Effects of oral administration of tea, decaffeinated tea, and caffeine on the formation and growth of tumors in high-risk SKH-1 mice previously treated with ultraviolet B light. Lou YR, Lu YP, Xie JG, Huang MT, Conney AH.

Ind Health 2000 Jan;38(1):99-102. Effects of coffee consumption against the development of liver dysfunction: a 4-year follow-up study of middle-aged Japanese male office workers. Nakanishi N, Nakamura K, Suzuki K, Tatara K.

Ind Health 2000 Jan;38(1):99-102. Effects of coffee consumption against the development of liver dysfunction: a 4-year follow-up study of middle-aged Japanese male office workers. Nakanishi N, Nakamura K, Suzuki K, Tatara K. .

Biochim Biophys Acta 1992 Dec 15; 1175(1):114-22. Caffeine promotes survival of cultured sympathetic neurons deprived of nerve growth factor through a cAMP-dependent mechanism. Tanaka S, Koike T.

Int J Epidemiol 1998 Jun;27(3):438-43. Coffee consumption and decreased serum gamma-glutamyltransferase and aminotransferase activities among male alcohol drinkers. Tanaka K, Tokunaga S, Kono S, Tokudome S, Akamatsu T, Moriyama T, Zakouji H. . . . recent epidemiological studies have suggested unexpected, possibly beneficial effects of coffee against the occurrence of alcoholic liver cirrhosis and upon serum liver enzyme levels. Increased coffee consumption was strongly and independently associated with decreased GGT activity among males (P trend < 0.0001); the inverse association between coffee and serum GGT was more evident among heavier alcohol consumers (P < 0.0001), and was absent among non-alcohol drinkers. Similar inverse associations with coffee and interactions between coffee and alcohol intake were observed for serum aspartate aminotransferase and alanine aminotransferase. Intake of green tea, another popular source of caffeine in Japan, did not materially influence the liver enzyme levels. CONCLUSIONS: Our results suggest that coffee may inhibit the induction of GGT in the liver by alcohol consumption, and may possibly protect against liver cell damage due to alcohol.

Am J Hosp Pharm 1989 Oct;46(10):2059-67. Abuse of drugs used to enhance athletic performance. Wagner JC.

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<span class="koboSpan" id="kobo.1.1">Coconut Oil</span> A R T I C L E

Coconut Oil

I have already discussed the many toxic effects of the unsaturated oils, and I have frequently mentioned that coconut oil doesn't have those toxic effects, though it does contain a small amount of the unsaturated oils. Many people have asked me to write something on coconut oil. I thought I might write a small book on it, but I realize that there are no suitable channels for distributing such a book--if the seed-oil industry can eliminate major corporate food products that have used coconut oil for a hundred years, they certainly have the power to prevent dealers from selling a book that would affect their market more seriously. For the present, I will just outline some of the virtues of coconut oil.

The unsaturated oils in some cooked foods become rancid in just a few hours, even at refrigerator temperatures, and are responsible for the stale taste of left-over foods. (Eating slightly stale food isn't particularly harmful, since the same oils, even when eaten absolutely fresh, will oxidize at a much higher rate once they are in the body, where they are heated and thoroughly mixed with an abundance of oxygen.) Coconut oil that has been kept at room temperature for a year has been tested for rancidity, and showed no evidence of it. Since we would expect the small percentage of unsaturated oils naturally contained in coconut oil to become rancid, it seems that the other (saturated) oils have an antioxidative effect: I suspect that the dilution keeps the unstable unsaturated fat molecules spatially separated from each other, so they can't interact in the destructive chain reactions that occur in other oils. To interrupt chain-reactions of oxidation is one of the functions of antioxidants, and it is possible that a sufficient quantity of coconut oil in the body has this function. It is well established that dietary coconut oil reduces our need for vitamin E, but I think its antioxidant role is more general than that, and that it has both direct and indirect antioxidant activities.

Coconut oil is unusually rich in short and medium chain fatty acids. Shorter chain length allows fatty acids to be metabolized without use of the carnitine transport system. Mildronate, which I discussed in an article on adaptogens, protects cells against stress partly by opposing the action of carnitine, and comparative studies showed that added carnitine had the opposite effect, promoting the oxidation of unsaturated fats during stress, and increasing oxidative damage to cells. I suspect that a degree of saturation of the oxidative apparatus by short-chain fatty acids has a similar effect--that is, that these very soluble and mobile short-chain saturated fats have priority for oxidation, because they don't require carnitine transport into the mitochondrion, and that this will tend to inhibit oxidation of the unstable, peroxidizable unsaturated fatty acids.

When Albert Schweitzer operated his clinic in tropical Africa, he said it was many years before he saw any cases of cancer, and he believed that the appearance of cancer was caused by the change to the European type of diet. In the l920s, German researchers showed that mice on a fat-free diet were practically free of cancer. Since then, many studies have demonstrated a very close association between consumption of unsaturated oils and the incidence of cancer.

Heart damage is easily produced in animals by feeding them linoleic acid; this "essential" fatty acid turned out to be the heart toxin in rape-seed oil. The addition of saturated fat to the experimental heart-toxic oil-rich diet protects against the damage to heart cells.

Immunosuppression was observed in patients who were being "nourished" by intravenous emulsions of "essential fatty acids," and as a result coconut oil is used as the basis for intravenous fat feeding, except in organ-transplant patients. For those patients, emulsions of unsaturated oils are used specifically for their immunosuppressive effects.

General aging, and especially aging of the brain, is increasingly seen as being closely associated with lipid peroxidation.

Several years ago I met an old couple, who were only a few years apart in age, but the wife looked many years younger than her doddering old husband. She was from the Philippines, and she remarked that she always had to cook two meals at the same time, because her husband couldn't adapt to her traditional food. Three times every day, she still prepared her food in coconut oil. Her apparent youth increased my interest in the effects of coconut oil.

In the l960s, Hartroft and Porta gave an elegant argument for decreasing the ratio of unsaturated oil to saturated oil in the diet (and thus in the tissues). They showed that the "age pigment" is produced in proportion to the ratio of oxidants to antioxidants, multiplied by the ratio of unsaturated oils to saturated oils. More recently, a variety of studies have demonstrated that ultraviolet light induces peroxidation in unsaturated fats, but not saturated fats, and that this occurs in the skin as well as in vitro. Rabbit experiments, and studies of humans, showed that the amount of unsaturated oil in the diet strongly affects the rate at which aged, wrinkled skin develops. The unsaturated fat in the skin is a major target for the aging and carcinogenic effects of ultraviolet light, though not necessarily the only one.

In the l940s, farmers attempted to use cheap coconut oil for fattening their animals, but they found that it made them lean, active and hungry. For a few years, an antithyroid drug was found to make the livestock get fat while eating less food, but then it was found to be a strong carcinogen, and it also probably produced hypothyroidism in the people who ate the meat. By the late l940s, it was found that the same antithyroid effect, causing animals to get fat without eating much food, could be achieved by using soy beans and corn as feed.

Later, an animal experiment fed diets that were low or high in total fat, and in different groups the fat was provided by pure coconut oil, or a pure unsaturated oil, or by various mixtures of the two oils. At the end of their lives, the animals' obesity increased directly in proportion to the ratio of unsaturated oil to coconut oil in their diet, and was not related to the total amount of fat they had consumed. That is, animals which ate just a little pure unsaturated oil were fat, and animals which ate a lot of coconut oil were lean.

In the l930s, animals on a diet lacking the unsaturated fatty acids were found to be "hypermetabolic." Eating a "normal" diet, these animals were malnourished, and their skin condition was said to be caused by a "deficiency of essential fatty acids." But other researchers who were studying vitamin B6 recognized the condition as a deficiency of that vitamin. They were able to cause the condition by feeding a fat-free diet, and to cure the condition by feeding a single B vitamin. The hypermetabolic animals simply needed a better diet than the "normal," fat-fed, cancer-prone animals did.

G. W. Crile and his wife found that the metabolic rate of people in Yucatan, where coconut is a staple food, averaged 25% higher than that of people in the United States. In a hot climate, the adaptive tendency is to have a lower metabolic rate, so it is clear that some factor is more than offsetting this expected effect of high environmental temperatures. The people there are lean, and recently it has been observed that the women there have none of the symptoms we commonly associate with the menopause.

By l950, then, it was established that unsaturated fats suppress the metabolic rate, apparently creating hypothyroidism. Over the next few decades, the exact mechanisms of that metabolic damage were studied. Unsaturated fats damage the mitochondria, partly by suppressing the repiratory enzyme, and partly by causing generalized oxidative damage. The more unsaturated the oils are, the more specifically they suppress tissue response to thyroid hormone, and transport of the hormone on the thyroid transport protein.

Plants evolved a variety of toxins designed to protect themselves from "predators," such as grazing animals. Seeds contain a variety of toxins, that seem to be specific for mammalian enzymes, and the seed oils themselves function to block proteolytic digestive enzymes in the stomach. The thyroid hormone is formed in the gland by the action of a proteolytic enzyme, and the unsaturated oils also inhibit that enzyme. Similar proteolytic enzymes involved in clot removal and phagocytosis appear to be similarly inhibited by these oils.

Just as metabolism is "activated" by consumption of coconut oil, which prevents the inhibiting effect of unsaturated oils, other inhibited processes, such as clot removal and phagocytosis, will probably tend to be restored by continuing use of coconut oil.

Brain tissue is very rich in complex forms of fats. The experiment (around 1978) in which pregnant mice were given diets containing either coconut oil or unsaturated oil showed that brain development was superior in the young mice whose mothers ate coconut oil. Because coconut oil supports thyroid function, and thyroid governs brain development, including myelination, the result might simply reflect the difference between normal and hypothyroid individuals. However, in 1980, experimenters demonstrated that young rats fed milk containing soy oil incorporated the oil directly into their brain cells, and had structurally abnormal brain cells as a result.

Lipid peroxidation occurs during seizures, and antioxidants such as vitamin E have some anti-seizure activity. Currently, lipid peroxidation is being found to be involved in the nerve cell degeneration of Alzheimer's disease.

Various fractions of coconut oil are coming into use as "drugs," meaning that they are advertised as treatments for diseases. Butyric acid is used to treat cancer, lauric and myristic acids to treat virus infections, and mixtures of medium-chain fats are sold for weight loss. Purification undoubtedly increases certain effects, and results in profitable products, but in the absence of more precise knowledge, I think the whole natural product, used as a regular food, is the best way to protect health. The shorter-chain fatty acids have strong, unpleasant odors; for a couple of days after I ate a small amount of a medium-chain triglyceride mixture, my skin oil emitted a rank, goaty smell. Some people don't seem to have that reaction, and the benefits might outweigh the stink, but these things just haven't been in use long enough to know whether they are safe.

We have to remember that the arguments made for aspartame, monosodium glutamate, aspartic acid, and tryptophan--that they are like the amino acids that make up natural proteins--are dangerously false. In the case of amino acids, balance is everything. Aspartic and glutamic acids promote seizures and cause brain damage, and are intimately involved in the process of stress-induced brain aging, and tryptophan by itself is carcinogenic. Treating any complex natural product as the drug industry does, as a raw material to be fractionated in the search for "drug" products, is risky, because the relevant knowledge isn't sought in the search for an association between a single chemical and a single disease.

While the toxic unsaturated paint-stock oils, especially safflower, soy, corn and linseed (flaxseed) oils, have been sold to the public precisely for their drug effects, all of their claimed benefits were false. When people become interested in coconut oil as a "health food," the huge seed-oil industry--operating through their shills--are going to attack it as an "unproved drug."

While components of coconut oil have been found to have remarkable physiological effects (as antihistamines, antiinfectives/antiseptics, promoters of immunity, glucocorticoid antagonist, nontoxic anticancer agents, for example), I think it is important to avoid making any such claims for the natural coconut oil, because it very easily could be banned from the import market as a "new drug" which isn't "approved by the FDA." We have already seen how money and propaganda from the soy oil industry eliminated long-established products from the U.S. market. I saw people lose weight stably when they had the habit of eating large amounts of tortilla chips fried in coconut oil, but those chips disappeared when their producers were pressured into switching to other oils, in spite of the short shelf life that resulted in the need to add large amounts of preservatives. Oreo cookies, Ritz crackers, potato chip producers, and movie theater popcorn makers have experienced similar pressures.

The cholesterol-lowering fiasco for a long time centered on the ability of unsaturated oils to slightly lower serum cholesterol. For years, the mechanism of that action wasn't known, which should have suggested caution. Now, it seems that the effect is just one more toxic action, in which the liver defensively retains its cholesterol, rather than releasing it into the blood. Large scale human studies have provided overwhelming evidence that whenever drugs, including the unsaturated oils, were used to lower serum cholesterol, mortality increased, from a variety of causes including accidents, but mainly from cancer.

Since the l930s, it has been clearly established that suppression of the thyroid raises serum cholesterol (while increasing mortality from infections, cancer, and heart disease), while restoring the thyroid hormone brings cholesterol down to normal. In this situation, however, thyroid isn't suppressing the synthesis of cholesterol, but rather is promoting its use to form hormones and bile salts. When the thyroid is functioning properly, the amount of cholesterol in the blood entering the ovary governs the amount of progesterone being produced by the ovary, and the same situation exists in all steroid-forming tissues, such as the adrenal glands and the brain. Progesterone and its precursor, pregnenolone, have a generalized protective function: antioxidant, anti-seizure, antitoxin, anti-spasm, anti-clot, anti-cancer, pro-memory, pro-myelination, pro-attention, etc. Any interference with the formation of cholesterol will interfere with all of these exceedingly important protective functions.

As far as the evidence goes, it suggests that coconut oil, added regularly to a balanced diet, lowers cholesterol to normal by promoting its conversion into pregnenolone. (The coconut family contains steroids that resemble pregnenolone, but these are probably mostly removed when the fresh oil is washed with water to remove the enzymes which would digest the oil.) Coconut-eating cultures in the tropics have consistently lower cholesterol than people in the U.S. Everyone that I know who uses coconut oil regularly happens to have cholesterol levels of about 160, while eating mainly cholesterol rich foods (eggs, milk, cheese, meat, shellfish). I encourage people to eat sweet fruits, rather than starches, if they want to increase their production of cholesterol, since fructose has that effect.

Many people see coconut oil in its hard, white state, and--as a result of their training watching television or going to medical school--associate it with the cholesterol-rich plaques in blood vessels. Those lesions in blood vessels are caused mostly by lipid peroxidation of unsaturated fats, and relate to stress, because adrenaline liberates fats from storage, and the lining of blood vessels is exposed to high concentrations of the blood-borne material. In the body, incidentally, the oil can't exist as a solid, since it liquefies at 76 degrees. (Incidentally, the viscosity of complex materials isn't a simple matter of averaging the viscosity of its component materials; cholesterol and saturated fats sometimes lower the viscosity of cell components.)

Most of the images and metaphors relating to coconut oil and cholesterol that circulate in our culture are false and misleading. I offer a counter-image, which is metaphorical, but it is true in that it relates to lipid peroxidation, which is profoundly important in our bodies. After a bottle of safflower oil has been opened a few times, a few drops that get smeared onto the outside of the bottle begin to get very sticky, and hard to wash off. This property is why it is a valued base for paints and varnishes, but this varnish is chemically closely related to the age pigment that forms "liver spots" on the skin, and similar lesions in the brain, heart, blood vessels, lenses of the eyes, etc. The image of "hard, white saturated coconut oil" isn't relevant to the oil's biological action, but the image of "sticky varnish-like easily oxidized unsaturated seed oils" is highly relevant to their toxicity.

The ability of some of the medium chain saturated fatty acids to inhibit the liver's formation of fat very likely synergizes with the pro-thyroid effect, in allowing energy to be used, rather than stored. When fat isn't formed from carbohydrate, the sugar is available for use, or for storage as glycogen. Therefore, shifting from unsaturated fats in foods to coconut oil involves several anti-stress processes, reducing our need for the adrenal hormones. Decreased blood sugar is a basic signal for the release of adrenal hormones. Unsaturated oil tends to lower the blood sugar in at least three basic ways. It damages mitochondria, causing respiration to be uncoupled from energy production, meaning that fuel is burned without useful effect. It suppresses the activity of the respiratory enzyme (directly, and through its anti-thyroid actions), decreasing the respiratory production of energy. And it tends to direct carbohydrate into fat production, making both stress and obesity more probable. For those of us who use coconut oil consistently, one of the most noticeable changes is the ability to go for several hours without eating, and to feel hungry without having symptoms of hypoglycemia.

One of the stylish ways to promote the use of unsaturated oils is to refer to their presence in "cell membranes," and to claim that they are essential for maintaining "membrane fluidity." As I have mentioned above, it is the ability of the unsaturated fats, and their breakdown products, to interfere with enzymes and transport proteins, which accounts for many of their toxic effects, so they definitely don't just harmlessly form "membranes." They probably bind to all proteins, and disrupt some of them, but for some reason their affinity for proteolytic and respiration-related enzymes is particularly obvious. (I think the chemistry of this association is going to give us some important insights into the nature of organisms.

Metchnikof's model that I have discussed elsewhere might give us a picture of how those factors relate in growth, physiology, and aging.) Unsaturated fats are slightly more water-soluble than fully saturated fats, and so they do have a greater tendency to concentrate at interfaces between water and fats or proteins, but there are relatively few places where these interfaces can be usefully and harmlessly occupied by unsaturated fats, and at a certain point, an excess becomes harmful. We don't want "membranes" forming where there shouldn't be membranes. The fluidity or viscosity of cell surfaces is an extremely complex subject, and the degree of viscosity has to be appropriate for the function of the cell. Interestingly, in some cells, such as the cells that line the air sacs of the lungs, cholesterol and one of the saturated fatty acids found in coconut oil can increase the fluidity of the cell surface.

In many cases, stressful conditions create structural disorder in cells. These influences have been called "chaotropic," or chaos-producing. In red blood cells, which have sometimes been wrongly described as "hemoglobin enclosed in a cell membrane," it has been known for a long time that lipid peroxidation of unsaturated fats weakens the cellular structure, causing the cells to be destroyed prematurely. Lipid peroxidation products are known to be "chaotropic," lowering the rigidity of regions of cells considered to be membranes. But the red blood cell is actually more like a sponge in structure, consisting of a "skeleton" of proteins, which (if not damaged by oxidation) can hold its shape, even when the hemoglobin has been removed. Oxidants damage the protein structure, and it is this structural damage which in turn increases the "fluidity" of the associated fats.

So, it is probably true that in many cases the liquid unsaturated oils do increase "membrane fluidity," but it is now clear that in at least some of those cases the "fluidity" corresponds to the chaos of a damaged cell protein structure. (N. V. Gorbunov, "Effect of structural modification of membrane proteins on lipid-protein interactions in the human erythrocyte membrane," Bull. Exp. Biol. & Med. 116(11), 1364-67. 1993.

Although I had stopped using the unsaturated seed oils years ago, and supposed that I wasn't heavily saturated with toxic unsaturated fat, when I first used coconut oil I saw an immediate response, that convinced me my metabolism was chronically inhibited by something that was easily alleviated by "dilution" or molecular competition. I had put a tablespoonful of coconut oil on some rice I had for supper, and half an hour later while I was reading, I noticed I was breathing more deeply than normal. I saw that my skin was pink, and I found that my pulse was faster than normal--about 98, I think. After an hour or two, my pulse and breathing returned to normal. Every day for a couple of weeks I noticed the same response while I was digesting a small amount of coconut oil, but gradually it didn't happen any more, and I increased my daily consumption of the oil to about an ounce. I kept eating the same foods as before (including a quart of ice cream every day), except that I added about 200 or 250 calories per day as coconut oil. Apparently the metabolic surges that happened at first were an indication that my body was compensating for an anti-thyroid substance by producing more thyroid hormone; when the coconut oil relieved the inhibition, I experienced a moment of slight hyperthyroidism, but after a time the inhibitor became less effective, and my body adjusted by producing slightly less thyroid hormone. But over the next few months, I saw that my weight was slowly and consistently decreasing. It had been steady at 185 pounds for 25 years, but over a period of six months it dropped to about 175 pounds. I found that eating more coconut oil lowered my weight another few pounds, and eating less caused it to increase.

The anti-obesity effect of coconut oil is clear in all of the animal studies, and in my friends who eat it regularly. It is now hard to get it in health food stores, since Hain stopped selling it. The Spectrum product looks and feels a little different to me, and I suppose the particular type of tree, region, and method of preparation can account for variations in the consistency and composition of the product. The unmodified natural oil is called "76 degree melt," since that is its natural melting temperature. One bottle from a health food store was labeled "natural coconut oil, 92% unsaturated oil," and it had the greasy consistency of old lard. I suspect that someone had confused palm oil (or something worse) with coconut oil, because it should be about 96% saturated fatty acids.

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<span class="koboSpan" id="kobo.1.1">Diabetes, scleroderma, oils and hormones</span> A R T I C L E

Diabetes, scleroderma, oils and hormones

The basic argument: Stress and aging make cells less responsive in many ways by damaging their ability to produce energy and to adapt. The polyunsaturated fats are universally toxic to the energy producing system, and act as a "misleading signal" channeling cellular adaptation down certain self-defeating pathways. Diabetes is just one of the "terminal" diseases that can be caused by the polyunsaturated vegetable oils. Coconut oil, in diabetes as in other degenerative diseases, is highly protective.

When the oral contraceptive pill was new (Enovid), it was found to produce signs of diabetes, including decreased glucose tolerance. Spellacy and Carlson (1966) suggested that an elevation of circulating free fatty acids might be responsible, and remarked that "Free fatty acids can block the Krebs cycle, with relative insulin action resistance resulting." "The potential danger of the oral contraceptives is one of prolonged pancreatic stimulation." Recent papers are reporting that the estrogen used to "treat menopause" causes an increase in free fatty acids. Spellacy and Carlson suggested that estrogen's effect was mediated by growth hormone, and that is now the consensus. Women are much more likely than men to develop diabetes.

Ephraim Racker observed that free unsaturated fatty acids inhibit mitochondrial respiration, and recent studies are finding that free linoleic and linolenic acids act as intracellular regulators, stimulating the protein kinase C (PKC) system, which is also stimulated by estrogen and the (cancer promoting) phorbol esters. They stimulate the cell while blocking the energy it needs to respond.

Scleroderma, or systemic sclerosis, is a supposedly mysterious condition in which tissues harden, with an excessive deposition of fibrous material. Besides hardening the skin, it can involve fibrosis of the heart and other organs, and can cause changes in blood vessels of the kidneys like those seen in some types of hypertension, and often involves Raynaud's phenomenon and osteoporosis of the fingers. (Silicone functions as an adjuvant, making exposure to irritants, solvents or infections more harmful. This seems to be the reason for the association between breast implants and scleroderma.) Another type of disease that involves hardening of the skin is scleredema, in which the skin thickens with an accumulation of "mucin" between collagen bundles, and in which fibroblasts are overactive in producing collagen. (Varga, et al.) This condition is believed to often follow a "febrile illness" and is associated with diabetes. My interest in these conditions comes from my awareness that estrogen promotes collagen formation, and that changes in the connective tissue are deeply associated with the processes of stress and aging, following the ideas of Metchnikov and Selye.

Many people are still committed to the various old theories of diabetes, though a few are showing ways in which multiple causes can lead to diabetes. Increasingly, old age itself is seen to be "like diabetes (Meneilly, et al.; Smith, et al.), and the situation is ripe for a recentering of our understanding of diabetes around some of the general facts about aging and stress.

Diabetes mellitus, as named, refers to excessive urination and sugary urine, but it is now often diagnosed in people who neither urinate excessively nor pass glucose in the urine, on the basis of a high level of glucose in the blood. Many other signs (abnormal mucopolysaccharide metabolism with thickening of basement membranes, leakage of albumin through capillary walls and into the urine, a high level of free fatty acids in the blood, insensitivity of tissues to insulin, or reduced sensitivity of the beta cells to glucose) are considered diagnostic by some people, who believe that the worst aspects of the disease can be prevented if they can diagnose early and take preventive measures. This attitude derives largely from the genetic theory of causation, though it incorporates a belief that (environmental) intervention can ameliorate the course of the disease. When I wrote Nutrition for Women, I mentioned that the sudden appearance of diabetes in non-European Jews when they moved to Isreal made the genetic theory of diabetes untenable, and since then other studies have made the similar point that environmental factors seem crucial. (Shaltout, et al.) Many people are arguing for the racial/genetic theory of diabetes, but they are failing to consider some simple dietary factors, especially the high consumption of unsaturated seed oils and the combination of nutritional deficiencies and environmental stress.

I have known adults and children who were diagnosed as diabetic, and given insulin (and indoctrinated with the idea that they had a terminal degenerative disease) on the strength of a single test showing excessive glucose. When I taught at the naturopathic medical school in Portland, I tried to make it clear that "diabetes" (a term referring to excessive urination) is a function, and that a high level of glucose in the blood or urine is also a function, and that the use of insulin should require a greater diagnostic justification than the use of aspirin for a headache does, because insulin use itself constitutes a serious health problem. (And we seldom hear the idea that "diabetes" might have a positive side [Robinson and Johnston], for example that it reduces the symptoms of asthma [Vianna and Garcialeme], which get worse when insulin is given. Normal pregnancy can be considered "diabetic" by some definitions based on blood sugar. I got interested in this when I talked to a healthy "diabetic" woman who had a two year old child whose IQ must have been over 200, judging by his spontaneous precocious hobbies. Old gynecologists told me that it was common knowledge that "diabetic" women had intellectually precocious children.)

When non-diabetic apes were given insulin treatments, they developed some of the same "complications of diabetes" that are seen in humans, and antibodies to insulin were found in their retinas, suggesting that some "complications of diabetes" were complications of insulin treatment. Patients were seldom well informed of the arguments against the use of insulin, but the justification for the new genetically engineered human insulin is precisely that it avoids immunological damage.

Insulin was introduced into medicine in the 1920s. According to the Britannica Book of the Year for 1947, page 265, "Mortality from diabetes in 1920 in the United States was 16.0 per 100,000, 14,062 deaths, but in 1944, it was 26.4 per 100,000, 34,948 deaths."

One of the theories of the cause of diabetes is that a virus damages the beta cells in the pancreas, and the main argument for that in the 1970s was that the onset of diabetes in children can often be dated to a time shortly after a severe viral infection. It is true that intense sickness and a high fever (and high doses of drugs given to treat the sickness) can cause very high levels of glucose in the blood, and even glucose in the urine, but this is a fairly well recognized consequence of stress. High doses of cortisone (prednisone, etc.) typically cause elevated glucose levels. Cushing's syndrome usually involves hyperglycemia. Normally, this is just a functional response to an excess of glucocorticoids, but studies in dogs suggested that intense and/or prolonged stress can damage the insulin-secreting cells in the pancreas. Dogs had half of their pancreas removed, to increase the burden put on the remaining tissue, and after a large dose of cortisone the dogs became (and remained) diabetic.

One of the problems associated with diabetes is the calcification of blood vessels, though now there is more emphasis on fatty degeneration. Other blood vessel problems include hypertension, and poor circulation in general, leading to gangrene of the feet, impotence, and degeneration of the retina. In muscles, and probably in other tissues of diabetics, capillaries are more widely spaced, as if the basal oxidative requirement were lower than normal. However, mitochondria contain more respiratory enzymes, as if to partly compensate for the poor delivery of oxygen to the cells. Osteoporosis or osteopenia is a common complication of diabetes, and seems to be associated with the calcification of soft tissues.

F. Z. Meerson's description of the stress-injured heart is very similar to the general changes that occur in chronic diabetes. He found that the stressed heart becomes rigid and unable to contract completely, or to relax completely. Excess calcium enters cells, and fatty acids are mobilized both locally and systemically, and both of these tend to damage the mitochondria. In diabetes, fatty acids are mobilized and oxidized instead of glucose, and calcium enters cells, increasing their rigidity and preventing relaxation of muscles in blood vessels. (I'm not sure whether it is relevant to cell physiology, but the presence of an excess of free unsaturated fatty acids, and of calcium, in cells makes me think of the insoluble soap that these substances form in other situations, including the intestine. It seems that this could form a harmful deposit in cells, blocking many metabolic processes.)

For many years, histologists have observed that calcium and iron tend to be deposited together in "devitalized" tissues. Now we know that cell death from a great variety of causes involves the cell's absorption of increased amounts of calcium. Simply the lack of energy increases the amount of calcium in a cell, and stimulation or excitation does the same, creating or exaggerating a deficiency of energy. In low thyroid people, many (if not all) tissues are very easily damaged. Since glucose is needed by liver cells to produce the active (T3) form of thyroid, diabetes almost by definition will produce hypothyroidism, since in diabetes glucose can't be absorbed efficiently by cells.

In the form of cell damage caused by the "excitotoxins," glutamic and aspartic acids, the damage seems to require both stimulation, and difficulty in maintaining adequate energy production. This combination leads to both calcium uptake and lipid peroxidation. When cells are de-energized, they tend to activate iron by chemical reduction, producing lipid peroxidation. This could explain the presence of chemically active iron, but an actual increase in the iron concentration suggests that there has been prolonged injury (oxidative stress) to the cell, with increased production of the heme group, which binds iron.

Hans Selye found that he could produce scleroderma (hardening and calcification of the skin) in rats by giving them a toxic dose of a heavy metal, and then irritating the skin a little by plucking hair. Iron is now tending to be recognized as a factor in inflammation. Vitamin E was able to prevent the development of scleroderma under Selye's experimental conditions, suggesting that the irritation allowed the heavy metal to cause oxidative damage to the skin. Selye found other ways to cause calcification of tissues, including the walls of arteries, but he directed most of his attention to the role of "pro-inflammatory" hormones. A decreased blood supply was often used to predispose an organ to calcification. In diabetes, a characteristic feature is that the blood supply is relatively remote from cells in muscle and skin, so the oxygen and nutrients have to diffuse farther than in normal individuals, and the ATP level of cells is characteristically lower than normal. In blood cells, both red (Garnier, et al.) and white cells are probably more rigid in diabetes, because of lower ATP production, and higher intracellular calcium and sodium.

Magnesium in the cell is largely associated with ATP, as the complex Mg-ATP. When ATP is "used" or converted to ADP, this lower-energy substance associates with calcium, as Ca-ADP. In a hypothyroid state, the energy charge can be depleted by stress, causing cells to lose magnesium. ATP is less stable when it isn't complexed with magnesium, so the stress-induced loss of magnesium makes the cell more susceptible to stress, by acting as a chronic background stimulation, forcing the cell to replace the ATP which is lost because of its instability. In this state, the cell takes up an excess of calcium.

The picture that I think explains many of the features of diabetes is that an energy deficit produces an alarm state, causing increased production of adrenalin and cortisol. Adrenalin mobilizes fat from storage, and the free fatty acids create a chronic problem involving 1) blocked ATP production, 2) activation of the protein kinase C system (increasing tension in blood vessels), 3) inhibition of thyroid function with its energetic, hormonal, and tissue-structure consequences, 4) availability of fats for prostaglandin synthesis, and 5) possibly a direct effect on clot dissolving, besides the PAI-1 (plasminogen activator inhibitor) effect seen in diabetes (Ceriello, et al., Udvardy, et al., Vague, et al.). (Estrogen has many pro-clotting effects, and one of them is a decreased activity of vascular plasminogen activator. K. E. Miller and S. V. Pizzo, "Venous and arterial thromboembolic disease in women using oral contraceptives," Am. J. Obst. Gyn. 144, 824, 1982. In 1968, D. G. Daniel et al., reported that estrogen promotes thromboembolism by increasing clotting factor IX in the blood.)

Increased entry of calcium into cells is complexly related to increased exposure to unsaturated fatty acids, decreased energy, and lipid peroxidation. Osteoporosis, calcification of soft tissues and high blood pressure are promoted by multiple stresses, hypothyroidism, and magnesium deficiency. The particular direction a disease takes--diabetes, scleroderma, lupus, Alzheimer's, stroke, etc.--probably results from the balance between resources and demands within a particular organ or system. Calcium overload of cells can't be avoided by avoiding dietary calcium, because the bones provide a reservoir from which calcium is easily drawn during stress. (In fact, the reason calcium can temporarily help prevent muscle cramps seems to be that it makes magnesium more available to the muscles.)

If we want to stop a disease that involves abnormal calcification or contraction of muscle (see Zenere, et al.), we can increase our consumption of magnesium, and to cause cells to absorb and retain the magnesium, we can increase our thyroid function. The use of coconut oil provides energy to stabilize blood sugar while protecting mitochondria and the thyroid system from the harmful effects of unsaturated fats.

In 1947, B. A. Houssay found that a diet based on sugar as a source of energy was more protective against diabetes than a diet based on lard, while the most protective diet was based on coconut oil. Lard reflects the pigs' diet, and is usually extremely unsaturated, especially since it became standard to fatten them on soybeans and corn. Essentially, his study seems to show that unsaturated (pork) fat permits diabetes to develop, sugar is slightly protective, and coconut oil is very protective against the form of diabetes caused by a poison.

At the same time, A. Lazarow was demonstrating that a low protein diet made animals more sensitive to diabetes, and that cysteine, glutathione, and thioglycolic acid (antioxidants) are protective against diabetes. The chelator of metals, BAL (British anti-lewisite), was also found to protect against diabetes.

Taken together, those studies suggest that the oxidizable unsaturated fats are involved in the process of producing diabetes. At the same time, other studies were showing that the unsaturated oils suppress the thyroid, and that coconut oil increases the metabolic rate, apparently by normalizing thyroid function. Hypothyroidism is known to include deposition of mucopolysaccharides in tissues, increased permeability of capillaries with leakage of albumin out of the blood, elevated adrenalin which can lead to increased production of cortisol, decreased testosterone production, high risk of heart and circulatory disease, including a tendency to ulceration of the extremities, and osteoporosis, all of which are recognized "complications of diabetes." Broda Barnes gave all of his diabetic patients a thyroid supplement, and found that none of them developed the expected complications of diabetes.

Recently, a high safflower oil diet was found to cause diabetes (Ikemoto, et al.), and obesity itself is thought to be a factor in developing diabetes. The hormone patterns associated with obesity can be seen as either cause or effect of the obesity (or both cause and effect), since, for example, low thyroid can increase both estrogen and cortisol, which support the formation of fat, and the fat cells can become a chronic source of estrogen synthesis.

On a diet lacking the "essential" unsaturated fatty acids, Benhamou (1995) found that nonobese diabetic mice didn't develop diabetes, that is, the unsaturated fats themselves, without obesity, are sufficient to cause diabetes. (Also see Girard; Golay, et al., and Kusunoki, et al.)

Estrogen and the polyunsaturated fatty acids (PUFA), linoleic and linolenic acid, alike activate the protein kinase C (PKC) system of cellular activation. Many of the functions of PUFA are similar to the functions of estrogen (e.g., antagonism to thyroid function, promotion of age pigment/lipofuscin), so this information showing that they both act similarly on the same basic regulatory pathway is important. Estrogen increases secretion of growth hormone (GH; it's closely associated with prolactin, also increased by estrogen), and GH causes an increase in free fatty acids in the blood. Estrogen promotes iron retention, so it sets the stage for oxidative stress. At least in some systems, both estrogen and PUFA promote the entry of calcium into the cell.

In diabetes, there is a generalized excess activation of the PKC system. The starch-based diet, emphasizing grains, beans, nuts, and vegetables, has been promoted with a variety of justifications. When people are urged to reduce their fat and sugar consumption, they are told to eat more starch. Starch stimulates the appetite, promotes fat synthesis by stimulating insulin secretion, and sometimes increases the growth of bacteria that produce toxins. It is often associated with allergens, and according to Gerhard Volkheimer, whole starch grains can be "persorbed" from the intestine directly into the blood stream where they may block arterioles, causing widely distributed nests of cell-death. I have heard dietitians urge the use of "complex carbohydrates" (starch) instead of sugar. In the first physiology lab I took, we fed rats a large blob of moist cornstarch with a stomach tube, and then after waiting a few minutes, were told to dissect the rat to find out "how far the starch had gone." In such a short time, we were surprised to find that not a trace of the starch could be found. The professor's purpose was to impress us with the rapidity with which starch is digested and absorbed. Various studies have demonstrated that starch (composed of pure glucose) raises blood glucose more quickly than sucrose (half fructose, half glucose) does. The sudden increase of blood glucose is sometimes thought to contribute to the development of diabetes, but if it does, it is probably mediated by fat metabolism and the hormones other than just insulin.

Brewer's yeast has been used successfully to treat diabetes. In the l930s, my father had severe diabetes, but after a few weeks of living on brewer's yeast, he recovered and never had any further evidence of diabetes. Besides its high B-vitamin and protein content, yeast is an unusual food that should be sparingly used, because of its high phosphorous/calcium ratio, high potassium to sodium ratio, and high estrogen content. The insulin-producing beta cells of the pancreas have estrogen receptors, but I don't know of any new research investigating this aspect of yeast therapy. In rabbit studies, diabetes produced by alloxan poisoning, which kills the beta cells, was cured by DHEA treatment, and beta cells were found to have regenerated in the pancreatic islets.

I think the basic anti-aging diet is also the best diet for prevention and treatment of diabetes, scleroderma, and the various "connective tissue diseases." This would emphasize high protein, low unsaturated fats, low iron, and high antioxidant consumption, with a moderate or low starch consumption. In practice, this means that a major part of the diet should be milk, cheese, eggs, shellfish, fruits and coconut oil, with vitamin E and salt as the safest supplements. It should be remembered that amino acids, especially in eggs, stimulate insulin secretion, and that this can cause hypoglycemia, which in turn causes cortisol secretion. Eating fruit (or other carbohydrate), coconut oil, and salt at the same meal will decrease this effect of the protein. Magnesium carbonate and epsom salts can also be useful and safe supplements, except when the synthetic material causes an allergic bowel reaction..

Although I started this newsletter with the thought of discussing the Mead acids--the unsaturated (n-9) fats that are formed under certain conditions, especially when the dietary polyunsaturated fatty acids are "deficient"--and their prostaglandin derivatives as a distinct anti-stress, anti-aging system, the loss of which makes us highly susceptible to injury, I will save that argument for a future time, leaving this newsletter as an addition to the view that an excess of the polyunsaturated fats is central to the development of degenerative diseases: Cancer, heart disease, arthritis, immunodeficiency, diabetes, hypertension, osteoporosis, connective tissue disease, and calcification.

REFERENCES WITH EXCERPTS AND COMMENTS

A. A. Alzaid, et al., "Effects of insulin on plasma magnesium in noninsulin-dependent diabetes mellitus: Evidence for insulin resistance," J. of Clin. Endocr. and Metab. 80(4), 1376-1381, 1995. "...insulin resistance in subjects with NIDDM impairs the ability of insulin to stimulate magnesium as well as glucose uptake."

A. B. Akella, et al., "Diminished Ca++ sensitivity of skinned cardiac muscle contractility coincident with troponin T-band shifts in the diabetic rat," Circulation Research 76(4), 600-606, 1995.D. A. Antonetti, et al., "Increased expression of mitochondrial-encoded genes in skeletal muscle of humans with diabetes mellitus--Rapid publication," J. of Clinical Investigation 95(3), 1383-1388, 1995. "The increased mitochondrial gene expression may contribute to the increase in mitochondrial respiration observed in uncontrolled diabetes." (Low ATP with high respiration would suggest uncoupling; unsaturated fatty acids are known uncouplers of respiration from energy production.)

S. Asakuma, et al., "The effects of antianginal drugs on energy expernditure during exercise in normal subjects," Japanese Circulation Journal--English Edition 59(3), 137-145, 1995. "RQ (carbohydrate consumption relative to fat consumption) during exercise was significantly increased and VO2 was decreased after propranolol, metoprolol and amosulalol." "These data suggest that propranolol, metoprolol and amosulalol [beta-blockers] increase the efficiency of energy expenditure during ordinary physical activity by increasing the utilization of carbohydrate and by decreasing the utilization of fat."

M. Bardicef, et al., "Extracellular and intracellular magnesium depletion in pregnancy and gestational diabetes," Amer. J. of Obst. and Gyn. 172(3), 1009-1013, 1995.

P. E. Beales, et al., "Baclofen, a gamma-aminobutyric acid-b receptor agonist, delays diabetes onset in the non-obese diabetic mouse," Acta Diabetologica 32(1), 53-56, 1995.

P. Y. Benhamou, et al., :"Essential fatty acid deficiency prevents autoimmune diabetes in nonobese diabetic mice through a positive impact on antigen-presenting cells and Th2 lymphocytes," Pancreas 11(1), 26-37, 1995.

C. D. Berdanier, "Diet, autoimmunity, and insulin-dependent diabetes mellitus: A controversy," Proc. Soc. Exp. Biol. Med. 209(3), 223-230, 1995. "The majority of the genetic mutations that result in the phenotypic expression of the insulin-dependent diabetes mellitus genotype are in the immune system." Antibodies to milk protein can be found in the patient, but these probably represent antigen mimicry, resulting from the loss of antibody specificity which is a feature of autoimmune disease.

G. Bianchi, et al., "Thyroid volume in type 1 diabetes patients without overt thyroid disease," Acta Diabetologica 32(1), 49-52, 1995. "An association between insulin-dependent diabetes mellitus (type 1) and thyroid diseases has long been reported...."

P. Bjorntorp, "Insulin resistance: The consequence of a neuroendocrine disturbance?" Int. J. Obes. 19(Suppl. 1), S6-S10, 1995. "The decreased capillary density may...be of importance for the apparent insulin resistance."

R. Bouillon, et al., "Influence of age, sex, and insulin on osteoblast function: Osteoblast dysfunction in diabetes mellitus," J. of Clin. Endocr. and Metab. 80(4), 1194-1202, 1995. "...the osteoblast function is significantly decreased in diabetic patients...."

A. Ceriello, et al., "The defence against free radicals protects endothelial cells from hyperglycaemia-induced plasminogen activator inhibitor 1 over-production," Blood Coagulation & Fibrinolysis 6(2), 133-137, 1995. "The hypothesis that oxidative stress may play an important role in the pathogenesis of diabetic complications is ... supported by this study." [GSH reduced PAI-1.]

V. Coiro, et al., "Low-dose ovine corticotropin-releasing hormone stimulation test in diabetes mellitus with or without neuropathy," Metabolism--Clinical and Experimental 44(4), 538-542, 1995. "...basal and CRH-induced cortisol levels were significantly higher in diabetics than in normal controls." "...even uncomplicated diabetes mellitus is associated with adrenal hyperfunction."

S. R. Colberg, et al., "Skeletal muscle utilization of free fatty acids in women with visceral obesity," J. Clin. Invest. 95(4), 1846-1853, 1995. "Visceral obesity is strongly associated with insulin resistance." "...visceral adiposity is clearly associated with skeletal muscle insulin resistance but this is not due to glucose-FFA [free fatty acid] substrate competition. Instead, women with visceral obesity have reduced postabsorptive FFA utilization by muscle."

G. A. Colditz, et al., "Weight gain as a risk factor for clinical diabetes mellitus in women," Annals of Internal Medicine 122(7), 481-486, 1995.

C. Douillet and M. Ciavatti, "Effect of vitamin E treatment on tissue fatty acids and cholesterol content in experimental diabetes," J. Nutr. Biochem. 6(6), 319-326, 1995. "Diabetes induced a decrease of monounsaturated fatty acids and particularly palmitoleic acid in all studied tissues: liver, aorta, plasma." C18:3 n-6 and C20:4 n-6 were increased by diabetes.

M. Garnier, et al., "Red blood cell sodium conent in NID diabetic patients with hemorheological abnormalities," Clinical Hemorheology 15(3), 325-333, 1995.

K. D. Gerbitz, et al., "Mitochondrial diabetes mellitus: A review," BBA--Mol. Basis Dis. 1271(1), 253-260, 1995. This particular kind of diabetes, which is combined with deafness in 60% of the patients, involves a variant mitochondrial gene and occurs in about 1.5% of diabetics. "The underlying pathomechanism is probably a delayed insulin secretion due to an impaired mitochondrial ATP production in consequence of the mtDNA defect." To know the "causal" value of this gene we have to know how often it occurs in people who never develop diabetes. It is interesting that it is suggested to operate by way of impaired ATP production, which can be the result of so many factors, such as excess unsaturated fats, low thyroid, low magnesium, low copper, etc. Pages 141-151 of the same journal as an article by D. C. Wallace, et al., "Mitochondrial DNA mutations in human degenerative diseases and aging," which makes the point that "Generally, individuals inheriting these mitochondrial diseases are relatively normal in early life, develop symptoms during childhood, mid-life, or old age depending on the severity of the ... mutation; and then undergo a progressive decline." Their energy-producing systems are supposedly more susceptible to the effects of aging.

J. Girard, "Role of free fatty acids in insulin resistance of subjects with non-insulin-dependent diabetes," Diabetes Metab. 21(2), 79-88, 1995. "Studies performed in the rat suggest that impaired glucose-induced insulin secretion could also be related to chronic exposure of pancreatic beta cells to elevated plasma free fatty acid levels." [This direct effect of free fatty acids on the beta cells is extremely important. Estrogen--probably via GH--increases free fatty acids, and adrenalin--which is elevated in hypothyroidism--increases the release of free fatty acids from storage. Free fatty acids impair mitochondrail energy production.]

A. Golay, et al., "Effect of lipid oxidation on the regulation of glucose utilization in obese patients," Acta Diabetologica 32(1), 44-48, 1995. [Free fatty acids strongly and quickly depress the ability to oxidize or store glucose.]

A. Gomes, et al., "Anti-hyperglycemic effect of black tea (Camellia sinensis) in rat," J. of Ethnopharmacology 45(3), 223-226, 1995. It "was found to possess both preventive and curative effects on experimentally produced diabetes in rats."

Y. Hattori, et al., "Phorbol esters elicit Ca++-dependent delayed contractions in diabetic rat aorta," Eur. J. Pharmacol. 279(1), 51-58, 1995. [Diabetic tissue is more responsive to activation of protein kinase C by phorbol esters.]

B. A. Houssay and C. Martinez, "Experimental diabetes and diet," Science 105, 548-549, 1947. [Mortality was zero on the high coconut oil diet, 100% on the high lard diet. It was 90% on the low protein diet, and 33% on the high protein diet. With a combination of coconut oil and lard, 20%.]

B. A. Houssay, et al., "Accion de la administracion prolongada de glucosa sobre la diabetes de la rata," Rev. Soc. argent. de biol. 23, 288-293, 1947.

S. Ikemoto, et al., "High fat diet-induced hyperglycemia: Prevention by low level expression of a glucose transporter (GLUT4) minigene in transgenic mice," Proc. Nat. Acad. Sci. USA 92(8), 3096-3099, 1995. "...mice fed a high-fat (safflower oil) diet develop defective glycemic control, hyperglycemia, and obesity."

M. Inaba, et al., "Influence of high glucose on 1,25-dihydroxyvitamin D-3-induced effect on human osteoblast-like MG-63 cells," J. Bone Miner. Res. 10(7), 1050-1056, 1995.

J. S. Jensen, et al., "Microalbuminuria reflects a generalized transvascular albumin leakiness in clinically healthy subjects," Clin. Sci. 88(6), 629-633, 1995.

G. Jorneskog, et al., "Skin capillary circulation severely impaired in toes of patients with IDDM, with and without late diabetic complications," Diabetologia 38(4), 474-480, 1995.

A. M. Kahn and T. Song, "Insulin inhibits dog vascular smooth muscle contraction and lowers Ca++[i] by inhibiting Ca++ influx," J. of Nutrition 125(6 Suppl.), S1732-S1737, 1995.

F. Kuhlencordt, et al., "Examination of the skeleton in diabetic patients up to age 45," Deutsche med. Wchnschr. 91, 1913-1917, 1966. "Some patients have a generalized osteoporosis-like process, and some have localized bone lesions...."

M. Kusunoki, et al., "Amelioration of high fat feeding-induced insulin resistance in skeletal muscle with the antiglucocorticoid RU486," Diabetes 44(6), 718-720, 1995. "These results suggest that glucocorticoids play, in a tissue-specific manner, a role in the maintenance and/or production of insulin resistance produced by high-fat feeding."

A. Lazarow, "Protection against alloxan diabetes," Anat. Rec. 97, 353, 1947.

A. Lazarow, "Protective effect of glutathione and cysteine against alloxan diabetes in the rat," Proc. Soc. Exp. Biol. & Med. 61, 441-447, 1946. [While certain doses of cysteine, glutathione, and thioglycolic acid completely prevented alloxan diabetes, it was interesting that all of the rats receiving ascorbic acid became diabetic. To me, this argues for the free radical cause of diabetes, rather than just the sulfhydryl oxidation. Lazarow suggested that succinic dehydrogenase, and various other sulfhydryl enzymes, including those involved in fatty acid oxidation, might be involved.]

R. B. Lipton and J. A. Fivecoate, "High risk of IDDM in African-American and Hispanic children in Chicago, 1985-1990," Diabetes Care 18(4), 476-482, 1995. "The relatively early age at onset may point to an environmental factor associated with this high incidence of the disease."

G. S. Meneilly, et al., "Insulin-mediated increase in blood flow is impaired in the elderly," J. Clin. Endocrinol. Metab. 80(6), 1899-1903, 1995. "Normal aging is characterized by resistance to insulin-mediated glucose uptake."

J. Ma, et al., "Associations of serum and dietary magnesium with cardiovascular disease, hypertension, diabetes, insulin, and carotid arterial wall thickness: The ARIC study," J. Clin. Epidemiol. 48(7), 927-940, 1995. [Carotid wall thickness increased in women as serum Mg level decreased.]

Y. Matsumoto, et al., "Creatine kinase kinetics in diabetic cardiomyopathy," Amer. J. Physiol.-Endocrinol. Met. 31(5), E1070-E1076, 1995.

F. Mercure and G. Vanderkraak, "Inhibition of gonadotropin-stimulated ovarian steroid production by polyunsaturated fatty acids in teleost fish," Lipids 30(6), 547-554, 1995. "The inhibitory actions by PUFAs were not restricted to long-chain PUFAs, as linoleic and linolenic acids had similar actions in the goldfish. The inhibitory action of EPA on testosterone production was reversible upon removal of the PUFA from medium." "[Stimulated] ...testosterone production ... was attenuated by PUFAs...."

H. Mulder, et al., "Non-parallelism of islet amyloid polypeptide (amylin) and insulin gene expression in rat islets following dexamethasone treatment," Diabetologia 38(4), 395-402, 1995.

S. Nagasaka, et al., "Effect of glycemic control on calcium and phosphorus handling and parathyroid hormone level in patients with non-insulin-dependent diabetes mellitus," Endocr. J. 42(3), 377-383, 1995. "...hyperglycemia causes excess urinary calcium and phosphorus excretion in patients with NIDDM. In response to urinary calcium loss, PTH secretion is mildly stimulated. Bone formation seems to be suppressed in the hyperglycemic state in spite of increased PTH secretion." [These are the changes I would expect to see in hypothyroid people with high cortisol.]

B. Oztas and M. Kucuk, "Influence of acute arterial hypertension on blood-brain barrier permeability in streptozocin-induced diabetic rats," Neuroscience Letters 188(1), 53-56, 1995.

S. Phillips, et al., "Neuropathic arthropathy of the spine in diabetes," Diabetes Care 18(6), 876-869, 1995.

J. F. Pouliot and R. Beliveau, "Palmitoylation of the glucose transporter in blood-brain barrier capillaries," Bioch. et Bioph. Acta--Biomembranes 1234(2), 191-196, 1995. "Palmitoylation may be involved in the regulation of glucose transport activity in hyperglycemia."

R. Ramakrishnan and A. Namasivayam, "Norepinephrine and epinephrine levels in the brain of alloxan diabetic rats," Neuroscience Letters 186(2-3), 200-202, 1995. [Epinephrine increased in striatum, hippocampus and hypothalamus, Norepinephrine increased in hypothalamus and decreased in pons and medulla.]

J. G. Regensteiner, et al., "Effects of non-insulin-dependent diabetes on oxygen consumption during treadmill exercise," Med. Sci. Sports Exerc. 27(6), 874-881, 1995. "The reduced rate of increase in oxygen consumption during increasing submaximal work loads in NIDDM suggests that limitations in oxygen delivery may impair exercise performance in otherwise healthy persons with diabetes."

A. A. Shaltout, et al., "High incidence of childhood-onset IDDM in Kuwait," Diabetes Care 18(7), 923-927, 1995. The incidence of IDDM in children is high in the region and has apparently increased nearly fourfold in the last decade. This is especially significant, since diabetes that appears in childhood is especially important for the theory of genetic causation. This study should give the gene people real trouble. They might have to call in the "gene for bed-wetting" people to help with their case.

M. A. Smith, et al., "Radical AGEing in Alzheimer's disease," Trends in Neurosciences 18(4), 172-176, 1995.

A. Tchernof, et al., "Relation of steroid hormones to glucose tolerance and plasma insulin levels in men: Importance of visceral adipose tissue," Diabetes Care 28(3), 292-299, 1995.

A. Tchernof, et al., "Reduced testosterone and adrenal C-19 steroid levels in obese men," Metabolism--Clin. and Exp. 44(4), 513-519, 1995. "...reduced concentrations of testosterone and adrenal C-19 steroid precursors are associated with increased body fatness rather than with excess visceral fat accumulation." [These results] "...emphasize the importance of adrenal steroids as correlates of body composition in men."

B. G. Trumper, et al., "Circadian variation of insulin requirement in insulin dependent diabetes mellitus--The relationship between circadian change in insulin demand and diurnal patterns of growth hormone, cortisol and glucagon during euglycemia," Hormone and Metabolic Research 27(3), 141-147, 1995. "The results of the study showed that the early morning rise in the insulin demand is related to the increased early morning cortisol secretion and to the nocturnal peaks of growth hormone concentration."

M. Udvardy, et al., "Altered lysis resistance of platelet-rich clots in patients with insulin-dependent diabetes mellitus," Thromb. Res. 79(1), 57-63, 1995. Suppression of clot-dissolving "...was remarkably stronger in IDDM, along with the highest PAI-1 activity concentration ratio of the platelet lysates, compared to plasmatic levels."

P. Vague, et al., "Hypofibrinolysis and the insulin resistance syndrome," Int. J. Obes. 19(Suppl. 1), S11-S15, 1995. Hypofibrinolysis is observed among obese subjects and it has been shown that an excess of plasminogen activator inhibitor 1 (PAI 1) the main regulator of the fibrinolytic system, is closely associated to other components of the insulin resistance syndrome, namely, excessive body weight, high waist to hip ratio, elevated blood pressure, hyperinsulinemia and hypertriglyceridemia."

E. O. Vianna and J. Garcialeme, "Allergen-induced airway inflammation in rats: Role of insulin," American J. of Respiratory and Critical Care Med. 151(3), 809-814, 1995. "Clinical asthma appears to be less severe when diabetes mellitus is superimposed."

A. Warley, et al., "Capillary surface area is reduced and tissue thickness from capillaries to myocytes is increased in the left ventricle of streptozotocin-diabetic rats," Diabetologia 38(4), 413-421, 1995.

G. C. Weir, "Which comes first in non-insulin-dependent diabetes mellitus: Insulin resistance or beta-cell failure? Both come first," JAMA 273(23), 1878-1879, 1995.

N. R. Williams, et al., "Plasma, granulocyte and mononuclear cell copper and zinc in patients with diabetes mellitus," Analyst 120(3), 887-890, 1995. "...the copper and zinc status of these diabetic patients was reduced, providing further evidence of a role for these antioxidant" trace elements in this disease.

T. Yamakawa, et al., "Augmented production of tumor necrosis factor-alpha in obese mice," Clinical Immunology and Immunopathology 75(1), 51-56, 1995. "...the TNF-alpha derived from adipose tissues might be involved in the induction of peripheral insulin resistance..."

T. Yamashita, et al., "Increased transendothelial permeation of albumin by high glucose concentration," Metabolism 44(6), 739-744, 1995.

M. B. Zemel, "Insulin resistance vs. hyperinsulinemia in hypertension: Insulin regulation of Ca++ transport and Ca++-regulation of insulin sensitivity," Journal of Nutrition 125(6 Suppl.), S1738-S1743, 1995.

B. M. Zenere, et al., "Noninvasive detection of functional alterations of the arterial wall in IDDM patients with and without microalbuminuria," Diabetes Care 18(7), 975-982, 1995. [There is a reduced vasodilatory capacity in diabetes, and especially in patients who are leaking albumin.]

D. B. Zilvermit, et al., "Oxidation of glucose labelled with radioactive carbon by normal and alloxandiabetic rats," J. Biol. Chem. 176, 389-400, 1948. [Diabetic rats had the same rate of glucose oxidation as normal rats, in this experiment. This is an artificial form of diabetes that doesn't immediately involve an excess of unsaturated fatty acids, as occurs during stress, estrogen excess, hypothyroidism, or diets high in polyunsaturated fats which can cause a more "natural" kind of diabetes. The artificial alloxandiabetes forces the animal to oxidize an excess of fatty acids, and eventually should lead to the same kind of mitochondrial damage seen in natural diabetes.]

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A R T I C L E

Eclampsia in the Real Organism: A Paradigm of General Distress Applicable in Infants, Adults, Etc.

To prevent the appropriation and abuse of our language by academic and professional cliques, I like to recall my grandparents' speech. When my grandmother spoke of eclampsia, the word was still normal English, that reflected the Greek root meaning, "shining out," referring to the visual effects that are often prodromal to seizures. The word was most often used in relation to pregnancy, but it could also be applied to similar seizures in young children. The word is the sort that might have been coined by a person who had experienced the condition, but the experience of seeing hallucinatory lights is seldom mentioned in the professional discussion of "eclampsia and preeclampsia."

Metaphoric thinking--using comparisons, models, or examples--is our natural way of gaining new understanding. Ordinary language, and culture, grow when insightful comparisons are generally adopted, extending the meaning of old categories. Although the free growth of insight and understanding might be the basic law of language and culture, we have no institutions that are amenable to that principle of free development of understanding. Institutions devoted to power and control are naturally hostile to the free development of ideas.

Among physicians, toxemia (meaning poisons in the blood) has been used synonymously with preeclampsia, to refer to the syndrome in pregnant women of high blood pressure, albumin in the urine, and edema, sometimes ending in convulsions. Eclampsia is reserved for the convulsions themselves, and is restricted to the convulsions which follow preeclampsia, when there is "no other reason" for the seizure such as "epilepsy" or cerebral hemorrhage. Sometimes it is momentarily convenient to use medical terms, but we should never forget the quantity of outrageous ignorance that is attached to so many technical words when they suggest the identity of unlike things, and when they partition and isolate things which have meaning only as part of a process. Misleading terminology has certainly played an important role in retarding the understanding of the problems of pregnancy.

In 1974, when I decided to write Nutrition for Women, I was motivated by the awful treatment I saw women receiving, especially during pregnancy, from physicians and dietitians. Despite the research of people like the Shutes and the Biskinds, there were still "educated" and influential people who said that the mother's diet had no influence on the baby. (That strange attitude affects many aspects of behavior and opinion.)

How can people believe that the mother's diet has no effect on the baby's health? Textbooks used to talk about the "insulated" fetus, which would get sufficient nutrients from the mother's body even if she were starving. To "prove" the doctrine, it was pointed out that the fetus gets enough iron to make blood even when the mother is anemic. In the last few years, the recognition that smoking, drinking, and using other drugs can harm the baby has helped to break down the doctrine of "insulation," but there is still not a medical culture in which the effects of diet on the physiology of pregnancy are appreciated. This is because of a mistaken idea about the nature of the organism and its development. "Genes make the organism," according to this doctrine, and if there are congenital defects in the baby, the genes are responsible. A simple sort of causality flows from the genes to the finished organism, according to that idea. It was taught that if "the genes" are really bad, the defective baby can make the mother sick, and she contributed to the baby's bad genes. The idea isn't completely illogical, but it isn't based on reality, and it is demonstrably false. (Race, age and parity have no effect on incidence of cerebral palsy; low birth weight and complications of pregnancy are associated with it: J. F. Eastman, "Obstetrical background of 753 cases of cerebral palsy," Obstet. Gynecol. Surv. 17, 459-497, 1962.)

Although Sigmund Freud sensibly argued in 1897 that it was more reasonable to think that an infant's cerebral palsy was caused by the same factors that caused the mother's sickness, than to think that the baby's cerebral palsy caused maternal sickness and premature labor, more than 50 years later people were still taking seriously the idea that cerebral palsy might cause maternal complications and prematurity. (A.M. Lilienfield and E. Parkhurst, "A study of the association of factors of pregnancy and parturition with the development of cerebral palsy," Am. J. Hyg. 53, 262-282, 1951.)

Medical textbooks and articles still commonly list the conditions that are associated with eclampsia: Very young and very old mothers, a first pregnancy or a great number of previous pregnancies, diabetes, twins, obesity, excessive weight gain, and kidney disease. Some authors, observing the high incidence of eclampsia in the deep South, among Blacks and on American Indian reservations, have suggested that it is a genetic disease because it "runs in families." If poverty and malnutrition are also seen to "run in families," some of these authors have argued that the bad genes which cause birth defects also cause eclampsia and poverty. (L. C. Chesley, et al., "The familial factor in toxemia of pregnancy," Obstet. Gynec. 32, 303-311, 1968, reported that women whose mothers suffered eclampsia during their gestation were likely to have eclampsia themselves. Some "researchers" have concluded that eclampsia is good, because many of the babies die, eliminating the "genes" for eclampsia and poverty.)* Any sensible farmer knows that pregnant animals must have good food if they are to successfully bear healthy young, but of course those farmers don't have a sophisticated knowledge of genetics.

The inclusion of obesity and "excessive weight gain" among the conditions associated with eclampsia has distracted most physicians from the fact that malnutrition is the basic cause of eclampsia. The pathologist who, knowing nothing about a woman's diet, writes in his autopsy report that the subject is "a well nourished" pregnant woman, reflects a medical culture which chooses to reduce "nutritional adequacy" to a matter of gross body weight. The attempt to restrict weight gain in pregnancy has expanded the problem of eclampsia beyond its association with poverty, into the more affluent classes.

Freud wasn't the first physician who grasped the idea that the baby's health depends on the mother's, and that her health depends on good nutrition. Between 1834 and 1843, John C. W. Lever, M.D., discovered that 9 out of 10 eclamptic women had protein in their urine. He described an eclamptic woman who bore a premature, low-weight baby, as having "...been living in a state of most abject penury for two or three months, subsisting for days on a single meal of bread and tea. Her face and body were covered with cachectic sores." ("Cases of puerperal convulsions," Guy's Hospital Reports, Volume 1, series 2, 495-517, 1843.) S. S. Rosenstein observed that eclampsia was preceded by changes in the serum (Traite Pratique des Maladies des Reins, Paris, 1874). L. A. A. Charpentier specifically documented low serum albumin as a cause of eclampsia (A Practical Treatise on Obstetrics, Volume 2, William Wood & Co., 1887). Robert Ross, M.D., documented the role of malnutrition as the cause of proteinuria and eclampsia (Southern Medical Journal 28, 120, 1935).

In outline, we can visualize a chain of causality beginning with a diet deficient in protein, impairing liver function, producing inability to store glycogen, to inactivate estrogen and insulin, and to activate thyroid. Low protein and high estrogen cause increased tendency of the blood to clot. High estrogen destroys the liver's ability to produce albumin (G. Belasco and G. Braverman, Control of Messenger RNA Stability, Academic Press, 1994). Low thyroid causes sodium to be lost. The loss of sodium albuminate causes tissue edema, while the blood volume is decreased. Decreased blood volume and hemoconcentration (red cells form a larger fraction of the blood) impair the circulation. Blood pressure increases. Blood sugar becomes unstable, cortisol rises, increasing the likelihood of premature labor. High estrogen, hypoglycemia, viscous blood, increased tendency of the blood to clot cause seizures. Women who die from eclampsia often have extensive intravascular clotting, and sometimes the brain and liver show evidence of earlier damage, probably from clots that have been cleared. (Sometimes prolonged clotting consumes fibrinogen, causing inability to clot, and a tendency to hemorrhage.) M. M. Singh, "Carbohydrate metabolism in pre-eclampsia," Br. J. Obstet. Gynaecol. 83, 124-131. 1976. Sodium decrease, R. L. Searcy, Diagnostic Biochemistry, McGraw-Hill, 1969. Viscosity, L. C. Chesley, 'Hypertensive Disorders in Pregnancy, Appleton-Century-Crofts, 1978. Clotting, T. Chatterjee, et al., "Studies on plasma fibrinogen level in preeclampsia and eclampsia, Experientia 34, 562-3, 1978; D. M. Haynes, "Medical Complications During Pregnancy, McGraw-Hill Co. Blakiston Div., 1969. Progesterone decrease, G. V. Smith, et al., "Estrogen and progestin metabolism in pregnant women, with especial reference to pre-eclamptic toxemia and the effect of hormone administration," Am. J. Obstet. Gynecol. 39, 405, 1940; R. L. Searcy, Diagnostic Biochemistry, McGraw-Hill, 1969.

But the simple chain of causality has many lines of feedback, exacerbating the problem, and the nutritional problem is usually worse than a simple protein deficiency. B vitamin deficiencies alone are enough to cause the liver's underactivity, and to cause estrogen dominance, and a simple vitamin A deficiency causes an inability to use protein efficiently or to make progesterone, and in itself mimics some of the effects of estrogen.

Anything that causes a thyroid deficiency will make the problem worse. Thyroid therapy alone has had spectacular success in treating and preventing eclampsia. (H. O. Nicholson, 1904, cited in Dieckman's Toxemias of Pregnancy, 1952; 1929, Barczi, of Budapest; Broda Barnes, who prescribed thyroid as needed, delivered more than 2,000 babies and never had a case of pre-eclampsia, though statistically 100 would have been expected.)

The clotting which sometimes kills women, can, if it is not so extensive, cause spotty brain damage, similar to that seen in "multiple sclerosis," or it can occur in the liver, or other organ, or in the placenta, or in the fetus, especially in its brain and liver. Some cases of supposed "post-partum psychosis" have been the result of multiple strokes. When large clots occur in the liver or placenta, the fibrinogen which has been providing the fibrin for disseminated intravascular coagulation can appear to be consumed faster than it is produced by the liver. I think its disappearance may sometimes be the result of the liver's diminished blood supply, rather than the "consumption" which is the way this situation is usually explained. It is at this point that hemorrhages, rather than clots, become the problem. The undernourished liver can produce seizures in a variety of ways--clots, hemorrhages, hypoglycemia, and brain edema, for example, so eclampsia needn't be so carefully discriminated from "the other causes of seizures."

Because I had migraines as a child, I was interested in their cause. Eating certain foods, or skipping meals, seemed to be involved, but I noticed that women often had migraines premenstrually. Epilepsy too, I learned, often occurred premenstrually.

In my experience of migraine, nausea and pain followed the visual signs, which consisted of a variable progression of blind spots and lights. When I eventually learned that I could stop the progression of symptoms by quickly eating a quart of ice cream, I saw that my insight could be applied to other situations in which similar visual events played a role, especially "eclampsia" and "epilepsy." For example, a woman who was 6 months pregnant called me around 10 o'clock one morning, to say that she had gone blind, and was alone in her country house. She said she had just eaten breakfast around 9 AM, and wasn't hungry, but I knew that the 6 month fetus has a great need for glucose, so I urged her to eat some fruit. She called me 15 minutes later to report that she had eaten a banana, and her vision had returned.

Early in pregnancy, "morning sickness" is a common problem, and it is seldom thought to have anything to do with eclampsia, because of the traditional medical idea that the fetus "causes" eclampsia, and in the first couple of months of pregnancy the conceptus is very small. But salty carbohydrate (soda crackers, typically) is the standard remedy for morning sickness. Some women have "morning sickness" premenstrually, and it (like the nausea of migraine) is eased by salt and carbohydrate. X-ray studies have demonstrated that there are spasms of the small intestine (near the bile duct) associated with estrogen-induced nausea.

Hypoglycemia is just one of the problems that develops when the liver malfunctions, but it is so important that orange juice or Coca Cola or ice cream can provide tremendous relief from symptoms. Sodium (orange juice and Pepsi provide some) helps to absorb the sugar, and--more basically--is essential for helping to restore the blood volume. Pepsi has been recommened by the World Health Organization for the rehydration of babies with diarrhea, in whom hypovolemia (thickening of the blood from loss of water) is also a problem.

The problem of refeeding starving people has many features in common with the problem of correcting the liver malfunction and hormone imbalances which follow prolonged malnutrition of a milder sort. The use of the highest quality protein (egg yolk or potato juice, or at least milk or meat) is important, but the supplementation of thyroid containing T 3 is often necessary. Intravenous albumin, hypertonic solutions of glucose and sodium, and magnesium in an effective form should be helpful (magnesium sulfate injected intramuscularly is the traditional treatment for eclampsia, since it is quickly effective in stopping convulsions). While the sodium helps to restore blood volume and to regulate glucose, under some circumstances (high aldosterone) it helps to retain magnesium; aldosterone is not necessarily high during eclampsia.. Triiodothyronine directly promotes cellular absorption of magnesium. Hypertonic glucose with minerals is known to decrease the destruction of protein during stress: M. Jeevanandam, et al., Metabolism 40, 1199-1206, 1991.

Katherina Dalton observed that her patients who suffered from PMS (and were benefitted by progesterone treatment) were likely to develop "toxemia" when they became pregnant, and to have problems at the time of menopause. In these women, it is common for "menstruation" to continue on the normal cycle during the first several months of pregnancy. This cyclic bleeding seems to represent times of an increased ratio of estrogen to progesterone, and during such periods of cyclic bleeding the risk of miscarriage is high. Researchers found that a single injection of progesterone could sometimes eliminate the signs of toxemia for the remainder of the pregnancy. Katherina Dalton, who continued to give her patients progesterone throughout pregnancy, later learned that the babies treated in this way were remarkably healthy and bright, while the average baby delivered after a "toxemic" pregnancy has an IQ of only 85.

Marian Diamond's work with rats clearly showed that increased exposure to estrogen during pregnancy reduced the size of the cerebral cortex and the animals' ability to learn, while progesterone increased the brain size and intelligence. Zamenhof's studies suggested that these hormones probably have their effects largely through their actions on glucose, though they also affect the availability of oxygen in the same way, and have a variety of direct effects on brain cells that would operate toward the same end.

If Katherina Dalton's patients' IQs averaged 130, instead of the expected 85, the potential social effects of proper health care during pregnancy are enormous.

But there is evidence that healthy gestation affects more than just the IQ. Strength of character, ability to reason abstractly, and the absence of physical defects, for example, are strongly associated with weight at birth.

Government studies and Social Security statistics suggest the size of the problem. The National Institute of Neurological Diseases and Stroke found that birth weight was directly related to IQ at age four, and that up to half of all children who were underweight at birth have an IQ under 70.(Chase.) According to standard definitions, about 8% of babies in the U.S. have low birth weight.

Among people receiving Social Security income because of disability that existed at the age of 18, 75% were disabled before birth. In 94% of these cases, the abnormality was neurological. (HEW.)

A study of 8 to 10-year-old children found that abstract verbal reasoning and perceptual/motor integration are more closely related to birth weight than they are to IQ. (Wiener.)

National nutritional data show that in the U.S. the development of at least a million babies a year is "substantially compromised" by prenatal malnutrition. Miscarriages, which are also causally related to poor nutrition, occur at a rate of a few hundred thousand per year. (Williams.)

When a muscle is fatigued, it swells, taking up sodium and water, and it is likely to become sore. Energy depletion causes any cell to take up water and sodium, and to lose potassium. An abnormal excess of potassium in the blood, especially when sodium is low, affects nerve, muscle, and secretory cells; a high level of potassium can stop the heart, for example. Cellular energy can be depleted by a combination of work, insufficient food or oxygen, or a deficiency of the hormones needed for energy production. When the swelling happens suddenly, the movement of water and sodium from the blood plasma into cells decreases the volume of blood, while the quantity of red cells remains the same, making the blood more viscous.

During the night, as adrenalin, cortisol, and other stress hormones rise, our blood becomes more viscous and clots more easily. In rats, it has been found that the concentration of serum proteins increases significantly during the night, presumably because water is moving out of the circulatory system. Even moderate stress causes some loss of water from the blood.

If a person is malnourished, a moderate stress can overcome the body's regulatory capacity. If tissue damage is extreme, or blood loss is great, even a healthy person experiences hypovolemia and shock.

C.A. Crenshaw, who was a member of the trauma team at Parkland Hospital in Dallas that worked on Kennedy and Oswald, had been involved in research with G. T. Shires on traumatic shock. In his words, "we made medical history by discovering that death from hemorrhagic shock (blood loss) can be due primarily to the body's adjunctive depletion of internal salt water into the cells." (Shires' work involved isotopes of sodium to show that sodium seems to be taken up by cells during shock.)

According to Crenshaw, "Oswald did not die from damaged internal organs. He died from the chemical imbalances of hemorrhagic shock. From the time he was shot...until the moment fluids were introduced into the body..." [19 minutes] "there was very little blood circulating in Oswald's body. As a result, he was not getting oxygen, and waste built up in his cells. Then, when the fluids were started, the collection of waste from the cells was dumped into the bloodstream, suddenly increasing the acid level, and delivering these impurities to his heart. When the contaminated blood reached the heart, it went into arrest...." The "waste" he refers to includes potassium and lactic acid. Crenshaw advocates the use of Ringer's lactate to replace some of the lost fluid. Since the blood already contains a large amount of lactate because the body is unable to consume it, this doesn't seem reasonable. I think a hypertonic version of Locke's solution, containing glucose and sodium bicarbonate as well as sodium chloride, would be better, though I think the potassium should be omitted too, and extra magnesium would seem desirable. Triiodothyronine, I suspect, would help tremendously to deal with the problems of shock, causing potassium, magnesium, and phosphate to move back into cells, and sodium to move out, helping to restore blood volume and reduce the wasteful conversion of glucose to lactic acid..

Albumin has been used therapeutically in preeclampsia (Kelman), to restore blood volume. Synthetic polymers with similar osmotic properties are sometimes used in shock, and might also be useful in eclampsia, but simply eating extra protein quickly restores blood albumin. For example, in a group of women who were in their seventh month of pregnancy, the normal women's serum osmotic pressure was 247 mm. of water, that of the women with nonconvulsive toxemia was 215 mm., and in the women with eclampsia, the albumin and osmotic pressure were lowest, with a pressure of 175 mm. In the eighth month, the toxemic women who ate 260 grams of protein daily had a 7% increase in osmotic pressure, and a group who ate 20 grams had a decline of 9%.(Strauss) In a group of preeclamptics, plasma volume was 39% below that of normal pregnant women.

If the physiology of shock has some relevance for eclampsia, so does the physiology of heart failure, since Meerson has shown that it is a consequence of uncompensated stress. The failing heart shifts from mainly glucose oxidation to the inefficient use of fatty acids, which are mobilized during stress, and with its decreased energy supply, it is unable to beat efficiently, since it remains in a partly contracted state. Estrogen (which is increased in men who have had heart attacks) is another factor which decreases the heart's stroke volume, and estrogen is closely associated with the physiology of the free unsaturated fatty acids. The partly contracted state of the heart is effectively a continuation of the partly contracted state of the blood vessels that causes the hypertension, and reduced tissue perfusion seen in shock and eclampsia. Since shock can be seen as a generalized inflammatory state, and since aspirin has been helpful in protecting against heart disease, it's reasonable that aspirin has been tried as a treatment in pre-eclampsia. It seems to protect the fetus against intrauterine growth retardation, an effect that I think relates to aspirin's ability to protect in several ways against excesses of uunsaturated fatty acids and of estrogen. But, since aspirin can interfere with blood clotting, its use around the time of childbirth can be risky, and it is best to correct the problem early enough that aspirin isn't needed.

Besides protein deficiency and other nutritional deficiencies, excess estrogen and low thyroid can also limit the liver's ability to produce albumin. Hypovolemia reduces liver function, and (like hepatic infarcts) will reduce its ability to maintain albumin production..

The studies which have found that hospitalized patients with the lowest albumin are the least likely to survive suggest that the hypovolemia resulting from hepatic inefficiency is a problem of general importance, and that it probably relates to the multiple organ failure which is an extremely common form of death among hospitalized patients. A diet low in sodium and protein probably kills many more people than has been documented. If old age is commonly a hypovolemic condition, then the common salt restriction for old-age hypertension is just as irrational as is salt-restriction in pregnancy or in shock. Thyroid (T 3), glucose, sodium, magnesium and protein should be considered in any state in which weakened homeostatic control of the composition of plasma is evident.

*Note: Although Konrad Lorenz (who later received the Nobel Prize) was the architect of the Nazi's policy of "racial hygiene" (extermination of those with unwanted physical, cultural, or political traits which were supposedly determined by "genes") he took his ideas from the leading U.S. geneticists, whose works were published in the main genetics journals. Following the Nazis' defeat, some of these journals were renamed, and the materials on eugenics were often removed from libraries, so that a new historical resume could be presented by the profession.

ADDITIONAL REFERENCES

G. Wiener, et al., "Correlates of low birth weight: Psychological status at eight to ten years of age," Pediatr. Res. 2, 110-118, 1968.

A. Chase, "The great pellagra cover-up," Psychol. Today, pp. 83-86, Feb., 1975.

Prevention Handbook, Natl. Assoc. for Retarded Citizens, 1974.

US HEW, The Women and Their Pregnancies, W.B. Saunders Co., 1972.

M. Winick and P. Rosso, "The effect of severe early malnutrition on cellular growth of human brain," Pediatr. Res. 3, 181-184, 1969.

Roger Williams, Nutrition Against Disease, Pitman Publ., 1971.

H.M. Schmeck, Jr., "Brain harm in US laid to food lack," N.Y. times, Nov. 2, 1975.

R. Hurley, Poverty and Mental Retardation: A Causal Relationship, Random House, 1970.

D. Shanklin and J. Hodin, Maternal Nutrition and Child Health, C. C. Thomas, 1978.

H.H. Reese, H. A. Paskind, and E. L. Sevringhaus, 1936 Year Book of Neurology, Psychiatry and Endocrinology, Year Book Publishers, Chicago, 1937.

M. B. Strauss, "Observations on the etiology of the toxemias of pregnancy: The relationship of nutritional deficiency, hypoproteinemia, and elevated venous pressure to water retention in pregnancy," Am. J. Med. Sci. 190, 811-824, 1935.

"Albumin concentration can be used for mild preeclampsia," Obstet. Gynecol. News, October 1, 1974.

L. Kelman, et al., "Effects of dietary protein restriction on albumin synthesis, albumin catabolism, and the plasma aminogram," Am. J. Clin. Nutr. 25, 1174-1178, 1972.

T. H. Brewer, "Role of malnutrition, hepatic dysfunction, and gastrointestinal bacteria in the pathogenesis of acute toxemia of pregnancy," Am. J. Obstet. Gynecol. 84, 1253-1256, 1962.

"Plasma volume 'a clue' to hypertension risks," Obstet. Gynecol. Observer, August/September, 1975.

C. A. Crenshaw, MD, J. Hansen and J. G. Shaw, JFK: Conspiracy of Silence, Signet, 1992.

T. Backstrom, "Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle," Acta Neurol. Scand. 54, 321-347, 1976.

C. Muller, et al., "Reversible bilateral cerebral changes on magnetic resonance imaging during eclampsia," Deutsche Medizinische Wochenschrift 121(39), 1184-1188, 1996. (Brain edema was demonstrated.)

Uzan S; Merviel P; Beaufils M; Breart G; Salat-Baroux J. [Aspirin during pregnancy. Indications and modalities of prescription after the publication of the later trials]. Presse Medicale, 1996 Jan 6-13, 25(1):31-6. Aspirin, an inhibitor of cyclo-oxygenase, is prescribed in a number of conditions related to abnormal production of prostaglandins including gravidic hypertension. Results of the most recent trials demonstrate that in patients with a past history of pre-eclampsia or intra-uterine growth retardation, a pathological Doppler examination of the uterus, a pathological angiotensin test or an antiphospholipid syndrome, prescription of aspirin at the dose of 100 mg/day can prevent recurrence or development of pre-eclampsia or intra-uterine growth retardation. Treatment should begin as soon as possible during pregnancy, certainly before development of clinical manifestations. After history taking and identification of possible contraindications, bleeding time (Ivy method) is recorded before and after prescription and should be lower than 8 minutes. In case bleeding time exceeds 10 minutes 10 to 15 days after initiating aspirin, doses may be reduced to 50 mg per day or even 50 mg every two or three days to reach the target level. Treatment should generally be continued up to 36 weeks gestation.

Randall, C L; Anton, R F; Becker, H C; Hale, R L; Ekblad, U. Aspirin dose-dependently reduces alcohol-induced birth defects and prostaglandin E levels in mice. Teratology, v.44, n.5, (1991): 521-530. The purpose of the present study was threefold. The first purpose was to determine if aspirin (ASA) decreases alcohol-induced birth defects in mice in a dose-dependent fashion. The second purpose was to see if the antagonism of alcohol-induced birth defects afforded by ASA pretreatment was related to dose-dependent decreases in prostaglandin E (PGE) levels in uterine/embryo tissue. The third purpose was to determine if ASA pretreatment altered maternal blood alcohol level.” In experiments 1 and 2, pregnant C57BL/6J mice were administered ASA (0, 18.75, 37.5, 75, 150, or 300 mg/kg) on gestation day 10. One hour following the subcutaneous injection of ASA, mice received alcohol (5.8 g/kg) or an isocaloric sucrose solution intragastrically. In experiment 1 the incidence of birth defects was assessed in fetuses delivered by caesarean section on gestation day 19. In experiment 2 uterine/embryo tissue samples were collected on gestation day 10 1 hr following alcohol intubation for subsequent PGE analysis. In experiment 3 blood samples were taken at five time points following alcohol intubation from separate groups of alcohol-treated pregnant mice pretreated with 150 mg/kg ASA or vehicle The results from the three experiments indicated that ASA dose-dependently reduced the frequency of alcohol-induced birth defects in fetuses examined at gestation day 19, ASA decreased the levels of PGE in gestation day 10 uterine/embryo tissue in a similar dose-dependentfashion, and ASA pretreatment did not significantly influence maternalblood alcohol levels. These results provide additional support for the hypothesis that PGs may play an important role in mediating the teratogenic actions of alcohol.

Prevention of fetal growth retardation with low-dose aspirin: findings of the EPREDA trial [see comments] Uzan S; Beaufils M; Breart G; Bazin B; Capitant C; Paris J. Lancet, 1991 Jun 15, 337:8755, 1427-31 The efficacy of low-dose aspirin in preventing fetal growth retardation was tested in a randomised, placebo-controlled, double-blind trial. A secondary aim was to find out whether dipyridamole improves the efficacy of aspirin. 323 women at 15-18 weeks' amenorrhoea were selected at twenty-five participating centres on the basis of fetal growth retardation and/or fetal death or abruptio placentae in at least one previous pregnancy. They were randomly allocated to groups receiving placebo, 150 mg/day aspirin, or 150 mg/day aspirin plus 225 mg/day dipyridamole, for the remainder of the pregnancy. In the first phase of the trial all actively treated patients (n = 156) were compared with the placebo group (n = 73). Mean birthweight was significantly higher in the treated than in the placebo group (2751 [SD 670] vs 2526 [848] g; difference 225 g [95% CI 129-321 g], p = 0.029) and the frequency of fetal growth retardation in the placebo group was twice that in the treated group (19 [26%] vs 20 [13%]; p less than 0.02). The frequencies of stillbirth (4 [5%] vs 2 [1%]) and abruptio placentae (6 [8%] vs 7 [5%]) were also higher in the placebo than in the treated group. The benefits of aspirin treatment were greater in patients with two or more previous poor outcomes than in those with only one. In the second analysis, of aspirin only (n = 127) vs aspirin plus dipyridamole (n = 119), no significant differences were found. There was no excess of maternal or neonatal side-effects in the aspirin-treated patients.

An aspirin a day to prevent prematurity. Sibai BM. Clin Perinatol, 1992 Jun, 19:2, 305-17. Intrauterine fetal growth retardation and preeclampsia remain a substantial cause of preterm birth world wide. There is evidence to suggest that a functional imbalance between vascular prostacyclin and platelet-derived thromboxane A2 production plays a central role in the pathogenesis of these disorders. Low-dose aspirin appears to reverse the above functional balance resulting in increased prostacyclin to thromboxane ratio. The efficacy and safety of low-dose aspirin in preventing preeclampsia and fetal growth retardation were tested in several randomized and uncontrolled trials. The data in the literature suggest that low-dose aspirin is effective in reducing preterm birth due to the above complications in selected high-risk pregnant women.

Rosental, D G; Machiavelli, G A; Chernavsky, A C; Speziale, N S; Burdman, J A. Indomethacin inhibits the effects of estrogen in the anterior pituitary gland of the rat. Journal of Endocrinology, v.121, n.3, (1989): 513-520. Two inhibitors of prostaglandin synthesis, indomethacin and aspirin, blocked the increase of oestrogen-binding sites in the nuclear subcellular fraction, an increase which occurs after the administration of oestradiol.

Zanagnolo, V; Dharmarajan, A M; Endo, K; Wallach, E E. Effects of acetylsalicylic acid (aspirin) and naproxen sodium (naproxen) on ovulation, prostaglandin, and progesterone production in the rabbit. Fertility and Sterility, v.65, n.5, (1996): 1036-1043.

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<span class="koboSpan" id="kobo.1.1">Epilepsy and Progesterone</span> A R T I C L E

Epilepsy and Progesterone

The length of the life-span, and of the period of youth or immaturity, is closely associated with the size of the brain, and the brain has a very high rate of metabolism. When something interferes with this very high metabolic rate, the consequences may be instantanteous,* or developmental, or chronic and degenerative, or even transgenerational. The issue of epilepsy centers on questions of brain metabolism, and so it has all of those dimensions.

As I discuss the mechanisms known to predispose a person to epilepsy, I will emphasize the centrality of oxidative energy production, and show how "stroke," "stress," "hyperactivity," "dementia," and other brain syndromes are related to "epilepsy." (Similar processes are being studied in the heart and other tissues; eventually, we might have a general language that will make it easier to understand the parallels in the various kinds of "seizure" in any organ.)

As an old term, "epilepsy" has aquired a burden of pseudoscientific ideas, covering old superstitions with an overlay of new superstitions. [Hereditary epilepsy has been discussed in countless textbooks and medical journals, but I think a much better case could be made for the inheritance of a tendency to offer stupid genetic explanations.] "Hereditary epilepsy" and "idiopathic epilepsy" are seriously pathogenic terms; "brain scar" sometimes has a factual basis, but most often the term is an evasion of understanding.

As long as we realize that the essential meaning of the word is "something that grabs you," "epilepsy" is a convenient way to refer to a cluster of convulsive states, fainting spells, night-terrors and nightmares, and strange sensations.

Seizures can be caused by lack of glucose, lack of oxygen, vitamin B6 deficiency, and magnesium deficiency. They are more likely to occur during the night, during puberty, premenstrually, during pregnancy, during the first year of life, and can be triggered by hyperventilation, running, strong emotions, or unusual sensory stimulation. Water retention and low sodium increase susceptibility to seizures. When I was in high school, our dog found and ate a pint of bacon grease, and shortly afterward had a convulsive seizure. I knew of veterinarians who treated seizures in dogs with a vermifuge, so it seemed obvious that a metabolic disturbance, especially if combined with intestinal irritation, could cause fits.

It was undoubtedly such observations that led some physicians to advocate removal of the colon as treatment for epilepsy. Pregnancy and the menstrual cycle have been recognized as having something to do with seizures, but when seizures occurred only during pregnancy, they were classified as nonepileptic, and when they had a clear premenstrual occurrence, they were likely to be classified as "hysterical fits," to be treated with punishment.

It has been observed that all "recognized" anti-seizure drugs are teratogenic, and women who are taking such drugs are told that pregnancy might kill them if they stop the drug, but that their babies will have a greatly increased risk of birth defects if they take the drugs during pregnancy. This is why a better understanding of epilepsy is very important. Old therapies are mainly important for the insight they can give into the nature of the physiological problem. Some of the well established clinical-laboratory observations (F. Mora, and C. S. Babel, for example) give strong hints as to the physiological problem, for example, low albumin, high prealbumin, low magnesium and high calcium all suggest hypothyroidism. (Problems with the bowel, liver, and sex hormones are highly associated with hypothyroidism, both as causes and as effects.) Water retention was so clearly involved in seizures that increased water intake was used as a diagnostic procedure. (R. Grinker) Unfortunately, animal experiments showed that water intoxication increased susceptibility to seizures even in normal individuals. Low sodium content in the body fluids also predisposed to seizures, so that someone with hyponatremia (low blood sodium) would be more susceptible to induction of a seizure by excessive water intake. (Excessive water uptake is still recognized as a factor in seizures, but now it is seen as part of a complex process, involving energy, hormones, and transmitter substances. E.g., Kempski; Chan.)

Hypothyroid people tend to lose sodium easily, and unopposed estrogen increases water retention, without an equivalent sodium retention, so low thyroid, high estrogen people have two of the conditions (edema and hyponatremia) known to predispose to seizures. Another outstanding feature of seizures of various sorts is that they are most likely to occur at night, especially in the early pre-dawn hours. Low blood sugar and high adrenalin predominate during those hours. Hypoglycemia, in itself, like oxygen deprivation, is enough to cause convulsions.

Progesterone and thyroid promote normal energy production, and their deficiency causes a tendency toward hypoglycemia, edema and instability of nerves.

Twenty years ago, a woman who was considered demented visited me. From the age of 21, she had been increasingly disabled by premenstrual migraines. When she was 35 she was a school teacher, and during the summer a neurologist told her that dilantin would help her headaches, because "migraine is similar to epilepsy." Although she told the neurologist that the drug made her "too stupid to teach school," he offered her no alternatives, and didn't mention that sudden withdrawal from the drug could trigger a seizure. When classes started she discontinued the dilantin and had a seizure. The neurologist said the seizure proved that migraines were a form of epilepsy. At the age of 52, she spent about 20 hours a day in bed, and couldn't go outside by herself, because she would get lost. After using a little progesterone for a few days, she stopped having seizures, discontinued her drugs, and was able to work. When she returned to graduate school, she got straight As, and earned her masters' degree in gerontology. But she had lost 17 years because the drug industry had covered up the role of the hormones in epilepsy, migraine, and the perimenstrual syndrome.

The most popular anticonvulsant drugs are both neurotoxic and teratogenic, that is, they damage the patient's brain, and greatly increase the incidence of birth defects. The Nazis justified their horrible medical experiments as "science," but the effects of epilepsy medicine in the last half century have been similar in effect, grander in scale, and without any scientific justification.

Besides the specific promotional efforts of the drug industry and their branch of government, there is a broader situation that makes their work easier. It is a culture of goony ideas, that ultimately emanates from the academic elite, which (since Descartes, and before) places "thought" above evidence. In biology, "genes" and "membranes" are confused ideas that are used to justify actions that aren't based on evidence. For the Nazis, "cultural degeneracy" was a medical-biological-political category based on that style of thinking. In the United States, "genes" for epilepsy, hyperactivity, language development, IQ, eclampsia, etc., are "found" at Harvard/MIT/Stan- ford/Yale/Univ. of California, etc., by an elite whose wits have been dulled by environmental deprivation, that is, by a lack of criticism.

By manipulating the diet and environment, animals can be made more or less seizure-prone, and it happens that the changes that affect the brain affect all other organs, in ways that are now fairly well understood. Examining the cellular events associated with a seizure is useful for therapy and prevention of seizures, but the same methods are helpful for many other conditions. It is now clearly established that stress can cause brain damage, as well as other diseases. Now that our public health establishment has eliminated smoking from public places, maybe they can find a way to reduce stress and disease by removing morons from positions of power.

Excitotoxicity, in its simplest sense, is the harmful cellular effect (death or injury) caused by an excitatory transmitter such as glutamate or aspartate acting on a cell whose energetic reserves aren't adequate to sustain the level of activity provoked by the transmitter. Once an excitotoxic state exists, the consequences of cell exhaustion can increase the likelihood that the condition will spread to other cells, since any excitation can trigger a complex of other excitatory processes. As calcium enters cells, potassium leaves, and enzymes are activated, producing free fatty acids (linoleic and arachidonic, for example) and prostaglandins, which activate other processes, including lipid peroxidation and free radical production. Protein kinase C (promoted by unsaturated fats and estrogen) facilitates the release of excitatory amino acids. (See J. W. Phillis and M. H. O'Regan, "Mechanisms of glutamate and aspartate release in the ischemic rat cerebral cortex," Br. Res. 730(1-2), 150-164, 1996.) Estrogen supports acetylcholine release, which leads to increased extracellular potassium and excitatory amino acids. (See R. B. Gibbs, et al., "Effects of estrogen on potassium-stimulated acetylcholine release in the hippocampus and overlying cortex of adult rats," Br. Res. 749(1), 143-146, 1997.)

Estrogen also stimulates the production of free radicals. Calcium, free radicals, and unsaturated free fatty acids impair energy production, decreasing the ability to regulate potassium and calcium. The increased estrogen associated with seizures is associated with reduced serum calcium (Jacono and Robertson, 1987). Feedback self-stimulation of free radicals, free fatty acids, and prostaglandins create a bias toward increased excitation.

Ammonia is produced by stimulated nerves, and normally its elimination helps to eliminate and control the excitotoxic amino acids, glutamate and aspartate. The production of urea consumes aspartic acid, converting it to fumaric acid, but this requires carbon dioxide, produced by normal mitochondrial function. A deficiency of carbon dioxide would reduce the delivery of oxygen to the brain by constricting blood vessels and changing hemoglobin's affinity for oxygen (limiting carbon dioxide production), and the failure to consume aspartate (in urea synthesis) and glutamate (as alpha-ketoglutarate) and aspartate (as oxaloacetate) in the Krebs cycle, means that as energy becomes deficient, excitation tends to be promoted. This helps to explain the fact that seizures can be induced by hypoxia. (Balloonists and mountain climbers at extremely high elevations have mentioned suffering from severe insomnia. The mechanisms of excitotoxicity are probably involved in other forms of insomnia, too.) Antioxidants help to control seizures, by reducing the excitatory contribution of free radicals and lipid peroxidation. Since excitation can promote the toxic forms of oxidation, many surprising substances turn out to have an "antioxidant" function. Magnesium, sodium (balancing calcium and potassium), thyroid and progesterone (increasing energy production), and in some situations, carbon dioxide. Aspirin, by inhibiting prostaglandin synthesis (and maybe other mechanisms) often lowers free radical production. Adenosine seems to have a variety of antioxidant functions, and one mechanism seems to be its function as an antiexcitatory transmitter. One of estrogen's excitant actions on the brain probably involves its antagonism to adenosine (Phillis and O'Regan, 1988).

Albumin, besides maintaining blood volume and preventing edema, serves to protect respiration, by binding free fatty acids. Estrogen blocks the liver's ability to produce albumin, and increases the level of circulating free fatty acids. Free fatty acids cause brain edema. This is probably another aspect of estrogen's contribution to seizure susceptibility. Magnesium sulfate has been used for generations in India to treat eclampsia and "toxemia" of pregnancy, and its effectiveness is gradually coming to be recognized in the U.S. Increasingly, magnesium deficiency is recognized as a factor that increases susceptibility to seizures. (Valenzuela and Benardo, 1995; Slandley, et al., 1995). Hypothyroidism reduces the ability of cells to retain magnesium. Thyroid does many things to protect against seizures. It keeps estrogen and adrenal hormones low, and increases production of progesterone and pregnenolone. It facilitates retention of magnesium and of sodium, and prevents edema in a variety of ways.

Progesterone, because of its normal anesthetic function (which prevents the pain of childbirth when its level is adequate), directly quiets nerves, and in this way suppresses many of the excitotoxic processes. It has direct effects on mitochondria, promoting energy production, and it facilitates thyroid hormone functions in various ways. It promotes the elimination of estrogen from tissues, and is a "diuretic" in several benign ways, that are compatible with maintenance of blood volume. It antagonizes the mineralocorticoids and the glucocorticoids, both of which promote seizures. (Roberts and Keith, 1995.) The combination of hypoglycemia with elevation of cortisone probably accounts for the nocturnal incidence of seizures.

If progesterone's antiepileptic effectiveness were not enough (and it is very effective even in irrational pharmaceutical formulations), the fact that it reduces birth defects, and promotes brain development and nerve repair should assure its general use in women with a history of seizures, until it is established that they are no longer "epileptic." Although thyroid, progesterone, and a high quality protein diet will generally correct the epilepsy problem, it is important to mention that the involvement of unsaturated fats and free radicals in seizure physiology implies that we should minimize our consumption of the unsaturated fats. Even years after eliminating them from the diet, their release from tissue storage can prolong the problem, and during that time the use of vitamin E is likely to reduce the intensity and frequency of seizures. Coconut oil lowers the requirement for vitamin E, and reduces the toxicity of the unsaturated fats (see Cleland, et al.), favoring effective respiration and improving thyroid and progesterone production. Endotoxin formed in the bowel can block respiration and cause hormone imbalances contributing to instability of the nerves, so it is helpful to optimize bowel flora, for example with a carrot salad; a dressing of vinegar, coconut oil and olive oil, carried into the intestine by the carrot fiber, suppresses bacterial growth while stimulating healing of the wall of the intestine. The carrot salad improves the ratio of progesterone to estrogen and cortisol, and so is as appropriate for epilepsy as for premenstrual syndrome, insomnia, or arthritis.

NOTES:

When the brain loses its oxygen supply, consciousness is lost immediately, before there is much decrease in the ATP concentration. This has led to the proposal of interesting "electronic" ideas of consciousness, but there is another way of viewing this. While ATP constitutes a kind of reservoir of cellular energy, the flow of carbon dioxide through the brain cell is almost the mirror image of the flow of oxygen. Oxygen scarcity leads directly to carbon dioxide scarcity. The "sensitive state," consciousness, might require the presence of carbon dioxide as well as ATP, to sustain a cooperative, semi-stable, state of the cytoplasmic proteins. The ability of ordinary light to trigger a conformation change in the hemoglobin-carbon monoxide-carbon dioxide system shows how sensitive a system with only a few elements can be. At the other extreme from consciousness, there is the evidence that carbon dioxide is essential for even the growing/living state of protozoa, algae, and bacteria.(O. Rahn, 1941.)

O. Rahn, "Protozoa need carbon dioxide for growth," Growth 5, 197-199, 1941. "On page 113 of this volume, the statement of Valley and Rettger that all bacteria need carbon dioxide for growth had been shown to apply to young as well as old cells." "...it is possible...to remove it as rapidly as it is produced, and under these circumstances, bacteria cannot multiply."

REFERENCES

E. Tauboll, et al., "The progesterone metabolite 5-alpha-pregnan-3-alpha-ol-20-one reduces K+-induced GABA and glutamate release from identified nerve terminals in rat hippocampus--a semiquantitative immunocytochemical study," Brain Research 623(2), 329-333, 1993.

E. Tauboll and S. Lindstrom, similar article in Epilepsy Research 14(1), 17-30, 1993.

G. K. Herkes, et al., "Patterns of seizure occurrence in catamenial epilepsy," Epilepsy Research 15(1), 47-52, 1993. (Seizures are more frequent at ovulation, during the two days before menstruation, and during menstruation.)

M. S. Myslobodsky, "Proconvulsant and anticonvulsant effects of stress--the role of neuroactive steroids," Neuroscience & Biobehavioral Reviews 17(2_, 129-139, 1993. (Discusses steroid-induced sedation, excitatory steroids, stress and epilepsy, GABA and respiratory functions, and asymmetric brain injury.)

P. Berbel, et al., "Organization of auditory callosal connections in hypothyroid adult rats," European J. of Neuroscience 5(11), 1465-1478, 1993.(Changes in cortical connectivity related to epilepsy associated with early hypothyroidism.)

D. A. Marks and B. L. Ehrenberg, "Migraine-related seizures in adults with epilepsy, with EEG correlation," Neurology 43(12), 2475-2483, 1993. ("Patients with catamenial epilepsy and patients with migraine with aura were at an increased risk for an association between..." migraine and epilepsy.)

R. D. Brinton, "The neurosteroid 3-alpha-hydroxy-5-alpha-pregnan-20-one induces cytoarchitectural regression in cultured fetal hippocampal neurons," J. of Neuroscience 145(5 part 1), 2763-2774, 1994. J. W. Phillis and M. H. O'Regan, "Effects of estradiol on certain cortical neurons and their responses to adenosine," Br. Res. Bull. 20(2), 151-155, 1988.

J. O. McNamara, "Human hypoxia and seizures: Effects and interactions," Advances in Neurology 26, S. Fahn, et al., eds., Raven Press, N.Y., 1979. (Seizures can cause hypoxia, etc.)

M. R. Liebowitz, et al., "Lactate provocation of panic attacks: 2. Biochemical and physiological findings." Arch. Gen. Psychiatry 42(7), 709-719, 1985. "Before receiving lactate, patients showed higher heart rates than controls and also signs of hyperventilation." R. H. Mattson, et al., "Treatment of seizures with medroxyprogesterone acetate: Preliminary report," Neurology 34, 1255-7, 1984. M. W. Newmark, et al, "Catamenial epilepsy: A review," Epilepsia 21, 281-300, 1980.

J. W. Phillis and M. H. O'Regan, "Effects of estradiol on cerebral cortex neurons and their responses to adenosine," Br. Res. Bull. 20(2), 151-155, 1966. (Antagonism to endogenous adenosine may account for the excitant actions of estradiol in the brain.)

J. W. Phillis, et al., "Acetylcholine output from the ischemic rat cerebral cortex: Effects of adenosine agonists," Br. Res. 613(2), 337-340, 1993. (Acetylcholine enhances excitotoxicity, could contribute to ischemic brain injury.)

T. Backstrom, "Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle," Acta Neurol. Scand. 54, 321-347, 1976. (Seizures are more frequent at menstruation and ovulation.) T. Backstrom, et al., "Effects of intravenous progesterone infusion on the epilepsy discharge frequency in women with partial epilepsy," Acta Naurol. Scan. 69(4), 240-248, 1984.

A. W. Zimmerman, "Hormones and epilepsy," Neurol. Clin. 4(4), 853-861, 1985. "Progesterone appears to be especially effective in treating seizures." J. Bauer, et al., "Catamenial seizures--an analysis," Nervenarzt 66(10), 760-769, 1995. "...when anticonvulsants have failed to suppress seizures, progesterone or progesterone-derivates have been administered with success." R. H. Mattson, et al., "Seizure frequency and the menstrual cycle: a clinical study," Epilepsia 22, 242, 1981. J. Logothetis, et al., "The role of estrogens in catamenial exacerbation of epilepsy," Neurology (Minneap) 9, 352-360, 1959. J Laidlaw, "Catamenial epilepsy," Lancet 2, 1235-7, 1956. S. Landgren and O. Selstam, "Interaction between 17-beta-oestradiol and 3alpha-hydroxy-5alpha pregnane- 20-one in the control of neuronal excitability in slices from the hippocampus in vitro of guinea-pigs and rats," Acta Physiologica Scandinavica 154(2), 165-176, 1995. C. A. Frye, "The neurosteroid 3 alpha, 5 alpha-THP has antiseizure and possible neuroprotective effects in an animal model of epilepsy," Brain Research 696(1-2), 113-120, 1995.

G. K. Herkes, "Drug treatment of catamenial epilepsy," CNS Drugs 3(4), 260-266, 1995. (Mentions use of diuretics, progesterone, and the very high incidence of premenstrucal seizure, and of abnormal menstrual cycles in women with epilepsy.)

E. Spiegel and H. Wycis, "Anticonvulsant effects of steroids," J. Lab. Clin. Med. 33, 945-957, 1947.

G. Holmes, "Anticonvulsant effect of hormones on seizures in animals," 265-268, in: R. Porter, R. H. Mattson, A. Ward, and M. Dam, eds., Advances in Epileptology, 15th Epilepsy International Symposium, New York, Raven Press, 1984.

H. W. Zimmerman, et al., "Medroxyprogesterone acetate in the treatment of seizures associated with menstruation," J. Pediatr. 83, 959-963, 1973. R. H. Mattson, et al., "Medroxy-progesterone treatment of women with uncontrolled seizures," Epilepsia 22, 242, 1981. A. Rosenfield, et al., "The Food and Drug Administration and medroxyprogesterone acetate: What are the issues?" JAMA 249, 2922-2928. 1983. V. Valenzuela and L. S. Benardo, "An in vitro model of persistent epileptiform activity in neocortex," Epilepsy Research 21(3), 195-204, 1995. C. A. Slandley, et al., "Magnesium sulfate reduces seizures induced by central administration of the excitatory amino acid N-methyl-D-aspartate in rats," Hypertension in Pregnancy 14(2), 235-244, 1995. ("Magnesium is a physiological blocker of the NMDA receptor.") M. Simonale, et al., "Adenosine JA(1) receptors in the rat brain in the kindled model of epilepsy," Eur. J. of Pharmac. 265(3), 121-124, 1994. (Adenosine has potent anticonvulsive effects in various seizure models.) P. S. Timiras and H. F. Hill, Chapter 43, in Antiepileptic Drugs: Mechanisms of Action, ed. by G. H. Glaser, et al, Raven Press, N.Y., 1980. (Estrogens increase cortical excitability, lower convulsive thresholds, and are clearly associated with certain cases of petit mal epilepsy. "The mechanisms of this so-called 'catamenial' epilepsy are unknown. Water retention and electrolyte changes in the brain...have been implicated..." "...acetazolamide (diamox), a carbonic anhydrase inhibitor and diuretic, is successful in the treatment of many cases of these seizures, and in refractory cases progestational agents are effective." "...seizures were more severe and frequent during the estrogen-dominated preovulatory phase of the menstrual cycle than in the progesterone-dominated postovulatory phase." "...ACTH may trigger epileptic convulsions by increasing intracellular sodium concentration throughout the body." "Progesterone can effectively reduce the frequency and severity of intractable seizures associated with menstruation..." "Considering the markedly proconvulsant effects of estrogens, it is surprising that the differential effects of sex hormones on central neurotransmitter mechanisms have been only sparingly investigated." "...estradiol decreases monoamine oxidase activity and increases choline acetyltransferase activity in various brain regions." "...hypothyroidism in perinatal animals has striking suppressant effects on GABA metabolism and also causes a persistent lowering of electroconvulsive threshold.")

P. S. Timiras and H. F. Hill, "Antiepileptic drugs," Chapter 43; E. Roberts, "Epilepsy and antiepileptic drugs: A speculative synthesis," Chapter 44, in Antiepileptic Drugs: Mechanisms of Action, ed. by G. H. Glaser, et al., Raven Press, New York, 1980. E. V. Nikushkin, et al.,"Relationship between peroxidation and phospholipase hydrolysis of lipids in synaptosomes," B.E.B.M.107(2)183-186, 1989. Free unsaturated fatty acids are liberated in nerve endings and contribute to lipid peroxidation in epileptic seizures. P. A. Long, et al., "Importance of abnormal glucose tolerance (hypoglycemia and hyperglycemia) in the aetiology of pre-eclampsia," Lancet 1, 923-925, 1977.

M. M. Singh, "Carbohydrate metabolism in pre-eclampsia," Br. J. Obstet. Gynaecol. 83, 124-131, 1976.

N. A. Ziboh, et al., Prostaglandins 5, 233, 1974. (Eicosatrienoic (20:3 n-9) acid is a potent inhibitor of prostaglandin synthetase.) C. Galli and C. Spagnuolo, "The release of brain free fatty acids during ischaemia in essential fatty acid-deficient rats," J. of Neurochemistry 26, 401-404, 1976.

B. Meldrum, "Excitatory amino acids and anoxic-ischemic brain damage," Trends Neurosci. 8, 47-48, 1985.

B. Halliwell, "Oxidants and human disease: Some new concepts," FASEB J. 1, 358-364, 1987. "...injury to the brain causes release of metal ions that stimulate lipid peroxidation." "..lipid peroxidation...could be important in spreading injury to adjacent cells...." P.H. Chan, et al., "Effects of excitatory neurotransmitter amino acids on swelling of rat brain cortical slices," J. Neurochem. 33, 1309, 1979. P. H. Chan and R. A. Fishman, "Alterations of membrane integrity and cellular constituents by arachidonic acid in neuroblastoma and glioma cells," Brain Res. 248, 151, 1982.

T. O. Kokate, et al., "Neuroactive steroids protect against pilocarpine- and kainic acid-induced limbic seizures and status epilepticus in mice," Neuropharmacology 35(8), 1049-1056, 1996. (With a second dose, "complete protection from the...limbic seizures and status epilepticus was obtained.") J. W. Phillis, et al., "Effect of adenosine receptor agonist on spontaneous and K+-evoked acetylcholine release from the in vivo rat cerebral cortex," Brain Res. 605(2), 293-297, 1993.

J. W. Phillis, et al., "Acetylcholine output from the ischemic rat cerebral cortex: Effectss of adenosine agonists," Brain Res. 613(2), 337-340, 1993. (Acetylcholine enhances excitotoxic depolarization, intracellular calcium levels, and neural degeneration, and could contribute to ischemic brain injury.

R. L. Grief, "Thyroid status influences calcium ion accumulation and retention by rat liver mitochondria," Proc. Soc. Exp. Biol. & Med. 189(1), 39-44, 1988.

L. G. Cleland, et al., "Effects of dietary n-9 eicosatrienoic acid on the fatty acid composition of plasma lipid fractions and tissue plasma lipids," Lipids 31(8), 829-837, 1996. "Dietary enrichment with ETrA warrants further investigation for possible beneficial effects in models of inflammation and autoimmunity, as well as in other conditions in which mediators derived from n-6 fatty acids can affect homeostasis adversely." A. A. Starkov, et al., "Regulation of the energy coupling in mitochondria by some steroid and thyroid hormones," Bioch. Biophys. Acta 1318(1-2), 173-183, 1997. (Thyroid and progesterone improve respiratory efficiency, lowering oxygen consumption which restoring energy production.) R. B. Gibbs, et al., "Effects of estrogen on potassium stimulated acetylcholine release in the hippocampus and overlying cortex of adult rats," Brain Res. 749(1), 143-146, 1997. (Increased response.) I. V. Gusakov, et al., "Investigation of the role of free-radical processes in epilepsy and epileptogenesis," Bull. Exp. Biol. & Medicine 117(2), 206, 1994.

B. K. Shakenova, "A new treatment of epilepsy resistant to traditional antiseizure pharmacotherapy," Bull. Exp. Biol. & Medicine 117(2), 227, 1994. (Antihypoxant with antioxidant activity.) R. N. Rzaev and M. N. Aliev, "The use of antioxidants in the treatment of tic-accompanied hyperkineses in children," Bull. Exp. Biol. & Medicine 117(2), 222, 1994.

D. A. Sutkovoi and N. I. Lisyanyi, "Relationship between the kinetics of lipid peroxidation and autoimmune reactions after craniocerebral injury," Bull. Exp. Biol. & Medicine 117(2), 2, 1994. Winfried G. Rossmanith, "Gonadotropin secretion during aging in women: Review article," Exp. Gerontology 30(3/4) 369-381, 1995. "...major functional derangements, primarily at a hypothalamic rather than a pituitary site, have been determined as concomitants of aging in women." "...aging may impair the negative feedback sensitivity to ovarian sex steroids...." Hormonal changes at menopause "may represent the sum of functional aberrations that were initiated much earlier in life...." "...prolonged estrogen exposure facilitates the loss of hypothalamic neurons...."

J. R. Brawer, et al., "Ovary-dependent degeneration in the hypothalamic arcuate nucleus," Endocrinology 107, 274-279, 1980. J. Herbert and S. Zuckerman, "Ovarian stimulation from cerebral lesion in ferrets," J. Endocrinology 17(4), 433-443, 1958. G. C. Desjardins, "Estrogen-induced hypothalamic beta-endorphin neuron loss: A possible model of hypothalamic aging," Exp. Gerontology 30(3/4), 253-267, 1995. "This loss of opioid neurons is prevented by treatment with antioxidants indicating that it results from estradiol-induced formation of free radicals." "...this beta-endorphin cell loss is followed by a compensatory upregulation of mu opioid receptors in the vicinity of LHRH cell bodies." Resulting supersensitivity of the cells results "in chronic opioid suppression of the pattern of LHRH release, and subsequently that of LH." The neurotoxic effects of estradiol cause a "cascade of neuroendocrine aberrations resulting in anovulatory acyclicity." Treatment with an opiod antagonist "reversed the cystic morphology of ovaries and restored normal ovarian cycles" in estrogen-treated rats. G. B. Melis, et al., "Evidence that estrogens inhibit LH secretion through opioids in postmenopausal women using naloxone," Neuroendocrinology 39, 60-63, 1984.

H. J. Sipe, et al., "The metabolism of 17 beta-estradiol by lactoperoxidase: A possible source of oxidative stress in breast cancer," Carcinogenesis 15(11), 2637-2643, 1994. "...molecular oxygen is consumed by a sequence of reactions initiated by the glutathione thiyl radical. ...the estradiol phenoxyl radical abstracts hydrogen from...NADH to generate the NAD radical." "...the futile metabolism of micromolar quantities of estradiol catalyzes the oxidation of much greater concentrations of biochemical reducing cofactors, such as glutathione and NADH, with hydrogen peroxide produced as a consequence." S. Santagati, et al., "Estrogen receptor is expressed in different types of glial cells in culture," J. Neurochem. 63(6), 2058-2064, 1994. "...in all three types of glial cell analyzed in almost equal amounts..." D. X. Liu and L. P. Li, "Prostaglandin F-2 alpha rises in response to hydroxyl radical generated in vivo," Free Radical Biol. Med. 18(3), 571-576, 1995. "Free radicals and some free fatty acids, such as arachidonic acid metabolites...may form a feedback loop in which generation of one type leads to formation of the other." "Prostaglandin F-2 alpha dramatically increased in response to hydroxyl radical generation...." J. Owens and P. A. Schwartzkroin, "Suppression of evoked IPSPs by arachidonic acid and prostaglandin F-2 alpha," Brain Res. 691(1-2), 223-228, 1995. "These findings suggest that high levels of AA and its metabolites may bias neurons towards excitation." [Estrogen appears to support this excitatory system at every level, while prostaglandin F2 alpha alters steroid balance, by suppressing progesterone synthesis.] J. G. Liehr, et al., "4-hydroxylation of estradiol by human uterine myometrium and myoma microsomes: Implications for the mechanism of uterine tumorigenesis," Proc Natl Acad Sci USA 92(20), 9220-9224, 1995. "... elicits biological activities distinct from estradiol, most notably an oxidant stress response induced by free radicals generated by metabolic redox cycling reactions."

J. G. Liehr and D. Roy, "Free radical generation by redox cycling of estrogens," Free Rad. Biol. Med. 8, 415-423, 1990. P. Aschheim, "Resultats fournis par la greffe heterochrone des ovaires dan l'etude de la regulation hypothalamo-hypophyso-ovarienne de la ratte senile," Gerontologia 10, 65-75, 1964/65. "Our last experiment, grafting ovaries...into senile rats which had been castrated (ovariectomized) when young, and its result, the appearance of estrous cycles, seems explicable by this hypothesis. Everything happens as if the long absence of ovarian hormones... had kept the cells of the hypothalamus in the state of youth. It's as if the messages of the circulating steroids fatigued the hypothalamic memory." "What are the factors that cause this diminution of the hypothalamic sensitivity...? Kennedy incriminates a decrease in the cellular metabolism in general...."

P. Ascheim, "Aging in the hypothalamic-hypophyseal-ovarian axis in the rat," pp. 376-418 in: A. V. Everitt and J. A. Burgess, editors, Hypothalamus, Pituitary and Aging, C. C. Thomas, Springfield, 1976. C. A. Frye and J. D. Sturgis, "Neurosteroids affect spatial reference, working, and long-term memory of female rats," Neurobiol. Learn. Memory 64(1), 83-96, 1995. [Female rats take longer to acquire a spatial task during behavioral estrus.] (CA Frye, boston univ., dept biol, behavioral neurosci lab, boston 02215) "Estrus-associated decrements in a water maze task are limited to acquisition," Physiol. Behav. 57(1), 5-14, 1995.

C. A. Kristensen, et al., "Effect of estrogen withdrawal on energy-rich phosphates and prediction of estrogen-dependence monitored by in vivo 31P magnetic resonance spectoscopy of four human breast cancer xenografts," Cancer Research 55(8), 1664-1669, 1995. This is a very important confirmation of the idea that estrogen, by blocking energy, constrains cell function.

A. J. Roberts and L. D. Keith, "Corticosteroids enhance convulsion susceptibility via central mineralocorticoid receptors," Psychoneuroendocrinology 20(8), 891-902, 1995. ("...increase corticosterone levels are associated with increased severity of ethanol, pentobarbitol, and diazepam withdrawal. Further work with chemical convulsants suggests that mineralocorticoid receptors mediate excitatory effects of corticosteroids on convulsion susceptibility. The circadian rhythm in convulsion susceptibility varies with the circadian rhythm of plasma corticosterone levels and MR binding." "...MR are substantially bound at rest and maximally occupied during the circadian peak in corticosteroid levels and during stressor exposure, these receptors are implicated in the maintenance of and in changes in the arousal state of animals.") L. Murri, et al., "Neuroendocrine evaluation in catamenial epilepsy," Funct. Neurol. 1(4) 399-403, 1986. "Our data showed a reduction of luteal phase progesterone secretion; an imbalanced secretion of ovarian steroids plays a role in the catamenial exacerbation of epilepsy." S. Bag, et al., "Pregnancy and epilepsy," J. Neurol. 236(5), 311-313, 1989.

"Patients with increased seizure frequency had significantly higher oestrogen levels, lower level of progesterone...." "...abortions and status epilepticus had high serum oestrogen levels." M. I. Balabolkin, et al., "The role of the female sex hormones in the pathogenesis of catamenial epileptic seizures," Ter. Arkh. 66(4), 68-71, 1994. "...a tendency to deficient luteal phase and relative hyperestrogenemia in all the cycle phases." C. A. Guerreiro, "Ovulatory period and epileptic crisis," Arq. Neuropsiquiatr. 49(2), 198-203, 1991. "We think the estrogen peak is probably the main cause of the increased frequency of epileptic seizures during the ovulatory period."

U. Bonuccelli, et al., "Unbalanced progesterone and estradiol secretion in catamenial epilepsy," Epilepsy Res. 3(2), 100-106, 1989. (Luteal secretion ratio, progesterone to estrogen, was significantly reduced in patients versus controls.)

T. Backstrom, "Epilepsy in women," Experientia 32(2), 248-249, 1976. "...a significant positive correlation between estrogen/progesterone ratio and scores of fits."

A. G. Herzog, "Hormonal changes in epilepsy," Epilepsia 36(4), 323-326, 1995. A. G. Herzog, "Progesterone therapy in women with partial and secondary generalized seizures," Neurology 45(9), 1660-1662, 1995. A. G. Herzog, "Reproductive endocrine considerations and hormonal therapy for women with epilepsy," Epilepsia 32(Suppl.6), S27-33, 1991. "Seizure frequency varies with the serum estradiol to progesterone ratio." "... propensity for onset at menarch and exacerbation of seizures during the months or years leading up to menopause..." polycystic ovarian syndrome and hypogonadotropic hypogonadism are significantly overrepresented among women with epilepsy.

R.H. Mattson and J. A. Cramer, "Epilepsy, sex hormones, and antiepileptic drugs," Epilepsia 26(Suppl. 1), S40-51, 1985. There were fewer seizures during the luteal phase but they increased when the progesterone level declined.

J.J. Jacono and J. M. Robertson, "The effects of estrogen, progesterone, and ionized calcium on seizures during the menstrual cycle of epileptic women," Epilepsia 28(5), 571-577, 1987. A positive relation of serum estrogen and seizures, negative relation between serum ionized calcium and seizures, and negative relation between serum estrogen and calcium. F. E. Jensen, et al., "Epileptogenic effect of hypoxia in the immature rodent brain," Ann. Neurol. 29(6),629-836, 1991. E. C. Wirrell, et al., "Will a critical level of hyperventilation-induced hypocapnia always induce an absence seizure?" Epilepsia 37(5), 459-462, 1996. A. Nehlig, et al., "Absence seizures induce a decrease in cerebral blood flow: Human and animal data," J. Cereb. Blood Flow Metab. 16(1), 147-155, 1996.

Some clinical laboratory findings in epilepsy: Folic acid, serum decrease, R. E. Davis, et al., "Serum pyridoxal, folate, and vitamin B12 levels in institutionalized epileptics," Epilepsia 16, 463-8, 1975.

Serum GGT, constantly elevated. Ewen and Griffiths, "Gamma-glutamyl transpeptidase: Elevated activities in certain neurologic diseases," Am. J. Clin. Pathol. 59, 2-9, 1973.

IgA, CSF decreased, F. Mora, et al.

Iron-binding capacity, total, serum decrease. F. Mora, et al. Magnesium, serum, decreased; between seizures. C S Babel, et al Prealbumin, CSF, increased, the only protein to increase in epileptics. F. Mora, et al.

Pyridoxine, serum, sometimes decreased. R. L. Searcy, Diagnostic Biochemistry, McGraw-Hill, 1969.

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A R T I C L E

Estriol, DES, DDT, etc.

A review of the use of estrogens reported in J.A.M.A. (only up to 1987) found nearly 200 different "indications" for its use. (Palmlund, 1996.) Using the conservative language of that journal, such use could be said to constitute wildly irresponsible "empirical" medical practice. More appropriate language could be used.

Pollution of the environment and food supply by estrogenic chemicals is getting increased attention. Early in the study of estrogens, it was noticed that soot, containing polycyclic aromatic hydrocarbons, was both estrogenic and carcinogenic. Since then, it has been found that phenolics and chlorinated hydrocarbons are significantly estrogenic, and that many estrogenic herbicides, pesticides, and industrial by-products persist in the environment, causing infertility, deformed reproductive organs, tumors, and other biological defects, including immunodeficiency. In the Columbia River, a recent study found that about 25% of the otters and muskrats were anatomically deformed.

Estrogenic pollution kills birds, panthers, alligators, old men, young women, fish, seals, babies, and ecosystems. Some of these chemicals are sprayed on forests by the US Department of Agriculture, where they enter lakes, underwater aquifers, rivers, and oceans. Private businesses spray them on farms and orchards, or put them into the air as smoke or vapors, or dump them directly into rivers. Homeowners put them on their lawns and gardens.

Natural estrogens, from human urine, enter the rivers from sewage. Many tons of synthetic and pharmaceutical estrogens, administered to menopausal women in quantities much larger than their bodies ever produced metabolically, are being added to the rivers.

In the same way that weak estrogens in the environment may become hundreds of times more estrogenic by synergistic interactions (J. A. McLachlan, et al., Science, June 7, 1996), combinations of natural, medical, dietary, and environmental estrogens are almost certain to have unexpected results. The concept of a "protective estrogen" is very similar to the idea of "protective mutagens" or "protective carcinogens," though in the case of estrogens, their promoters don't even know what the normal, natural functions of estrogen are.

In November, 1995, an international conference was held to study the problem of "Environmental endocrine-disrupting chemicals," and to devise strategies for increasing public awareness of the seriousness of the problem. Their "Statement from the work session" says "New evidence is especially worrisome because it underscores the exquisite sensitivity of the developing nervous system to chemical perturbations that result in functional abnormalities." "This work session was convened because of the growing concern that failure to confront the problem could have major economic and societal implications." "We are certain of the following: Endocrine-disrupting chemicals can undermine neurological and behavioral development and subsequent potential of individuals...." "Because the endocrine system is sensitive to perturbation, it is a likely target for disturbance." "Man-made endocrine-disrupting chemicals range across all continents and oceans. They are found in native populations from the Arctic to the tropics, and, because of their persistence in the body, can be passed from generation to generation." "...many endocrine-disrupting contaminants, even if less potent than the natural products, are present in living tissue at concentrations millions of times higher than the natural hormones." "The developing brain exhibits specific and often narrow windows during which exposure to endocrine disruptors can produce permanent changes in its structure and function."

In spite of this increased exposure to estrogens, there is a new wave of advertising of estrogenic substances, based on the idea that weak estrogens will provide protection against strong estrogens. The environmental background of estrogenic pollution already provides a continuous estrogenic exposure. In the 1940s, Alexander Lipshuts demonstrated that a continuous, weak estrogenic stimulus was immensely effective in producing, first fibromas, then cancer, in one organ after another, and the effect was not limited to the reproductive system. How is it possible that the idea of "protection" from a weak estrogen seems convincing to so many? Isn't this the same process that we saw when the nuclear industry promoted Luckey's doctrine of "radiation hormesis," literally the claim that "a little radiation is positively good for us"?

DES (diethyl stilbestrol) is one of the most notorious estrogens, because studies in humans revealed that its use during pregnancy not only caused cancer, miscarriages, blood clots, etc., in the women who used it, but also caused cancer, infertility, and deformities in their children, and even in their grandchildren. (But those transgenerational effects are not unique to it.)

Besides the absurd use of DES to prevent miscarriages, around 1950 it was also used to treat vulvovaginitis in little girls, for menstrual irregularity at puberty, to treat sterility, dysfunctional bleeding, endometriosis, amenorrhea, oligomenorrhea, dysmenorrhea, migraine headaches, nausea and vomiting, and painful breast engorgement or severe bleeding after childbirth.

DES is a "weak" estrogen, in the sense that it doesn't compete with natural estrogens for the "estrogen receptors." (Estriol binds more strongly to receptors than DES does: "Cytosolic and nuclear estrogen receptors in the genital tract of the rhesus monkey," J. Steroid Bioch. 8(2), 151-155, 1977.) Pills formerly contained from 5 to 250 mg. of DES. The 1984 PDR lists doses for hypogonadism and ovarian failure as 0.2 to 0.5 mg. daily. In general, dosage of estrogens decreased by a factor of 100 after the 1960s.

An aggressively stupid editorial by Alvin H. Follingstad, from the Jan. 2, 1978, issue of JAMA, pages 29-30, "Estriol, the forgotten estrogen?" is being circulated to promote the use of estriol, or the phytoestrogens. It argues that women who secrete larger amounts of estriol are resistant to cancer.

By some tests, estriol is a "weak estrogen," by others it is a powerful estrogen.

When estriol was placed in the uterus of a rabbit, only 1.25 mcg. was sufficient to prevent implantation and destroy the blastocyst. (Dmowski, et al., 1977.) Since the effect was local, the body weight of the animal doesn't make much difference, when thinking about the probable effect of a similar local contentration of the hormone on human tissues. The anti-progestational activity of estriol and estradiol are approximately the same. (Tamotsu and Pincus, 1958.)

When 5 mg. of estriol was given to women intravaginally, this very large dose suppressed LH within 2 hours, and suppressed FSH in 5 hours. Given orally, 8 mg. had similar effects on LH and FSH after 30 days, and also had an estrogenic effect on the vaginal epithelium.. These quick systemic effects of a "weak estrogen" are essentially those of a strong estrogen, except for the size of the dose. (Schiff, et al., 1978.)

When administered subcutaneously, estriol induced abortions and stillbirths (Velardo, et al.)

Another indication of the strength of an estrogen is its ability to cause the uterus to enlarge. Estriol is slightly weaker, in terms of milligrams required to cause a certain rate of uterine enlargement, than estradiol. (Clark, et al., 1979.) But isn't the important question whether or not the weak estrogen imitates all of the effects of estradiol, including carcinogenesis and blood clotting, in addition to any special harmful effects it might have?

When added to long-term culture of human breast cancer cells, estriol stimulated their growth, and overcame the antiestrogenic effects of tamoxifen, even at concentrations hundreds of times lower than that of tamoxifen. "The data do not support an antiestrogenic role for estriol in human breast cancer." (Lippman, et al., 1977.)

Studies of the urinary output of estriol/estradiol in women with or without breast cancer do not reliably show the claimed association between low estriol/estradiol and cancer, and the stimulating effect of estriol on the growth of cancer cells suggests that any alteration of the estrogen ratio is likely to be a consequence of the disease, rather than a cause. The conversion of estradiol to other estrogens occurs mainly in the liver, in the non-pregnant woman, as does the further metabolism of the estrogens into glucuronides and sulfates. The hormonal conditions leading to and associated with breast cancer all affect the liver and its metabolic systems. The hydroxylating enzymes are also affected by toxins. Hypothyroidism (low T3), low progesterone, pregnenolone, DHEA, etiocholanolone, and high prolactin, growth hormone, and cortisol are associated with the chronic high estrogen and breast cancer physiologies, and modify the liver's regulatory ability.

The decreased output of hormones when the fetal-placental system is dying is a natural consequence, since the placenta produces hormones, and during pregnancy converts estradiol to estriol. Since estradiol in excess kills the fetus, its conversion by the placenta to estriol is in accord with the evidence showing that estriol is the more quickly excreted form. (G. S. Rao, 1973.) The conversion of 16-hydroxy androstenedione and 16-hydroxy-DHEA into estriol by the placenta (Vega Ramos, 1973) would also cause fetal exhaustion or death to result in lower estriol production. But a recent observation that a surge of estriol production precedes the onset of labor, and that its premature occurrence can identify women at risk of premature delivery (McGregor, et al., 1995) suggests that the estriol surge might reflect the mother's increased production of adrenal androgens during stress. (This would be analogous to the situation in the polycystic ovary syndrome, in which excessive estradiol drives the adrenals to produce androgens.)

Estetrol, which has one more hydroxyl group than estriol, is a "more sensitive and reliable indicator of fetal morbidity than estriol during toxemic pregnancies," because it starts to decrease earlier, or decreases more, than estriol. (Kundu, et al., 1978.) This seems to make it even clearer that the decline of estriol is a consequence, not a cause, of fetal sickness or death.

A 1994 publication (B. Zumoff, "Hormonal profiles in women with breast cancer," Obstet. Gynecol. Clin. North. Am. (U.S.) 21(4), 751-772) reported that there are four hormonal features in women with breast cancer: diminished androgen production, luteal inadequacy, increased 16-hydroxylation of estradiol, and increased prolactin. The 16-hydroxylation converts estradiol into estriol.

A new technique for radiographically locating a hormone-dependent breast cancer is based on the fact that estriol-sulfate is a major metabolite of estradiol. The technique showed the tumor to have about a six times higher concentration of estriol-sulfate than liver or muscle. (N. Shimura, et al., "Specific imaging of hormone-dependent mammary carcinoma in nude mice with [131I]-anti-estriol 3-sulfate antibody," Nucl. Med. Biol. (England) 22(5), 547-553, 1995.)

Another association of elevated conversion of estradiol to estriol with disease was found to occur in men who had a myocardial infarction, compared to controls who hadn't. (W. S. Bauld, et al., 1957.)

The estrogens in clover have been known for several decades to have a contraceptive action in sheep, and other phytoestrogens are known to cause deformities in the genitals, feminization of men, and anatomical changes in the brain as well as functional masculinization of the female brain. (Register, et al., 1995; Levy, et al, 1995; Clarkson, et al., 1995; Gavaler, et al., 1995.) The effects of the phytoestrogens are very complex, because they modify the sensitivity of cells to natural estrogens, and also modify the metabolism of estrogens, with the result that the effects on a given tissue can be either pro-estrogenic and anti-estrogenic. For example, the flavonoids, naringenin, quercetin and kaempherol (kaempherol is an antioxidant, a phytoestrogen, and a mutagen) modify the metabolism of estradiol, causing increased bioavailability of both estrone and estradiol. (W. Schubert, et al., "Inhibition of 17-beta-estradiol metabolism by grapefruit juice in ovariectomized women," Maturitas (Ireland) 30(2-3), 155-163, 1994.)

Why do plants make phytoestrogens? There is some information indicating that these compounds evolved to regulate the plants' interactions with other organisms--to attract bacteria, or to repel insects, for example, rather than just as pigment-forming materials. (Baker, 1995.) The fact that some of them bind to our "estrogen receptors" is probably misleading, because of their many other effects, including inhibiting enzyme functions involved in the regulation of steroids and prostaglandins. Their biochemistry in animals is much more complicated than that of natural estrogens, which is itself so complicated that we can only guess what the consequences might be when we change the concentration and the ratio of substances in that complex system. (See quotation from Velardo, et al., page 6)

These "natural" effects in sheep were forerunners of the observed estrogenic effects in wild animals, caused by pollutants. Twenty-five years ago I reviewed many of the issues of estrogen's toxicity, and the ubiquity of estrogenic substances, and since then have regularly spoken about it, but I haven't concentrated much attention on the phytoestrogens, because we can usually just choose foods that are relatively free of them. They are so often associated with other food toxins--antithyroid factors, inhibitors of digestive enzymes, immunosuppressants, etc.--that the avoidance of certain foods is desirable. Recently an advocate of soybeans said "if they inhibit the thyroid, why isn't there an epidemic of hypothyroidism in Asia?" I happened to hear this right after seeing newspaper articles about China's problem with 100,000,000 cretins; yes, Asia has endemic hypothyroidism, and beans are widely associated with hypothyroidism.

When I first heard about clover-induced miscarriages in sheep, I began reading about the subject, because it was relevant to the work I was doing at that time on reproductive aging. Sheep which are adapted to living at high altitude, where all animals have reduced fertility, have an adaptive type of hemoglobin, with a greater affinity for oxygen. Fetal hemoglobin, in animals at sea-level, has a great affinity for oxygen, making it possible for the fetus to get enough oxygen, despite its insulation from the mother's direct blood supply. The high-altitude-tolerant sheep have hemoglobin which is able to deliver sufficient oxygen to the uterus to meet the needs of the embryo/fetus, even during relative oxygen-deprivation. These sheep are able to sustain pregnancy while grazing on clover. It seemed evident that estrogen and high altitude had something in common, namely, oxygen deprivation, and it also seemed evident that these sheep provided the explanation for estrogen's abortifacient effects.

Estrogen's effects, ranging from shock to cancer, all seem to relate to an interference with the use of oxygen. Different estrogens have different affinities for various tissues, and a given substance is likely to have effects other than estrogenicity, and the presence of other substances will modify the way a tissue responds, but the stressful shift away from oxidative production of energy is the factor that all estrogens have in common. Otherwise, how could suffocation and x-irradiation have estrogenic effects?

Pharmaceutical misrepresentations regarding the estrogens rank, in terms of human consequences, with the radiation damage from fall-out from bomb tests and reactor-leaks, with industrial pollution, with degradation of the food supply--with genocide, in fact.

Advertising gets a bad name when it can't be distinguished from mass murder. At a certain point, we can't afford to waste our time making subtle distinctions between ignorance and malevolence. If we begin pointing out the lethal consequences of "stupid" or quasi-stupid commer- cial/governmental policies, the offenders will have the burden of proving that their actions are the result of irresponsible ignorance, rather than criminal duplicity. From the tobacco senators to the chemical/pharmaceutical/food/energy industries and their agents in the governmental agencies, those who do great harm must be held responsible.

The idea of corporate welfare, in which public funds are given in massive subsidies to rich corporations, is now generally recognized. Next, we have to increase our consciousness of corporate responsibility, and that ordinary criminal law, especially RICO, can be directly applied to corporations. It remains to be seen whether a government can be made to stop giving public funds to corporations, and instead, to begin enforcing the law against them--and against those in the agencies who participated in their crimes.

In the U.S., the death penalty is sometimes reserved for "aggravated homicide." If those who kill hundreds of thousands for the sake of billions of dollars in profits are not committing aggravated homicide, then it must be that no law written in the English language can be objectively interpreted, and the legal system is an Alice in Wonderland convenience for the corporate state.

Copyright: Raymond Peat, PhD 1997

PO Box 5764 Eugene, OR 97405

REFERENCES

Dr. Bernard Weiss, Dept. of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY. and 17 others, work session on environmental endocrine-disrupting chemicals, Nov. 5-10, 1995.

Isaac Schiff, et al., "Effects of estriol administration on the hypogonadal woman," Fertil. Steril. 30(3), 278-282, 1978.

N. P. J. Kundu, et al., "Sequential determination of serum human placental lactogen, estriol, and estetrol for assessment of fetal morbidity," Obstet. Gynecol. 52(5), 513-520, 1978.

M. E. Lieberman, et al., "Estrogen control of prolactin synthesis in vitro," P.N.A.S. (USA) 75(12), 5946-5949, 1978.

Marc Lippman, et al., "Effects of estrone, estradiol and estriol on hormone-responsive human breast cancer in long term tissue culture," Cancer Res. 37(6), 1901-1907, 1977.

W. P. Dmowski, et al., "Effect of intrauterine estriol on reproductive function in the rabbit," Fertil. Steril. 28(3), 262-8, 1977.

W. S. Bauld, et al, "Abnormality of estrogen metabolism in human subjects with myocardial infarction," Canadian Jour. Biochem. and Physiol. 35(12), 1277-1288, 1957. (The conversion of estradiol to estriol was higher in men with previous myocardial infarction than in controls.)

R. A. Edgren and D. W. Calhoun, "Interaction of estrogens on the vaginal smear of spayed rats," Am. J. Physiol. 189(2), 355-357, 1957. "Employing the vaginal smear as an index of effect, combinations of various estrogenic substances were tested for interaction. Studies were concentrated at the approximate 50% response level." "These data are interpreted as indicating simple additive relationships among the compounds tested." "Curiously then, estrogens that showed inhibitory interrelationships when tested on uterine growth had simple additive interactions when tested on the vaginal smears." "...it seems reasonable to postulate that a given hormone combination may evoke differing levels of response in different target organs, and particularly, that increase of one component may increase response at one site while decreasing it at another. Many steroids...are present in the mammalian circulation during various phases of the sex cycle and are known to modify the effects of any given estrogen. This hormonal multiplicity apparently constitutes an estrogen-buffering system and supports the hypothesis that sexual responses depend '...upon a rather precise hormonal homeostasis.'"

R. C. Merrill, "Estriol: A review," Physiol. Revs. 38(3), 463-480, 1958. "...estriol itself is a potent estrogen, contrary to the usual conception of its being just a metabolite of the more potent estrone and estradiol. Although ordinarily less effective than estrone and estradiol in promoting vaginal cornification, estriol, under optimum conditions, approaches their effectiveness for this purpose. Estriol is more potent than estrone or estradiol in causing establishment and opening of the vaginal orifice, in promoting imbibition of uterine fluid, in increasing lactic dehydrogenase activity in the uterus, and in stimulating mitotic activity in the epidermis of the mouse ear. The activity of estriol is of the same order of magnitude as that of estrone and estradiol in other estrogenic actions, such as to promote uterine growth at low concentrations (although less effective at high doses), to increase beta-glucuronidase and reduced diphosphopyridine nucleotide oxidase activity in the uterus, to reduce motility of the uterus in vivo, and to stimulate ovarian growth, body weight, phagocytosis of carbon by reticuloendothelial cells, ciliary movements of the buccopharyngeal mucose of the frog, and new bone formation. The fibromatogenic activity of estriol in the guinea pig is much less than that of estrone or estradiol. Recent experiments suggest and partly verify the hypothesis that estriol stimulates the cervix, vagina and vulva more effectively than estrone or estradiol, whereas the latter are much more effective on the corpus uteri."

T. Miyake and G. Pincus, "Anti-progestational activity of estrogens in rabbit endometrium," Proc. Soc. Exptl. Biol. and Med. 99(2) 478-482, 1958. "The anti-progestational activity of 4 estrogens--estrone, estradiol, estriol, and stilbestrol--administered subcutaneously with progesterone into Clauberg rabbits has been demonstrated...." "The anti-progestational activities of these estrogens are approximately the same." "...estrogen may depress reactivity of the endometrium to progesterone rather than neutralize or inactivate progesterone in the body."

J. T. Velardo, et al., "Effect of various steroids on gestation and litter size in rats," Fertility and Sterility 7(4), 301-311, 1956. "...certain metabolites of estrogenic and progestative substances that were previously considered to be 'weak' or inert may well play a role in the reproductive process." "We have been impressed with the probability that any endocrine receptor-organ response is not accomplished by the independent action of one hormone alone. It appears more likely that such response is the physiological expression of the sum total of the biologic hormones and their metabolites in concert on the receptor organs." "The effect of estriol on the birth rate of these rats was more dramatic." "...when estriol was used before mating, it reduced the litter size to 66 per cent of the controls." "However, when the same dose was employed from the day of mating and daily thereafter beyond the time of usual implantation, 6 days later, a reduction of live births to 33 per cent of the controls was produced. In this experiment the medication was withheld until after ovulation had presumably occurred. The presence of placental scars and an increased incidence of abortions and stillbirths argues against the possibility that the fertile ova have been 'locked' by the estrogen in the tubes." "...the incidence of placental scars, abortions, and stillbirths further bears witness to the possibility that the steroids employed interfered with the optimum differentiation of progestational endometrial changes, rather than affecting any suppression of ovulatory mechanisms."

B. Register, et al., "Effect of neonatal exposure to diethylstilbestrol, coumestrol, and beta-sitosterol on pituitary responsiveness and sexually dimorphic nucleus volume," P.S.E.B.M. 208, 72, 1995.

J. R. Levy, et al., "Effect of prenatal exposure to the phytoestrogen genistein on sexual differentiation in rats," P.S.E.B.M. 208, 60, 1995.

B.D. Lyn-Cook, et al., "Methylation profile and amplification of proto-oncogenes in rat pancreas induced with phytoestrogens," PSEBM 208, 116, 1995.

J. S. Gavaler, et al., "Phytoestrogen congeners of alcoholic beverages: Current status,: PSEBM 208, 98, 1995.

A. I. Nwannenna, et al., "Clinical changes in ovariectomized ewes exposed to phytoestrogens and 17beta-estradiol implants," PSEBM 208, 92, 1995.

P. L. Whitten, et al., "Influence of phytoestrogen diets on estradiol action in the rat uterus," Steroids 59, 443-449, 1994. "Coumestrol did not antagonize the uterotrophic action of estradiol when administered either prior to, or jointly with, E2 treatment, or when administered orally or parenterally." "These findings contradict the assumption that all phytoestrogens are necessarily antiproliferative agents...."

M. E. Baker, "Endocrine activity of plant-derived compounds: An evolutionary perspective," PSEBM 208, 131, 1995.

I. Palmlund, "To cell from environment," Chapter 19 in Cellular and Molecular Mechanisms of Hormonal Carcinogenesis, published by Wiley-Liss.

J. H. Clark, et al., "Nuclear binding of the estrogen receptor: Heterogeneity of sites and uterotropic response," Steroid Hormone Receptor Systems, page 17, 1979.

P. Vega Ramos, et al., "Formation of oestriol from C19, 16-oxygenated steroids by microsomal preparations of human placenta," Res. on Steroids, vol. V, page 79, Proc. of the Fifth Meeting of the International Study Group for Steroid Hormones, edited by M. Finkelstein, et al., 1973.

G. S. Rao, "Enzymes in steroid metabolism," Res. on Steroids, vol. V, page 175, 1973.

L. H. Carter and C. B. Harrington, Administrative Law and Politics HarperCollins, 1991. "Capture occurs when agencies informally promote the very interests they are officially responsible for regulating." In 1925, Coolidge's appointment of "anti-public" W. E. Humphrey to the FTC led some of its former supporters to call for the abolition of the FTC.

"If nearly a century of regulatory history tells us anything, it is that the rules-making agencies of government are almost invariably captured by the industries which they are established to control." Robert Heilbroner, In the Name of Profit, 1972, p. 239. "Federal economic regulation was generally designed by the regulated interest to meet its own end, and not those of the public or the commonweal." Gabriel Kolko, The Triumph of Conservatism: A Reinterpretation of American History, 1900-1916, 1963.

"It is a given in the modern doctrine of most tort laws that the existence of potential liability if anything encourages citizens to use greater thoughtfulness and care in their daily actions, and no obvious reasons suggest the same dynamic should not affect public officials." Adm. Law. & Pols., p. 404. "That Congress decided, after the passage of the Fourteenth Amendment, to enact legislation specifically requiring state officials to respond in federal court for their failures to observe the constitutional limitations on their powers is hardly a reason for excusing their federal counterparts for the identical constitutional transgressions." "In situations of abuse, an action for damages against the responsible official can be an important means of vindicating constitutional guarantees...." Justice White, Butz v. Economou, p. 409, Adm. Law & Pols.

Ray Peat's Newsletter

Not for republication without written permission. Copyright 1997 Raymond Peat P.O. Box 5764, Eugene, OR 97405

What we call inflammation offers a good conceptual link between the studies on excitotoxicity or cellular stress, and the newer approaches to the treatment of aging and degenerative diseases, based on ideas of regeneration and development. Controlling inflammation becomes part of promoting regeneration..

Apoptosis is a type of cell death in which the cell appears to melt, with the DNA being cut into short fragments. It can be considered to be the end result of an extreme excitotoxic process. It should serve to stimulate nearby cells.

As the result of industrial promotion, including product advertising and grants for research, "weak estrogens" and "antioxidants" derived from soy are being discussed as means to prevent breast and prostate cancer, heart disease, stress and aging. Another so-called weak estrogen, estriol, is being promoted by drug companies for the "alternative medical" market, with the circulation of an editorial from JAMA, recommending it for preventing breast cancer.

Japanese women used to be very free of breast cancer, and when their children grew up in the U.S., their incidence of the disease was like that of Americans. How odd that the soybean should be singled out for responsibility. Japanese breast cancer incidence has risen sharply in recent years. Did they stop eating tofu? Did their traditional use of seaweed as food have nothing to do with their health? Did the traditional home-bound isolation of Japanese women, their avoidance of smoking and drinking, have no effect on hormones and cancer? Their calorie intake? Iodine and trace minerals? What types of protein and fat, in what quantities, did they use?

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A R T I C L E

Estrogen and brain aging in men and women: Depression, energy, stress

Although the incidence of Alzheimer's disease is 2 or 3 times as high among women as among men, there is a major campaign under way to convince the public that taking estrogen supplements will prevent the disease. Estrogen is now mainly promoted to prevent osteoporosis (another problem that is more common in women) and heart disease (which is more common in men).

This substance, which came into medical use as "the female hormone" for the treatment of "female problems," especially for improving fertility, and then for preventing fertility as the oral contraceptive, is now being aimed primarily at the post-reproductive population, for problems that are essentially unrelated to femininity. It is, in fact, being presented to the public as something to prevent major age-related conditions.

Brain degeneration, like osteoporosis, takes years to develop. Analysis of letters written by young women, for example, showed limited mental functioning in those who many years later developed Alzheimer's disease, and young women who have small bones are the ones most likely to develop osteoporosis later. It seems clear that the course of degenerative aging processes is set in young adulthood (or even earlier), and that it is never too early to be concerned with correcting processes that are going in the wrong direction. (See Walker, et al., 1988, and Smith, et al., 1992.)

In "The Biological Generality of Progesterone" (1979) I proposed that the life-long trajectory of energy production and longevity was strongly influenced by prenatal nutrition and progesterone. This idea was based on work by people such as Marion Diamond, who showed that prenatal progesterone enlarges the cortex of the brain, and that estrogen makes it smaller, and Leonell Strong, who showed that a treatment that lowered the estrogen function in a young mouse could produce cancer-free offspring for several generations. Strong's work was very encouraging, because it showed that biological problems that had been "bred in" over many generations could be corrected by some simple metabolic treatments.

Seeing these profoundly toxic long-range effects of estrogen, which shaped the animal's growth, development, function, and even its heredity, made it important to learn how estrogen works, because such fundamental changes covering the whole range of biology, produced by a simple little molecule, promised to reveal interesting things about the nature of life.

Aging is an energy problem, and in the brain, which has extremely high energy requirements, interference with the energy supply quickly causes cells to die.

I believe that estrogen's "principle," in all of its actions, is to interfere with the respiratory mode of energy production. This is an integrating principle that explains estrogen's immediate, direct effects on cells and organisms, which aren't explained by the idea that it acts on the genes through a specific "estrogen receptor." (It's hard to imagine, for example, how the "estrogen receptor" doctrine could explain the fact that a single injection of estrogen can kill a large portion of brain cells.) It explains why estrogen causes cells to take up water, allowing calcium to enter, activating various enzymes and cell division. On the organismic level, it explains why estrogen mimics "shock," releasing histamine and activating the nervous and glandular stress response system. The inefficiency of metabolism which doesn't use oxygen in the normal way causes glucose to be used rapidly, and this in itself is enough to trigger the release of pituitary ACTH and adrenal cortisol. The ACTH, and related hormones, liberate free fatty acids, which cells take up instead of glucose, and this (in the so-called Randall cycle) further limits the body's ability to oxidize glucose.

People have spoken of "cascades" in relation to the adrenal glucocorticoids (e.g., cortisol) and estrogen, leading to cell damage, but really both of these hormonal cascades have to be seen as part of a more general collapse of adaptive systems, as a result of both chronic and immediate inadequacies of energy production.

Estrogen activates the adrenal stress reaction by way of the hypothalamus and pituitary, by direct actions on the adrenal glands, and by a variety of indirect effects, such as the increase of free fatty acids. It activates the excitotoxic glutamic acid pathway, and interferes with protective adenosine inhibition of nerves. It has both direct and indirect ways of promoting the formation of nitric oxide and carbon monoxide. These, and other estrogen-promoted factors, quickly and seriously interfere with mitochondrial respiration. Many of these effects contribute to increased intracellular calcium and free radical production, contributing to both the excitatory excess and the energy deficit.

The biochemical details of these cascades are mainly interesting because they show how many different kinds of stress converge on a few physiological processess--mitochondrial energy production, cellular excitation, and intercellular communication--which, when damaged thousands of times, lead to the familiar states of old age. These few functions, damaged by an infinite variety of stresses, have their own complexly adaptive ways of deteriorating, producing the various degenerative diseases.

This perspective brings dementia, heart failure, autoimmunity, immunodeficiency and other diseases of aging together, in ways that allow generalized therapeutic and preventive approaches.

The antistress, antiestrogen approaches become fundamental to prevention of aging.

The pro-estrogenic nature of the unsaturated fatty acids is probably the biggest barrier to the radical elimination of degenerative diseases. Various saturated fatty acids, including butyric, octanoic, and palmitic, have protective effects on mitochondrial respiration.

Progesterone is the basic brain-protective antiestrogen. It works to protect the brain at many levels (preventing lipid peroxidation, exitotoxicity, nitric oxide damage, energy deficit, edema, etc.) and it promotes repair and recovery.

Progesterone in most cases has effects opposite to estrogen's, improving mitochondrial energy production while preventing excessive excitation. Along with pregnenolone, progesterone is recognized as a neurosteroid with anti-excitotoxic actions, with the ability to promote repair and regeneration of the nervous system. (Roof, Stein, Faden; Schumacher, et al.; Baulieu.)

The use of aspirin, which reduces inflammation and inhibits the formation of neurotoxic prostaglandins, is known to be associated with a lower incidence of Alzheimer's disease, and in other contexts, it offers protection against estrogen. Naloxone, the antiendorphin, has been found to reverse some of the cumulative effects of stress, restoring some pituitary and ovarian function, and it promotes recovery after brain injury; in a variety of ways, it corrects some of estrogen's toxic effects.

Adenosine helps to maintain brain glycogen stores, which are lost in stress and aging. Vitamin B12 protects against nitric oxide, and improves alertness.

Pyruvic acid has brain-protective effects, apparently through its decarboxylation (producing carbon dioxide) rather than through its use as an energy source, since other ketoacids are similarly protective. (The ketoacids occur in some natural foods.) The directly brain-protective effect of carbon dioxide offers many clues that should be interpreted in relation to estrogen's toxicity, since many of their effects on nerves are opposite. Estrogen blocks the production of energy while it stimulates nerve cells to use energy more rapidly, and carbon dioxide promotes the production of energy, while restraining the excitation which expends energy. The presence of carbon dioxide is an indicator of proper mitochondrial respiratory functioning.

Pharmaceutical blockers of glutamic acid transmission, and of calcium and sodium uptake, prevent some deterioration following brain injury, but the most physiological way to protect against those toxic processes is to maintain metabolic energy at a high level. Magnesium, which is protective against excitatory damage and is a calcium antagonist, tends to be retained in proportion to the activity of thyroid hormone.

As I have discussed previously, progesterone alone has brought people out of post-epileptic dementia and senile dementia, but it is reasonable to use a combined physiological approach, including thyroid.

Besides providing new insights into biological energy and aging, the recognition that estrogen activates the stress hormone system--the pituitary-adrenal system--also provides clear insights into other problems, such as the polycystic ovary syndrome, hirsutism, adrenal hyperplasia, Cushing's disease, etc.

REFERENCES

[The references are clustered into groups, showing estrogen's indirect toxicity through its activation of the adrenal hormones, its direct brain-toxicity, and some of the interactions between these and fats, nitric oxide, etc.]

.

Stress 1996 Jul;1(1):1-19 Stress, Glucocorticoids, and Damage to the Nervous System: The Current State of Confusion. Sapolsky RM Department of Biological Sciences, Stanford University, Stanford, CA 94305. An extensive literature demonstrates that glucocorticoids (GCs), the adrenal steroids secreted during stress, can have a broad range of deleterious effects in the brain. The actions occur predominately, but not exclusively, in the hippocampus, a structure rich in corticosteroid receptors and particularly sensitive to GCs. The first half of this review considers three types of GC effects: a) GC-induced atrophy, in which a few weeks' exposure to high GC concentrations or to stress causes reversible atrophy of dendritic processes in the hippocampus; b) GC neurotoxicity where, over the course of months, GC exposure kills hippocampal neurons; c) GC neuroendangerment, in which elevated GC concentrations at the time of a neurological insult such as a stroke or seizure impairs the ability of neurons to survive the insult. The second half considers the rather confusing literature as to the possible mechanisms underlying these deleterious GC actions. Five broad themes are discerned: a) that GCs induce a metabolic vulnerability in neurons due to inhibition of glucose uptake; b) that GCs exacerbate various steps in a damaging cascade of glutamate excess, calcium mobilization and oxygen radical generation. In a review a number of years ago, I concluded that these two components accounted for the deleterious GC effects. Specifically, the energetic vulnerability induced by GCs left neurons metabolically compromised, and less able to carry out the costly task of containing glutamate, calcium and oxygen radicals. More recent work has shown this conclusion to be simplistic, and GC actions are shown to probably involve at least three additional components: c) that GCs impair a variety of neuronal defenses against neurologic insults; d) that GCs disrupt the mobilization of neurotrophins; e) that GCs have a variety of electrophysiological effects which can damage neurons. The relevance of each of those mechanisms to GC-induced atrophy, neurotoxicity and neuroendangerment is considered, as are the likely interactions among them.

J Clin Endocrinol Metab 1996 Oct;81(10):3639-43 Short-term estradiol treatment enhances pituitary-adrenal axis and sympathetic responses to psychosocial stress in healthy young men. Kirschbaum C, Schommer N, Federenko I, Gaab J, Neumann O, Oellers M, Rohleder N, Untiedt A, Hanker J, Pirke KM, Hellhammer DH Center for Psychobiological, University of Trier, Germany. Evidence from animal studies and clinical observations suggest that the activity of the pituitary-adrenal axis is under significant influence of sex steroids. The present study investigated how a short term elevation of estradiol levels affects ACTH, cortisol, norepinephrine, and heart rate responses to mental stress in healthy men. In a double blind study, 16 men received a patch delivering 0.1 mg estradiol/day transdermally, and age- and body mass index-matched control subjects received a placebo patch. Twenty-four to 48 h later, they were exposed to a brief psychosocial stressor (free speech and mental arithmetic in front of an audience). In response to the psychosocial stressor, ACTH, cortisol, norepinephrine, and heart rate were increased in both experimental groups (all P < 0.0001). However, the estradiol-treated subjects showed exaggerated peak ACTH (P < 0.001) and cortisol (P < 0.002) responses compared to the placebo group. Also, the norepinephrine area under the response curve was greater in the estradiol group (P < 0.05). Although heart rate responses differences failed to reach statistical significance, they, too, tended to be larger in the estradiol group. Neither mood ratings before or after the stressor, nor ratings of the perception of the stressor could explain the observed endocrine response differences. In conclusion, short term estradiol administration resulted in hyperresponses of the pituitary-adrenal axis and norepinephrine to psychosocial stress in healthy young men independent of psychological effects, as assessed in this study.

J Appl Physiol 1996 Mar;80(3):931-9 Treadmill exercise training and estradiol increase plasma ACTH and prolactin after novel footshock. White-Welkley JE, Warren GL, Bunnell BN, Mougey EH, Meyerhoff JL, Dishman RK "We examined whether rats that were treadmill exercise trained (Tr) or chronically immobilized (CI) had similar responses by the hypothalamic-pituitary-adrenal (HPA) cortical axis to acute stress and whether the HPA responses interacted with the hypothalamic-pituitary-gonadal (HPG) axis." "[ACTH] and [prolactin] after footshock were higher in Tr rats with E2 compared with CI and sedentary rats without E2; recovery levels for sedentary animals were higher after Run compared with Im. The elevation in [corticosterone] from minute 1 to 15 of recovery was higher after the familiar Run and Im conditions. Our findings are consistent with an increased responsiveness of the HPA axis to novel footshock after treadmill exercise training that is additionally modulated by the HPG axis."

Endocrinology 1992 Sep;131(3):1261-9. Chronic estrogen-induced alterations in adrenocorticotropin and corticosterone secretion, and glucocorticoid receptor-mediated functions in female rats. Burgess LH, Handa RJ "The effect of estrogen (E) on the hypothalamic-pituitary-adrenal axis was investigated in female Sprague-Dawley rats." "...the ACTH and CORT secretory responses to ether stress could be suppressed by exogenous RU 28362 (a specific glucocorticoid receptor agonist; 40 micrograms/100 g BW for 4 days) in OVX controls (P less than 0.05), but not in E-treated animals. These data suggest that E can impair glucocorticoid receptor-mediated delayed or slow negative feedback." "Thus, E treatment results in a loss of the glucocorticoid receptor's ability to autoregulate; this suggests that E may cause a functional impairment of the glucocorticoid receptor even though receptor binding appears normal. These findings suggest that hyperactivation of the hypothalamic-pituitary-adrenal axis after stress in E-treated rats is due in part to impaired glucocorticoid receptor-mediated slow negative feedback."

Am J Physiol 1994 Jul;267(1 Pt 1):E32-8 Lesions of hypothalamic paraventricular nuclei do not prevent the effect of estradiol on energy and fat balance. Dagnault A, Richard D. "Plasma levels of corticosterone and ACTH were higher in E2-treated rats than in animals receiving the placebo treatment. The present results provide evidence that the hypothalamic PVH is not an essential neuroanatomical structure in the effects of E2 on energy and fat balances."

Fertil Steril 1994 Oct;62(4):738-43 Ovarian suppression reduces clinical and endocrine expression of late-onset congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Carmina E, Lobo RA "OBJECTIVE: To determine the effectiveness of GnRH-agonist (GnRH-a) treatment in women with late onset congenital adrenal hyperplasia." "CONCLUSIONS: Suppression of the ovary with GnRH-a treatment was beneficial in these patients with late-onset congenital adrenal hyperplasia. An ovarian influence on the clinical and biochemical findings of the disorder is suggested."

Life Sci 1995;57(9):833-7. Effects of sex hormones on the steroidogenic activity of dispersed adrenocortical cells of the rat adrenal cortex. Nowak KW, Neri G, Nussdorfer GG, Malendowicz LK "The effect of 17 beta-estradiol and testosterone on glucocorticoid secretion were studied in vitro by using dispersed inner adrenocortical cells obtained from gonadectomized female and male rats. Independently of the sex of animals, estradiol enhanced basal, but not ACTH-stimulated corticosterone (B) secretion; conversely, testosterone inhibited ACTH-stimulated, but not basal B output." "Testosterone inhibited by about 30% ACTH-stimulated PREG production and by about 54% total post-PREG secretion (B was decreased to 56% of the control value, and other steroid hormones were below the limit of sensitivity of our assay system). These findings indicate that sex hormones directly affect rat adrenocortical secretion, mainly by acting on the rate-limiting step of steroidogenesis (i.e. the conversion of cholesterol to PREG); moreover, they suggest that testosterone is also able depress the activity of the enzymes operating distally to cholesterol side-chain cleavage."

J Endocrinol 1995 Feb;144(2):311-21 The influence of ovarian steroids on hypothalamic-pituitary-adrenal regulation in the female rat. Carey MP, Deterd CH, de Koning J, Helmerhorst F, de Kloet ER "The present study examined the association between hypothalamic- pituitary-adrenal (HPA) and hypothalamic-pituitary-ovarian axes. HPA activity determined by plasma levels of adrenocorticotropin (ACTH) and corticosterone (B) was assessed in intact female rats as a function of oestrous cycle stage under resting conditions and after exposure to a 20 min restraint stress. To delineate the roles of oestradiol and progesterone in HPA axis modulation, plasma concentrations of ACTH and B were determined in ovariectomised (OVX) animals treated with oestradiol and/or progesterone under resting conditions and during exposure to the stress of a novel environment. The effects of these steroid treatments on the transcription and/or binding properties of the two corticosteroid receptors, the mineralocorticoid (MR) and glucocorticoid (GR) receptors, were also examined in hippocampal tissue, (i) Fluctuations in basal and stress-induced plasma ACTH and B concentrations were found during the oestrous cycle with highest levels at late pro-oestrus. (ii) In OVX steroid-replaced animals, basal and stress-induced activity was enhanced in oestradiol and oestradiol plus progesterone-treated animals compared with OVX controls." "In conclusion, we find that sex steroids modulate HPA activity and suggest that the observed effects of these steroids on hippocampal MR may underlie their concerted mechanism of action in inducing an enhanced activity at the period of late pro-oestrus."

J Clin Endocrinol Metab 1995 Feb;80(2):603-7 The impact of estrogen on adrenal androgen sensitivity and secretion in polycystic ovary syndrome. Ditkoff EC, Fruzzetti F, Chang L, Stancyzk FZ, Lobo RA "Adrenal hyperandrogenism is a common feature of patients with polycystic ovary syndrome (PCO). This may be due to enhanced adrenal sensitivity to ACTH. Because enhanced ovarian androgen secretion does not appear to explain this phenomenon, we explored the role of estrogen in inducing enhanced adrenal sensitivity, in that a state of relative hyperestrogenism exists in PCO." "Steroid ratio responses to oCRH suggested that 17,20-desmolase activity (delta maximum change in the ratio of A4/17-hydroxyprogesterone) was lowered with estrogen suppression and increased again after transdermal E2 administration." "In conclusion, these data provide evidence that estrogen is at least one factor that influences adrenal androgen sensitivity in PCO and may help explain the frequent finding of adrenal hyperandrogenism in this syndrome."

Endocrinology 1993 Nov;133(5):2284-91 Estrogen and hydroxysteroid sulfotransferases in guinea pig adrenal cortex: cellular and subcellular distributions. Whitnall MH, Driscoll WJ, Lee YC, Strott CA "The high concentration of EST immunoreactivity in nuclei suggests that EST may play a role in modulating the ability of active estrogens to regulate gene expression in ACTH-responsive cells. The distribution of HST labeling suggests that sulfonation of adrenocortical 3-hydroxysteroids takes place largely within smooth endoplasmic reticulum in the zona reticularis in adult guinea pigs."

J Clin Endocrinol Metab 1993 Sep;77(3):754-8. Interaction of insulin-like growth factor-II and estradiol directs steroidogenesis in the human fetal adrenal toward dehydroepiandrosterone sulfate production. Mesiano S, Jaffe RB

J Clin Endocrinol Metab 1993 Aug;77(2):494-7. Estradiol stimulates cortisol production by adrenal cells in estrogen-dependent primary adrenocortical nodular dysplasia. Caticha O, Odell WD, Wilson DE, Dowdell LA, Noth RH, Swislocki AL, Lamothe JJ, Barrow R. Adrenal glands from a patient with ACTH-independent Cushing's syndrome, whose symptoms worsened during pregnancy and oral contraceptive use, were cultured in different concentrations of estradiol. Estradiol stimulated cortisol secretion in a dose-response manner in the absence of ACTH." . "This is the first description of estradiol stimulation of cortisol production by cultured adrenal cells in ACTH-independent Cushing's syndrome."

Endocrinology 1992 Nov;131(5):2430-6 Effects of gonadectomy and sex hormone therapy on the endotoxin-stimulated hypothalamo-pituitary-adrenal axis: evidence for a neuroendocrine-immunological sexual dimorphism. Spinedi E, Suescun MO, Hadid R, Daneva T, Gaillard RC "Bacterial lipopolysaccharide (LPS) stimulates the hypothalamo-pituitary-adrenal axis by a mechanism involving the release of cytokines, which activate the CRH-ACTH system and, as a result, increase glucocorticoid secretion. In the present study we investigated the possibility that endogenous sex hormones modulate the in vivo endotoxin-stimulated adrenal and immune responses in adult BALB/c mice." "Our results indicate that 1) randomly cycling female mice have significantly more pronounced corticosterone secretion than males 2 h after endotoxin injection, although the tumor necrosis factor responses were similar....".

J Neurosci Res 1995 Oct 1;42(2):228-35 Activation of the hypothalamo-anterior pituitary corticotropin- releasing hormone, adrenocorticotropin hormone and beta-endorphin systems during the estradiol 17 beta-induced plasma LH surge in the ovariectomized monkey. Kerdelhue B, Jones GS, Gordon K, Seltman H, Lenoir V, Melik Parsadaniantz S, Williams RF, Hodgen GD. "These results suggest that there may be a marked activation of the hypothalamo-anterior pituitary-adrenal axis during the negative and positive feedback phases of the E2B-induced LH surge in the ovariectomized monkey."

Biol Reprod 1995 Nov;53(5):996-1002 Activation of the baboon fetal pituitary-adrenocortical axis at midgestation by estrogen: responsivity of the fetal adrenal gland to adrenocorticotropic hormone in vitro. Berghorn KA, Albrecht ED, Pepe G.J.

Fertil Steril 1996 May;65(5):950-3 Ovarian hyperstimulation augments adrenal dehydro- epiandrosterone sulfate secretion. Casson PR, Kristiansen SB, Umstot E, Carson SA, Buster JE.

Hinyokika Kiyo 1997 Apr;43(4):275-8 [A case of concurrent bilateral adrenocortical adenoma causing Cushing's syndrome]. Koga F, Sumi S, Umeda H, Maeda S, Honda M, Hosoya Y, Yano M, Konita A, Suzuki S, Yoshida K. "All 14 previously reported cases of bilateral adrenocortical adenoma (BAA) causing Cushing's syndrome as well as the present case were concurrent and dominant in females of reproductive age. This suggests that some cofactors other than ACTH, such as estrogen, contribute to the pathogenesis of BAA."

Endocrinology 1991 Nov;129(5):2503-11 Variations in the hypothalamic-pituitary-adrenal response to stress during the estrous cycle in the rat. Viau V, Meaney MJ. "In cycling rats, we found significantly higher peak ACTH (P less than 0.01) and B (P less than 0.05) responses to stress during proestrus compared to the estrous and diestrous phases." "In response to stress, ACTH levels were higher (P less than 0.01) in the E' group compared to the EP' and O' groups. Although the peak B response was similar in all groups, the E' and EP' groups secreted more B after the termination of stress than did the O' group. Within the 20 min stress period, ACTH levels in the E' group were significantly (P less than 0.05) higher at 5, 10, and 15 min after the onset of stress, compared to the EP' and O' groups. Plasma B levels were significantly higher in the E' group at 5 and 10 min (P less than 0.05 and P less than 0.01, respectively) compared to the EP' and O' group. beta-endorphin-like immunoreactive responses to restraint stress were also significantly higher in the E' group compared to the EP' (P less than 0.05) and O' (P less than 0.01) groups. In contrast to the effect seen at 24 h, ACTH responses to stress 48 h after E2 injection in the E' group were comparable to O' animals. There was no effect of E2 on ACTH clearance, whereas B clearance was enhanced in E' treated animals vs. O'-treated animals. These results indicate that the HPA axis in the female rat is most sensitive to stress during proestrous. Such enhanced HPA responses to stress are limited to the early portion of proestrous, as progesterone appears to inhibit the facilitatory effects of estrogen on ACTH release during stress. Taken together, these results suggest an ovarian influence on both activational and inhibitory components of HPA activity."

Semin Reprod Endocrinol 1997 May;15(2):137-57 Adrenal involvement in polycystic ovary syndrome. Gonzalez F. "Whereas 17,20 lyase hyperactivity diagnosed by defined criteria in response to pharmacological ACTH may be an intrinsic genetic defect, increases in 17,20 lyase activity and adrenal androgen hyper-responsiveness to ACTH in response to physiological ACTH may be promoted by the functional elevation of estrogen of ovarian origin in PCOS. The latest in vitro data suggest the estrogen may elicit its effect on the adrenal cortex through a receptor mediated mechanism."

Metabolism 1997 Aug;46(8):902-7. Mild adrenal and ovarian steroidogenic abnormalities in hirsute women without hyperandrogenemia: does idiopathic hirsutism exist? Escobar-Morreale HF, Serrano-Gotarredona J, Garcia-Robles R, Sancho J, Varela C "Basal and ACTH-stimulated 17OHP and delta 4-A, and stimulated DHEA concentrations were reduced with ovarian suppression, but their net increment and ratio to the increase of F in response to ACTH remained unchanged, reflecting the ovarian contribution to the secretion of these steroids.".

Am J Physiol 1997 Apr;272(4 Pt 2):R1128-34. Modulation of ovine fetal adrenocorticotropin secretion by androstenedione and 17beta-estradiol. Saoud CJ, Wood CE "Parturition in sheep is initiated by increases in activity of the fetal hypothalamic-pituitary-adrenal axis. We have previously reported that cortisol negative feedback efficacy is decreased at the end of gestation. The present study was designed to test the hypothesis that increasing plasma estrogen and/or androgen concentrations in the fetus might increase plasma adrenocorticotropic hormone (ACTH) concentration, either by stimulating ACTH secretion or by altering the negative feedback effect of cortisol on ACTH." "We conclude that increased fetal cortisol and ACTH secretion at the end of gestation may be due to the combined effects of the gonadal steroids in that estradiol increases basal plasma ACTH secretion while androstenedione reduces cortisol negative feedback efficacy."

J Clin Endocrinol Metab 1998 Sep;83(9):3083-8. Menstrual abnormalities in women with Cushing's disease are correlated with hypercortisolemia rather than raised circulating androgen levels. Lado-Abeal J, Rodriguez-Arnao J, Newell-Price JD, Perry LA, Grossman AB, Besser GM, Trainer PJ.

Eur J Endocrinol 1998 Apr;138(4):430-5. Hypothalamo-pituitary-adrenal axis and adrenal function before and after ovariectomy in premenopausal women. De Leo V, la Marca A, Talluri B, D'Antona D, Morgante G The hypothalamo-pituitary-adrenal (HPA) axis is modulated by sex hormones. Few data exist on the relation between acute estrogen deficit and HPA axis response to corticotropin-releasing hormone (CRH). The effects of a sudden drop in estradiol levels on basal and CRH-stimulated levels of ACTH, cortisol, testosterone, androstenedione and 17-hydroxyprogesterone (17-OHP) were assessed in nine premenopausal women (44-48 years of age), before and after ovariectomy. The CRH test was performed before and 8 days after ovariectomy. A significant reduction in ACTH and adrenal steroids but not in cortisol response to CRH was observed after ovariectomy. The ratio of deltamax androstenedione/17-OHP after CRH stimulation was substantially the same before and after ovariectomy, whereas deltamax 17-OHP/cortisol was significantly lower in ovariectomized women showing increased 21- and 11beta-hydroxylase activity. The results show that the acute estrogen deficit induces changes in the HPA xis characterized by reduced stimulated secretion of ACTH and steroids but normal stimulated cortisol production.

Biokhimiia 1987 Sep;52(9):1501-11 [Activation of lipolysis and ketogenesis in tumor-bearing animals as a reflection of chronic stress states]. [Article in Russian] Chekulaev VA, Shelepov VP, Pasha-zade GR, Shapot VS In order to elucidate the peculiarities of brain metabolism in tumour-bearing organisms, the arterio-venous (A-V) content of glucose, acetoacetate (Ac-Ac), beta-hydroxybutyrate (beta-HB) and non-esterified fatty acids (NEFA) in growing Zajdela ascite hepatoma (ZAH) and solid hepatoma 27 (H-27) was compared. Analysis of metabolic patterns of healthy, starving and fed recipients (ZAH and H-27) revealed the inadequacy of the concepts on anorexia as being the cause of carbohydrate-lipid metabolic disturbances. In tumour-bearing organisms lipolysis and ketogenesis reflect the tumour-induced chronic stress. Absorption of beta-HB and release of Ac-Ac by brain were observed at all stages of malignant growth. This is probably due to a partial switch-over of brain metabolism to non-carbohydrate energy sources. Besides, certain stages of tumour growth are associated with active assimilation of NEFA by brain. A correlation between the A-V difference with respect to glucose and Ac-Ac as well as between the glucose and NEFA contents was established. It was assumed that the A-V difference in glucose is the main regulator of ketone body metabolism.

R. Sanchez Olea, et al., "Inhibition by polyunsaturated fatty acids of cell volume regulation and osmolyte fluxes in astrocytes," Amer. J. of Physiology--cell physiology 38(1), C96-C102, 1995. "...potent blockers of regulatory volume decrease and of the swelling-activated efflux of taurine, D-aspartate, inositol, and I-125 (used as marker of Cl). ...oleic and ricinoleic acids and saturated fatty acids were ineffective." "...polyunsaturated fatty acids directly inhibit the permeability pathways correcting cell volume after swelling in cultured astrocytes."

P. H. Chan and R. A. Fishman, "Brain edema: Induction in cortical slices by polyunsaturated fatty acids," Science 201, 358-369, 1978. "This cellular edema was specific, since neither saturated fatty acids nor a fatty acid containing a single double bond had such effect."

Endocrinology 1992 Aug;131(2):662-8 Estradiol selectively regulates agonist binding sites on the N-methyl-D-aspartate receptor complex in the CA1 region of the hippocampus. Weiland NG. Laboratory of Neuroendocrinology, Rockefeller University. "Estradiol alters cognitive function and lowers the threshold for seizures in women and laboratory animals. Both of these activities are modulated by the excitatory neurotransmitter glutamate in the hippocampus. To assess the hypothesis that estradiol increases the sensitivity of the hippocampus to glutamate activation by increasing glutamate binding sites, the densities of N-methyl-D-aspartate (NMDA) agonist sites...." "Two days of estradiol treatment increased the density of NMDA agonist, but not of competitive nor noncompetitive NMDA antagonist binding sites exclusively in the CA1 region of the hippocampus." "The increase in NMDA agonist sites with ovarian hormone treatment should result in an increase in the sensitivity of the hippocampus to glutamate activation which may mediate some of the effects of estradiol on learning and epileptic seizure activity."

J Neurochem 1994 Sep;63(3):953-62 Corticosterone regulates heme oxygenase-2 and NO synthase transcription and protein expression in rat brain. Weber CM, Eke BC, Maines MD."We suggest that glucocorticoid-mediated deficits in hippocampal functions may reflect their negative effect on messenger-generating systems."

Gen Pharmacol 1993 Nov;24(6):1383-6 Changes in microtubular tau protein after estrogen in a cultured human neuroblastoma cell line. Lew GM. "4. The estrogen (10(-7) M) also caused a 31% reduction in the total number of cells."

Rodriguez, P; Fernandez-Galaz, C; Tejero, A. Controlled neonatal exposure to estrogens: A suitable tool for reproductive aging studies in the female rat. Biology of Reproduction, v.49, n.2, (1993): 387-392.

O'Rourke, M T; Lipson, S F; Ellison, P T. Ovarian function in the latter half of the reproductive lifespan. American Journal of Human Biology, v.8, n.6, (1996): 751-759.

Schumacher, M; Robel, P; Baulieu, E-E. Development and regeneration of the nervous system: A role for neurosteroids. Developmental Neuroscience, v.18, n.1-2, (1996): 6-21.

Life Sci 1996;58(17):1461-7 The endogenous estrogen metabolite 2-methoxyestradiol induces apoptotic neuronal cell death in vitro. Nakagawa-Yagi Y, Ogane N, Inoki Y, Kitoh N. "We examined the effects of 2-methoxyestradiol, a metabolite of estradiol, on cell death in retinoic acid (RA)-differentiated neuroblastoma SH-SY5Y cell cultures. Cell death was induced by 2-methoxyestradiol in a concentration- dependent manner." [Provides evidence] "...for an endogenous neuroactive steroid metabolite in the etiology of some neurodegenerative diseases."

Recent Prog Horm Res 1997;52:279-303 Aging of the female reproductive system: a window into brain aging. Wise PM, Kashon ML, Krajnak KM, Rosewell KL, Cai A, Scarbrough K, Harney JP, McShane T, Lloyd JM, Weiland NG "The menopause marks the permanent end of fertility in women. It was once thought that the exhaustion of ovarian follicles was the single, most important explanation for the transition to the menopause. Over the past decade, this perception has gradually changed with the realization that there are multiple pacemakers of reproductive senescence. We will present evidence that lends credence to the hypothesis that the central nervous system is a critical pacemaker of reproductive aging and that changes at this level contribute to the timing of the menopause."

Neuroendocrinology 1989 Nov;50(5):605-612 N-methyl-aspartic acid lesions of the arcuate nucleus in adult C57BL/6J mice: a new model for age-related lengthening of the estrous cycle. May PC, Kohama SG, Finch CE. "We report a new effect of the excitotoxin N-methyl-aspartic acid (NMA) on adult mice. Besides confirming cell loss in the arcuate nucleus of animals treated as adults, we also observed lengthened estrous cycles. Cycling female C57BL/6J mice were treated with subcutaneous injections of NMA and estrous cycles monitored for 30 days. NMA treatment lengthened average estrous cycle length by 1 day, to 5.6 days." "Consistent with the regional pattern of cell loss, little specific binding of any glutamatergic ligand was observed in the VMN. NMA caused weight gain in all age groups." "The transition from 4-day to 5- and 6-day estrous cycles produced by NMA treatment mimics the early age-related changes in estrous cycle patterns in rodents." This new model will be useful in analyzing the contributions of neuroendocrine changes in the arcuate nucleus to reproductive senescence."

Pathologic effect of estradiol on the hypothalamus. Brawer JR; Beaudet A; Desjardins GC; Schipper HM. Biol Reprod, 1993 Oct, 49:4, 647-52. "In addition to its multiple physiological actions, we have shown that estradiol is also selectively cytotoxic to beta-endorphin neurons in the hypothalamic arcuate nucleus. The mechanism underlying this neurotoxic action appears to involve the conversion of estradiol to catechol estrogen and subsequent oxidation to o-semiquinone free radicals. The estradiol-induced loss of beta-endorphin neurons engenders a compensatory increment in mu opioid binding in the medial preoptic area rendering this region supersensitive to residual beta-endorphin or to other endogenous opioids. The consequent persistent opioid inhibition results in a cascade of neuroendocrine deficits that are ultimately expressed as a chronically attenuated plasma LH pattern to which the ovaries respond by becoming anovulatory and polycystic. This neurotoxic action of estradiol may contribute to a number of reproductive disorders in humans and in animals in which aberrant hypothalamic function is a major component."

Vitamin E protects hypothalamic beta-endorphin neurons from estradiol neurotoxicity. Desjardins GC; Beaudet A; Schipper HM; Brawer JR. Endocrinology, 1992 Nov, 131:5, 2482-4 "Estradiol valerate (EV) treatment has been shown to result in the destruction of 60% of beta-endorphin neurons in the hypothalamic arcuate nucleus."

Estrogen-induced hypothalamic beta-endorphin neuron loss: a possible model of hypothalamic aging. Desjardins GC; Beaudet A; Meaney MJ; Brawer JR. Exp Gerontol, 1995 May-Aug, 30:3-4, 253-67 Over the course of normal aging, all female mammals with regular cycles display an irreversible arrest of cyclicity at mid-life. Males, in contrast, exhibit gametogenesis until death. Although it is widely accepted that exposure to estradiol throughout life contributes to reproductive aging, a unified hypothesis of the role of estradiol in reproductive senescence has yet to emerge. Recent evidence derived from a rodent model of chronic estradiol-mediated accelerated reproductive senescence now suggests such a hypothesis. It has been shown that chronic estradiol exposure results in the destruction of greater than 60% of all beta-endorphin neurons in the arcuate nucleus while leaving other neuronal populations spared. This loss of opioid neurons is prevented by treatment with antioxidants indicating that it results from estradiol-induced formation of free radicals. Furthermore, we have shown that this beta-endorphin cell loss is followed by a compensatory upregulation of mu opioid receptors in the vicinity of LHRH cell bodies. The increment in mu opioid receptors presumably renders the opioid target cells supersensitive to either residual beta-endorphin or other endogenous mu ligands, such as met-enkephalin, thus resulting in chronic opioid suppression of the pattern of LHRH release, and subsequently that of LH. Indeed, prevention of the neuroendocrine effects of estradiol by antioxidant treatment also prevents the cascade of neuroendocrine aberrations resulting in anovulatory acyclicity. The loss of beta-endorphin neurons along with the paradoxical opioid supersensitivity which ensues, provides a unifying framework in which to interpret the diverse features that characterize the reproductively senescent female.

The 21-aminosteroid antioxidant, U74389F, prevents estradiol-induced depletion of hypothalamic beta-endorphin in adult female rats. Schipper HM; Desjardins GC; Beaudet A; Brawer JR. Brain Res, 1994 Jul 25, 652:1, 161-3 "A single intramuscular injection of 2 mg estradiol valerate (EV) results in neuronal degeneration and beta-endorphin depletion in the hypothalamic arcuate nucleus of adult female rats."

J Neurochem 1998 Sep;71(3):1187-93 Energy dependency of glucocorticoid exacerbation of gp120 neurotoxicity. Brooke SM, Howard SA, Sapolsky RM "The HIV envelope glycoprotein, gp120, a well documented neurotoxin, may be involved in AIDS-related dementia complex. gp120 works through an NMDA receptor- and calcium-dependent mechanism to damage neurons. We have previously demonstrated that both natural and synthetic glucocorticoids (GCs) exacerbate gp120-induced neurotoxicity and calcium mobilization in hippocampal mixed cultures. GCs, steroid hormones secreted during stress, are now shown to work in conjunction with gp120 to decrease ATP levels and to work synergistically with gp120 to decrease the mitochondrial potential in hippocampal cultures. Furthermore, energy supplementation blocked the ability of GCs to worsen gp120's effects on neuronal survival and calcium mobilization. A GC-induced reduction in glucose transport in hippocampal neurons, as previously documented, may contribute to this energetic dependency. These results may have clinical significance, considering the common treatment of severe cases of Pneumocystis carinii pneumonia, typical of HIV infection, with large doses of synthetic GCs."

Acta Otolaryngol Suppl (Stockh) 1990;476:32-6. Glutamate neurotoxicity in the cochlea: a possible consequence of ischaemic or anoxic conditions occurring in ageing. Pujol R, Rebillard G, Puel JL, Lenoir M, Eybalin M, Recasens M.

Br J Pharmacol 1996 Jan;117(1):189-95. Metabotropic glutamate receptors, transmitter output and fatty acids: studies in rat brain slices. Lombardi G, Leonardi P, Moroni F. "The requirement of both unsaturated fatty acids and 1S,3R-ACPD in the facilitation of transmitter exocytosis may play an important role in the regulation of synaptic plasticity."

Adv Exp Med Biol 1992;318:147-58 A role for the arachidonic acid cascade in fast synaptic modulation: ion channels and transmitter uptake systems as target proteins. Volterra A, Trotti D, Cassutti P, Tromba C, Galimberti R, Lecchi P, Racagni G. "Recent evidence indicates that arachidonic acid (AA) and its metabolites play a fast messenger role in synaptic modulation in the CNS." "Other types of K+ channels in vertebrate excitable cells have been found to be sensitive to arachidonic acid, lipoxygenase products, and polyunsaturated fatty acids (PUFA). In the mammalian CNS, arachidonic acid is released upon stimulation of N-methyl-D-aspartate (NMDA)-type glutamate receptors." "Polyunsaturated fatty acids mimic arachidonate with a rank of potency parallel to the degree of unsaturation. Since the effect of glutamate on the synapses is terminated by diffusion and uptake, a slowing of the termination process may potentiate glutamate synaptic efficacy. However, excessive extracellular accumulation of glutamate may lead to neurotoxicity."

J Neurochem 1999 Jan;72(1):129-38. Transient inhibition of glutamate uptake in vivo induces neurodegeneration when energy metabolism is impaired. Sanchez-Carbente MR, Massieu L. "Impairment of glutamate transport during ischemia might be related to the elevation of the extracellular concentration of glutamate and ischemic neuronal damage. Additionally, impairment of energy metabolism in vivo leads to neurodegeneration apparently mediated by a secondary excitotoxic mechanism. In vitro observations show that glucose deprivation and inhibition of energy metabolism exacerbate the toxic effects of glutamate." "Our results show that glutamate uptake inhibition leads to marked neuronal damage in energy-deficient rats but not in intact animals...."

J Neurochem 1998 Nov;71(5):1993-2005. Glia modulate NMDA-mediated signaling in primary cultures of cerebellar granule cells. Beaman-Hall CM, Leahy JC, Benmansour S, Vallano ML "Nordihydroguaiaretic acid, a lipoxygenase inhibitor, blocked NMDA-mediated toxicity in astrocyte-poor cultures, raising the possibility that glia effectively reduce the accumulation of highly diffusible and toxic arachidonic acid metabolites in neurons. Alternatively, glia may alter neuronal development/phenotype in a manner that selectively reduces susceptibility to NR-mediated toxicity."

J Neurosci 1997 Dec 1;17(23):9060-7. Pyruvate protects neurons against hydrogen peroxide-induced toxicity. Desagher S, Glowinski J, Premont J. "Pyruvate strongly protected neurons against both H2O2 added to the external medium and H2O2 endogenously produced through the redox cycling of the experimental quinone menadione. The neuroprotective effect of pyruvate appeared to result rather from the ability of alpha-ketoacids to undergo nonenzymatic decarboxylation in the presence of H2O2 than from an improvement of energy metabolism. Indeed, several other alpha-ketoacids, including alpha-ketobutyrate, which is not an energy substrate, reproduced the neuroprotective effect of pyruvate. In contrast, lactate, a neuronal energy substrate, did not protect neurons from H2O2." "Together, these results indicate that pyruvate efficiently protects neurons against both exogenous and endogenous H2O2. Its low toxicity and its capacity to cross the blood-brain barrier open a new therapeutic perspective in brain pathologies in which H2O2 is involved."

J Neurosci 1998 Jan 1;18(1):156-63. Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington's disease. Matthews RT, Yang L, Jenkins BG, Ferrante RJ, Rosen BR, Kaddurah-Daouk R, Beal MF .

M. C. Diamond, Enriching Heredity: The Importance of the Environment on the Anatomy of the Brain. Free Press, N.Y., 1988.

C. Finch and L. Hayflick, Handbook of the Biology of Aging. Van Nostrand Reinhold, N.Y., 1977.

Swanson RA Physiologic coupling of glial glycogen metabolism to neuronal activity in brain. Can J Physiol Pharmacol, 1992, 70 Suppl:, S138-44. Brain glycogen is localized almost exclusively to glia, where it undergoes continuous utilization and resynthesis. We have shown that glycogen utilization increases during tactile stimulation of the rat face and vibrissae. Conversely, decreased neuronal activity during hibernation and anesthesia is accompanied by a marked increase in brain glycogen content. These observations support a link between neuronal activity and glial glycogen metabolism. The energetics of glycogen metabolism suggest that glial glycogen is mobilized to meet increased metabolic demands of glia rather than to serve as a substrate for neuronal activity. An advantage to the use of glycogen may be the potentially faster generation of ATP from glycogen than from glucose. Alternatively, glycogen could be utilized if glucose supply is transiently insufficient during the onset of increased metabolic activity. Brain glycogen may have a dynamic role as a buffer between the abrupt increases in focal metabolic demands that occur during normal brain activity and the compensatory changes in focal cerebral blood flow or oxidative metabolism.

"Free fatty acids activate the hypothalamic-pituitary-adrenocortical axis in rats." Widmaier EP; Rosen K; Abbott B. Endocrinology, 1992 Nov, 131:5, 2313-8. "Intravenous administration of Intralipid 10% increases blood levels of essential free fatty acids." "Since corticosterone, the final secretory product of the rat hypothalamic-pituitary-adrenocortical (HPA) axis, is also lipolytic, we tested the hypothesis that FFA would inhibit the HPA axis." "At 60 min, plasma ACTH levels were significantly elevated to over 1500 pg/ml in Intralipid-infused rats, but were unchanged in saline controls. This dose of Intralipid increased corticosterone levels by nearly 20-fold at 120 min. At 180 min, corticosterone levels were still significantly greater than those in saline controls. Lower doses of Intralipid also significantly elevated both FFA and corticosterone levels, but by 180 min, levels of both were similar to those in controls." "The results suggest that high circulating FFA levels activate, rather than inhibit, the HPA axis in rats. Since stress activates glucocorticoid production and increases FFA levels due to lipolysis, it is possible that FFA and the HPA axis constitute a previously unrecognized positive feedback loop."

"Impairment of glucose disposal by infusion of triglycerides in humans: role of glycemia," Felley CP; Felley EM; van Melle GD; Frascarolo P; Jéquier E; Felber JP, Am J Physiol, 1989 Jun, 256:6 Pt 1, E747-52. "These results suggest the existence of physiological regulatory mechanisms by which 1) the rise in plasma free fatty acid inhibits both oxidative and nonoxidative glucose disposal, and 2) the rise in glycemia stimulates predominantly nonoxidative glucose disposal."

Nature 1998 Jan 15;391(6664):281-5. Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Bezzi P, Carmignoto G, Pasti L, Vesce S, Rossi D, Rizzini BL, Pozzan T, Volterra A. Astrocytes in the brain form an intimately associated network with neurons. They respond to neuronal activity and synaptically released glutamate by raising intracellular calcium concentration ([Ca2+]i), which could represent the start of back-signalling to neurons. Here we show that coactivation of the AMPA/kainate and metabotropic glutamate receptors (mGluRs) on astrocytes stimulates these cells to release glutamate through a Ca2+-dependent process mediated by prostaglandins. Pharmacological inhibition of prostaglandin synthesis prevents glutamate release, whereas application of prostaglandins (in particular PGE2) mimics and occludes the releasing action of GluR agonists. PGE2 promotes Ca2+-dependent glutamate release from cultured astrocytes and also from acute brain slices under conditions that suppress neuronal exocytotic release. When applied to the CA1 hippocampal region, PGE2 induces increases in [Ca2+]i both in astrocytes and in neurons. The [Ca2+]i increase in neurons is mediated by glutamate released from astrocytes, because it is abolished by GluR antagonists. Our results reveal a new pathway of regulated transmitter release from astrocytes and outline the existence of an integrated glutamatergic cross-talk between neurons and astrocytes in situ that may play critical roles in synaptic plasticity and in neurotoxicity.

Prog Neurobiol 1998 Jan;54(1):99-125. Microglia as effector cells in brain damage and repair: focus on prostanoids and nitric oxide. Minghetti L, Levi G. "The present article deals with two classes of compounds that activated microglial cells can produce in large amounts: prostanoids (that derive from arachidonic acid through the cyclooxygenase pathway), and nitric oxide (that is synthesized from arginine by nitric oxide synthase). Prostanoids and nitric oxide have a number of common targets, on which they may exert similar or opposite actions, and have a crucial role in the regulation of inflammation, immune responses and cell viability. Their synthesis can massively increase when the inducible isoforms of cyclooxygenase and nitric oxide synthase are expressed."

In Vitro Cell Dev Biol Anim 1998 Mar;34(3):265-74. Prostaglandins act as neurotoxin for differentiated neuroblastoma cells in culture and increase levels of ubiquitin and beta-amyloid. Prasad KN, La Rosa FG, Prasad JE. "Although chronic inflammatory reactions have been proposed to cause neuronal degeneration associated with Alzheimer's disease (AD), the role of prostaglandins (PGs), one of the secretory products of inflammatory reactions, in degeneration of nerve cells has not been studied. Our initial observation that PGE1-induced differentiated neuroblastoma (NB) cells degenerate in vitro more rapidly than those inducedby RO20-1724, an inhibitor of cyclic nucleotide phosphodiesterase, has led us to postulate that PGs act as a neurotoxin. This study has further investigated the effects of PGs on differentiated NB cells in culture. Results showed that PGA1 was more effective than PGE1 in causing degeneration of differentiated NB cells as shown by the cytoplasmic vacuolation and fragmentation of soma, nuclei, and neurites. Because increased levels of ubiquitin and beta-amyloid have been implicated in causing neuronal degeneration, we studied the effects of PGs on the levels of these proteins during degeneration of NB cells in vitro...." "Results showed that PGs increased the intracellular levels of ubiquitin and beta-amyloid prior to degeneration, whereas the degenerated NB cells had negligible levels of these proteins. These data suggest that PGs act as external neurotoxic signals which increase levels of ubiquitin and beta-amyloid that represent one of the intracellular signals for initiating degeneration of nerve cells."

Brain Res Bull 1998 Apr;45(6):637-40. The fatty acid composition of maternal diet affects the response to excitotoxic neural injury in neonatal rat pups.Valencia P, Carver JD, Wyble LE, Benford VJ, Gilbert-Barness E, Wiener DA, Phelps C Fatty acids and their derivatives play a role in the response to neural injury. The effects of prenatal and postnatal dietary fatty acid composition on excitotoxic neural injury were investigated in neonatal rat pups."

Proc Soc Exp Biol Med 1998 Nov;219(2):120-5. Prostaglandins as putative neurotoxins in Alzheimer's disease. Prasad KN, Hovland AR, La Rosa FG, Hovland PG. "Chronic inflammatory reactions in the brain appear to be one of the primary etiological factors in the pathogenesis of Alzheimer's disease (AD). This is supported by the fact that the secretory products of inflammatory reactions, which include cytokines, complement proteins, adhesion molecules, and free radicals, are neurotoxic. We have recently reported that prostaglandins (PGs), which are also released during inflammatory reactions, cause rapid degenerative changes in differentiated murine neuroblastoma cells (NB) in culture." "The mechanisms underlying Abeta-induced neuronal degeneration have been under intense investigation, and several mechanisms of action have been proposed. We postulate that PG-induced elevation of Abeta may lead to an increased binding of Abeta to the 20S proteasome, resulting in a reduction of 20S proteasome-mediated degradation of ubiquitin-conjugated proteins. This is predicted to lead to an increase in an accumulation of abnormal proteins, which ultimately contribute to neuronal degeneration and death. Based on our hypothesis and on studies published by others, we propose that a combination of nonsteroidal anti-inflammatory drugs, which inhibit the synthesis of PGs, and antioxidant vitamins, which quench free radicals and both of which have been recently reported to be of some value in AD treatment when used-individually, may be much more effective in the prevention and treatment of AD than the individual agents alone."

Mol Chem Neuropathol 1998 May;34(1):79-101. Effects of EGb 761 on fatty acid reincorporation during reperfusion following ischemia in the brain of the awake gerbil. Rabin O, Drieu K, Grange E, Chang MC, Rapoport SI, Purdon AD.

Regulation of arcuate nucleus synaptology by estrogen. Leedom L; Lewis C; Garcia-Segura LM; Naftolin F. Ann N Y Acad Sci, 1994 Nov 14, 743:, 61-71 "Estrogen modulates the synaptology of the hypothalamic arcuate nucleus during sexual differentiation of the rat brain in both males and females. In males, testosterone of gonadal origin is converted to estrogen in the brain by an enzyme, aromatase, which is also present in females. The exposure of the male's hypothalamus to relatively high levels of estrogen (following a perinatal testosterone surge) leads to the development of a pattern of synaptogenesis which does not support an estrogen-induced gonadotrophin surge in the adult. In female rats, hypothalamic development occurs with permissively low levels of estrogen, enabling a midcycle estrogen-induced gonadotrophin surge and ovulation in adulthood. During adult reproductive life in female rats, circulating estrogen modulates the synaptology of the arcuate nucleus. The most physiological example of this is the 30-50% loss of axosomatic synapses following the preovulatory estrogen surge on diestrus-proestrus. Studies on post-synaptic membranes of the arcuate nucleus reveal sex differences in membrane organization and protein content which are estrogen-dependent. Estrogen apparently stimulates endocytosis of areas of post-synaptic membrane that are dense with small intramembranous protein particles, resulting in a reduction in the number of small intramembranous particles. This also appears to be the physiologic mechanism of neuronal changes in females during the estrus cycle. Repeated exposure to preovulatory levels of estrogen may lead to an age-related decline in reproductive capacity in female rats. Aging females lose the estrogen-induced gonadotrophin surge responsible for ovulation. This loss of function may result from a cumulative estrogen effect during the repeated ovarian cycles which results in a reorganization of the synaptology on which regulates the estrogen-induced gonadotrophin surge." ". . .recent research has shown that GABA, the monoamines, and several neuropeptides are participants in the estrogen-sensitive network which regulates GNRH secretion. In this regard, present work shows estrogen-induced changes in GABA and dopamine synapses in the arcuate nucleus."

17 beta Estradiol-induced increase in brain dopamine D-2 receptor: antagonism by MIF-1. Rajakumar G; Chiu P; Chiu S; Johnson RL; Mishra RK Department of Psychiatry, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada. Peptides, 1987 Nov-Dec, 8:6, 997-1002 Animal behavioral and neurochemical studies implicate dopaminergic systems in the neurological sequelae induced by estrogen. In the present study, we demonstrated for the first time that MIF-1, a neuropeptide unrelated to classical dopamine agonists, when given prior to, concurrently with, and after 17 beta-estradiol, antagonized significantly the estrogen-induced increase in the density of dopamine D-2 receptor both in the striatum and the mesolimbic area of male rat brain. The current findings have implications for the prophylactic and therapeutic potential for MIF-1 in extrapyramidal motor disorders caused by estrogen imbalance in humans.

Eur J Clin Invest 1984 Dec;14(6):431-4 Effect of ovulation on haem metabolism in rabbits. Lindahl J, Werner B, Lerner R. "To investigate the origin of the cyclic changes in the rate of endogenous carbon-monoxide production (nCO) during the menstrual cycle, haem turnover was determined before and after chorion gonadotropic hormone-induced ovulation in six female rabbits. 14C-labelled delta-aminolevulinic acid and glycine were administered and the excretion rate of 14CO (A14CO) was measured for determination of hepatic and bone-marrow haem turnover, respectively." ". . . nCO was increased 34% (P less than 0.05) during the post-ovulation period. As the increase in 'unassigned' haem turnover was small and may be unaccompanied by a contemporary increase in bilirubin/CO production, it was concluded that the increase in nCO during the post-ovulation period essentially depends on increased destruction of circulating red cells in the rabbit."

J Neurotrauma 1993 Winter;10(4):373-84. Beneficial effect of the nonselective opiate antagonist naloxone hydrochloride and the thyrotropin-releasing hormone (TRH) analog YM-14673 on long-term neurobehavioral outcome following experimental brain injury in the rat. McIntosh TK, Fernyak S, Hayes RL, Faden AI

J Neurosci 1990 Nov;10(11):3524-30. Opiate antagonist nalmefene improves intracellular free Mg2+, bioenergetic state, and neurologic outcome following traumatic brain injury in rats. Vink R, McIntosh TK, Rhomhanyi R, Faden AI. "Treatment of CNS trauma with the opiate antagonist naloxone improves outcome, though the mechanisms of action remain speculative."

Brain Res 1989 Mar 20;482(2):252-60. Magnesium protects against neurological deficit after brain injury. McIntosh TK, Vink R, Yamakami I, Faden AI.

Adv Neurol 1988;47:531-46. Role of thyrotropin-releasing hormone and opiate receptor antagonists in limiting central nervous system injury. Faden AI. "Opiate antagonists, including receptor antagonists and physiologic antagonists, have been shown to produce beneficial effects in a variety of models of CNS injury and in a variety of species. Opiate antagonists improve spinal cord blood flow, electrical conduction of the spinal cord, pathological changes, and motor recovery following traumatic spinal cord injury in cats. TRH appears to be superior to naloxone in this regard, although direct comparisons between receptor-selective opiate receptor antagonists and TRH have not been made."

Exp Neurol 1994 Sep;129(1):64-9.Progesterone facilitates cognitive recovery and reduces secondary neuronal loss caused by cortical contusion injury in male rats. Roof RL, Duvdevani R, Braswell L, Stein DG.

Exp Neurol 1996 Apr;138(2):246-51. Progesterone rapidly decreases brain edema: treatment delayed up to 24 hours is still effective. Roof RL, Duvdevani R, Heyburn JW, Stein DG.

Mol Chem Neuropathol 1997 May;31(1):1-11. Progesterone protects against lipid peroxidation following traumatic brain injury in rats. Roof RL, Hoffman SW, Stein DG.

Jiang N, et al. Progesterone is neuroprotective after transient middle cerebral artery occlusion in male rats. Brain Res. 1996 Sep 30;735(1):101-7.

Roof RL, et al. Progesterone rapidly decreases brain edema: treatment delayed up to 24 hours is still effective. Exp Neurol. 1996 Apr;138(2):246-51.

Duvdevani R, et al. Blood-brain barrier breakdown and edema formation following frontal cortical contusion: does hormonal status play a role? J Neurotrauma. 1995 Feb;12(1):65-75.

Exp Neurol 1997 Dec;148(2):453-63. Endogenous repair after spinal cord contusion injuries in the rat. Beattie MS, Bresnahan JC, Komon J, Tovar CA, Van Meter M, Anderson DK, Faden AI, Hsu CY, Noble LJ, Salzman S, Young W. "In addition to signs of regeneration, we noted evidence for the proliferation of cells located in the ependymal zone surrounding the central canal at early times following contusion injuries."

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<span class="koboSpan" id="kobo.1.1">Estrogen and Osteoporosis</span> A R T I C L E

Estrogen and Osteoporosis

"How does estrogen enhance endotoxin toxicity? Let me count the ways."
J.J. Maher (Liver Center and Department of Medicine, University of California San Francisco) in Hepatology, 1998, 28(6):1720-1.

The government declared victory in the war on cancer, though the age-specific death rate from cancer keeps increasing. In the equally well publicized effort to prevent disability and death from osteoporosis, no one is declaring victory, because the only trend in its incidence that has been reported is an increase. The estrogen-promoting culture tells us that this is because of the aging of the population, but the age corrected numbers still show a great increase--for example, in Finland between 1970 and 1995, the number of women (for a given population of women older than 60) breaking their forearm because of osteoporosis more than doubled (Palvanen, et al., 1998). That this happened during a time when the use of estrogen had become much more common doesn't present a good argument for the protective effects of estrogen treatment. (And during this period there was a large increase in the consumption of estrogenic soy products.) Recently our local newspaper had a story at the bottom of the front page reporting that lean women who used estrogen and synthetic progestins had an 80% higher rate of breast cancer. Several days later, across the top of the front page, there was a rebuttal article, quoting some doctors including a "world class expert on hormone replacement therapy" and a woman who has taken Premarin for forty years and urges everyone to take it. The "protection against osteoporosis" and against heart disease, they said, must be weighed against a trifle such as the 80% increase in cancer. It appeared that the newspaper was apologizing for reporting a fact that could make millions of women nervous. (Jan 26, Register-Guard).

Medical magazines, like the mass media, don't like to miss any opportunity to inform the public about the importance of using estrogen to prevent osteoporosis. Their attention to the bone-protective effect of progesterone has been noticeably less than their mad campaign to sell estrogen, despite the evidence that progesterone can promote bone rebuilding, rather than just slowing its loss. Although I have spoken about progesterone and osteoporosis frequently in the last 25 years, I have only occasionally considered what estrogen does to bones; generally, I described estrogen as a stress-promoting and age-promoting hormone. In the 1970s, pointing out progesterone's protective antagonism to excessive amounts of other hormones, and that the catabolic glucocorticoids tend to increase with aging, I began referring to progesterone as the "anticatabolic" hormone that should be used to prevent stress-induced atrophy of skin, bones, brain, etc.

A former editor of Yearbook of Endocrinology had reviewed a series of studies showing that excess prolactin can cause osteoporosis. Then, he presented a group of studies showing how estrogen promotes the secretion of prolactin, and can cause hyperprolactinemia. In that review, he wryly wondered how something that increases something that causes osteoporosis could prevent osteoporosis.

Women have a higher incidence of osteoporosis than men do. Young women have thinner more delicate bones than young men. The women who break bones in old age are generally the women who had the thinnest bones in youth. Menstrual irregularities, and luteal defects, that involve relatively high estrogen and low progesterone, increase bone loss.

Fatter women are less likely to break bones than thinner women. Insulin, which causes the formation of fat, also stimulates bone growth. Estrogen however, increases the level of free fatty acids in the blood, indicating that it antagonizes insulin (insulin decreases the level of free fatty acids), and the fatty acids themselves strongly oppose the effects of insulin. Estrogen dominance is widely thought to predispose women to diabetes.

Between the ages of 20 and 40, there is a very considerable increase in the blood level of estrogen in women. However, bone loss begins around the age of 23, and progesses through the years when estrogen levels are rising. Osteoarthritis, which involves degeneration of the bones around joints, is strongly associated with high levels of estrogen, and can be produced in animals with estrogen treatment.

Thirty years ago, when people were already claiming that estrogen would prevent or cure osteoporosis, endocrinologists pointed out that there was no x-ray evidence to support the claim. Estrogen can cause a positive calcium balance, the retention of more calcium than is excreted, and the estrogen promoters argued that this showed it was being stored in the bones, but the endocrine physiologists showed that estrogen causes the retention of calcium by soft tissues. There are many reasons for not wanting calcium to accumulate in the soft tissues; this occurs normally in aging and stress.

Then, it was discovered that, although estrogen doesn't improve the activity of the cells that build bone, it can reduce the activity of the cells that remove bone, the osteoclasts. The osteoclast is a type of phagocytic cell, and is considered to be a macrophage, the type of cell that can be found in any organ, which can eat any sort of particle, and which secretes substances (cytokines, hormone-like proteins) that modify the functions of other cells. When estrogen was found to impair the activity of this kind of cell, there wasn't much known about macrophage cytokines.

With the clear evidence that estrogen inhibits the osteoclasts without activating the bone-building osteoblasts, estrogen was said to "prevent bone loss," and from that point on we never heard again about estrogen promoting a positive calcium balance. Calcium retention by soft tissues has come to be an accepted marker of tissue aging, tissue damage, excitotoxicity, and degeneration. Positive calcium balance had been the essence of the argument for using estrogen to prevent osteoporosis: "Women are like chickens, estrogen makes them store calcium in their bones." But if everyone now recognizes that calcium isn't being stored in bones, it's better for the estrogen industry if we forget about the clearly established positive calcium balance produced by estrogen.

The toxic effects of excessive intracellular calcium (decreased respiration and increased excitation) are opposed by magnesium. Both thyroid and progesterone improve magnesium retention. Estrogen dominance is often associated with magnesium deficiency, which can be an important factor in osteoporosis (Abraham and Grewal, 1990; Muneyyirci-Delale, et al., 1999). As part of the campaign to get women to use estrogen, an x-ray (bone density) test was devised which can supposedly measure changes in the mineral content of bone. However, it happens that fat and water interfere with the measurements. Estrogen changes the fat and water content of tissues. By chance, the distortions produced by fat and water happen to be such that estrogen could appear to be increasing the density of a bone, when it is really just altering the soft tissues. Ultrasound measurements can provide very accurate measurements of bone density, without the fat and water artifacts that can produce misleading results in the x-ray procedure, and don't expose the patient to radiation, but the ultrasound method is seldom used.

In recent years, there has been quite a lot of research into the effects of the macrophage cytokines. Immune therapy for cancer was considered quackery when Lawrence Burton identified some substances in blood serum that could cause massive tumors in rodents to disappear in just a few hours. One of the serum factors was called Tumor Necrosis Factor, TNF. An official committee was formed to evaluate his work, but it reported that there was nothing to it. A member of the committee later became known as "the authority" on tumor necrosis factor, which was thought to have great potential as an anticancer drug. However, used by itself, TNF killed only a few cancers, but it damaged every organ of the body, usually causing the tissues to waste away. Other names, lymphotoxin and cachectin, reflected its toxic actions on healthy tissues.

Aging involves many changes that tend to increase the inflammatory reaction, and generally the level of TNF increases with aging. Although cancer, heart failure, AIDS, and extreme hormone deficiency (from loss of the pituitary or thyroid gland, for example) can cause cachexia of an extreme and rapid sort, ordinary aging is itself a type of cachexia. Progeria, or premature aging, is a kind of wasting disease that causes a child's tissues (including bones) to atrophy, and to change in many of the ways that would normally occur in extreme old age.

Recent studies have found that both men and women lose minerals from their bones at the rate of about 1% per year. Although men have lower estrogen in youth than women do, their bones are much heavier. During aging, as their bones get thinner, men's estrogen levels keep rising.

Besides having weaker bones, old people have weaker muscles, and are more likely to injure themselves in a fall because their muscles don't react as well. Muscle loss occurs at about the rate of 1% per year.

Women's muscles, like their bones, are normally smaller than men's, and estrogen contributes significantly to these differences.

TNF can produce very rapid loss of tissue including bone, and in general, it rises with aging. Some of the people who like to say that "osteoporosis is caused by estrogen deficiency" know about the destructive actions of TNF, and argue that it rises at menopause "because of estrogen deficiency." There are very good reasons for rejecting that argument; the experiments sometimes seem to have been designed purely for propaganda purposes, using toxic levels of estrogen for a specific result.

One researcher noted that the effects of estrogen on cells in vitro are biphasic: Low doses increased TNF, high doses decreased TNF. Everyone knows that unphysiologically high doses (50 or 100 or more times above the physiological level of around 0.25 micrograms per liter) of estrogen are toxic to cells, producing functional and structural changes, and even rapid death. So, when a researcher who wants to show estrogen's "bone protective" effect of lowering TNF adds a lethal dose of estrogen to his cell culture, he can conclude that "estrogen inhibits TNF production." But the result is no more interesting than the observation that a large dose of cyanide inhibits breathing.

TNF is produced by endotoxin, and estrogen increases the amount of endotoxin in the blood. Even without endotoxin, though, estrogen can stimulate the production of TNF. Lactic acid and unsaturated fats and hypoxia can stimulate increased formation of TNF. Estrogen increases production of nitric oxide systemically, and nitric oxide can stimulate TNF formation. How does TNF work, to produce tissue damage and wasting? It causes cells to take up too much calcium, which makes them hypermetabolic before it kills them. It increases formation of nitric oxide and carbon monoxide, blocking respiration. TNF can cause a 19.5 fold increased in the enzyme which produces carbon monoxide (Rizzardini, et al., 1993), which blocks respiration.

All of the normal conditions associated with high estrogen also are found to involve increased production of TNF, and treatment of animals with estrogen clearly increases their TNF. Premature ovarian failure (with low estrogen levels) leads to reduced TNF, as does treatment with antiestrogens. If bone resorption is significantly regulated by TNF, then it should be concluded that increased estrogenic influence will tend to produce osteoporosis.

Tamoxifen, which has some estrogenic effects, including the inhibition of osteoclasts, can kill osteoclasts when the dose is high enough. The inhibition of osteoclast activity by either estrogen or tamoxifen is probably a toxic action, that has been characterized as "beneficial" by the estrogen industry simply because they didn't have any better argument for getting women to use their products.

Some types of dementia, such as Alzheimer's disease, involve a life-long process of degeneration of the brain, with an inflammatory component, that probably makes them comparable to osteoporosis and muscle-wasting. (In the brain, the microglia, which are similar to macrophages, and the astrocytes, can produce TNF.) The importance of the inflammatory process in Alzheimer's disease was appreciated when it was noticed that people who used aspirin regularly had a low incidence of that dementia. Aspirin inhibits the formation of TNF, and aspirin has been found to retard bone loss. In the case of osteoporosis (A. Murrillo-Uribe, 1999), as in Alzheimer's disease, the incidence is two or three times as high in women as in men. In both Alzheimer's disease and osteoporosis, the estrogen industry is arguing that the problems are caused by a suddenly developing estrogen deficiency, rather than by prolonged exposure to estrogen.

Similar arguments were made fifty years ago regarding the nature of the menopause itself--that it was caused by a sudden decrease in estrogen production. The evidence that has accumulated in the last forty years has decisively settled that argument: Menopause is the result of prolonged exposure to estrogen. (Even one large dose destroys certain areas in the brain, and chronic, natural levels damage the nerves that regulate the pituitary. Overactivity of the pituitary leads to many other features of aging.)

The links between estrogen and TNF appear to be essential factors in aging and its diseases. Each of these substances has its constructive, but limited, place in normal physiology, but as excitatory factors, they must operate within the appropriate constraints. The basic constraint is that resources, including energy and oxygen, must be available to terminate their excitatory actions. Adequate oxygen, a generous supply of carbon dioxide, saturated fats, thyroid, and progesterone restrain TNF, while optimizing other cytokines and immune functions, including thymic protection. In the development of the organism and its adaptive functions, there are patterned processes, functional systems, that can clarify the interactions of growth and atrophy. The respiratory production of energy and carbon dioxide, and the respiratory defect in which lactic acid is produced, correspond to successful adaptation, and to stressful/excitotoxic maladaptation, respectively. Excitotoxicity, and Meerson's work on the protective functions of the antistress hormones, have to be understood in this framework. This framework integrates the understanding of cancer metabolism with the other stress metabolisms, and with the metabolism of normal growth.

Unsaturated fats, iron, and lactic acid are closely related to the actions and regulation of TNF, and therefore they strongly influence the nature of stress and the rate of aging.

The fact that cancer depends on the presence of polyunsaturated fats probably relates to the constructive and destructive actions of TNF: The destructive effects such as multiple organ failure/congestive heart failure/shock-lung, etc., apparently involve arachidonic acid and its metabolites, which are based on the so-called essential fatty acids. When oxygen and the correct nutrients are available, the hypermetabolism produced by TNF could be reparative (K. Fukushima, et al., 1999), rather than destructive. Stimulation in the presence of oxygen produces carbon dioxide, allowing cells to excrete calcium and to deposit it in bones, but stimulation in the absence of oxygen produces lactic acid and causes cellular calcium uptake.

It is in this context that the therapeutic effects of saturated fats, carbon dioxide, progesterone, and thyroid can be understood. They restore stability to a system that has been stimulated beyond its capacity to adapt without injury.

REFERENCES

J Reprod Med 1990 May;35(5):503-7. A total dietary program emphasizing magnesium instead of calcium. Effect on the mineral density of calcaneous bone in postmenopausal women on hormonal therapy. Abraham GE, Grewal H. J Immunol 1999 Feb 15;162(4):2154-61. Increased TNF-alpha-induced apoptosis in lymphocytes from aged humans: changes in TNF-alpha receptor expression and activation of caspases. Aggarwal S, Gollapudi S, Gupta S.

Mech Ageing Dev 1995 Oct 13;84(2):113-26. Cytokine production and lymphocyte subpopulations in aged humans. An assessment during nocturnal sleep. Born J, Uthgenannt D, Dodt C, Nunninghoff D, Ringvolt E, Wagner T, Fehm HL. "While monocyte counts were unchanged in the elderly production of IL-1 beta and TNF-alpha mainly derived from these cells, was enhanced (p < 0.05). Results indicate a state of enhanced responsiveness of the T cell compartment and of monocytes in aged which may compensate for the substantial decrease in T cells."

Eur J Appl Physiol 1999 Oct;80(5):452-60 Impact of three different types of exercise on components of the inflammatory response. Brenner IK, Natale VM, Vasiliou P, Moldoveanu AI, Shek PN, Shephard RJ.

J Surg Res 1994 Jul;57(1):65-8. Dietary fish oil enhances macrophage production of nitric oxide. Chaet MS, Garcia VF, Arya G, Ziegler MM. "In group A, BAM from animals fed omega 3 produced significantly more NO . . . and TNF . . . than BAM from omega 6-fed animals." "These data demonstrate that PUFA influence BAM production of NO and TNF. Changes in the omega 6-derived prostanoids may account for the differences in TNF production, but these data suggest that PGE2 and PGI2 are not responsible for the observed differences in NO production."

J Immunol 1996 Feb 15;156(4):1525-30. Age-associated differences in TNF-alpha and nitric oxide production in endotoxic mice. Chorinchath BB, Kong LY, Mao L, McCallum RE.

Am J Physiol 1999 Sep;277(3 Pt 1):G671-7. Estriol sensitizes rat Kupffer cells via gut-derived endotoxin. Enomoto N, Yamashina S, Schemmer P, Rivera CA, Bradford BU, Enomoto A, Brenner DA, Thurman RG

Scand J Gastroenterol 1999, Mar; 34(3):291-6. Lipopolysaccharide- and proinflammatory cytokine-induced energy production in intestinal and colonic epithelial cell lines. Fukushima K, Sasaki I, Takahashi K, Naito H, Matsuno S.

Mech Ageing Dev 1995 Sep 29;84(1):39-54 Age-related enhancement of tumor necrosis factor (TNF) production in mice. Han D, Hosokawa T, Aoike A, Kawai K "We previously reported that systemic production of TNF increases with aging. The present study of TNF production at the cellular level in mice indicated (1) that TNF production per macrophage increased with aging, and (2) that the number of T and B cells involved in the production of TNF in the presence of macrophages also increased at least up to middle age." J Clin Endocrinol Metab 1996 Feb;81(2):513-8. Cytokine production in the bone marrow microenvironment: failure to demonstrate estrogen regulation in early postmenopausal women. Kassem M, Khosla S, Spelsberg TC, Riggs BL Fertil Steril 1999 May;71(5):869-72. Serum ionized magnesium and calcium in women after menopause: inverse relation of estrogen with ionized magnesium. Muneyyirci-Delale O, Nacharaju VL, Dalloul M, Altura BM, Altura BT.

Ginecol Obstet Mex 1999 May;67:227-33. [Osteoporosis in Mexican postmenopausal women. Magnitude of the problem. Multicenter study]. Murrillo-Uribe A, Deleze-Hinojosa M, Aguirre E, Villa A, Calva J, Cons F, Briseno A, Gonzalez G, Morales J, Pena H, Guerrero G, Orozco J, Morales G, Elizondo J.

Hepatology 1997 Dec;26(6):1538-45. Dietary saturated fatty acids down-regulate cyclooxygenase-2 and tumor necrosis factor alfa and reverse fibrosis in alcohol-induced liver disease in the rat. Nanji AA, Zakim D, Rahemtulla A, Daly T, Miao L, Zhao S, Khwaja S, Tahan SR, Dannenberg AJ. "The data indicate that a diet enriched in saturated fatty acids (groups 3 and 4) effectively reverses alcohol-induced liver injury, including fibrosis. The therapeutic effects of saturated fatty acids may be explained, at least in part, by reduced endotoxemia and lipid peroxidation, which in turn result in decreased levels of TNF-alpha and Cox-2." Eur J Epidemiol 1998 Feb;14(2):159-64. Secular trends in the osteoporotic fractures of the distal humerus in elderly women. Palvanen M, Kannus P, Niemi S, Parkkari J.

Biochem J 1993 Mar 1;290 ( Pt 2):343-7. Cytokine induction of haem oxygenase mRNA in mouse liver. Interleukin 1 transcriptionally activates the haem oxygenase gene. Rizzardini M, Terao M, Falciani F, Cantoni L. Nitric Oxide 1997;1(6):453-62..Effects of female hormones (17beta-estradiol and progesterone) on nitric oxide production by alveolar macrophages in rats. Robert R, Spitzer JA.

Nitric Oxide 1997;1(6):453-62.. Effects of female hormones (17beta-estradiol and progesterone) on nitric oxide production by alveolar macrophages in rats. Robert R, Spitzer JA.

J Gerontol A Biol Sci Med Sci 1998 Jan;53(1):M20-6. Monocyte cytokine production in an elderly population: effect of age and inflammation. Roubenoff R, Harris TB, Abad LW, Wilson PW, Dallal GE, Dinarello CA. "OBJECTIVE: To determine the association among aging, inflammation, and cytokine production by peripheral blood mononuclear cells." "We examined production of interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), IL-1 receptor antagonist (IL-1Ra), and IL-6 in 711 elderly participants in the Framingham Heart Study (mean age, 79 y) and 21 young healthy volunteers (mean age, 39 y)." CONCLUSION: "Production of IL-6 and IL-1Ra--but not IL-1 beta or TNF-alpha--was increased in the elderly compared to healthy, young subjects. The increase in IL-6 also correlated with increased production of CRP, a marker of inflammation. However, IL-1Ra was increased in the elderly independently of CRP production. Although limited by the small control group, these data suggest that dysregulation of some inflammatory cytokines occurs with age, but the role of inflammation in aging remains unclear."

J Gerontol A Biol Sci Med Sci 1998 Jan;53(1):M20-6. MMonocyte cytokine production in an elderly population: effect of age and inflammation. Roubenoff R, Harris TB, Abad LW, Wilson PW, Dallal GE, Dinarello CA. Br J Cancer Suppl 1996 Jul;27:S133-5. The influence of oxygen and carbon dioxide tension on the production of TNF alpha by activated macrophages. Sampson LE, Chaplin DJ.

Mech Ageing Dev 1997 Feb;93(1-3):87-94. Calorie restriction inhibits the age-related dysregulation of the cytokines TNF-alpha and IL-6 in C3B10RF1 mice. Spaulding CC, Walford RL, Effros RB. "TNF-alpha and IL-6 are generally increased in the sera of aged humans and mice. The dysregulation of these cytokines may be critical in autoreactivity and immune dysfunction." "Serum levels of both cytokines were significantly higher in old versus young mice. However, in old mice subjected to long term CR the serum levels were comparable to those of young mice. The potential involvement of normalization of TNF-alpha and IL-6 levels in the life extension effect of CR are discussed."

Cytokine 1999 May; 11(5):326-33. Induction of haem oxygenase contributes to the synthesis of pro-inflammatory cytokines in re-oxygenated rat macrophages: role of cGMP. Tamion F, Richard V, Lyoumi S, Hiron M, Bonmarchand G, Leroy J, Daveau M, Thuillez C, Lebreton JP. Clin Sci (Colch) 1994 Aug;87(2):173-8. Complex modulation of cytokine induction by endotoxin and tumour necrosis factor from peritoneal macrophages of rats by diets containing fats of different saturated, monounsaturated and polyunsaturated fatty acid composition. Tappia PS, Grimble RF.

Infect Immun 1996 Mar;64(3):769-74. Lipopolysaccharide-induced lethality and cytokine production in aged mice. Tateda K, Matsumoto T, Miyazaki S, Yamaguchi K

Hepatology 2000 Jan;31(1):117-23. Estrogen is involved in early alcohol-induced liver injury in a rat enteral feeding model. Yin M, Ikejima K, Wheeler MD, Bradford BU, Seabra V, Forman DT, Sato N, Thurman RG. "Blood endotoxin and hepatic levels of CD14 messenger RNA (mRNA) and protein were increased by ethanol. This effect was blocked in ovariectomized rats and elevated by estrogen replacement. Moreover, Kupffer cells isolated from ethanol-treated rats with estrogen replacement produced more tumor necrosis factor alpha (TNF-alpha) than those from control and ovariectomized rats. It is concluded, therefore, that the sensitivity of rat liver to alcohol-induced injury is directly related to estrogen, which increases endotoxin in the blood and CD14 expression in the liver, leading to increased TNF-alpha production."

Shock 1998 Dec;10(6):436-41. Acetazolamide treatment prevents in vitro endotoxin-stimulated tumor necrosis factor release in mouse macrophages. West MA, LeMieur TL, Hackam D, Bellingham J, Claire L, Rodriguez JL. Hepatology 2000 Jan;31(1):117-23. Estrogen is involved in early alcohol-induced liver injury in a rat enteral feeding model. Yin M, Ikejima K, Wheeler MD, Bradford BU, Seabra V, Forman DT, Sato N, Thurman RG Anim Reprod Sci 1998 Feb 27;50(1-2):57-67. Elevation in tumour necrosis factor-alpha (TNF-alpha) messenger RNA levels in the uterus of pregnant gilts after oestrogen treatment. Yu Z, Gordon JR, Kendall J, Thacker PA Immunology 1995 Sep;86(1):18-24. In vivo modulation of murine serum tumour necrosis factor and interleukin-6 levels during endotoxemia by oestrogen agonists and antagonists. Zuckerman SH, Bryan-Poole N, Evans GF, Short L, Glasebrook AL. "Oestrogen treatment resulted in a significant increase in serum TNF while serum IL-6 levels, relative to the placebo group, decreased in response to an endotoxin challenge."

Inflammation 1996 Dec;20(6):581-97. Estriol: a potent regulator of TNF and IL-6 expression in a murine model of endotoxemia. Zuckerman SH, Ahmari SE, Bryan-Poole N, Evans GF, Short L, Glasebrook AL.

Proc Assoc Am Physicians 1996 Mar;108(2):155-64 Potential mechanism of estrogen-mediated decrease in bone formation: estrogen increases production of inhibitory insulin-like growth factor-binding protein-4. Kassem M, Okazaki R, De Leon D, Harris SA, Robinson JA, Spelsberg TC, Conover CA, Riggs BL.

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A R T I C L E

Fats and degeneration

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50 years ago, in the first phase of marketing the polyunsaturated fatty acids (PUFA), linoleic acid was heart protective, and the saturated fats raised cholesterol and caused heart disease.

In the second phase, the other essential fatty acid, linolenic acid, was said to be even better than linoleic acid.

In the third phase, the longer chain omega -3 (omega minus three, or n minus three) fatty acids, DHA and EPA, are said to be even better than linolenic acid.

Along the way, the highly unsaturated arachidonic acid, which we and other animals make out of the linoleic acid in foods, was coming to be identified with the harmful animal fats. But we just didn't hear much about how the amount of arachidonic acid in the tissues depended on the amount of linoleic acid in the diet.

U.S. marketing dominates the world economy, including of course the communication media, so we shouldn't expect to hear much about the role of PUFA in causing cancer, diabetes, obesity, aging, thrombosis, arthritis and immunodeficiency, or to hear about the benefits of the saturated fats.

The saturated fats include the tropical fats, because they are synthesized in very warm organisms, and are very stable at those temperatures. Their stability offers some protection against the unstable PUFA.

Several of the degenerative conditions produced by the essential fatty acids can be reversed by use of saturated fats, varying in length from the short chains of coconut oil to the very long chains of waxes.

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When a person uses a drug, there is generally an awareness that the benefit has to be weighed against the side effects. But if something is treated as a nutrient, especially an essential nutrient, there is an implication that it won't produce undesirable side effects.

Over the last thirty years I have asked several prominent oil researchers what the evidence is that there is such a thing as an essential fatty acid. One professor cited a single publication about a solitary sick person who recovered from some sickness after being given some unsaturated fat. (If he had known of any better evidence, wouldn't he have mentioned it?) The others (if they answered at all) cited Burr and Burr, 1929. The surprising thing about that answer is that these people can consider any nutritional research from 1929 to be definitive. It's very much like quoting a 1929 opinion of a physicist regarding the procedure for making a hydrogen bomb. What was known about nutrition in 1929? Most of the B vitamins weren't even suspected, and it had been only two or three years since vitamin B had been subdivided into two factors, the antineuritic factor, B₁, and the growth factor, B₂. Burr had no way of really understanding what deficiencies or toxicities were present in his experimental diet.

A few years after the first experiments, Burr put one of his essential fatty acid deficient rats under a bell jar to measure its metabolic rate, and found that the deficient animals were metabolizing 50% faster than rats that were given linoleic and linolenic acids as part of their diet. That was an important observation, but Burr didn't understand its implications. Later, many experiments showed that the polyunsaturated fats slowed metabolism by profoundly interfering with the function of the thyroid hormone and the cellular respiratory apparatus. Without the toxic fats, respiratory energy metabolism was very intense, and a diet that was nutritionally sufficient for a sluggish animal wouldn't necessarily be adequate for the vigorous animals.

Several publications between 1936 and 1944 made it very clear that Burr's basic animal diet was deficient in various nutrients, especially vitamin B₆. The disease that appeared in Burr's animals could be cured by fat free B-vitamin preparations, or by purified vitamin B6 when it became available. A zinc deficiency produces similar symptoms, and at the time Burr did his experiments, there was no information on the effects of fats on mineral absorption. If a diet is barely adequate in the essential minerals, increasing the metabolic rate, or decreasing intestinal absorption of minerals, will produce mineral deficiencies and metabolic problems.

Although Burr's disease clearly turned out to be a B-vitamin deficiency, probably combined with a mineral deficiency, it continues to be cited as the basis justifying the multibillion dollar industry that has grown up around the essential oils.

Two years before Burr's experiment, German researchers found that a fat-free diet prevented almost all spontaneous cancers in rats. Later work showed that the polyunsaturated fats both initiate and promote cancer. With that knowledge, the people who kept claiming that linoleic, linolenic, and maybe arachidonic acid are the essential fatty acids, should have devoted some effort to finding out how much of that essential nutrient was enough, so that people could minimize their consumption of the carcinogenic stuff.

Between the first and second world wars, cod liver oil was recommended as a vitamin supplement, at first as a source of vitamin A, and later as a source of vitamins A and D. But in the late 1940s, experimenters used it as the main fat in dogs' diet, and found that they all died from cancer, while the dogs on a standard diet had only a 5% cancer mortality. That sort of information, and the availability of synthetic vitamins, led to the decreased use of cod liver oil.

But around that time, the seed oil industry was in crisis because the use of those oils in paints and plastics was being displaced by new compounds made from petroleum. The industry needed new markets, and discovered ways to convince the public that seed oils were better than animal fats. They were called the heart protective oils, though human studies soon showed the same results that the animal studies had, namely, that they were toxic to the heart and increased the incidence of cancer.

The lipid hypothesis of heart disease argued that cholesterol in the blood caused atherosclerosis, and that the polyunsaturated oils lowered the amount of cholesterol in the blood. Leaving behind the concept of nutritional essentiality, this allowed the industry (and their academic supporters, such as Frederick Stare at Harvard) to begin promoting the oils as having drug-like therapeutic properties. Larger amounts of polyunsaturated fat were supposed to be more protective by lowering the cholesterol, and were to be substituted for the saturated fats, which supposedly raised cholesterol and increased heart disease, producing atherosclerotic plaques in the blood vessels and increasing the formation of blood clots.

Since all ordinary foods contain significant amounts of the polyunsaturated fats, there was no reason to think that, even if they were essential nutrients, people were likely to become deficient in them. So the idea of treating the seed oils as drug-like substances, to be taken in large amounts, appealed to the food oil industry.

Prostaglandins, which are produced in the body by oxidizing the polyunsaturated fatty acids, provided an opportunity for the drug industry to get involved in a new market, and the prostaglandins offered a new way of arguing for the nutritional essentiality of linoleic and related acids: A whole system of hormones is made from these molecules. Since some of the prostaglandins suppress immunity, cause inflammation and promote cancer growth, some people have divided them into the good prostaglandins and the bad prostaglandins.

PGI2, or prostacyclin, is considered to be a good prostaglandin, because it causes vasodilatation, and so drug companies have made their own synthetic equivalents: Epoprostenol, iloprost, taprostene, ciprostene, UT-15, beraprost, and cicaprost. Some of these are being investigated for possible use in killing cancer.

But many very useful drugs that already existed, including cortisol and aspirin, were found to achieve some of their most important effects by inhibiting the formation of the prostaglandins. It was the body's load of polyunsaturated fats which made it very susceptible to inflammation, stress, trauma, infection, radiation, hormone imbalance, and other fundamental problems, and drugs like aspirin and cortisone, which limit the activation of the stored essential fatty acids, gain their remarkable range of beneficial effects partly by the restraint they impose on those stored toxins.

Increasingly, the liberation of arachidonic acid from tissues during stress is seen as a central factor in all forms of stress, either acute (as in burns or exercise) or chronic (as in diabetes or aging). And, as the fat stores become more toxic, it seems that they more readily liberate the free fatty acids. (For example, see Iritani, et al., 1984)

During this same period, a few experimenters were finding that animals which were fed a diet lacking the essential fatty acids had some remarkable properties: They consumed oxygen and calories at a very high rate, their mitochondria were unusually tough and stable, their tissues could be transplanted into other animals without provoking immunological rejection, and they were very hard to kill by trauma and a wide variety of toxins that easily provoke lethal shock in animals on the usual diet. As the Germans had seen in 1927, they had a low susceptibility to cancer, and new studies were showing that they weren't susceptible to various fibrotic conditions, including alcoholic liver cirrhosis.

In 1967 a major nutrition publication, Present Knowledge in Nutrition, published Hartroft and Porta's observation that the age pigment, lipofuscin, was formed in proportion to the amount of polyunsaturated fat and oxidants in the diet. The new interest in organ transplantation led to the discovery that the polyunsaturated fats prolonged graft survival, by suppressing the immune system. Immunosuppression was considered to have a role in the carcinogenicity of the essential fatty acids.

Around the same time, there were studies that showed that unsaturated fats retarded brain development and produced obesity.

Substances very much like the prostaglandins, called isoprostanes and neuroprostanes, are formed spontaneously from highly unsaturated fatty acids, and are useful as indicators of the rate of lipid peroxidation in the body. Most of the products of lipid peroxidation are toxic, as a result of their reactions with proteins, DNA, and the mitochondria. The age-related glycation products that are usually blamed on sugar, are largely the result of peroxidation of the polyunsaturated fatty acids.

Through the 1970s, this sort of information about the harmful effects of the PUFA was being slowly assimilated by the culture, though many dietitians still spoke of the essential fatty acids, vitamin F. By 1980, it looked as though responsible researchers would see the promotion of cancer, heart disease, mitochondrial damage, hypothyroidism and immunosuppression caused by the polyunsaturated fats as their most important feature, and would see that there had never been a basis for believing that they were essential nutrients.

But then, without acknowledging that there had been a problem with the doctrine of essentiality, fat researchers just started changing the subject, shifting the public discourse to safer, more profitable topics. The fats that had been called essential, but that had so many toxic effects, were no longer emphasized, and the failed idea of essentiality was shifted to different categories of polyunsaturated fats.

The addition of the long chain highly unsaturated fats to baby food formulas was recently approved, on the basis of their supposed essentiality for brain development. One of the newer arguments for the essentiality of the PUFA is that they are needed for making cell membranes. But human cells can grow and divide in artificial culture solutions which contain none of the polyunsaturated fats, and no one has claimed that they are growing without membranes.

The long chain fats found in fish and some algae don't interfere with animal enzymes as strongly as the seed oils do, and so by comparison, they aren't so harmful. They are also so unstable that relatively little of them is stored in the tissues. (And when they are used as food additives, it's necessary to use antioxidants to keep them from becoming smelly and acutely toxic.)

When meat is grilled at a high temperature, the normally spaced double bonds in PUFA migrate towards each other, becoming more stable, so that linoleic acid is turned into conjugated linoleic acid. This analog of the essential linoleic acid competes against the linoleic acid in tissues, and protects against cancer, atherosclerosis, inflammation and other effects of the normal PUFA. Presumably, anything which interferes with the essential fatty acids is protective, when the organism contains dangerous amounts of PUFA. Even the trans-isomers of the unsaturated fatty acids (found in butterfat, and convertible into conjugated linoleic acid) can be protective against cancer.

In the 1980s the oil promoters were becoming more sophisticated, and were publishing many experiments in which the fish oils were compared with corn oil, or safflower, or soy oil, and in many of those experiments, the animals' health was better when they didn't eat the very toxic seed oils, that contained the essential fatty acids, linoleic and linoleic acids.

Besides comparing the fish oils to the stronger toxins, another trick is to take advantage of the same immunosuppressive property that had seemed troublesome, and to emphasize their ability to temporarily alleviate some autoimmune or allergic diseases. X-rays were once used that way, to treat arthritis and ringworm, for example.

And, knowing that cancer cells have the ability to consume large amounts of fatty acids, they would test these fats in tissue culture dishes, and demonstrate that they were poisonous, cytotoxic, to the fast growing cancer cells. Although they caused cancer in animals, if they could be shown to kill cancer cells in a dish, they could be sold as anticancer drugs/nutrients, with the special mystique of being essential fatty acids. Strangely, their ability to kill cancer cells under some circumstances and to suppress some immunological reactions is being promoted in close association with the doctrine that these fats are nutritionally essential.

Arachidonic acid is made from linoleic acid, and so those two oils were considered as roughly equivalent in their ability to meet our nutritional needs, but a large part of current research is devoted to showing the details of how fish oils protect against arachidonic acid. The balance between the omega -3 and the omega -6 fatty acids is increasingly being presented as a defense against the toxic omega -6 fats. But the accumulation of unsaturated fats with aging makes any defense increasingly difficult, and the extreme instability of the highly unsaturated omega -3 fats creates additional problems.

PUFA and x-rays have many biological effects in common. They are immunosuppressive, but they produce their own inflammatory reactions, starting with increased permeability of capillaries, disturbed coagulation and proteolysis, and producing fibrosis and tumefaction or tissue atrophy. This isn't just a coincidence, since ionizing radiation attacks the highly unstable polyunsaturated molecules, simply accelerating processes that ordinarily happen more slowly as a result of stress and aging.

Prolonged stress eventually tends to be a self-sustaining process, impairing the efficient respiratory production of energy, converting muscle tissue to amino acids, suppressing the thyroid, and activating further mobilization of fatty acids. Fatty acids are mobilized from within the structure of cells by phospholipases, and from fat tissues by other lipases.

The highly unsaturated fatty acids, as well as the ordinary essential fatty acids, act directly to increase capillary permeability, even without conversion into prostaglandins, and they interfere in many ways with the clotting and clot removal systems. The effects of PUFA taken in a meal probably disturb the clotting system more than the same quantity of saturated fat, contrary to many of the older publications. The PUFA are widely believed to prevent clotting, but when cod liver oil is given to EFA deficient animals, it activates the formation of clots (Hornstra, et al., 1989). An opposite effect is seen when a long chain fatty acid synergizes with aspirin, to restrain clotting (Molina, et al., 2003).

Fibrosis is a generalized consequence of the abnormal capillary permeability produced by things that disrupt the clotting system. Estrogen, with its known contribution to the formation of blood clots and edema and fibrosis and tumors, achieves part of its effect by maintaining a chronically high level of free fatty acids, preferentially liberating arachidonic acid, rather than saturated fatty acids.

Butter, beef fat, and lamb fat are the only mostly saturated fats produced on a large scale in the U.S., and the cheapness/profitability of the seed oils made it easy to displace them. But, in the face of the immense amount of propagandistic health claims that have been made against the saturated fats, it's instructive to look at some of their actual effects, especially on the clotting system, and the related fibrotic reactions.

The saturated fatty acids are very unreactive chemically. Coconut oil, despite containing about 1% of the unstable PUFA, can be left in a bucket at room temperature for a year or more without showing any evidence of deterioration, suggesting that the predominance of saturated fat acts as an antioxidant for the unsaturated molecules. In the body, the saturated fats seem to act the same way, preventing or even reversing many of the conditions caused by oxidation of fats.

The stress-induced liberation of arachidonic acid causes blood vessels to leak, and this allows fibrin to escape from the blood stream, into the basement membrane and beyond into the extracellular matrix, where it produces fibrosis. (Cancer, autoimmune diseases, and heart disease involve the same inflammatory, thrombotic, fibrotic processes as the nominal fibroses.) Scleroderma, liver cirrhosis, fibrosis of the lungs, heart, and other organs, and all the diseases in which fibrous tissue becomes dense and progressively contracts, involve similar processes, and the treatments which are successful are those that stop the inflammation produced by the oxidation of the polyunsaturated fatty acids.

Retroperitoneal fibrosis is now known to be produced by estrogen, and is treated by antiestrogenic and antiserotonergic drugs, but as early as 1940 Alejandro Lipschutz demonstrated that chronic exposure to very low doses of estrogen produced fibromas in essentially every part of the body. Earlier, Loeb had studied the action of large doses of estrogen, which produced fibrosis of the uterus, as if it had accelerated aging. Following Lipschutz' work, in which he demonstrated the antifibromatogenic actions of pregnenolone and progesterone, several Argentine researchers showed that progesterone prevented and cured abdominal adhesions and other fibrotic conditions, including retroperitoneal fibrosis.

Since estrogen produces both leakiness of the capillaries and excessive formation of fibrin, its effects will be seen first in the organs where it concentrates, but eventually anywhere capillaries leak fibrin. Estrogen activates the phospholipase which liberates arachidonic acid, and progesterone inhibits that phospholipase.

As the fat tissues become more burdened with arachidonic acid, they release it more easily in response to moderately lipolytic stress signals. This could explain the increased levels of free fatty acids and lipid peroxidation that occur with aging. In animals that are deficient in the polyunsaturated fatty acids, adrenalin doesn't have the lipolytic effect that it does in animals on the standard diet. With aging, there is not only a tendency to have chronically higher free fatty acids in the blood, but for those fatty acids to be more unsaturated. The phospholipids of mitochondria and microsomes become more unsaturated with aging (Laganiere and Yu, 1993, Lee, et al., 1999). In the human retina there is a similar accumulation of PUFA with aging (Nourooz-Zadeh and Pereira, 1999), which implies that the aged retina will be more easily damaged by light.

Several studies suggest that a high degree of unsaturation in the fats is fundamentally related to the aging process, since long lived species have a lower degree of unsaturation in their fats. Caloric restriction decreases the age-related accumulation of the fatty acids with 4 and 5 double bonds.

Although publicity has emphasized the anti-inflammatory effects of fish oil, experiments show that it is extremely effective in producing alcohol-related liver cirrhosis. Breakdown products of polyunsaturated fats (isoprostanes and 4-HNE) are found in the blood of people with alcoholic liver disease (Aleynik, et al., 1998). In the absence of polyunsaturated fats, alcohol doesn't produce cirrhosis. Saturated fats allow the fibrosis to regress:

A diet enriched in saturated fatty acids effectively reverses alcohol-induced necrosis, inflammation, and fibrosis despite continued alcohol consumption. The therapeutic effects of saturated fatty acids may be explained, at least in part, by reduced endotoxemia and lipid peroxidation.... (Nanji, et al., 1995, 2001)

In these studies, the animals were switched from fish oil to either palm oil or medium chain triglycerides (a major fraction of coconut oil). In other studies, Knittel, et al. (1995), show that fibrinogen, in a clotting-like process, is involved in the development of liver fibrosis, and that this appears to provide a basis for the growth of additional extracellular matrix.

Brown, et al. (1989), discussed this developmental process (leaky capillaries, fibrosis) in relation to wound healing, lung disease, and tumor growth.

The relatively few studies of fish oil and linoleic acid that compare them with palmitic acid or coconut oil have produced some very important results. For example, pigs exposed to endotoxin developed severe lung problems (resembling shock lung) when they had been on a diet with either fish oil or Intralipid (which is mostly linoleic acid, used for intravenous feeding in hospitals), but not after palmitic acid (Wolfe, et al., 2002).

Eating low-fat seafood (sole, whitefish, turbot, scallops, oysters, lobster, shrimp, squid, etc.) once in a while can provide useful trace minerals, without much risk. However, fish from some parts of the ocean contain industrial contaminants in the fat, and large fish such as tuna, swordfish, Chilean sea bass and halibut contain toxic amounts of mercury in the muscles. Chilean sea bass (Patagonian toothfish) is very high in fat, too.

About ten years ago I met a young man with a degenerative brain disease, and was interested in the fact that he (working on a fishing boat) had been eating almost a pound of salmon per day for several years. There is now enough information regarding the neurotoxic effects of fish oil to justify avoidance of the fatty fish.

Some of the current advertising is promoting fish oil to prevent cancer, so it's important to remember that there are many studies showing that it increases cancer.

The developmental and physiological significance of the type of fatty acid in the diet has been established for a long time, but cultural stereotypes and commercial interests are threatened by it, so it can't be discussed publicly.

REFERENCES

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Mech Ageing Dev 2001 Apr 15;122(4):427-43. Effect of the degree of fatty acid unsaturation of rat heart mitochondria on their rates of H2O2 production and lipid and protein oxidative damage. Herrero A, Portero-Otin M, Bellmunt MJ, Pamplona R, Barja G. Previous comparative studies have shown that long-lived animals have lower fatty acid double bond content in their mitochondrial membranes than short-lived ones. In order to ascertain whether this trait protects mitochondria by decreasing lipid and protein oxidation and oxygen radical generation, the double bond content of rat heart mitochondrial membranes was manipulated by chronic feeding with semi-purified AIN-93G diets rich in highly unsaturated (UNSAT) or saturated (SAT) oils. UNSAT rat heart mitochondria had significantly higher double bond content and lipid peroxidation than SAT mitochondria. They also showed increased levels of the markers of protein oxidative damage malondialdehyde-lysine, protein carbonyls, and N(e)-(carboxymethyl)lysine adducts. These results demonstrate that increasing the degree of fatty acid unsaturation of heart mitochondria increases oxidative damage to their lipids and proteins, and can also increase their rates of mitochondrial oxygen radical generation in situations in which the degree of reduction of Complex III is higher than normal. These observations strengthen the notion that the relatively low double bond content of the membranes of long-lived animals could have evolved to protect them from oxidative damage.

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Gerontology 1993;39(1):7-18. Modulation of membrane phospholipid fatty acid composition by age and food restriction. Laganiere S, Yu BP. H.M. Phospholipids from liver mitochondrial and microsomal membrane preparations were analyzed to further assess the effects of age and lifelong calorie restriction on membrane lipid composition. The data revealed characteristic patterns of age-related changes in ad libitum (AL) fed rats: membrane levels of long-chain polyunsaturated fatty acids, 22:4 and 22:5, increased progressively, while membrane linoleic acid (18:2) decreased steadily with age. Levels of 18:2 fell by approximately 40%, and 22:5 content almost doubled making the peroxidizability index increase with age. We concluded that the membrane-stabilizing action of long-term calorie restriction relates to the selective modification of membrane long-chain polyunsaturated fatty acids during aging.

Medicina (B Aires). 1978 Mar-Apr;38(2):123-32. [Effective treatment of several types of fibromatosis with progesterone. Fibrous mediastinitis, desmoid tumors, paraneoplastic fibrosis] [in Spanish] Lanari A, Molinas FC, Castro Rios M, Paz RA.

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Free Radic Biol Med 1999 Feb;26(3-4):260-5. Modulation of cardiac mitochondrial membrane fluidity by age and calorie intake. Lee J, Yu BP, Herlihy JT. The fatty acid composition of the mitochondrial membranes of the two ad lib fed groups differed: the long-chain polyunsaturated 22:4 fatty acid was higher in the older group, although linoleic acid (18:2) was lower. DR eliminated the differences. Considered together, these results suggest that DR maintains the integrity of the cardiac mitochondrial membrane fluidity by minimizing membrane damage through modulation of membrane fatty acid profile.

Lipids 2001 Jun;36(6):589-93. Effect of dietary restriction on age-related increase of liver susceptibility to peroxidation in rats. Leon TI, Lim BO, Yu BP, Lim Y, Jeon EJ, Park DK.

Acta Chir Scand. 1976;142(1):20-5. Induction of endogenous fibrinolysis inhibition in the dog. Effect of intravascular coagulation and release of free fatty acids. Lindquist O, Bagge L, Saldeen T. In all groups subjected to infusion of thrombin an increase in plasma free fatty acids (FFA) was observed. The role of this increase for the development of fibrinolysis inhibition was tested by infusion of norepinephrine alone and in combination with nicotinic acid. Norepinephrine caused an increase of FFA after 2 hours and in urokinase inhibitor activity after 24-48 hours. Both of these were diminished by high doses of nicotinic acid, indicating that the release of FFA rather than intravascular coagulation might be the principal mechanism underlying the occurrence of fibrinolysis inhibition following trauma.

Proc Natl Acad Sci U S A 1990 Nov;87(22):8845-9. Incorporation of marine lipids into mitochondrial membranes increases susceptibility to damage by calcium and reactive oxygen species: evidence for enhanced activation of phospholipase A2 in mitochondria enriched with n-3 fatty acids. Malis CD, Weber PC, Leaf A, Bonventre JV.

Prostaglandins Leukot Essent Fatty Acids 1994 Jul;51(1):33-40. Suppression of human T-cell growth in vitro by cis-unsaturated fatty acids: relationship to free radicals and lipid peroxidation. Madhavi N, Das UN, Prabha PS, Kumar GS, Koratkar R, Sagar PS.

Clin Exp Metastasis 1998 Jul;16(5):407-14. Diminution of the development of experimental metastases produced by murine metastatic lines in essential fatty acid-deficient host mice. Mannini A, Calorini L, Mugnai G, Ruggieri S.

Biochem Pharmacol. 1990 Mar 1;39(5):879-89. Histamine release from rat mast cells induced by metabolic activation of polyunsaturated fatty acids into free radicals. Masini E, Palmerani B, Gambassi F, Pistelli A, Giannella E, Occupati B, Ciuffi M, Sacchi TB, Mannaioni PF.

Journal of Lipid Research, Vol. 44, 271-279, February 2003. Arachidonic acid and prostacyclin signaling promote adipose tissue development : a human health concern? F. Massiera, P. Saint-Marc, J. Seydoux , T. Murata , T. Kobayashi , S. Narumiya , P. Guesnet, Ez-Zoubir Amri, R. Negrel and G. Ailhaud1.

Infection. 1994 Mar-Apr;22(2):106-12. Influence of dietary (n-3)-polyunsaturated fatty acids on leukotriene B4 and prostaglandin E2 synthesis and course of experimental tuberculosis in guinea pigs. Mayatepek E, Paul K, Leichsenring M, Pfisterer M, Wagner D, Domann M, Sonntag HG, Bremer HJ.

Biochim Biophys Acta 1994 Sep 15;1214(2):209-20. Reinvestigation of lipid peroxidation of linolenic acid. Mlakar A, Spiteller G. Thus, a great number of previously unknown lipid peroxidation products was detected. It is assumed that these compounds also occur--at least as intermediates--in lipid peroxidation processes in mammalian tissue.

Prostaglandins Leukot Essent Fatty Acids. 2003 May;68(5):305-10. Synergistic effect of D-003 and aspirin on experimental thrombosis models. Molina V, Arruzazabala ML, Carbajal D, Mas R.

Chem Res Toxicol. 2001 Apr;14(4):431-7. Defining mechanisms of toxicity for linoleic acid monoepoxides and diols in Sf-21 cells. Moran JH, Mon T, Hendrickson TL, Mitchell LA, Grant DF.

J Biochem (Tokyo). 1977 Aug;82(2):529-33. Effects of free fatty acids on fibrinolytic activity. Muraoka T, Okuda H. A novel method for the estimation of fibrinolytic activity is proposed. In this method, a fibrin clot suspension is used as a substrate (fibrin is known to be a physiological substrate of plasmin). The fibrin clot suspension was prepared by homogenization of human fibrin clots. With this method, we found that free fatty acids inhibited the plasmin activity, and long-chain, unsaturated free fatty acids had a particularly strong inhibitory action on plasmin. As regards the mechanism of the inhibitory action, free fatty acids may not inhibit complex formation between plasmin and fibirin, but may make it impossible for plasmin to act on fibrin due to deformation of the surface of the fibrin clot.

Alcohol Clin Exp Res. 1986 Jun;10(3):271-3. Dietary factors and alcoholic cirrhosis. Nanji AA, French SW.

Gastroenterology. 1995 Aug;109(2):547-54. Dietary saturated fatty acids: a novel treatment for alcoholic liver disease. Nanji AA, Sadrzadeh SM, Yang EK, Fogt F, Meydani M, Dannenberg AJ.

J Pharmacol Exp Ther. 1996 Jun;277(3):1694-700. Medium chain triglycerides and vitamin E reduce the severity of established experimental alcoholic liver disease. Nanji AA, Yang EK, Fogt F, Sadrzadeh SM, Dannenberg AJ.

Hepatology. 1997 Dec;26(6):1538-45. Dietary saturated fatty acids down-regulate cyclooxygenase-2 and tumor necrosis factor alfa and reverse fibrosis in alcohol-induced liver disease in the rat. Nanji AA, Zakim D, Rahemtulla A, Daly T, Miao L, Zhao S, Khwaja S, Tahan SR, Dannenberg AJ.

J Pharmacol Exp Ther. 2001 Nov;299(2):638-44. Dietary saturated fatty acids reverse inflammatory and fibrotic changes in rat liver despite continued ethanol administration. Nanji AA, Jokelainen K, Tipoe GL, Rahemtulla A, Dannenberg AJ.

Gastroenterology 1995 Apr;108(4):1124-35. Accumulation and cellular localization of fibrinogen/fibrin during short-term and long-term rat liver injury. Neubauer K, Knittel T, Armbrust T, Ramadori G Fibrinogen/fibrin deposition in damaged livers was studied by immunohistology. Immunohistology showed striking amounts of fibrinogen and fibrin deposits in pericentral necrotic areas (short-term damage) and within fibrotic septa (long-term damage). The results show fibrinogen/fibrin deposition during short-term liver injury and liver fibrogenesis, which may suggest the involvement of a "clotting-like process" in short-term liver damage and liver fibrosis. The data might indicate that fibrin/fibronectin constitute a "provisional matrix," which affects the attraction and proliferation of inflammatory and matrix-producing cells.

Ophthalmic Res. 1999;31(4):273-9. Age-related accumulation of free polyunsaturated fatty acids in human retina. Nourooz-Zadeh J, Pereira P.

Chem Res Toxicol. 2002 Mar;15(3):367-72. Formation of cyclic deoxyguanosine adducts from omega-3 and omega-6 polyunsaturated fatty acids under oxidative conditions. Pan J, Chung FL.

Radiobiologiia. 1985 Nov-Dec;25(6):763-7. [Mechanism of circulatory disorders in animals irradiated at high doses] [in Russian] Pozharisskaia TD, Vasil'eva TP, Sokolova EN, Alekseeva II. Some data are reported on pathoanatomical changes, a status of the microcirculatory channel and the coagulogram of animals affected by high doses of ionizing radiation. The signs of disseminated intravascular blood coagulation have been revealed.

J Biol Chem. 1998 May 29;273(22):13605-12. Formation of isoprostane-like compounds (neuroprostanes) in vivo from docosahexaenoic acid. Roberts LJ 2nd, Montine TJ, Markesbery WR, Tapper AR, Hardy P, Chemtob S, Dettbarn WD, Morrow JD.

Nutr Cancer 1995;24(1):33-45. Effects of linoleic acid and gamma-linolenic acid on the growth and metastasis of a human breast cancer cell line in nude mice and on its growth and invasive capacity in vitro. Rose DP, Connolly JM, Liu XH

Arch Toxicol. 1997;71(9):563-74. Impaired cellular immune response in rats exposed perinatally to Baltic Sea herring oil or 2,3,7,8-TCDD. Ross PS, de Swart RL, van der Vliet H, Willemsen L, de Klerk A, van Amerongen G, Groen J, Brouwer A, Schipholt I, Morse DC, van Loveren H, Osterhaus AD, Vos JG.

Nutr Cancer 1998;30(2):137-43. Effects of dietary n-3-to-n-6 polyunsaturated fatty acid ratio on mammary carcinogenesis in rats. Sasaki T, Kobayashi Y, Shimizu J, Wada M, In'nami S, Kanke Y, Takita T. An increase in the n-3/n-6 ratio did not suppress the incidence or reduce the latency of mammary tumor development. The number and weight of mammary tumors per tumor-bearing rat tended to be large in the group with an n-3/n-6 ratio of 7.84 compared with those in the other groups. As the n-3/n-6 ratios were elevated, the total number and weight of tumors increased gradually.

J. Biol. Chem. 1940 132: 539-551. Essential fatty acids, vitamin B₆, and other factors in the cure of rat acrodynia. H. Schneider, H. Steenbock, and Blanche R. Platz

Science. 1988 May 20;240(4855):1032-3. Essential fatty acid depletion of renal allografts and prevention of rejection. Schreiner GF, Flye W, Brunt E, Korber K, Lefkowith JB.

Physiol Bohemoslov. 1990;39(2):125-34. Proportion of individual fatty acids in the non-esterified (free) fatty acid (FFA) fraction in the serum of laboratory rats of different ages. Smidova L, Base J, Mourek J, Cechova I.

Placenta. 2003 Nov;24(10):965-73. Augmented PLA(2)Activity in Pre-eclamptic Decidual Tissue-A Key Player in the Pathophysiology of 'Acute Atherosis' in Pre-eclampsia? Staff AC, Ranheim T, Halvorsen B.

Acta Neurochir Suppl (Wien) 1994;60:20-3. Mechanisms of glial swelling by arachidonic acid. Staub F, Winkler A, Peters J, Kempski O, Baethmann A.

Arch Biochem Biophys. 1991 Aug 15;289(1):33-8. A possible mechanism of mitochondrial dysfunction during cerebral ischemia: inhibition of mitochondrial respiration activity by arachidonic acid. Takeuchi Y, Morii H, Tamura M, Hayaishi O, Watanabe Y.

J Drug Target. 2003 Jan;11(1):45-52. Modulation of tumor-selective vascular blood flow and extravasation by the stable prostaglandin 12 analogue beraprost sodium. Tanaka S, Akaike T, Wu J, Fang J, Sawa T, Ogawa M, Beppu T, Maeda H.

Am J Clin Nutr. 2003 May;77(5):1125-32. Effect of individual dietary fatty acids on postprandial activation of blood coagulation factor VII and fibrinolysis in healthy young men. Tholstrup T, Miller GJ, Bysted A, Sandstrom B.

Biochem Soc Trans. 2003 Oct;31(Pt 5):1075-9. Regression of pre-established atherosclerosis in the apoE-/- mouse by conjugated linoleic acid. Toomey S, Roche H, Fitzgerald D, Belton O.

Int J Biochem Cell Biol. 2003 May;35(5):749-55. Increased muscle proteasome activities in rats fed a polyunsaturated fatty acid supplemented diet. Vigouroux S, Farout L, Clavel S, Briand Y, Briand M. Changes in the proteasome system, a dominant actor in protein degradation in eukaryotic cells, have been documented in a large number of physiological and pathological conditions. With the polyunsaturated fatty acid enriched diet, the chymotrypsin-like and peptidylglutamylpeptide hydrolase activities increased by 45% in soleus and extensor digitorum longus (EDL), and by 90% in the gastrocnemius medialis (GM) muscle. Trypsin-like activity of the proteasome increased by 250% in soleus, EDL and GM. Proteasome activities and level were less stimulated with a monounsaturated fatty acid supplemented diet. Unsaturated fatty acids are particularly prone to free radical attack. Thus, we suggest that alterations in muscle proteasome may result from monounsaturated and polyunsaturated fatty acid-induced peroxidation, in order to eliminate damaged proteins.

J Am Coll Nutr. 2000 Aug;19(4):478S-486S. Conjugated linoleic acid and bone biology. Watkins BA, Seifert MF. Recent investigations with growing rats given butter fat and supplements of CLA demonstrated an increased rate of bone formation and reduced ex vivo bone PGE2 production, respectively.

Ups J Med Sci. 1979;84(3):195-201. Effect of nicotinic acid on the posttraumatic increase in free fatty acids and fibrinolysis inhibition activity in the rat. Wegener T, Bagge L, Saldeen T. Nicotinic acid effectively inhibited the posttraumatic increase in both free fatty acids (FFA) and fibrinolysis inhibition activity (FIA) in the blood in rats, indicating that FFA might be involved in the posttraumatic increase of FIA. The FIA in the liver was greater than that in other organs studied and was increased in the posttraumatic phase. The possible role of the liver in the posttraumatic increase of FIA is discussed.

Am J Physiol Regul Integr Comp Physiol. 2001 Mar;280(3):R908-12. CLA reduces antigen-induced histamine and PGE(2) release from sensitized guinea pig tracheae. Whigham LD, Cook EB, Stahl JL, Saban R, Bjorling DE, Pariza MW, Cook ME.

Toxicol Appl Pharmacol 1993 May;120(1):72-9. Essential fatty acid deficiency in cultured human keratinocytes attenuates toxicity due to lipid peroxidation. Wey HE, Pyron L, Woolery M.

Nutrition. 2002 Jul-Aug;18(7-8):647-53. Dietary fat composition alters pulmonary function in pigs. Wolfe RR, Martini WZ, Irtun O, Hawkins HK, Barrow RE.

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Food-junk and some mystery ailments: Fatigue, Alzheimer's, Colitis, Immunodeficiency.

Years ago, I noticed that Oregon was one of the few states that still had real whipping cream and cottage cheese without additives, so I have been trustingly using cream in my coffee every day. Last week, I noticed that my cream listed carrageenan in its ingredients. Over the years, I have avoided carrageenan-containing foods such as apple cider, hot dogs, most ice creams and prepared sauces and jellies, because they caused me to have serious allergic symptoms. Carrageenan has been found to cause colitis and anaphylaxis in humans, but it is often present in baby “formulas” and a wide range of milk products, with the result that many people have come to believe that it was the milk-product that was responsible for their allergic symptoms. Because the regulators claim that it is a safe natural substance, it is very likely that it sometimes appears in foods that don’t list it on the label, for example when it is part of another ingredient.

In the 1940s, carrageenan, a polysaccharide made from a type of seaweed, was recognized as a dangerous allergen. Since then it has become a standard laboratory material to use to produce in-flammatory tumors (granulomas), immunodeficiency, arthritis, and other in-flammations. It has also become an increasingly common material in the food industry. Articles are often written to praise its usefulness and to claim that it doesn't produce cancer in healthy animals. Its presence in food, like that of the polyester imitation fat, microcrystalline cellulose, and many other polymers used to stabilize emulsions or to increase smoothness, is often justified by the doctrine that these molecules are too large to be absorbed. There are two points that are deliberately ignored by the food-safety regulators, 1) these materials can interact dangerously with intestinal bacteria, and 2) they can be absorbed, in the process called "persorption."

The sulfites (sodium bisulfite, potassium metabisulfite, etc.) have been used as preservatives in foods and drugs for a long time, even though they were known to cause intense allergic reactions in some people. Fresh vegetables and fish, dried fruits, ham and other preserved meats, hominy, pickles, canned vegetables and juices, and wines were commonly treated with large amounts of the sulfites to prevent darkening and the development of unpleasant odors. People with asthma were known to be more sensitive than other people, but the sulfites could cause a fatal asthma-like attack even in someone who had never had asthma. Even when this was known, drugs used to treat asthma were preserved with sulfites. Was the information just slow to reach the people who made the products? No, the manufacturers knew about the deadly nature of their products, but they kept on selling them. The FDA didn't answer letters on the subject, and medical magazines such as J.A.M.A. declined to publish even brief letters seriously discussing the issue. Obviously, since many people died from what the drug companies called "paradoxical bronchoconstriction" when they used the products, the drug companies had to be protected from lawsuits, and the medical magazines and the government regulators did that through the control of information.

I think a similar situation exists now in relation to the effects of carrageenan.

Stress and anxiety sharply reduce the circulation of blood to the intestine and liver. Prolonged stress damages the ability of the in-testinal cells to exclude large molecules. Local irritation and inflammation of the intestine also increase its permeability and decrease its ability to exclude harmful materials. But even the normal intestine is able to permit the passage of large molecules and particles, in many cases particles larger than the cells that line the intestine; this persorption of particles has been demonstrated using particles of plastic, starch grains which are sometimes several times larger than blood cells, and many other materials, including carrageenan. One of the reasons it has been easy to convince the public that persorption doesn't happen is that there is a powerful myth in our culture about the existence of a "semipermeable" "plasma membrane" on cells through which only certain specific substances may pass.

About 30 years ago some biologists made a movie of living cells under the microscope, showing an ameboid cell entering another cell, swimming around, and leaving, without encountering any perceptible resistance; persorption of food particles, moving in one side of a cell and out the other, wouldn't seem so mysterious if more people had seen films of that sort.

Also in the 1960s, Gerhard Volkheimer rediscovered the phenomenon of persorption, which had been demonstrated a century earlier. Starch grains, or other hard particles, can be found in the blood, urine, and other fluids after they have been ingested. The iodine stain for starch, and the characteristic shape of the granules, makes their observation very easy. The absorption of immunologically intact proteins and other particles has been demonstrated many times, but myth is more important than fact; all of my biol-ogy professors, for example, denied that proteins could be absorbed by any part of the digestive system.

The accepted description of the absorption of chylomicrons, tiny particles of fat, helps to understand the way medical professors think about the intestine. These particles, they say, are disassembled by the intestine cells on one side, their molecular parts are taken up by the cells, and similar particles are excreted out the other side of the cells, into the lymphatic vessels. As they visualize one of these cells, it consists of at least four barriers, with each theoretical cell surface membrane consisting of an outer water-compatible phase, in intramembranal lipid region, and an inner water-compatible phase where the membrane rests on the “cell contents.” Endocytosis, for example the ingestion of a bacterial particle by a phagocyte, is described in a similar way, to avoid any breach in the “lipid bilayer membrane.”

This mental armature has made it essentially impossible for the biomedical culture to assimilate the facts of persorption, which would have led 150 years ago to the scientific study of allergy and immunology in relation to the digestive system.

Volkheimer found that mice fed raw starch aged at an abnormally fast rate, and when he dissected the starch-fed mice, he found a multitude of starch-grain-blocked arterioles in every organ, each of which caused the death of the cells that depended on the blood supplied by that arteriole. It isn’t hard to see how this would affect the functions of organs such as the brain and heart, even without considering the immunological and other implications of the presence of foreign particles randomly distributed through the tissue.

In 1979 some of my students in Mexico wanted a project to do in the lab. Since several traditional foods are made with corn that has been boiled in alkali, I thought it would be valuable to see whether this treatment reduced the ability of the starch grains to be persorbed. For breakfast one day, they ate only atole, tamales, and tortillas, all made from the alkali treated corn. None of the students could find any starch grains after centrifuging their blood and urine. That led me to substitute those foods whenever possible for other starches.

I have written previously about some of the environmental factors, including radiation, estrogens, and unsaturated fats, that are known to damage the immune system and the brain, and that we have been increasingly exposed to since 1940.

To better understand the nature of the diseases that are now becoming so common, we can look at them in a series, from the bowel, to the liver, to the immune system, and to the brain and hormones.

The incidence of several inflammatory diseases, for example Crohn's disease, a chronic inflammation of the intestine, has been increasing during the last 50 years in the industrialized countries, and at the same time, the incidence of several liver diseases has also been increasing.

The entry of bacteria into the blood stream, which can lead to septicemia, is ordinarily considered to be of importance only in extreme immunodeficiency states, such as old age or in premature infants, but the death rate of young adults from septicemia has been increasing rapidly since the 1940s.

The permeability of the intestine that allows bacteria to enter the blood stream is very serious if the phagocytic cells are weakened. Carrageenan poisoning is one known cause of the disappearance of macrophages. Its powerful immunosuppression would tend to be superimposed onto the immunological damage that has been produced by radiation, unsaturated fats, and estrogens.

The liver tumor that is characteristic of young women using the oral contraceptive pill is a hepatocellular adenoma, which is considered to be a premalignant tumor. In Japan, Mexico, and several European countries, the incidence of hepatocellular tu-mors has increased steadily and tremendously in recent decades, and it has increased in men as well as in women. This is the sort of tumor that very likely represents an increased burden of toxins absorbed from the bowel. Carrageenan contributes to the disappearance of the liver enzymes (the cytochrome P-450 system) that detoxify drugs, hormones, and a variety of other chemicals.

Carrageenan enters even the intact, uninflamed gut, and damages both chemical defenses and immunological defenses. When it has produced inflammatory bowel damage, the amount absorbed will be greater, as will the absorption of bacterial endotoxin. Carra-geenan and endotoxin synergize in many ways, including their effects on nitric oxide, prostaglandins, toxic free radicals, and the defensive enzyme systems.

The continuing efficient production of energy is a basic aspect of metabolic defense, and this is interrupted by carrageenan and endotoxin. The energy failure becomes part of a vicious circle, in which permeability of the intestine is increased by the very factors that it should exclude.

Once the protective barrier-functions of the intestine and liver have been damaged, allergens and many materials with specific biological effects can enter the tissues. The polysaccharide components of connective tissue constitute a major part of our regulatory system for maintaining differentiated cell functioning, and absorbed starches act as “false signals,” with a great capacity for deranging cellular functioning. Several types of research indicate that carrageenan changes cellular function in complex ways, imitating changes seen in cancer, for example.

R.J.V. Pulvertaft found "a close similarity between Burkitt cells and human lymphocytes stimulated by bean extract." He concluded that "…the possibility of a relation between Burkitt's lymphoma and a diet of beans should not be neglected," though he emphasized that other factors must be considered, since most people who eat beans don't develop the disease. The intestinal parasites which are common in tropical Africa can cause inflammation of the bowel, leading to the absorption of large amounts of antigens.

Since the bowel becomes inflamed in influenze, it is reasonable to think that some of the symptoms of "the flu" are produced by absorbed bowel toxins.

The variations in the post-influenza syndromes are very likely influenced by the nature of the bacteria or foods which are present, chronically or at the time of an uncompensated stress or inflammatory disease. K.M. Stevens has argued that while rheumatic fever and glomerulonephritis are caused by the antigens of streptococci, systemic lupus erythematosis (SLE) is probably caused by the antigens of gram-positive lactobacilli found in the normal flora.

Migraine, SLE, chronic fatigue syndrome, thyroid problems, and some kinds of porphyria seem to be more common in women of re-productive age, and are often exacerbated by premenstrual hormone changes. According to Stevens, "SLE is almost entirely a disease of women of child-bearing age. One possibility for this selection could be that women during this period harbour a peculiar flora. This is indeed the case; large numbers of gram-positive lactobacilli are present in the vagina only during the thirty-odd years when regular menstrual activity is present."

In 1974, I noticed that I consistently got a migraine headache after drinking a lactobacillus milk product, and stopped using (and recommending) yogurt and other lactobacillus foods, though I suspected it was the lactic acid which caused the immediate symptoms. Lactic acid is a metabolic burden, especially when combined with an estrogen excess, but Stevens' main point, about the significance of our immunological response to systemic bacterial antigens, deserves more attention.

On a typical diet, tissues progressively accumulate linoleic acid, and this alters the structure of mitochondrial cardiolipin, which governs the response of the mitochondrial enzymes to the thyroid hormone. This process is especially evident in the female liver. In the “autoimmune” diseases, such as lupus, there are typically antibodies to cardiolipin, as if the body were trying to reject its own tissues, which have been altered by the storage of linoleic acid. The altered mitochondrial function, which is involved in so many symptoms, can become part of a vicious circle, with endotoxin and estrogen having central roles, once the stage has been set by the combination of diet, stress, and toxins.

A few months ago I had a questionnaire circulated in a “fibromyositis” discussion group on the internet, and the consistency of responses was interesting.

The questions were: 1) Have you noticed that any of your symptoms are worse premenstrually?

2) Have you noticed that any symptom is less severe premenstrually?

3) Do any symptoms seem to be worse periodically, but without being associated with the premenstrual time?

4) Did your symptoms appear after use of oral contraceptives or IUD?

Except for one woman who was taking oral contraceptives at the time she became sick, and kept taking them, and who didn’t notice any cycle, all of the answers to the first three questions (15 of the 16 who responded) were identical: 1) yes, 2) no, 3) no.

The premenstrual estrogen-dominance usually leads progressively to higher prolactin and lower thyroid function. Estrogen is closely associated with endotoxinemia, and with histamine and nitric oxide formation, and with the whole range of inflammatory and “autoimmune” diseases. Anything that irritates the bowel, leading to increased endotoxin absorption, contributes to the same cluster of metabolic consequences.

I have previously discussed the use of antibiotics (and/or carrot fiber and/or charcoal) to relieve the premenstrual syndrome, and have mentioned the study in which the lifespan was extended by occasionally adding charcoal to the diet. A few years ago, I heard about a Mexican farmer who collected his neighbors' runt pigs, and got them to grow normally by adding charcoal to their diet. This probably achieves the same thing as adding antibiotics to their food, which is practiced by pig farmers in the US to promote growth and efficient use of food. Charcoal, besides binding and removing toxins, is also a powerful catalyst for the oxidative destruction of many toxic chemicals. In a sense, it anticipates the action of the protective enzymes of the intestinal wall and the liver.

Some women with premenstrual fatigue have found that the “premenstrual” phase tends to get longer and longer, until they have chronic fatigue. I found that to be one of the easiest "PMS" problems to correct. When people are older, and have been sick longer, the fatigue problem is likely to involve more systems of the body. The larger the quantity of "toxic fat" stored in the body, the more careful the person must be about increasing metabolic and physical activity. Using more vitamin E, short-chain saturated fats, and other anti-lipid-peroxidation agents is important.

The inflammatory diseases that develop after prolonged stress are sometimes hard to correct. But avoiding exposure to the major toxic allergens--such as carrageenan--is an essential consideration, just as important as correcting the thyroid function and avoiding the antithyroid substances.

Low cholesterol is very commonly involved in the diseases of stress, and--like inadequate dietary protein--will make the system less responsive to supplementary thryoid hormone.

The proliferative aspects of the inflammatory diseases represent, I think, a primitive form of regeneration. Arthritis, atherosclerosis, various granulomatous processes, breast diseases, liver adenomas, etc., provide an opportunity for investigating the various systems and substances that guide cell proliferation toward reconstruction, rather than obstructive and deformative, degenerative, processes. Degenerative diseases probably all contain clues for understanding regeneration, as I have suggested in relation to Alzheimer’s disease and inflammation. I will be talking about these in other newsletters, but the first step will always be to minimize exposure to the disruptive substances.

REFERENCES

Pathol Biol (Paris) 1979 Dec;27(10):615-626 [Biological and pharmacological effects of carrageenan].[Article in French] Roch-Arveiller M, Giroud JP “Carrageenan is sulfated polysaccharide which has been extensively used as emulsifier and thickening agent in the food industry, for its ability to induce acute inflammation in pharmacology and for its selectively toxic effect for macrophages in immunology. Carrageenan is a complex substance which displays various biological properties. The authors have shown the extent of these actions and reviewed the latest investigations on this subject.”

Kirchheiner B J Allergy Clin Immunol 1995 May;95(5 Pt 1):933-936 Anaphylaxis to carrageenan: a pseudo-latex allergy. Tarlo SM, Dolovich J, Listgarten C “Anaphylactic reactions during a barium enema have been attributed to allergy to latex on the barium enema device. The observation of anaphylaxis during barium enema without latex exposure or latex allergy led to the performance of an allergy skin test to the barium enema solution.” “Individual components of the barium enema solution were obtained for double-blind skin testing. A RAST to identify specific IgE antibodies to the skin test active agent was established.” “Carrageenan, a component of the barium enema solution, produced positive reactions to allergy skin test and RAST. Gastrointestinal symptoms for which the patient was being investigated by the barium enema subsequently disappeared with a diet free of carrageenan. CONCLUSIONS: Carrageenan is a previously unreported cause of anaphylaxis during barium enema. It is an allergen widely distributed in common foods and potentially could account for some symptoms related to milk products or baby formula.”

Cancer Detect Prev 1981;4(1-4):129-134 Harmful effects of carrageenan fed to animals. Watt J, Marcus R “An increased number of reports have appeared in the literature describing the harmful effects of degraded and undegraded carrageenan supplied to several animal species in their diet or drinking fluid. The harmful effects include foetal toxicity, teratogenicity, birth defects, pulmonary lesions, hepatomegaly, prolonged storage in Kupffer cells, ulcerative disease of the large bowel with hyperplastic, metaplastic, and polypoidal mucosal changes, enhancement of neoplasia by carcinogens, and, more ominously, colorectal carcinoma. Degraded carrageenan as a drug or food additive has been restricted in the United States by the FDA, but undegraded carrageenan is still widely used throughout the world as a food additive. Its harmful effects in animals are almost certainly associated with its degradation during passage through the gastrointestinal tract. There is a need for extreme caution in the use of carrageenan or carrageenan-like products as food additives in our diet, and particularly in slimming recipes.”

Acta Pathol Microbiol Scand [A] 1980 May;88(3):135-141 Stereomicroscopic and histologic changes in the colon of guinea pigs fed degraded carrageenan. Olsen PS, Poulsen SS “A colitis-like state induced in Guinea Pigs fed degraded carrageenan orally. By means of a combined semimacroscopic and histologic technique the course of the disease was followed during 28 days. The changes were primarily seen and became most prominent in the caecum. The first lesions were observed following 24 hours of treatment as small rounded foci initially with degenerative changes and inflammation in the surface epithelium, later forming superficial focal ulcerations. Ulcerative changes gradually progressed during the experiment, forming linear and later large, geographical ulcerations. Topographically the ulcerative process was strongly related to the larger submucosal vessels. Nonulcerated parts of the mucosa were not changed until following 7-14 days of treatment. The mucosa became bulging, granulated and finally villus-like. Accumulation of macrophages was found under the surface epithelium after 7-17 days. Possible pathogenetic mechanisms are discussed, especially the development of the early lesions and the significance of the macrophages.

Cancer Res 1997 Jul 15;57(14):2823-2826 Filament disassembly and loss of mammary myoepithelial cells after exposure to lambda-carrageenan. Tobacman JK “Carrageenans are naturally occurring sulfated polysaccharides, widely used in commercial food preparation to improve the texture of processed foods. Because of their ubiquity in the diet and their observed preneoplastic effects in intestinal cells, their impact on human mammary myoepithelial cells in tissue culture was studied. At concentrations as low as 0.00014%, lambda-carrageenan was associated with disassembly of filaments with reduced immunostaining for vimentin, alpha-smooth muscle-specific actin, and gelsolin; increased staining for cytokeratin 14; and cell death. The absence of mammary myoepithelial cells is associated with invasive mammary malignancy; hence, the destruction of these cells in tissue culture by a low concentration of a widely used food additive suggests a dietary mechanism for mammary carcinogenesis not considered previously.”

Agents Actions 1981 May;11(3):265-273 Carrageenan: a review of its effects on the immune system. Thomson AW, Fowler EF “Carrageenans (kappa, lambda and iota) are sulphated polysaccharides isolated from marine algae that can markedly suppress immune responses both in vivo and in vitro. Impairment of complement activity and humoral responses to T-dependent antigens, depression of cell-mediated immunity, prolongation of graft survival and potentiation of tumour growth by carrageenans have been reported. The mechanism responsible for carrageenan-induced immune suppression is believed to be its selective cytopathic effect on macrophages. This property of carrageenan has led to its adoption as a tool for analysing the role of these cells in the induction and expression of immune reactivity. Systemic administration of carrageenan may, however, induce disseminated intravascular coagulation and inflict damage on both the liver and kidney. This is an important consideration in the interpretation of the effects of carrageenan in vivo and precludes its use as a clinical immune suppressant.”

Biomedicine 1978 May;28(3):148-152 Carrageenan and the immune response. Thomson AW “Since the biological effects of carrageenan were reviewed in 1972 by Di Rosa it has become clear from a large number of reports that this algal polysaccharide markedly influences immune responses. Profound suppression of immunity evidenced by impaired antibody production, graft rejection, delayed hypersensitivity and anti-tumour immunity, has been observed in carrageenan-treated animals and the immunodepressive ability of carrageenan confirmed by in vitro studies. Efforts at analysis of carrageenan-induced immune suppression have focussed on the selective cy-totoxic effect of this agent onmononuclear phagocytes. Faith in the ability of carrageenan to eliminate those cells has led to its use in examination of the role played by mononuclear phagocytes in various aspects of immune reactivity. This review documents and discusses the effects of carrageenan on immune responses and assesses the value of carrageenan as a useful tool in both current and future work aimed at broadening our knowledge of mechanisms underlying immune reactions.”

Teratology 1981 Apr;23(2):273-278 Teratogenic effect of lambda-carrageenan on the chick embryo. Monis B, Rovasio RA “Carrageenans are widely used as food additives. Thus, it seemed of interest to test their possible teratogenic action. For this purpose, 530 chick eggs were injected in the yolk sac with 0.1 ml of a solution of 0.1% lambda-carrageenan in 0.9% sodium chloride. As controls, 286 eggs were injected with 0.1 ml of 9.0% sodium chloride. In addition, 284 eggs received no treatment. After incubation for 48--50 hours at 39 degrees C, embryos were fixed, cleared, and observed with a stereoscopic microscope. The frequency of abnormal embryos in the group receiving lambda-carrageenan was higher than in the controls (p less than 0.04). Partial duplication of the body, abnormal flexures of the trunk, anencephaly, a severely malformed brain, thickening of the neural tube wall, an irregular neural tube lumen with segmentary occlusion and a reduction in crown-rump length and number of somites were distinctly seen in thelambda-carrageenan-injected group. Moreover, the average number of anomalies per embryo in the lambda-carrageenan-injected group was nearly twice that in the controls. Present data indicate that lambda-carrageenan has teratogenic effects on early stages of the development of the chick embryo.”

Food Addit Contam 1989 Oct;6(4):425-436 Intestinal uptake and immunological effects of carrageenan--current concepts. Nicklin S, Miller K “Carrageenans are a group of high molecular weight sulphated polygalactans which find extensive use inthe food industry as thickening, gelling and protein-suspending agents. Although there is no evidence to suggest that the persorption of small amounts of carrageenans across the intestinal barrier poses an acute toxic hazard, they are known to be biologically active in a number of physiological systems and extended oral administration in laboratory animals has been shown to modify both in vivo and in vitro immune competence. Whereas this effect could be attributed to carrageenan having a selective toxic effect on antigen-processing macrophages, additional studies suggest that macrophages can also influence immune responses by the timed release of immunoregulatory mediators. Evidence in support of this comes from in vitro studies which demonstrate that carrageenan-treated macrophages can, depending on conditions and time of administration, release either stimulatory or inhibitory factors. The former is known to be the immunostimulatory agent interleukin 1 (IL-1). The inhibitory factor, which is produced at an early stage following exposure to non-toxic doses of carrageenans, has yet to be formally identified but it is believed to be a prostaglandin because of its specific mode of action and short biological half-life. At present it is impossible to relate these studies to the human situation. Although it is established that carrageenans can cross the intestinal barrier of experimental animals, there is no evidence to suggest that the limited uptake that may occur in man in any way interferes with normal immune competence. Nevertheless, increased exposure may occur in the neonate during weaning, and adults and children following allergic reactions and episodes of gastrointestinal disease. Further studies under such conditions now seem warranted in order to elucidate the possible immunological consequences which may be associated with enhanced uptake of carrageenans in vulnerable groups.”

Health Rep 1990;2(4):343-359 “Crohn's disease and ulcerative colitis: morbidity and mortality,” Rod Riley. “This study analyzes hospital discharges and deaths from 1971 to 1986 for patients with inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis. The data are based on hospital morbidity and mortality statistics provided to Statistics Canada by the provinces. For Crohn's disease, age-standardized rates per 100,000 population for hospital discharges increased by 148% for males and by 192% for females over the study period. In 1986, the rate for females was 48% higher than the rate for males. For both males and females, age-specific discharge rates were highest in the 20-24 age group. For ulcerative colitis, male age-standardized discharge rates decreased by 17% from 1971 to 1977, and then increased by 41% from 1977 to 1986. For females, the rates decreased by 18% from 1971 to 1976, then remained fairly stable from 1976 to 1986. Male and female discharge rates were similar over the study period. For females, rates were highest in the 20-34 age groups; for males, they were highest in the 65 and older age groups. In 1971, rates for both types of IBD were almost the same, but by the end of the study period the rate per 100,000 population for Crohn's disease was 34 for females and 23 for males, while for ulcerative colitis the rates were 13 for females and 14 for males. During the 16-year study period, cause of death data showed 556 deaths directly attributed to Crohn's disease and 761 deaths at-tributed to ulcerative colitis. The under 45 age group accounted for 25% of deaths due to Crohn's disease and for 17% of deaths due to ulcerative colitis. The time trends for IBD hospital discharge rates in Canada closely parallel the findings of hospital discharge rates in the United States and England-Wales. A comparison with epidemiological population surveys strongly suggests that increased discharge rates are due mostly to increases in incidence and prevalence of IBD in the general population.”

Q J Med 1992 Feb;82(298):125-138 Epidemiology of Crohn's disease in Indian migrants and the indigenous population in Leicestershire. Jayanthi V, Probert CS, Pinder D, Wicks AC, Mayberry JF “A retrospective, epidemi-ological community study of Crohn's disease was performed in Leicestershire from 1972 to 1989. The county population of 930,000 includes 93,000 South Asians. Potential cases were identified from hospital departments of pathology, endoscopy and medical records, in addition to general practitioners. There were 582 cases in Europeans and 28 in South Asians. The incidence of Crohn's disease in Europeans and South Asians has increased, particularly in Muslims. The standardized incidence in South Asians during the 1980s was 2.4/10(5)/year in Hindus, 3.4/10(5)/year in Sikhs and 5.4/10(5)/year in Muslims. The standardized incidence in Europeans has risen significantly to 4.7/10(5)/year from 3.4/10(5)/year in the 1970s (chi 2 = 8.1, p less than 0.005). In Leicester this increase can be accounted for entirely by new cases of colonic disease. All ethnic groups had a similar disease distribution. Small bowel disease was inversely associated with age, whilst colonic disease increased with age. However, the difference in age-specific incidence of Crohn's disease for different age bands at various sites was not significant. Overall, Hindus have a much lower incidence of Crohn's disease than Europeans.”

Gastroenterology 1991 Feb;100(2):350-358 The epidemiology of inflammatory bowel disease: a large, population-based study in Sweden. Ekbom A, Helmick C, Zack M, Adami HO “Previous population-based incidence studies of inflammatory bowel disease are limited by small numbers, short duration, or inadequate case-finding. To address these problems, we identified all persons with confirmed ulcerative colitis (n = 2509) or Crohn's disease (n = 1469) in the Uppsala Health Care Region from 1965 to 1983. Age-specific incidence rates by sex were slightly greater for males with ulcerative colitis and females with Crohn's disease. Incidence rates for ulcerative colitis and Crohn's disease were higher in urban than rural areas. The annual incidence rate of ulcerative colitis increased from less than 7 per 100,000 to more than 12 per 100,000 during the study period, while the rate for Crohn's disease remained between 5 and 7 per 100,000. The increase in the incidence of ulcerative colitis was the result of a marked increase in the number of patients with ulcerative proctitis. Analyses by 5-year birth cohorts suggest that those born from 1945 through 1954 were at higher risk for ulcerative colitis and Crohn's disease, and that this effect was accounted for by those born in the first half of the year. The seasonality in the cohort effect, combined with the urban preponderance of disease, suggests that environmental causes may be involved in ulcerative colitis and Crohn's disease.”

Gut 1988 Mar;29(3):346-351, Cardiff Crohn's disease jubilee: the incidence over 50 years. Rose JD, Roberts GM, Williams G, Mayberry JF, Rhodes J “The incidence of Crohn's disease in Cardiff between 1931 and 1985 has been examined using hospital diagnostic indices supplemented in recent years by records from clinicians, and the departments of pathology and radiology. Four hundred and seven new patients were confirmed after all notes had been reviewed. There has been a large increase from 0.18 cases/10(5) of the population per year in the 1930s to current values of 8.3/10(5)/year. The incidence continues to rise and shows an increasing proportion of patients with colorectal disease. Peak age specific incidences occur in the third and eighth decades of life.”

Am J Hematol 1992 Mar;39(3):176-182 Polysaccharide encapsulated bacterial infection in sickle cell anemia: a thirty year epidemiologic experience. Wong WY, Powars DR, Chan L, Hiti A, Johnson C, Overturf G “Annual age-specific incidence rates of Streptococcus pneumoniae or Haemophilus influenzae bacterial septicemia in sickle cell anemia (SS) were determined for the years of 1957 through 1989. Forty-nine patients had 64 episodes of septicemia among a population of 786 SS patients observed for 8,138 person-years. Peak frequency of infection occurred between 1968-1971 and 1975-1981 with a conspicuous absence of episodes in 1972, 1973, 1982-1984, and 1986-1987, thus demonstrating cycles of high and low attack rates. The annual age-specific incidence rate of septicemia varied from 64.5 (1965) to 421.1 (1980) per 1,000 person-years for those under 2 years of age and never exceeded 10.2 per 1,000 in those over 4 years of age. Following the introduction of pneumococcal polyvalent vaccine in 1978, incidence of infection decreased in SS children greater than 2 years of age. No modification of the risk of infection was observed in immunized children less than 2 years of age. During these three decades, there has been a ten-fold increase in the number of SS adults over 20 years of age. The relative risk of chronic sickle complications comparing the survivors of septicemia to the non-infected patients was: subsequent death 1.76, retinopathy 4.06, avascular necrosis 1.95, symptomatic cholelithiasis 1.33, stroke 1.30, and priapism 1.26. These data suggest that prognosis for lifetime severe SS is initially manifested as an increased risk of septicemia during childhood.”

Gastroenterol Clin Biol 1986 Jun;10(6-7):468-474 [Trends of mortality from cirrhosis in France between 1925 and 1982 Coppere H, Audigier JC “In 1982, 13,866 deaths secondary to cirrhosis were reported. Between 1925 and 1982, the number of deaths increased by 163 p. 100. This overall change was observed gradually: profound drop in the cirrhosis mortality rate during the Second World War, increase between 1945 and 1967, stabilization between 1967 and 1975 and more pronounced decline from then on. Cirrhosis mortality rate per 100,000 increased from 9.17 to 28.21 (+208 p. 100) in males and from 3.63 to 10.38 (+186 p. 100) in females from 1945 to 1982. The increase was approximately the same whatever the age. A cohort effect was observed in both sexes. There were two successive waves of increased mortality separated by an interval of non augmentation for the cohorts born between 1906 and 1915 and between 1931 and 1940. Since 1967, mortality due to cirrhosis has stopped increasing in both sexes. These changes may be related to decreasing alcohol consumption in France, certainly one of the major objectives in present day health programs. Abrupt reduction of alcohol consumption should be followed by a dramatic fall in the number of deaths from cirrhosis. Progressive decline of consumption is possibly associated with a decrease in the incidence of the disease. In 2,000, the rate for cirrhosis mortality is expected to be the same as that observed in the middle of the 20th century.”

Cancer Res 1987 Sep 15;47(18):4967-4972 Changing incidence of hepatocellular carcinoma in Japan. Okuda K, Fujimoto I, Hanai A, Urano Y “A trend in the incidence of hepatocellular carcinoma (HCC) in Japan was studied from the data of the Osaka Cancer Registry (population, 8,512,351 in 1981) for the period of 1963-1983, the Vital Statistics of Japan, Ministry of Health and Welfare, and the Japan Autopsy Registry which contained 594,132 individually filed cases in the 26-year period from 1958 to 1983. Both cancer registry data and autopsy records showed a more than 2-fold increase in HCC incidence, particularly in the last 10 years or so, among males and a less pronounced increase in females. The same trend was borne out by the cancer registries of Nagasaki City and Miyagi Prefecture and the Vital Statistics. When studied with the autopsy data, it was found that the numbers of autopsies for cirrhosis without HCC and autopsies for HCC (with and without cirrhosis) were about the same in 1958-1961 and that currently (1980-1983) the latter is about 2 times the former. As one of the possible causes of increase in HCC incidence other than prolonged survival of patients with cirrhosis, chronic non-A, non-B hepatitis is discussed. “

Hepatogastroenterology 1997 Sep;44(17):1401-1403 Hepatocellular carcinoma and hepatic cirrhosis in Mexico: a 25 year necroscopy review. Cortes-Espinosa T, Mondragon-Sanchez R, Hurtado-Andrade H, Sanchez-Cisneros R “BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is a common form of cancer which is found throughout the world. In recent years, the rates of HCC seem to have increased in European and North American countries.” “RESULTS: Of 12556 autopsies studied, 73 cases of histologically proven HCC were reported, representing a total necropsy carcinoma incidence of 0.59%. Fifty-five cases were associated with cirrhosis (0.43%), and 18 were not (0.14%). HCC was two times more common in males (67%) than in females (33%), with a ratio of 2:1. During this period, the necropsy incidence of HCC rose steadily to twice its original level (1965-69 incidence 0.35%; 1985-89 incidence 0.69%). The necropsy incidence of cirrhosis was 4% (329 males, 185 females). The overall TC/T index was 75% (87% for males and 50% for females). The overall TC/C index was 10.7% (13% for males and 6.4% for females). CONCLUSIONS: There was a two-fold increase in the incidence of HCC in the Mexican population studied over a 25-year period. HCC was associated with cirrhosis in the majority of cases. HCC was two times more common in males than in females in patients with cirrhosis; in patients without cirrhosis, the ratio was 1:1. The incidence of cirrhosis was 4%, which remained unchanged with the passage of time.”

Hepatogastroenterology 1984 Oct;31(5):215-217 Hepatocellular carcinoma and cirrhosis: a review of their relative incidence in a 25-year period in the Florence area. Bartoloni St Omer F, Giannini A, Napoli P “An eight-fold increase in the incidence of hepatocellular carcinoma in the Florence area was detected in a 25-year retrospective review of adult autopsy records in the Institute of Pathology of the University of Florence. During the same period, the incidence of cirrhosis did not show a parallel increase. The relationship between hepatocellular carcinoma, cirrhosis and HB virus is briefly discussed in the light of these findings.”

J Clin Pathol 1978 Feb;31(2):108-110 Hepatocellular carcinoma and hepatic cirrhosis in the west of Scotland: a 25-year necropsy review. Burnett RA, Patrick RS, Spilg WG, Buchanan WM, Macsween RN “A two-fold increase in the incidence of hepatocellular carcinoma in the west of Scotland is reported on the basis of a 25-year retrospective necropsy review (313 cases). This increase is not accompanied by a corresponding increase in the incidence of hepatic cirrhosis. The relationship between hepatocellular carcinoma and hepatic cirrhosis is discussed in the light of these findings.”

J Hyg Epidemiol Microbiol Immunol 1990;34(4):343-348 “Increasing trend of hyperbilirubinemia incidence in the blood donors population,” Pintera J.

Hepatogastroenterology 1984 Oct;31(5):211-214 Primary hepatic cancer and liver cirrhosis. Autopsy study covering fifty years. Bethke BA, Schubert GE “Autopsy reports from 1931 to 1980 were used to study the incidence of liver cirrhosis (LC) and the association between LC and hepatocellular carcinoma (HCC) in our area (Wuppertal, Germany). An increase in LC and in LC with HCC has occurred since World War II, with HCC being most frequently associated with postnecrotic cirrhosis. The prevalence of HCC in men with LC was highest (13.5%) in 1966-1970, whereas the prevalence of HCC with LC in women rose abruptly to a peak (11.8%) during the last 5 years of the study. Possible etiological factors for the association between LC and HCC are discussed.”

Riv Eur Sci Med Farmacol 1990 Jun;12(3):165-168 [Oral contraceptive and hepatic effects].[Article in Italian] Tarantino G, Morelli L, Califano C “The general use of synthetic estrogens like DC pointed out that near many skilled collateral effects, some others that are showing with a decrease of bile excretion (cholestasis), reversible with their administration interruption; with hepatic cells adenoma that are potentially premalignant and can transform into hepatocellular carcinoma; with vascular complications such as (most frequently in carcinomatousis) "hepatic peliosis" and "thrombosis" of suprahepatic veins (Budd-Chiari's syndrome). There is no overall increase in the incidence of gallbladder disease (cholelithiasis and cholecystitis).”

Hepatology 1990 Nov;12(5):1106-1110 Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Wanless IR, Lentz JS “Steatohepatitis (fatty liver hepatitis), histologically identical to alcoholic disease, occurs in some obese patients after jejunoileal bypass. A similar lesion occurs rarely in obese patients without bypass surgery, but the risk factors are poorly understood. Hepatic steatosis, steatohepatitis and fibrosis were sought in 351 apparently nonalcoholic patients at autopsy and various risk factors were evaluated.” “Thus this study supports the hypothesis that fatty acids have a role in the hepatocellular necrosis found in some obese individuals.”

Prostaglandins 1977 Aug;14(2):295-307 Reduced exudation and increased tissue proliferation during chronic inflammation in rats deprived of endogenous prostaglandin precursors. Bonta IL, Parnham MJ, Adolfs MJ “Two models of chronic inflammation were studied in rats deprived of endogenous precursors of prostaglandins by feeding the animals on essential fatty acid deficient (EFAD) food. During kaolin-induced pouch-granuloma, exudate production was markedly reduced in EFAD rats, when compared with normal animals. The exudates from normal rats contained large amounts of PGE, but in the exudates from EFAD rats the amount of PGE was very markedly reduced. Similarly, with carrageenan-impregnated polyether sponges, the exudative component of inflammation was reduced in EFAD rats. However, the proliferative component was significantly increased, particularly in relation to the stunted growth of EFAD rats. Sponge exudates from EFAD rats contained fewer leucocytes than those from normal animals but the fall in leucocyte count was much smaller than the very marked reduction in PGE activity. EFAD rats also exhibited a significant increase in adrenal weights. The results are discussed in the light of the ambivalent (pro- or anti-inflammatory) role of endogenous PGS. It appears that, in the proliferative phase of inflammation, the anti-inflammatory role of PGs is more dominant.”

J Hepatol 1997 Sep;27(3):578-582 Subfulminant hepatic failure in autoimmune hepatitis type 1: an unusual form of presentation. Herzog D, Rasquin-Weber AM, Debray D, Alvarez F “Autoimmune hepatitis type 1 is known to progress insidiously and in many cases cirrhosis is already established at the first presentation of symptoms. It affects mostly females, with peaks of incidence around 10 and 50 years of age. Subfulminant hepatic failure is an unusual initial form of presentation of AIH type 1 and it was observed in three post-pubertal female patients. Rapid disease evolution or no response to immunosuppressive therapy led to liver transplantation in all patients. Two did not have cirrhosis, and the third had focal cirrhosis. The occurrence of the unusual subfulminant form of autoimmune hepatitis in three latepubertal girls (Tanner V) suggests that estrogen may play a role in the severity of the disease.”

Acta Hepatogastroenterol (Stuttg) 1977 Apr;24(2):97-101 Plasma prolactin and prolactin release in liver cirrhosis. Wernze H, Schmitz E “A significant increase of basal plasma prolactin levels (radioimmunoassayed) in 75 patients with liver cirrhosis was found in comparison to 50 male controls (8.5+/-4.5 (SD) vs. 5.5+/-1.7 ng/ml p less than 0.001). The extent and incidence of hyperprolactinaemia in 48 patients with alcoholic cirrhosis was more pronounced than in 27 cases of cirrhosis of non-alcoholic aetiologies (mean 9.7+/-4.8 vs. 5.7+/-2.1 ng/ml). No relation to ascites formation as well as to the development of gynaecomastia was apparent. Prolactin release following thyrotropin-releasing hormone was markedly enhanced in alcoholic as compared to non-alcoholic cirrhosis. Possibly hyperprolactinaemia and increased pituitary hormone reserve reflects hyperoestrogenism but changes of the hypothalamic regulation cannot be excluded as yet.”

Jpn J Pharmacol 1991 Apr;55(4):551-554 Endotoxin- and inflammation-induced depression of the hepatic drug metabolism in rats. Ishikawa M, Sasaki K, Nishimura K, Takayanagi Y, Sasaki K “Carrageenan-induced inflammation and exposure to endotoxin considerably decreased the content of cytochrome P-450 and activities of ethylmorphine N-demethylase and meperidine N-demethylase, but did not decrease the activities of aniline hydroxylase or NADPH-cytochrome c reductase, compared with the respective activities in rats treated with carrageenan alone. These results suggest that under these experimental conditions, the two host-related environmental factors interact and enhance a decrease in rat hepatic microsomal drug metabolizing enzymes depending on the substrate used.”

Infect Immun 1991 Feb;59(2):679-683 Enhancement of lipopolysaccharide-induced tumor necrosis factor production in mice by carrageenan pretreatment. Ogata M, Yoshida S, Kamochi M, Shigematsu A, Mizuguchi Y “Tumor necrosis factor (TNF) is a cytokine which mediates endotoxin shock and causes multiple organ damage. It is thought that macrophage (MP) activation is necessary to increase lipopolysaccharide (LPS)-induced TNF production and lethality. Carrageenan (CAR) is sulfated polygalactose which destroys MP; it is used as a MP blocker. We found that CAR pretreatment can increase both endotoxin-induced TNF production and the mortality rate in mice. The ddY mice (7 to 8 weeks old) were injected intraperitoneally with CAR (5-mg dose) and challenged intravenously with LPS 24 h later. Without CAR pretreatment, LPS doses of less than 10 micrograms did not induce TNF in sera. After pretreatment, however, about 3 x 10(3) to 4 x 10(4) U of TNF per ml was produced after LPS injection at doses of 0.1 to 10 micrograms, respectively. TNF production was significantly increased by CAR pretreatment at LPS doses of more than 10 micrograms. CAR pretreatment rendered the mice more sensitive to the lethal effect of LPS; 50% lethal doses of LPS in CAR-pretreated mice and nonpretreated mice were 26.9 and 227 micrograms, respectively. The mortality of the two groups was significantly different at doses of 50, 100, and 200 mi-crograms of LPS. CAR increased LPS-induced TNF production and mortality within 2 h, much earlier than MP activators, which needed at least 4 days. Our results made clear that TNF production is enhanced not only by a MP activator but also by a MP blocker.”

Prog Clin Biol Res 1989;286:237-242 Effect of macrophage inhibition in carrageenan- and D-galactosamine-induced sensitivity to low-dose endotoxin. Kujawa KI, Berning A, Odeyale C, Yaffe LJ.

J Surg Res 1984 Jul;37(1):63-68 Evidence for aerobic glycolysis in lambda-carrageenan-wounded skeletal muscle. Caldwell MD, Shearer J, Morris A, Mastrofrancesco B, Henry W, Albina JE “Classically, increased lactate production in wounded tissue is ascribed to anaerobic glycolysis although its oxygen consumption has been found to be similar to normal tissue. This apparent inconsistency was studied in a standardized isolated perfused wound model. Male Sprague-Dawley rats were wounded (group W) with intramuscular injections of lambda-carrageenan and fed ad lib.; not wounded and pair fed to the decreased food intake of the wounded animals (group PFC); or not wounded and fed ad lib. (group ALC). After 5 days, the hindlimbs of animals from each group were either perfused using a standard perfusate with added [U-14C]glucose or [1-14C]pyruvate or assayed for the tissue content of lactate and pyruvate. In addition, the effect of a 30% hemorrhage on the tissue lactate and pyruvate concentration was examined. Wounding increased glucose uptake and lactate production by 100 and 96%, respectively, above that seen in ALC animals. Oxygen consumption was unchanged by wounding (5.74, 5.14, and 5.83 mumole/min/100 g in W, PFC, and ALC, respectively). Glucose and pyruvate oxidation were also unaltered among the groups. Hemorrhage resulted in a comparable increase in lactate and pyruvate in tissue from wounded and pair-fed control animals (above those concentrations found in tissue harvested without preexisting hemorrhage). As a consequence, the same relationship in L/P ratio was maintained after hemorrhage. Taken together, these results confirm the presence of aerobic glycolysis in wounded tissue (unchanged oxygen consumption, glucose, and pyruvate oxidation). In addition, pyruvate dehydrogenase activity in the wound was apparently the same as that found in muscle from pair-fed control animals.”

Food Chem Toxicol 1984 Aug;22(8):615-621 Effect of orally administered food-grade carrageenans on antibody-mediated and cell-mediated immunity in the inbred rat. Nicklin S, Miller K “Experiments were performed to investigate the immunological consequences associated with the persorption of poorly degradable carregeenans from the diet. Using an inbred strain of rat it was demonstrated histochemically, by the carrageenan-specific Alcian blue staining technique, that small quantities of food-grade carrageenans given at 0.5% in drinking-water for 90 days could penetrate the intestinal barrier of adult animals. This apparently occurred via an intact mucosa in the absence of inflammatory or pathological lesions. The carrageenan was demonstrated in macrophage-like cells present within the villi and lamina propria of the small intestine. The oral administration of kappa, lambda or iota food-grade carrageenans did not affect local (biliary) or systemic antibody responses to gut commensal microorganisms, or to orally-administered sheep erythrocytes. However, when sheep red blood cells were administered parenterally the ensuing anti-sheep red blood cell haemagglutinating antibody response was temporarily suppressed in carrageenan-fed rats. lambda-Carrageenan and iota-carrageenan both significantly (P less than or equal to 0.01 and P less than or equal to 0.05, respectively) reduced the mid-phase (14-28 days) haemagglutinin response; kappa-carrageenan (L100) was less effective but caused significant depression at day 21 (P less than or equal to 0.01). Individual responses were, however, within the control range 35 days after sheep erythrocyte administration, thus indicating the temporary nature of this effect. Although carrageenan administration depressed the anti-sheep erythrocyte antibody response, it did not affect T-cell immune competence as measured by the popliteal lymph node assay for graft-versus-host reactivity.”

J Nutr 1986 Feb;116(2):223-232 Effects of certain dietary fibers on apparent permeability of the rat intestine. Shiau SY, Chang GW “Apparent intestinal permeability was determined indirectly by orally administering a poorly absorbed dye, phenol red, to rats and measuring its recovery in feces and in urine. Increased apparent permeability was recognized by increased dye recovery in urine and by an increased ratio of urinary to fecal dye recovery. Guar gum, pectin, carrageenan type I (80% kappa, 20% lambda), carra-geenan type II (iota) and cellulose were each fed at levels of 5 and 15% (wt/wt) of the diet for 31 d to male Fischer 344 rats. The average initial weight of rats was 230 g. Rats fed 15% guar gum gained significantly less weight than most of the other rats (P less than 0.05). Phenol red recovery was measured at 2 and 4 wk after the beginning of the experiment. At 2 wk urinary recoveries of phenol red were high in rats fed fiber-free and carrageenan type II diets, indicating increased apparent permeability. By 4 wk, adaptation had apparently taken place.” “These data are consistent with the hypothesis that intestinal permeability to foreign substances may be altered considerably by diet.”

Pathologe 1993 Sep;14(5):247-252 [Persorption of microparticles].[Article in German] Volkheimer G “Solid, hard microparticles, such as starch granules, pollen, cellulose particles, fibres and crystals, whose diameters are well into the micrometre range, are incorporated regularly and in considerable numbers from the digestive tract. Motor factors play an important part in the paracellular penetration of the epithelial cell layer. From the subepithelial region the microparticles are transported away via lymph and blood vessels. They can be detected in body fluids using simple methods: only a few minutes after oral administration they can be found in the peripheral blood-stream. We observed their passage into urine, bile, cerebrospinal fluid, the alveolar lumen, the peritoneal cavity, breast milk, and transplacentally into the fetal blood-stream. Since persorbed microparticles can embolise small vessels, this touches on microangiological problems, especially in the region of the CNS. The long-term deposit of embolising microparticles which consist of potential allergens or contaminants, or which are carriers of contaminants, is of immunological and environmental-technical importance. Numerous ready-made foodstuffs contain large quantities of microparticles capable of persorption.”

Eur J Pediatr 1993 Jul;152(7):592-594 Oral cornstarch therapy: is persorption harmless? Gitzelmann R, Spycher MA ”Sediments prepared from freshly voided urine of four patients with glycogenosis Ia, or leucine-sensitive hypoglycaemia, on oral cornstarch therapy contained starch granules, evidence for persorption i.e. the incorporation of undissolved starch particles. In these patients, amyluria was more marked than in untreated controls. While cornstarch therapy is successful and causes few side-effects, the possibility of late adverse reactions to persorbed starch should not be disregarded.”

Med Hypotheses 1991 Jun;35(2):85-87 “Persorption of raw starch: a cause of senile dementia? Freedman BJ “Intact starch granules in food can pass through the intestinal wall and enter the circulation. They remain intact if they have not been cooked for long enough in the presence of water. Some of these granules embolise arterioles and capillaries. In most organs the collateral circulation suffices for continued function.In the brain, however, neurones may be lost. Over many decades the neuronal loss could be of clinical importance. To test this hypothesis, there is a need to examine brains for the presence of embolised starch granules. Examining tissues polariscopically clearly distinguishes starch granules from other objects of similar appearance.”

Kitasato Arch Exp Med 1990 Apr;63(1):1-6 [The Herbst-Volkheimer effect]” [Article in German], Prokop, O. “More than 150 years ago the foundations were laid for the so-called HERBST effect which was subsequently forgotten. In the sixties the phenomenon was rediscovered by VOLKHEIMER at the Charite Hospital in Berlin and then reviewed through many experiments and publications. What is meant by the HERBST effect? If an experimental animal or even human being is given a larger amount of maize starch or also biscuits or some other products containing starch, starch bodies can be detected rapidly in venous blood already after minutes or half an hour later and in the urine after one hour and later. The term "persorption" has been coined for this interesting phenomenon. It is indeed surprising that it has met with so little attention. As a matter of fact, it constitutes the basis for our understanding of peroral immunization and of allergies. In the same way, feeding of carbon particles results in their appearance and detection in blood, kidney and urine. The same result is obtained by the intake of diatoms and what is even more important with meat fibres. I hope you are aware of the implications. When Professor NAGAI stayed in Berlin, we tried to receive the phenomenon. Since only a few cell nuclei are necessary for "genetic fingerprinting" we thought that after intake of 200 or 400 g of raw meat the type of food eaten could be determined from the urinary sediment by means of the fingerprint method which would be of forensic significance. Therefore, we eat meat and raw liver and examined the urinary sediment.”

Z Arztl Fortbild (Jena) 1993 Mar 12;87(3):217-221 [The phenomenon of persorption--history and facts].[Article in German] Volkheimer G.

J Pediatr 1994 Sep;125(3):392-399 Clinical and molecular epidemiology of enterococcal bacteremia in a pediatric teaching hospital. Christie C, Hammond J, Reising S, Evans-Patterson J “An apparent increase in the in-cidence of enterococcal bacteremias from 7 to 48/1000 bacteremias during 1986 to 1991 (p < 0.01) prompted this descriptive clinical and molecular epidemiologic study of 83 episodes occurring in 80 children between 1986 and 1992.” “The increase in enterococcal bacteremias was not due to a clonal strain dissemination but to an increase in cases of heterogeneous enterococcal strains. We conclude that enterococcal septicemia is now an important cause of serious morbidity and death in critically ill children.”

R.F.V. Pulvertaft, PHA in relation to Burkitt's tumour, Lancet sept 12, pp 552-554, 1964.

K.M. Stevens, The aetiology of SLE, Lancet, Sept. 5, 506-508, 1964.

Am J Physiol 1991 May;260(5 Pt 1):C910-C916 “Effect of exogenous and endogenous nitric oxide on mitochondrial respiration of rat hepatocytes.” Stadler J, Billiar TR, Curran RD, Stuehr DJ, Ochoa JB, Simmons RL. “Although nitric oxide (.N = O) biosynthesis is inducible in rat hepatocytes (HC), the physiological significance of .N = O production by these cells is unknown. Short exposure of HC to authentic .N = O led to a concentration-dependent inhibition of mitochondrial aconitase, NADH-ubiquinone oxidoreductase, and succinate-ubiquinone oxidoreductase (complexes I and II of the mitochondrial electron transport chain). Most susceptible to .N = O inhibition was mitochondrial aconitase, in which a reduction in enzyme activity to 20.2 +/- 1.6% of control was observed. In contrast to mitochondrial aconitase, cytosolic aconitase activity was not inhibited by .N = O. After exposure to a maximal inhibitory concentration of .N = O, mitochondrial aconitase activity recovered completely within 6 h. Complex I did not fully recover within this incubation period. Endogenous .N = O biosynthesis was induced in HC by a specific combination of cytokines and lipopolysaccharide. After 18 h of incubation with these stimuli, a significant inhibition of mitochondrial aconitase activity to 70.8 +/- 2.4% of controls was detected. However, this was due only in part to the action of .N = O. A non-.N=O-dependent inhibition of mitochondrial function appeared to be mediated by tumor necrosis factor.”

Ray Peat's Newsletter

Not for republication without written permission PO Box 5764, Eugene, OR 97405 Raymond PeatJuly, 1995

Persorption refers to a process in which relatively large particles pass through the intact wall of the intestine and enter the blood or lymphatic vessels. It can be demonstrated easily, but food regulators prefer to act as though it didn't exist. The doctrine that polymers--gums, starches, peptides, polyester fat substitutes--and other particulate substances can be safely added to food because they are "too large to be absorbed" is very important to the food in-dustry and its shills.

When the bowel is inflamed, toxins are absorbed. The natural bacterial endotoxin produces many of the same inflammatory effects as the food additive, carrageenan. Like inflammatory bowel disease, the incidence of liver tumors and cirrhosis has increased rapidly. Liver damage leads to hormonal imbalance. Carrageenan produces inflammation and immunodeficiency, synergizing with estrogen, endotoxin and unsaturated fatty acids.

“Volkheimer found that mice fed raw starch aged at an abnormally fast rate, and when he dissected the starch-fed mice, he found a multitude of blocked arterioles in every organ, each of which caused the death of the cells that depended on the blood supplied by that arteriole. It isn’t hard to see how this would affect the functions of organs such as the brain and heart, even without considering the immunological and other implications....”

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<span class="koboSpan" id="kobo.1.1">Immunodeficiency, dioxins, stress, and the hormones</span> A R T I C L E

Immunodeficiency, dioxins, stress, and the hormones

CRITICAL POINTS:

*There are many toxins which modify hormonal responses, activating cells and altering the immune system (including estrogens and dioxins.) When these act early in life, extremely small amounts can cause life-long changes.

*When respiratory energy production is blocked in stimulated cells, the cells are likely to die. (Cortisol, estrogen, polyunsaturated oils have this effect, especially on thymus cells.)

*Antibodies are involved in removing the debris of cells that have disintegrated. Intense cellular damage causes many "autoantibodies" to be produced. People with AIDS have a high incidence of "autoimmunity."

*Endogenous retroviruses are activated by toxins known to be associated with immunodeficiency. Everyone has endogenous retroviruses. The antibodies which are used to diagnose "HIV" infection can, in the demonstrated absence of that virus, be produced in connection with lupus, Sjogren's syndrome, and arthritis. These autoimmune conditions are promoted by estrogen.

*Estrogen activates the production of cortisol, and damages the normal feedback control, causing both cortisol and ACTH to be elevated.

*Estrogen causes chronically elevated free fatty acids, and synergizes with unsaturated fats.

*Estrogen inhibits thyroid function.

Hypercortisolism is typically associated with hypothyroidism, and both tend to cause the loss of lean body mass.

*AIDS is often compared to Addison's disease, because of hyponatremia (loss of sodium) and fatigue. Hypothyroidism causes hyponatremia and many other features seen in AIDS.

*Increased levels of cortisol, estrogen, and polyunsaturated fatty acids, and decreased levels of the active thyroid hormone (T3) and (placental) progesterone have been found to occur in AIDS.

*Progesterone can contribute to the inhibition of HIV replication and transmission.

*Common environmental factors can produce hormonal changes leading to immunodeficiency.

    One hospital in southern Vietnam admitted 437 septicemia patients between mid-1993 and 1994; 23% of the adults died.
In 8 months, 17,000 seals died of infections in Europe. In California, many seals die with an unusual form of metastatic cancer. Seals are highly contaminated with industrial dioxins.
    In Africa, aflatoxin is strongly associated with immunodeficiency. In animals, both dioxin and aflatoxin activate the expression of viruses.
Endometriosis is stimulated by dioxins. Environmental estrogens affect the immune system.

It has been over ten years since I wrote about "AIDS" (e.g., "Repairing the Immune System," in Cofactors in AIDS and HIV infection, edited by R.R. Watson, l989) and the official doctrine that it is caused by the "HIV" virus still hasn't been supported by anything that resembles real science. Duesberg's arguments have never been answered (except by bureaucratic thuggery).
In 1989 I pointed out that septicemia, blood stream infection, in young adults, which used to be a rare thing, and which indicates defective immunity, has been increasing in a remarkably continuous way since the late 1940s, and I reviewed the many things in our environment that are known to suppress immunity, and which have become increasingly prevalent in our environment--unsaturated vegetable oils, ferrous iron and carrageenan in our foods, lead in air, food, and water, exposure to medical, military, and industrial ionizing radiation, vaccinations, pesticides, chlorinated hydrocarbons, nitric oxide (smog and medications) and oral contraceptives and environmental estrogens, in particular. Of these factors, only radiation and lead exposure have decreased in the last several years, after several decades of rapid increase. The widespread use of diuretics in pregnancy, which began in the 1950s and contributed to an epidemic of premature births, also declined after the late 1960s. Most of these environmental factors damage the thymus gland, which regulates the immune system, and by acting on the thymus their effects tend to be additive with other immunosuppressive factors, including cancer, traumatic injury, inflammation, toxins in spoiled food (e.g., aflatoxins) and malnutrition.

Cancer, AIDS, and extreme hypothyroidism have several features in common--they cause tissue loss and organ damage, with immunodeficiency and intense activation of the stress hormones, including cortisol. In cancer and AIDS, a good case has been made for the primacy of stress-induced wasting as the main cause of death. Whatever one might believe to be the cause of cancer and AIDS, it is always good for the patient to prevent tissue damage from the stress associated with the sickness. Since the stress hormones primarily destroy tissues by the activation of specific proteases, the use of protease inhibitors for treating AIDS could conceivably be affecting the stress response. However, the body's normal protection against the cortisol-activated proteases is centered on the protective hormones, progesterone, thyroid, and the androgens.

Environmental stress
One of the most broadly substantiated principles in biology is that a great variety of harmful causes all lead to a few forms of biological harm--the concept of the stress reaction shows the powerful implications of the principle. Stress, no matter what the specific cause, has a particularly destructive effect on three organ systems: The nervous system, the immune system, and the reproductive system. Inflammation, lipid peroxidation, tissue atrophy, the "calcium catastrophe" (when almost anything goes wrong, calcium can transmit and amplify and extend the problem, but isn't itself the source of the problem), mitochondrial decay, and similar events help to define the stress reaction in greater detail.
Hans Selye showed that the thymus shrinks very early in the stress reaction. In his understanding of the process, when adaptation was followed by the "exhaustion phase," the adrenal glands had simply become exhausted from overuse. F. Z. Meerson's work showed that cortisol, and the free fatty acids mobilized by stress, have a toxic influence on the mitochondrial energy production system. Both cortisol and the free fatty acids block the efficient use of glucose for producing energy, creating a diabetes-like condition. The exhaustion problem caused by excessive stress is generalized, not just a matter of adrenal insufficiency.
Meerson's work created the basis for undersanding several degenerative processes, especially the phenomenon of "excitotoxicity," in which the combination of excessive stimulation and deficient energy supply damages or kills cells.
Selye believed that some hormones are antagonistic to each other. A few of the oppositions that he identified have been thoroughly researched, especially the catabolic/anabolic functions of glucocorticoids and androgens, and the shock/antishock functions of estrogen and progesterone, respectively.
Puberty, because of hormonal changes, especially increased estrogen, can be seen as the first stage of a chronic stress, resembling diabetes, since elevated free fatty acids cause "insulin resistance," with slightly impaired oxidation of glucose. The thymus shrinks considerably at puberty, under the influence of the hormonal changes and the increased free fatty acids (caused mainly by estrogen). The degenerative diseases can be seen as the cumulative result of stress, in which tissue damage results from the diabetes-like impairment of energy production.

The thymus, and the thymus-dependent areas of the spleen, are required for full and subtle control of immunity. In the absence of thymic control, the B cells are still able to produce antibodies, but they are more likely to produce autoantibodies.

Stress produces a variety of cellular changes, including the production of the "shock proteins." These proteins can make up 20% of the cell's total protein content. In themselves, the shock proteins are immunosuppressive. They can be recognized by the immune system as antigens, and so are a factor in the appearance of "autoimmune" antibodies. The autoantibodies themselves are often blamed for the diseases they are sometimes associated with, but since they can be present (for example, following removal of the spleen) in people who have no symptoms, their function is probably to facilitate the removal of tissues which are defective for some other reason. The shock proteins could be one of the signals that activate the immune system to remove damaged tissue, and they might be involved in the removal of senescent cells, though I don't think any experiments have been done to test this idea.

Besides activating the cells to produce massive amounts of the shock proteins, stress can also activate the so-called hormone receptors, such as estrogen receptors, even in the absence of the hormones. Stress also activates the endonucleases, which cut sections out of the DNA molecules, and activates mobile genetic elements, producing genetic instability. Like cortisol and estrogen, stress itself activates integrated retroviruses. The "endogenous retroviruses" make up nearly 10% of the human genome, and many of them locate themselves in regulatory sites in the chromosomes.
Since stress lowers the discriminatory ability of the immune system, and stimulates the expression of retroviruses, the antibodies sometimes seen in association with immunodeficiency may be similar to the various autoantibodies that are also produced by stress.
People who have autoimmune diseases such as lupus and Sjogrens syndrome (which are promoted by estrogen: Ahmed and Talal) have antibodies which sometimes react positively in the AIDS test, and searches for the HIV virus in such people have found no evidence of it. (Nelson, et al., 1994; Deas, et al., 1998.) Treatments for roundworms and other parasites cause antibodies to retroviruses to appear in animals that previously tested negative; this might account for the high rates of positive tests for HIV in areas such as Africa in which treatment for filiariasis is common (Kitchen and Cotter, 1988).

Organisms are most sensitive to environmental damage early in life, especially prenatally. This is the period in which normal hormone exposure masculinizes the brain, for example. The term "imprinting" refers to the extreme responsiveness of the organism at this time, and it has been extended to include long lasting influences which may result from abnormally high or low levels of natural substances, or from the presence of other, abnormal substances during the sensitive period. The effects of early "imprinting" can cause permanently altered sensitivities. In animal studies, L. C. Strong showed that prenatal influences determine the age at which puberty and reproductive senescence occur. In humans, premature birth, a powerful stressor, is associated with premature puberty. The thymus is damaged both by premature birth and by puberty. The effects of damage early in life will increase vulnerability in subsequent decades.
When babies are imprinted by the mother's disturbed hormones, or by diuretics, by milk substitutes, or by industrial effluents, the worst effects are likely to be seen decades later, or even generations later. A similar long-range effect can be produced by nutritional deficiencies.
Although more mature organisms are less sensitive to stress, both early imprinting, and the cumulative effects of exposure, will cause some individuals to be much more sensitive than others, and aging itself increases vulnerability.

If the present epidemic of immunodeficiency is produced by environmental stress, then we should expect to see a variety of other stress-related diseases increasing at roughly the same time. When a stressor is acting through imprinting, then the harmful effects may not be seen until 20 or 30 years later, but when the stressor has acute and immediate effects, the effects should rise and fall at roughly the same time as the environmental cause.

The rise of the Acquired Immunodeficiency Syndrome during the last 50 years hasn't been the only health problem that has grown rapidly during that time. The "flesh eating bacteria," causing necrotizing fasciitis and related conditions, should probably be classed along with septicemia/bacteremia as the consequence of a weakened immune system, but there are many other diseases that have followed a similar pattern, which might be caused by the same factors which are causing immunodeficiency. Thyroid diseases (mostly in women), some autoimmune diseases including primary biliary cirrhosis (mostly in women) and inflammatory bowel disease, liver cancer, diabetes (doubling in children since 1949), prostate cancer, decreased sperm counts, premature births and birth defects, minimal brain dysfunction-attention deficit-hyperactivity, cerebral palsy, premature puberty (which is associated with premature birth), congestive heart failure, osteoporosis (independently of the changing age-structure of the population), depression (most common in women, more than doubling among children in recent decades), and multiple sclerosis have increased in prevalence during this period. Some of these conditions are strongly associated with each other, for example, primary biliary cirrhosis, breast cancer, and osteoporosis.

It is common knowledge, among people who study immunity, that radiation, polyunsaturated fatty acids, estrogens, and dioxins are toxic to the thymus gland, and can produce immuno-deficiency. They mimic or accelerate the thymic atrophy of aging, causing a deficient thymus-dependent immune response, usually without harming the ability of B cells to produce antibodies. There are probably many examples of damage to immune systems, besides immunodeficiency, caused by these agents. Slight damage to the immune system, such as can be produced by hypoglycemia or other energy deficit--creates an exaggerated inflammatory response, and the release of the mediators of inflammation, including histamine, serotonin, and prostaglandins, activates the stress hormone system, leading to further biological damage. Liver disease and several other "autoimmune" diseases involve abnormal immune responses, probably including thymic deficiency and an intensified inflammatory response. The fact that livers transplanted from female donors to male recipients are less successful than are livers from male donor transplanted into female recipients, is consistent with the idea that autoantibodies (which are far more common in women than in men) are a relatively harmless response to changes in the organs themselves.

Are antiviral therapies working? Ivan Ilich, in Medical Nemesis, showed that historically, many diseases have had characteristic incidence curves, rising to a maximum, and then falling away to relative insignificance, independently of what people were doing as treatment or prevention. As susceptible people are exposed to conditions that cause a disease, they will get sick, and then either die or develop resistance. The conditions which at first caused increasing disease incidence, will eventually tend to affect only children who haven't developed resistance.
If AIDS mortality rose rapidly to a peak a few years ago, and then began falling, we should ask whether this pattern fits that of other diseases discussed by Ilich. Looking for causes other than the virus, we might find a parallel in the rise and fall of some other factor.
In the 1950s, new diuretics came on the market, and millions of pregnant women took them. It was predicted that there would be an epidemic of brain damage as a result, and in fact the incidence of hyperactivity, attention-deficit, and other "minimal" brain damage disorders did rise during those years. After about 15-20 years, experiences such as the Thalidomide episode caused physicians to temper their enthusiasm for the use of drugs during pregnancy. The incidence of low birth-weight babies in the U.S. peaked around 1965, and 28 years later AIDS mortality in the US peaked. The rising curve had followed both the increase in radioactive fallout from atmospheric testing of large numbers of atomic bombs up to 1963, and the intense promotion of the new diuretics beginning in the early 1950s. The peak in AIDS mortality in 1993 came ten or twelve years after the long decline in SAT scores had stopped. (The most extreme declines in SAT scores had occurred among the brightest students, disproving the contention that the average score fell simply because more students were taking the tests.) The same prenatal damage which caused the extreme decline in SAT scores 18 years later (when the damaged babies reached that age) would have left many of the same individuals with weakened immune systems, which would fail prematurely, but at varying intervals, depending on the exposure to other factors.
The use of unleaded gasoline increased into the 1990s, and there was a corresponding decrease in tissue lead content, reflecting the smaller amount of lead being put into the environment. According to some reports, medical and dental x-ray exposures were declining during this period. Yet other factors, including dioxins and unsaturated dietary fats, were probably increasing.
Although the new protease inhibitors wouldn't be used until years after the AIDS mortality had begun falling, the government and drug companies are claiming that it is the drugs which are decreasing the mortality.

A Synthesis
Many things in our environment are increasing the incidence of certain kinds of liver disease. The liver processes things that are ingested or that enter the blood stream after being inhaled or absorbed through the skin, so in a toxic environment it is susceptible to injury. If deprived of good nutrition or adequate thyroid hormone it is especially sensitive to toxins. The body's own estrogen is a burden on the liver, causing women's livers to be on average slower than men's in processing enviornmental chemicals.
Almost any kind of toxin causes the liver to be less efficient at excreting other substances, including hormones. In malnutrition, sickness, and in aging, there is a tendency for higher levels of estrogen to remain circulating in the blood.
Natural estrogen, and environmental substances that act like estrogen, act as excitants in many types of cell, and at the same time, reduce the efficiency of energy production. Both of these properties relate to its known ability to activate the adrenal glands. A. L. Soderwall, who was my thesis adviser at the University of Oregon, found that estrogen caused hamsters' adrenal glands to enlarge, and that larger doses overstimulated the glands sufficiently to cause tissue damage. It is now known that estrogen acts directly on the adrenal cells to stimulate cortisol production, and that it also stimulates the pituitary to produce more adrenocorticotropin (ACTH), which also stimulates the adrenals; estrogen's effect is to impair the negative feedback, in which cortisol normally shuts down ACTH production. This impaired feedback is characteristic of aging.
Estrogen directly causes the thymus gland to atrophy, and several of its effects, such as increased adrenal activity and elevated free fatty acids, also contribute to the shrinkage of the thymus and the inhibition of its functions. While this is happening, the B cells, which normally are under the control of the thymus cells, are not killed by estrogen, and actually seem to be stimulated by estrogen to produce certain types of antibodies. This combination of effects, weakening the thymus and stimulating antibody production, is thought to contribute to the development of autoimmune diseases. Estrogen also stimulates mast cells and similar cells to release histamine and other promoters of inflammation, and these effects are probably closer to the actual problem in the autoimmune diseases. Several of the substances formed under the influence of estrogen interfere with energy production and contribute to cellular excitation, causing tissue injury.
Cortisol also stimulates antibody production while suppressing thymic immunity (Norbiato, et al., 1997).
Estrogen and stress cause increased levels of free fatty acids to circulate. The polyunsaturated fatty acids are immunosuppressive, antithyroid, diabetogenic, inhibit respiration, and promote the actions of estrogen and cortisol.
People suffering from AIDS have been found to have increased estrogen, with high cortisol and ACTH, and very low T3. (Unfortunately, some researchers and the editors who publish their ideas, conclude that the hormones don't cause the stress and wasting symtpoms, because they call thyroid a "catabolic hormone," and because they describe the fatigue and sodium deficiency as evidence of "deficiency of cortisol." Such is the state of the research establishment.)
In animal experiments, and a few human tests, the HIV and similar viruses have produced effects that could plausibly explain some of the conditions seen in AIDS, such as damage to brain cells (C. Pert, R. Sapolsky), and altered steroid secretion. But this is real science, that promises to link up with information about stress, aging, allergy, and biological adaptability.
For example, Sapolsky's group (Brooke, et al., 1998) found that the nerve toxicity caused by a viral protein (called gp120) synergizes with glucocorticoid toxicity, lowering the ATP level and inhibiting mitochondrial function, and that simply supplying the nerve with additional energy protects it from destruction. In other words, the viral peptide just increases excitotoxicity.
Another group (Amirhessami-Aghili and Spector, 1991) found that the presence of the virus can decrease the production of progesterone. Since progesterone blocks (Lee, et al., 1997) the expression (and transmission) of the virus, this suggests how the overgrowth of the virus might be triggered by stress--once progesterone synthesis falls, a vicious circle could get started.
Lee, et al., found that progesterone can help to prevent transmission of the virus from an infected mother to the fetus. But the most interesting study of the virus in pregnancy involved mice that were engineered to contain extremely large quantities of the HIV provirus (De, et al., 1997). At birth, they seemed normal, but within a few days their skin became diseased, and they quickly wasted away and died. The experimenters realized that something present in the mother's body had permitted normal development up to the point of birth, and then the wasting disease set in. The placental hormone, chorionic gonadotropin, is produced in large amounts during pregnancy. The experimenters gave newborn infected mice regular doses of human chorionic gonadotropin (hCG), and they developed normally.
Rodents don't respond to gonadotropins or other ovarian stimulation exactly the way pigs and primates and people do. For example, prolactin and melatonin usually inhibit progesterone synthesis in people, but in rodents, they increase it. So it's necessary to see exactly what happens to the ovarian hormones when a mouse is given hCG. In 1996, another group (H. Krzanowska and M. Szoltys) had done that, and found that hCG greatly increases progesterone synthesis, but decreases estrogen.
Considering the progesterone-HIV experiments together, I am reminded of a science fiction movie, in which a disease from another planet killed everyone in the lab that was studying it, except for one woman, who turned out to be pregnant.

The medical version of AIDS research, though, pushes aside all of the real science, in favor of a simplistic idea that the virus kills the cells of the immune system, and uses false diagnostic methods and deadly drugs to treat something which too often doesn't exist, while denying that there are other real causes of immune deficiency and wasting-sickness, etc.

Aging is characterized by loss of lean body mass, immunodeficiency, and a variety of autoimmune reactions. My perennial argument has been that decreased thyroid and progesterone, associated with increased estrogen and stress hormones, are largely responsible for those changes. The huge investment in AIDS research has found that these occur in AIDS, but, because of the medical pharmaceutical culture which has created myths about these hormones, no one is yet interpreting the hormone imbalances in ways that would reveal their responsibility for the symptoms. While the institutionalized theory claims that the HIV virus is responsible for the syndrome, the hormones are reduced to epiphenomena.

REFERENCES

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J Infect 1989 May;18(3):231-48 Invasive streptococcal infections in the era before the acquired immune deficiency syndrome: a 10 years' compilation of patients with streptococcal bacteraemia in North Yorkshire. Barnham M. Significant streptococcal (non-pneumococcal, non-enterococcal) bacteraemia was detected in 100 patients in two Health Districts of North Yorkshire in the decade 1978-1988.
Transpl Immunol 1998 Jun;6(2):84-93 Stress protein-induced immunosuppression: inhibition of cellular immune effector functions following overexpression of haem oxygenase (HSP 32). Woo J, Iyer S, Cornejo MC, Mori N, Gao L, Sipos I, Maines M, Buelow R. The results indicate that overexpression of HO results in the inhibition of several immune effector functions and thus provides an explanation for stress-induced immunosuppression.
Genome 1998 Oct;41(5):662-8. A single-primer PCR-based retroviral-related DNA polymorphism shared by two distinct human populations. Deb P, Klempan TA, O'Reilly RL, Singh SM Department of Zoology, University of Western Ontario, London, Canada. "Almost 10% of the human genome consists of DNA sequences that share homology with retroviruses. These sequences, which represent a stable component of the human genome (although some may retain the ability to transpose), remain poorly understood." "Such novel polymorphisms should provide useful markers and permit assessment of evolutionary mechanisms associated with retroviral-related genomic evolution. "
Gen Pharmacol 1998 May;30(5):685-7, Imprinting of thymic glucocorticoid receptor and uterine estrogen receptor by a synthetic steroid hormone at different times after birth. Csaba G, Inczefi-Gonda A.
J Clin Endocrinol Metab 1998 Dec;83(12):4373-81. Human immunodeficiency virus induction of corticotropin in lymphoid cells. Hashemi FB, Hughes TK, Smith EM.
Eur J Cancer Clin Oncol 1988 Jul;24(7):1179-83. Abnormal free fatty acids and cortisol concentrations in the serum of AIDS patients. Christeff N, Michon C, Goertz G, Hassid J, Matheron S, Girard PM, Coulaud JP, Nunez EA. The serum free fatty acid (FFA), cortisol and urinary creatinine, 17-hydzoxycorticosteroid and 17-oxosteroid concentrations of acquired immunedeficiency syndrome (AIDS-I: beginning and AIDS-II: end phase) and AIDS-related complex (ARC) patients were determined. Both groups were compared to a control group (healthy men). ARC and AIDS-I patients. The ratios of stearic (C18:0) to oleic (C18:1) acid were 75%, P less than 0.01 (ARC) and 45%, P less than 0.05 (AIDS-I) greater than normal, due to a decrease in the relative percentage of monounsaturated fatty acids by 25%, P less than 0.001 (ARC) and 20%, P less than 0.01 (AIDS-I). In contrast, the relative percentage of polyunsaturated fatty acids was 85% greater than normal (P less than 0.001) in ARC and 100% greater than normal (P less than 0.001) in AIDS-I patients. Total FFA levels did not differ from controls. Serum cortisol levels were 35% (P less than 0.01) above normal in ARC and 60% (P less than 0.001) above normal in AIDS-I patients. Urinary 17-hydroxycorticosteroids and 17-oxosteroids were very low (2-3-fold lower than normal values, P less than 0.001) in both groups of patients. Urinary creatinine did not differ from controls. In AIDS-II patients the total FFA concentration was below normal 35% (P less than 0.01) and the stearic/oleic acid ratio was 50% above normal (P less than 0.05). The relative percentages of monounsaturated and polyunsaturated fatty acids in this group were similar to those of controls. Serum cortisol concentrations were significantly higher, 50% (P less than 0.001), but the urinary 17-hydroxycorticosteroids and 17-oxosteroids were 2-fold lower (P less than 0.001) than those of controls. Urinary creatinine did not differ from controls.
J Clin Endocrinol Metab 1992 May;74(5):1045-52. Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. Grunfeld C, Pang M, Doerrler W, Shigenaga JK, Jensen P, Feingold KR. Infection causes disturbances in lipid metabolism that may be mediated by cytokines. Therefore we studied plasma lipids, lipoproteins, triglyceride (TG) metabolism, and serum cytokines in three groups: patients with the acquired immunodeficiency syndrome (AIDS) without active secondary infection, patients with evidence of human immunodeficiency virus infection but without clinical AIDS (HIV+), and controls. Plasma TGs and FFA were increased in AIDS, while plasma cholesterol, high density lipoprotein (HDL) cholesterol, apolipoprotein-A-1 (Apo-A-1), low density lipoprotein (LDL) cholesterol, and Apo-B-100 levels were decreased.
J Virol 1991 May;65(5):2231-6. Human immunodeficiency virus type 1 infection of human placenta: potential route for fetal infection. Amirhessami-Aghili N, Spector SA.
AIDS Res Hum Retroviruses 1997 Sep 20;13(14):1235-42. Interaction of pregnancy steroid hormones and zidovudine in inhibition of HIV type 1 replication in monocytoid and placental Hofbauer cells: implications for the prevention of maternal-fetal transmission of HIV. Lee AW, Mitra D, Laurence J.
Folia Biol (Krakow) 1996;44(3-4):111-6. Preovulatory dynamics of ovarian steroid hormones in two mouse strains differing in the rate of meiotic maturation. Krzanowska H, Szoltys M.
J Clin Invest 1997 Apr 1;99(7):1484-91. Human chorionic gonadotropin hormone prevents wasting syndrome and death in HIV-1 transgenic mice. De SK, Wohlenberg CR, Marinos NJ, Doodnauth D, Bryant JL, Notkins AL., Metabolism 1993 Oct;42(10):1270-6.
Indices of function and weight loss in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. Grunfeld C, Pang M, Doerrler W, Jensen P, Shimizu L, Feingold KR, Cavalieri RR.
Int J Health Serv 1994;24(2):311-35 Nuclear fallout, low birthweight, and immune deficiency. Gould JM, Sternglass EJ Radiation and Public Health Project, New York, NY 10024. An investigation of the mortality rates of young adults born in the postwar period of large-scale atmospheric nuclear testing (1945-1965) in the United States and other western industrial nations reveals an increasingly anomalous rise in mortality from its previous secular decline. Beginning in the late 1970s and particularly since 1983, the deterioration in the health of the 25-44 age group is related to in utero exposure to fission products in the milk and diet, associated with an unprecedented rise in underweight births and neonatal mortality known to be accompanied by loss of immune resistance. The 1945-1965 rise in the percentage of live births below 2500 grams is highly correlated with the amount of strontium-90 in human bone, both peaking in the mid-1960s. In the 1980s, for the baby boom generation (those born between 1945 and 1965), cancer incidence and mortality due to infectious diseases associated with a rising degree of immune deficiency, such as pneumonia, septicemia, and AIDS, increased sharply. This process of increasing immune deficiency appears to have been exacerbated by continuing secondary exposures to accidental reactor releases and by an acceleration of radiation-induced mutation of pathogenic microorganisms increasingly resistant to drugs.
Biokhimiia 1987 Sep;52(9):1501-11 [Activation of lipolysis and ketogenesis in tumor-bearing animals as a reflection of chronic stress states]. Chekulaev VA, Shelepov VP, Pasha-zade GR, Shapot VS.
Arkh Patol 1987;49(6):10-8 [Combination of immunodepression and disorders in nucleic acid metabolism of lymphoid tissue as a manifestation of a paraneoplastic syndrome]. [Article in Russian] Potapova GI, Shapot VS Several physiological, biochemical, and molecular biological approaches to the study of factors determining immunodepression in tumor-bearing animals are considered. Cancer cells release substances of nucleic and peptide nature that suppress the functional activity of macrophages and lymphocytes and stimulate cell proliferation in organs and tissues of the host. Suppressor T cells capable of inhibiting the function of helper T cells and impairing the differentiation of killer T cells are activated. The suppression of T- and B-cell-mediated immunity in the tumor host involves disturbances of nucleic acid metabolism in those cells as well as hypersecretion of glucocorticoids. The impairments of lymphocyte proliferation and differentiation that result in reduced immune responsiveness are attributable to drastic alterations in the metabolism of purine and pyrimidine nucleotides and to the damage sustained by the lymphocyte's DNA.
Eksp Onkol 1987;9(6):62-7 [Relation between disorders of glucose metabolism, secretion of somatotropic hormone, thyroxine, thyrotropin and hematocrit indices in rats with transplanted hepatomas]. Shelepov VP, Pasha-zade GR, Chekulaev VA, Shapot VS.
Am J Pathol 1987 Jan;126(1):103-13 Dietary fatty acid effects on T-cell-mediated immunity in mice infected with mycoplasma pulmonis or given carcinogens by injection. Bennett M, Uauy R, Grundy SM. To test whether or not diets enriched in w-6 polyunsaturated fatty acids are significantly immunosuppressive . . . mice were fed diets enriched for fatty acids: linoleic (POLY), oleic (MONO), palmitic (SAT), or eicosapentanoic (FISH). . . . only mice on the POLY diet were significantly immunosuppressed, and only T-cell-mediated cutaneous sensitivity reactions were affected. After instillation, mice on the POLY and MONO diets were suppressed for T-cell cutaneous responses. Deliberate infection with Mycoplasma pulmonis resulted in suppressed cutaneous T-cell responses in the POLY group of C3B6F1 mice, and aspirin partially reversed the immunosuppression. Mice on the FISH diet were resistant to immunosuppression. It is tentatively concluded that diets rich in w-6 polyunsaturated diets, while not directly immunosuppressive, do predispose animals to suppression of certain T-cell-mediated immune responses. This immunosuppression can be "triggered" by infection and/or by exposure to carcinogens.
Tumour Biol 1988;9(5):225-32 Modulation of cell-mediated immune response by steroids and free fatty acids in AIDS patients: a critical survey. Nunez EA. The overall data presented in this review show that cortisol and free fatty acids, in particular long-chain polyunsaturated fatty acids, each have immunoinhibitory properties on lymphoblastic transformation of certain T lymphocytes. This effect is enhanced when the two factors are associated. These data could explain in part the immunosuppression observed in acquired immunodeficiency syndrome (AIDS) patients where enhanced concentrations of cortisol and polyunsaturated fatty acids have been observed.
Basic Life Sci 1988;49:615-20 Vitamin E and immune functions. Bendich A. Supplementation of these diets with higher than nutritionally adequate levels of vitamin E enhances immune responses. High levels of PUFA are immunosuppressive, and vitamin E can partially overcome this immunosuppression. High levels of vitamin C can protect tissue levels of vitamin E and may indirectly contribute to the immunoenhancement by vitamin E. Severe selenium deficiency is immunosuppressive. Vitamin E can protect some aspects of immune responses from the adverse effects of selenium deficiency. These data clearly indicate that nutrients that affect the overall antioxidant status have important effects on immune functions. In addition, antioxidant nutrient interactions can synergize to overcome the adverse effects of polyunsaturated fatty acids on immune functions.
Transplantation 1989 Jul;48(1):98-102 Enhancement of immunosuppression by substitution of fish oil for olive oil as a vehicle for cyclosporine. Kelley VE, Kirkman RL, Bastos M, Barrett LV, Strom TB.
J Am Coll Nutr 1992 Oct;11(5):512-8 Role of nutrition in the management of malnutrition and immune dysfunction of trauma. Cerra FB Dept. of Clinical Nutrition, University of Minnesota, Minneapolis. Current nutrition support improves patient outcome in trauma patients. It appears to do so by limiting the adverse effects of specific nutrient or generalized nutrient deficiencies. Immunosuppression, however, continues as a significant clinical problem. This immunosuppression appears to be part of the inflammatory response that accompanies trauma, and in part, to represent the need for conditional nutrients in this setting. Three nutrients that are being evaluated include arginine, uracil as ribonucleic acid and omega-3 polyunsaturated fatty acids. Animal studies report improved immune function. Early clinical trials are reporting improved immune function and patient outcomes.
J Nutr 1996 Mar;126(3):681-92 Dietary butter protects against ultraviolet radiation-induced suppression of contact hypersensitivity in Skh:HR-1 hairless mice. Cope RB, Bosnic M, Boehm-Wilcox C, Mohr D, Reeve VE. Dietary fats modulate a wide variety of T cell functions in mice and humans. This study examined the effects of four different dietary fats, predominantly polyunsaturated sunflower oil, margarine, and predominantly saturated butter, clarified butter, on the T cell-mediated, systemic suppression of contact hypersensitivity by ultraviolet radiation. There was a linear relationship (r > 0.9) between protection against photoimmunosuppression and the proportion of clarified butter in mice fed a series of 200 g/kg mixed fat diets that provided varying proportions of clarified butter and sunflower oil. The dietary fats did not modulate the contact hypersensitivity reaction in unirradiated animals. The observed phenomena were not primary due to the carotene, tocopherol, cholecalciferol, retinol, lipid hydroperoxide or the nonfat solid content of the dietary fats used and appeared to be a result of the different fatty acid composition of the fats.
Cancer Lett 1996 Nov 29;108(2):271-9 Dependence of photocarcinogenesis and photoimmunosuppression in the hairless mouse on dietary polyunsaturated fat. Reeve VE, Bosnic M, Boehm-Wilcox C. The photocarcinogenic response was of increasing severity as the polyunsaturated content of the mixed dietary fat was increased, whether measured as tumour incidence, tumour multiplicity, progression of benign tumours to squamous cell carcinoma, or reduced survival. When mice were exposed acutely to UV radiation (UVR), a diet of 20% saturated fat provided almost complete protection from the suppression of CHS, whereas feeding 20% polyunsaturated fat resulted in 57% suppression; the CHS of unirradiated mice was unaffected by the nature of the dietary fat. These results suggest that the enhancement of photocarcinogenesis by the dietary polyunsaturated fat component is mediated by an induced predisposition to persistent immunosuppression caused by the chronic UV irradiation, and supports the evidence for an immunological role in dietary fat modulation of photocarcinogenesis in mice.
Ann Acad Med Singapore 1991 Jan;20(1):84-90. Clinical implications of food contaminated by aflatoxins. Hendrickse RG.
Arch Toxicol 1996;70(10):661-71. Host resistance to rat cytomegalovirus (RCMV) and immune function in adult PVG rats fed herring from the contaminated Baltic Sea. Ross PS, Van Loveren H, de Swart RL, van der Vliet H, de Klerk A, Timmerman HH, van Binnendijk R, Brouwer A, Vos JG, Osterhaus AD. In a semi-field study, we previously showed that harbour seals (Phoca vitulina) fed herring from the contaminated Baltic Sea had lower natural killer cell activity, T-lymphocyte functionality and delayed-type hypersensitivity responses than seals fed herring from the relatively uncontaminated Atlantic Ocean. A novel model was established to assess the specific T-cell response to rat cytomegalovirus (RCMV). When applied to the feeding study, no differences between the Atlantic and Baltic groups in the RCMV-induced proliferative T-lymphocyte responses could be detected, but virus titres in salivary glands of infected rats of the Baltic Sea group were higher. These elevated RCMV titres and changes in thymus cellularity suggest that the dietary exposure to low levels of contaminants may have been immunotoxic at a level which our immune function test could not otherwise detect. While the herring diet per se appeared to have an effect on several immune function parameters, lower plasma thyroid hormone levels in the Baltic Sea group of rats confirmed that exposure to the environmental mixture of contaminants led to adverse PHAH-related health effects.
Environ Health Perspect 1995 Apr;103(4):366-71 Dioxin activates HIV-1 gene expression by an oxidative stress pathway requiring a functional cytochrome P450 CYP1A1 enzyme. Yao Y, Hoffer A, Chang CY, Puga A. Aflatoxin B1, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) and benzo[a]pyrene cause a significant increases in CAT expression in mouse hepatoma Hepa-1 cells. We conclude that induction of a functional CYP1A1 monooxygenase by TCDD stimulates a pathway that generates thiol-sensitive reactive oxygen intermediates which, in turn, are responsible for the TCDD-dependent activation of genes linked to the LTR. These data might provide an explanation for findings that TCDD increases infectious HIV-1 titers in experimental systems and for epidemiologic reports suggesting that exposure to aromatic hydrocarbons, such as found in cigarette smoke, is associated with an acceleration in AIDS progression.
Ann Trop Med Parasitol 1997 Oct;91(7):787-93 Of sick turkeys, kwashiorkor, malaria, perinatal mortality, heroin addicts and food poisoning: research on the influence of aflatoxins on child health in the tropics. Hendrickse RG. Aflatoxin exposure occurs in > or = 30% of pregnancies in tropical Africa and the toxins are often in cord blood, sometimes at extremely high concentrations. Aflatoxins are now incriminated in neonatal jaundice and there is circumstantial evidence that they cause perinatal death and reduced birthweight. Aflatoxin-induced immunosuppresion may explain the aggressive behaviour of HIV infection in Africa. There are similarities between observations on HIV cases in Africa and those on heroin addicts in Europe, where 'street' heroin is frequently contaminated with aflatoxin. Aflatoxins were found in 20% of random urine samples from heroin addicts in the U.K. and the Netherlands.
Ann N Y Acad Sci 1986;475:320-8. Hormonal approaches to immunotherapy of autoimmune disease. Talal N, Ahmed SA, Dauphinee M.
Cell Immunol 1998 Nov 1;189(2):125-34. Estrogen increases the number of plasma cells and enhances their autoantibody production in nonautoimmune C57BL/6 mice. Verthelyi DI, Ahmed SA.
J Rheumatol 1987 Jun;14 Suppl 13:21-5. Interleukin 2, T cell receptor and sex hormone studies in autoimmune mice. Talal N, Dang H, Ahmed SA, Kraig E, Fischbach M. The administration of estrogen to pregnant mice late in gestation results in offspring with a permanently altered immune system. These mice develop features of autoimmunity similar to those that occur spontaneously in genetically susceptible autoimmune mice. This phenomenon may have etiopathological significance for familial SLE.
Endocrinology 1994 Dec;135(6):2615-22. 17 beta-estradiol, but not 5 alpha-dihydrotestosterone, augments antibodies to double-stranded deoxyribonucleic acid in nonautoimmune C57BL/6J mice. Verthelyi D, Ahmed SA.
J Autoimmun 1993 Jun;6(3):265-79 Antibodies to cardiolipin in normal C57BL/6J mice: induction by estrogen but not dihydrotestosterone. Ahmed SA, Verthelyi D.
J Autoimmun 1989 Aug;2(4):543-52. Estrogen induces the development of autoantibodies and promotes salivary gland lymphoid infiltrates in normal mice. Ahmed SA, Aufdemorte TB, Chen JR, Montoya AI, Olive D, Talal N. . . . normal mice were prenatally exposed to estrogens. . . . mice prenatally exposed to estrogens had accelerated development of autoimmune salivary gland lesions indistinguishable from Sjogren's syndrome (SS) in humans. Further experiments are warranted to confirm these findings. The prenatal effects of estrogen may have relevance for familial and neonatal autoimmune syndromes.
Isr J Med Sci 1988 Dec;24(12):725-8. Sex hormones, CD5+ (Lyl+) B-cells, and autoimmune diseases. Talal N, Ahmed SA.
Ann N Y Acad Sci 1986;475:320-8 Hormonal approaches to immunotherapy of autoimmune disease. Talal N, Ahmed SA, Dauphinee M.
Life Sci 1998;63(20):1815-22. Exacerbated immune stress response during experimental magnesium deficiency results from abnormal cell calcium homeostasis. Malpuech-Brugere C, Rock E, Astier C, Nowacki W, Mazur A, Rayssiguier Y. These studies first showed that an abnormal calcium handling induced by extracellular magnesium depression in vivo may be at the origin of exacerbated inflammatory response.
Magnes Res 1998 Sep;11(3):161-9. Early morphological and immunological alterations in the spleen during magnesium deficiency in the rat. Malpuech-Brugere C, Kuryszko J, Nowacki W, Rock E, Rayssiguier Y, Mazur A. Dietary magnesium deficiency in rodents, and especially in rats, causes inflammation and leads to alterations in the immune response.

Ann Rheum Dis 1994 Nov;53(11):749-54 Polymerase chain reaction fails to incriminate exogenous retroviruses HTLV-I and HIV-1 in rheumatological diseases although a minority of sera cross react with retroviral antigens. Nelson PN, Lever AM, Bruckner FE, Isenberg DA, Kessaris N, Hay FC.
Clin Diagn Lab Immunol 1998, Mar;5(2):181-5. Reactivity of sera from systemic lupus erythematosus and Sjogren's syndrome patients with peptides derived from human immunodeficiency virus p24 capsid antigen. Deas, JE, et al. We have previously demonstrated that about one-third of patients with either Sjogren's syndrome (SS) or systemic lupus erythematosus (SLE) react to human immunodeficiency virus (HIV) p24 core protein antigen without any evidence of exposure to, or infection with, HIV itself.
J Clin Lab Immunol 1988 Feb;25(2):101-3. Effect of diethylcarbamazine on serum antibody to feline oncornavirus-associated cell membrane antigen in feline leukemia virus cats. Kitchen LW, Cotter SM. Department of Cancer Biology, Harvard School of Public Health, Boston. Diethylcarbamazine (N,N-diethyl-4-methyl-1- piperazine carboxamide; DEC) is a drug frequently used for prevention and treatment of the filariases. An opsonic action of DEC may generate increased immune responses to microfilariae. We tested the hypothesis that DEC treatment could result in higher antibody levels to other infectious agents. A retroviral animal model was studied, in light of the consideration that use of DEC as an antifilarial agent could conceivably alter seroepidemiologic surveys as well as serologic outcomes of vaccine trials in Africa regarding human immunodeficiency virus (HIV). The effect of DEC treatment on serum antibody to feline oncornavirus-associated cell membrane antigen (FOCMA) in domestic cats exposed to feline leukemia virus (FeLV) was examined. Nine cats that tested negative before treatment tested positive (greater than or equal to 1:10 serum dilution, geometric mean titer [GMT] = 278) for antibody to FOCMA after DEC treatment. Among 19 cats initially testing positive for FOCMA antibody, higher titers were noted after treatment in 17 (pretreatment GMT = 264; posttreatment GMT = 6,158). We conclude that a history of DEC treatment should be considered in evaluating humoral responses to infectious agents. Whether use of ivermectin, a recently introduced antifilarial agent, in lieu of DEC will affect clinical expression of HIV infection in humans also warrants analysis.

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<span class="koboSpan" id="kobo.1.1">Iron's Dangers</span> A R T I C L E

Iron's Dangers

Q: You believe iron is a deadly substance. Why?

Iron is a potentially toxic heavy metal. In excess, it can cause cancer, heart disease, and other illnesses.

Q: Could you tell us about some of these studies?

In the 1960s the World Health Organization found that when iron supplements were given to anemic people in Africa, there was a great increase in the death rate from infectious diseases, especially malaria. Around the same time, research began to show that the regulation of iron is a central function of the immune system, and that this seems to have evolved because iron is a basic requirement for the survival and growth of cells of all types, including bacteria, parasites, and cancer. The pioneer researcher in the role of iron in immunity believed that an excess of dietary iron contributed to the development of leukemia and lymphatic cancers. Just like lead, mercury, cadmium, nickel and other heavy metals, stored iron produces destructive free radicals. The harmful effects of iron-produced free radicals are practically indistinguishable from those caused by exposure to X-rays and gamma rays; both accelerate the accumulation of age-pigment and other signs of aging. Excess iron is a crucial element in the transformation of stress into tissue damage by free radicals.

For about 50 years, it has been known that blood transfusions damage immunity, and excess iron has been suspected to be one of the causes for this. People who regularly donate blood, on the other hand, have often been found to be healthier than non-donors, and healthier than they were before they began donating.

In one of Hans Selye's pioneering studies, he found that he could experimentally produce a form of scleroderma (hardening of the skin) in animals by administering large doses of iron, followed by a minor stress. He could prevent the development of the condition by giving the animals large doses of vitamin E, suggesting that the condition was produced by iron's oxidative actions.

Excess iron's role in infectious diseases is now well established, and many recent studies show that it is involved in degenerative brain diseases, such as Parkinson's, ALS (Lou Gehrig's disease), Huntington's chorea, and Alzheimer's disease. Iron is now believed to have a role in skin aging, atherosclerosis, and cataracts of the lenses of the eyes, largely through its formation of the "age pigment."

Q: How does excess iron accelerate our aging process?

During aging, our tissues tend to store an excess of iron. There is a remarkably close association between the amount of iron stored in our tissues and the risk of death from cancer, heart disease, or from all causes. This relationship between iron and death rate exists even during childhood, but the curve is downward until the age of 12, and then it rises steadily until death. The shape of this curve, representing the iron burden, is amazingly similar to the curves representing the rate of death in general, and the rate of death from cancer. There is no other relationship in biology that I know of that has this peculiar shape, with its minimum at the age of 12, and its maximum in old age at the time of death.

One of the major lines of aging research, going back to the early part of this century, was based on the accumulation of a brown material in the tissues known as "age-pigment." The technical name for this material, "lipofuscin," means "fatty brown stuff." In the 1960s, the "free radical theory" of aging was introduced by Denham Harman, and this theory has converged with the age-pigment theory, since we now know that the age-pigment is an oxidized mass of unsaturated fat and iron, formed by uncontrolled free radicals. Until a few years ago, these ideas were accepted by only a few researchers, but now practically every doctor in the country accepts that free radicals are important in the aging process. A nutrition researcher in San Diego suspected that the life-extending effects of calorie restriction might be the result of a decreased intake of toxins. He removed the toxic heavy metals from foods, and found that the animals which ate a normal amount of food lived as long as the semi-starved animals. Recently, the iron content of food has been identified as the major life-shortening factor, rather than the calories. [Choi and Yu, Age vol. 17, page 93, 1994.]

Q: Exactly how much iron do we need to eat?

Children's nutritional requirements are high, because they are growing, but there are indications that in the U.S. even children eat too much iron.

Some researchers are concerned that the iron added to cereals is contributing to the incidence of leukemia and cancers of the lymphatic tissues in children. [Goodfield, 1984.] During the time of rapid growth, children are less likely than adults to store too much iron. At birth, they have a large amount of stored iron, and this decreases as they "grow into it." It is after puberty, when growth slows and the sex hormones are high, that the storage of iron increases. [Blood, Sept., 1976.] In a study of the "malnourished" children of migrant fruit pickers in California, these children who were "seriously anemic" were actually more resistant to infectious diseases than were the "well nourished" middle class children in the same region.

If the normal amount of dietary iron causes an increased susceptibility to infections even in children, and if a subnormal amount of iron slows the aging process, I think we are going to have to reconsider our ideas of nutritional adequacy, to look at the long range effects of diet, as well as the immediate effects. My current studies have to do with analyzing our ability to handle stress safely, in relation to our diet. I believe our nutritional recommendations for iron have to be revised sharply downward.

Q. Don't women need extra iron?

That's a misunderstanding.

Doctors generally don't realize that only a few milligrams of iron are lost each day in menstruation. The real issue is that you can hardly avoid getting iron, even when you try.

Women absorb iron much more efficiently than men do. From a similar meal, women will normally absorb three times as much iron as men do. When pregnant, their higher estrogen levels cause them to absorb about nine times as much as men. Every time a woman menstruates, she loses a little iron, so that by the age of 50 she is likely to have less iron stored in her tissues than a man does at the same age, but by the age of 65 women generally have as much excess iron in their tissues as men do. (During those 15 years, women seem to store iron at a faster rate than men do, probably because they have more estrogen.) At this age their risk of dying from a heart attack is the same as that of men. Some women who menstruate can donate blood regularly without showing any tendency to become anemic.

Since the custom of giving large iron supplements to pregnant women has been established, there has been an increase in jaundice of the newborn. It has been observed that women who didn't take iron supplements during pregnancy have healthy babies that don't develop jaundice. I have suggested that this could be because they haven't been poisoned by iron. Those supplements could also be a factor in the increased incidence of childhood cancer.

Q: Don't you need iron supplements if you are anemic?

In general, no.

Many doctors think of anemia as necessarily indicating an iron deficiency, but that isn't correct. 100 years ago, it was customary to prescribe arsenic for anemia, and it worked to stimulate the formation of more red blood cells. The fact that arsenic, or iron, or other toxic material stimulates the formation of red blood cells doesn't indicate a "deficiency" of the toxin, but simply indicates that the body responds to a variety of harmful factors by speeding its production of blood cells. Even radiation can have this kind of stimulating effect, because growth is a natural reaction to injury. Between 1920 and 1950, it was common to think of "nutritional growth factors" as being the same as vitamins, but since then it has become common to use known toxins to stimulate the growth of farm animals, and as a result, it has been more difficult to define the essential nutrients. The optimal nutritional intake is now more often considered in terms of resistance to disease, longevity or rate of aging, and even mental ability.

An excess of iron, by destroying vitamin E and oxidizing the unsaturated fats in red blood cells, can contribute to hemolytic anemia, in which red cells are so fragile that they break down too fast. In aging, red cells break down faster, and are usually produced more slowly, increasing the tendency to become anemic, but additional iron tends to be more dangerous for older people.

Anemia in women is caused most often by a thyroid deficiency (as discussed in the chapter on thyroid), or by various nutritional deficiencies. Estrogen (even in animals that don't menstruate) causes dilution of the blood, so that it is normal for females to have lower hemoglobin than males. Q. What should I do if my doctor tells me I'm anemic? Is there any situation in which a person needs to take iron supplements?

Iron deficiency anemia does exist, in laboratory situations and in some cases of chronic bleeding, but I believe it should be the last-suspected cause of anemia, instead of the first. It should be considered as a possible cause of anemia only when very specific blood tests show an abnormally low degree of iron saturation of certain proteins. Usually, physicians consider the amount of hemoglobin or of red cells in the blood as the primary indicator of a need for iron, but that just isn't biologically reasonable.

If a large amount of blood is lost in surgery, a temporary anemia might be produced, but even then it would be best to know whether the iron stores are really depleted before deciding whether an iron supplement would be reasonable. Liver (or even a water extract of wheat germ) can supply as much iron as would be given as a pill, and is safer.

Q. What foods contain iron?

Flour, pasta, etc., almost always contain iron which has been artificially added as ferrous sulfate, because of a federal law. Meats, grains, eggs, and vegetables naturally contain large amounts of iron. A few years ago, someone demonstrated that they could pick up a certain breakfast cereal with a magnet, because of the added iron. Black olives contain iron, which is used as a coloring material. You should look for "ferrous" or "ferric" or "iron" on the label, and avoid foods with any added iron. Many labels list "reduced iron," meaning that iron is added in the ferrous form, which is very reactive and easily absorbed.

Q.: Why does federal law require the addition of iron to those foods?

Industrially processed grains have most of the nutrients, such as vitamin E, the B vitamins, manganese, magnesium, etc., removed to improve the products' shelf life and efficiency of processing, and the government required that certain nutrients be added to them as a measure to protect the public's health, but the supplementation did not reflect the best science even when it was first made law, since food industry lobbyists managed to impose compromises that led to the use of the cheapest chemicals, rather than those that offered the greatest health benefits. For example, studies of processed animal food had demonstrated that the addition of iron (as the highly reactive form, ferrous sulfate, which happens to be cheap and easy to handle) created disease in animals, by destroying vitamins in the food. You should read the label of ingredients and avoid products that contain added iron, when possible.

Q: Can cooking in an iron frying pan put iron into food?

Yes, especially if the food is acidic, as many sauces are. The added iron will destroy vitamins in the food, besides being potentially toxic in itself.

Q: What about aluminum?

Aluminum and iron react similarly in cells and are suspected causes of Alzheimer's disease.

The aluminum industry started propagandizing more than 50 years ago about the "safety" of aluminum utensils, claiming that practically none of the toxic metal gets into the food. Recent research showed that coffee percolated in an aluminum pot contained a large amount of dissolved aluminum, because of coffee's acidity.

Q: What kind of cooking pots or utensils are safe?

Glass utensils are safe, and certain kinds of stainless steel are safe, because their iron is relatively insoluble. Teflon-coated pans are safe unless they are chipped.

Q: How do I know which stainless steels are safe?

There are two main types of stainless steel, magnetic and nonmagnetic. The nonmagnetic form has a very high nickel content, and nickel is allergenic and carcinogenic. It is much more toxic than iron or aluminum. You can use a little "refrigerator magnet" to test your pans. The magnet will stick firmly to the safer type of pan.

Q: Why is there iron in most multi-vitamin and mineral products?

Although several researchers have demonstrated that iron destroys vitamins, there is enough wishful thinking in industry, government, and the consuming public, that such mistakes can go on for generations before anyone can mobilize the resources to bring the truth to the public. 10 years ago, I thought it was a hopeful sign of increased awareness of iron's danger when the manufacturer of a new iron product mentioned in the Physician's Desk Reference that it hadn't yet been reported to cause cancer.

Q. I can't avoid all those foods, especially the bread and grains. What can I do to keep the iron I ingest from harming me?

Iron destroys vitamin E, so vitamin E should be taken as a supplement. It shouldn't be taken at the same time as the iron-contaminated food, because iron reacts with it in the stomach. About 100 mg. per day is adequate, though our requirement increases with age, as our tissue iron stores increase. Coffee, when taken with food, strongly inhibits the absorption of iron, so I always try to drink coffee with meat. Decreasing your consumption of unsaturated fats makes the iron less harmful. Vitamin C stimulates the absorption of iron, so it might be a good idea to avoid drinking orange juice at the same meal with iron-rich foods. A deficiency of copper causes our tissues to retain an excess of iron, so foods such as shrimp and oysters which contain abundant copper should be used regularly.

Q: How does copper help us?

Copper is the crucial element for producing the color in hair and skin, for maintaining the elasticity of skin and blood vessels, for protecting against certain types of free radical, and especially for allowing us to use oxygen properly for the production of biological energy. It is also necessary for the normal functioning of certain nerve cells (substantia nigra) whose degeneration is involved in Parkinson's disease. The shape and texture of hair, as well as its color, can change in a copper deficiency. Too much iron can block our absorption of copper, and too little copper makes us store too much iron. With aging, our tissues lose copper as they store excess iron. Because of those changes, we need more vitamin E as we age.

SUMMARY:

Iron is a potentially toxic heavy metal; an excess can cause cancer, heart disease, and other illnesses.

Other heavy metals, including lead and aluminum, are toxic; pans and dishes should be chosen carefully.

Iron causes cell aging.

Drinking coffee with iron rich foods can reduce iron's toxic effects.

Use shrimp and oysters, etc., to prevent the copper deficiency which leads to excess storage of iron.

Avoid food supplements which contain iron.

Take about 100 units of vitamin E daily; your vitamin E requirement increases with your iron consumption.

GLOSSARY:

Free radicals are fragments of molecules that are very destructive to all cells and system of the body.

Respiration refers to the absorption of oxygen by cells, which releases energy. The structure inside the cell in which energy is produced by respiration is called the mitochondrion. Oxidation refers to the combination of a substance with oxygen. This can be beneficial, as in normal respiration that produces energy, or harmful, as in rancidity, irradiation, or stress reactions. Antioxidants: Vitamin E and vitamin C are known as antioxidants, because they stop the harmful free-radical chain reactions which often involve oxygen, but they do not inhibit normal oxidation processes in cells. "Chain breaker" would be a more suitable term. It is often the deficiency of oxygen which unleashes the dangerous free-radical processes. Many substances can function as antioxidants/chain breakers: thyroxine, uric acid, biliverdin, selenium, iodine, vitamin A, sodium, magnesium, and lithium, and a variety of enzymes. Saturated fats work with antioxidants to block the spread of free-radical chain reactions. Age pigment is the brown material that forms spots on aging skin, and that accumulates in the lens of the eye forming cataracts, and in blood vessels causing hardening of the arteries, and in the heart and brain and other organs, causing their functions to deteriorate with age. It is made up of oxidized unsaturated oils with iron.

Anemic means lacking blood, in the sense of not having enough red blood cells or hemoglobin. It is possible to have too much iron in the blood while being anemic. Anemia in itself doesn't imply that there is nutritional need for iron.

REFERENCES

Allen, D. R., et al., "Catechol adrenergic agents enhance hydroxyl radical generation in xanthine oxidase systems containing ferritin: Implications for ischemia reperfusion," Arch. Biochem. Biophys. 315(2), 235-243, 1994.

M. Bartal, et al., "Lipid peroxidation in iron deficiency anemia--Reply," Acta Haematol. 91(3), 170, 1994.

R. J. Bergeron, et al., "Influence of iron on in vivo proliferation and lethality of L1210 cells," J. Nutrition 115(3), 369-374, 1985.

P. Carthew and A. G. Smith, "Pathological mechanisms of hepatic tumor formation in rats exposed chronically to dietary hexachlorobenzene," J. Applied Toxicology 14(6), 447-52, 1994.

Chen, Y., et al., "Weak antioxidant defenses make the heart a target for damage in copper-deficient rats," Free Radical Biol. Med. 17(6), 529-536, 1994.

J. J. C. Chiao, et al., "Iron delocalization occurs during ischemia and persists on reoxygenation of skeletal muscle," J. Lab. Clin. Med. 124(3), 432-438, 1994.

Choi, J. H. and B. P. Yu, "Modulation of age-related alterations of iron, ferritin, and lipid peroxidation in rat serum," Age 17(3), 93-97, 1994.

P. C. Elwood, "Iron, magnesium, and ischemic heart disease," Proc. of Nutrition Society 53(3), 599-603, 1994.

J. Goodfield, An Imagined World, Penguin Books, N.Y., 1984.

M. Galleano and S. Puntarulo, "Mild iron overload effect on rat liver nuclei," Toxicol. 93(2-3), 125-34, 1994.

E. C. Hirsch, "Biochemistry of Parkinson's disease with special reference to the dopaminergic systems," Mol. Neurobiol. 9(1-3), 135-142, 1994.

G. M. Kainova, et al., "Activation of endogenous lipid peroxidation in the brain during oxidation stress induced by iron and its prevention by vitamin E," Bull. Exp. Biol. & Med. 109(1), 43-45, 1989.

S. Kiechl, et al., "Body iron stores and presence of carotid atherosclerosis--results from the Bruneck study," Arterioscler. Thromb. 14(10), 1625-1630, 1994.

A. V. Kozlov, et al., "Role of endogenous free iron in activation of lipid peroxidation during ischemia," Bull. Exp. Biol. Med. 99(1), 1984.

D. J. Lamb and D. S. Leake, "Iron released from transferrin at acidic pH can catalyse the oxidation of low density lipoprotein," FEBS Lett 352(1), 15-18, 1994.

E. E. Letendre, "Importance of iron in the pathogenesis of infection and neoplasm," Trends in Biochemical Sci., April, 1985, 166-168.

V. M. Mann, et al., "Complex 1, iron and ferritin in Parkinson's disease substantia nigra," Ann. of Neurology 36(6), 876-81, 1994.

Z. Maskos and W. H. Koppenol, "Oxyradicals and multivitamin tablets," Free Radical Biol. & Med. 11, 669-670, 1991.

S. Ozsoylu, "Lipid peroxidation in iron deficiency anemia," Acta Haematol. 91(3), 170, 1994.

Pecci, L., et al., "Aminoethylcystein ketimine decarboxylated dimer protects submitochondrial particles from lipid peroxidation at a concentration not inhibitory of electron transport," Biochem. Biophys. Res. Commun. 205(1), 264-268, 1994.

M. Savoiardo, et al., "Magnetic resonance imaging in progressive supranuclear palsy and other parkinsonian disorders," J. Neural Trans. (suppl. 42), 93-110, 1994.

J. J. Strain, "Putative role of dietary trace elements in coronary heart disease and cancer," Brit. J. Biomed. Sci. 51(3), 241-251, 1994.

Vanrensburg, S. J., et al., "Lipid peroxidation and platelet membrane fluidity--implications for Alzheimer's disease?", Neuroreport 5(17), 2221-2224, 1994.

L. J. Wesselius, et al., "Increased release of ferritin and iron by iron-loaded alveolar macrophages in cigarette smokers," Amer. J. Respir. Crit. Care Med. 150(3), 690-695, 1994.

Transfusions: Amer. J. of Surgery 155, p. 43, 1988. *A Finnish study, two years ago, indicated that high iron stores may increase heart attack risk: In People magazine, 1994: "Is iron a killer?" Dr. Jerome L. Sullivan, director of clinical labs of Veterans Affairs Medical Center at Charleston, S.C., in 1983 proposed that excess iron contributes to heart attacks. University of Kuopio in Finland: Large-scale study (nearly 2,000 men, for up to five years; next to smoking, excess stored iron is the most significant identifiable risk factor for heart attacks. It is a stronger risk factor for heart attack than high blood pressure and cholesterol.

*Dec. 7, page 6E, Register Guard (Eugene, OR): US studies showed a weak connection between iron and heart disease, and a weak connection with the iron in red meat. Epidemiologists at the Pacific Northwest Laboratory in Washington have reported that the greater the concentration of iron in a person's blood, the greater his or her risk of cancer. Richard Stevens and his co-workers found the connection from examining cancer rates in more than 8,000 people who participated in the l971 National Health and Nutrition Examination survey. A second Finnish study with similar findings accompanied Stevens's report in the International Journal of Cancer, and suggets that there may be cause for concern. Register Guard (Eugene, OR), Jan. 16, 95; p 7A: Number of heart failures doubles, AP: 1982-92, heart disease death rate dropped 24.5%; number of cases of congestive heart failure doubled during roughly the same period. It killed 39,000 Americans in 1991, costs system $40 billion per year. Cancer is the biggest killer of women under 64, heart disease far surpasses cancer in women of ages 65-84.

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<span class="koboSpan" id="kobo.1.1">Leakiness, aging, and cancer</span> A R T I C L E

Leakiness, aging, and cancer

A thin layer of fibrin lining blood vessels provides a filtering barrier that helps to strengthen the wall and prevent other proteins from leaking out of the vessels, and it participates in repair processes when the blood vessel is broken.

Cellular energy metabolism is the basis for maintaining the barrier functions. Energy depletion causes the endothelial cells lining blood vessels to become excessively permeable.

When the organism's resistance is low, proteins and fats that normally remain inside the bloodstream can escape into the extracellular matrix and enter cells, contributing to their stress and disorganization, and other materials can escape from cells and enter the bloodstream.

One of the simplest demonstrations of fibrin leakage is to shine a beam of light into the eye; the presence of fibrin and other inappropriate molecules diffuses the light, causing a "flare" in the aqueous compartment. Albumin, a small protein from the blood, is often seen in the urine during stress. The effects of that sort of leakage vary with each organ.

Fibrin is an essential structural and functional part of the organism, but when it escapes from the bloodstream it participates in the degenerative processes of inflammation, fibrosis, and tumor formation. (Its fragments stimulate secretion of inflammatory mediators: Hamaguchi et al., 1991.)

In the hormonal environment dominated by estrogen, mild stresses such as exertion, or even restless sleep, allow toxins (and sometimes bacteria) from the intestine to enter the bloodstream, triggering a complex chain of events that create a systemic inflammatory state. Although these processes have been observed in many simple experiments, their implications are almost always neglected or denied or explained away. Incorporation of certain polyunsaturated fats into the tissues increases the leakiness of blood vessels, and amplifies the reactions to stresses and inflammatory stimuli.

Antioxidants, thyroid hormone, progesterone, and antiinflammatory agents, including glycine or gelatin, niacin, and saturated fats, can prevent, and in many cases reverse, these degenerative inflammatory processes.

Even a single celled organism has to keep its parts separate, and highly differentiated multicelled organisms have many special systems that serve to keep their parts separate, so the different tissues and organs can maintain their distinct functions.

The movement of substances from blood to cell, and from cell to cell, is normally very tightly controlled, and when the systems that control those movements of water and its solutes are damaged, the tissues' structures and functions are altered. The prevention of inappropriate leakiness can protect against the degenerative processes, and against aging itself, which is, among other things, a state of generalized leakiness.

When cells' energy is depleted, water and various dissolved molecules are allowed to move into the cells, out of the cells, and through or around cells inappropriately. The weakened cells can even permit whole bacteria and similar particles to pass into and out of the blood stream more easily.

One of the earliest investigators of the effects of stress and fatigue on nerves and other cells was A.P. Nasonov, in the first half of the 20th century. A.S. Troshin (1956) has reviewed his work in detail. He showed that in cells as different as algae and nerve cells, fatigue caused them to take up dyes, and that the dyes were extruded, if the cells were able to recover their energy. When nerve cells are excited for a fraction of a second, they take up sodium and calcium, but quickly eliminate them. Prolonged excitation, leading to fatigue, can gradually shift the balance, allowing more substances to enter, and to stay longer.

When nerves or other cells are quickly killed with heavy metals such as osmium, the metals are visible in a layer at the surface, which is sometimes taken as evidence of a "cytoplasmic membrane," but if the cells have suffered oxygen deprivation or have been injured by X-rays, the metal will be visible as a grey color evenly distributed through the cell. The deposition of the metal occurs when it reacts with electrons. In the relatively vital cell, the heavy metal stops at the surface, and is mostly reduced there, but the devitalized cell presents no structural or chemical barrier to the entry of the metal, and the reactive electrons appear to be evenly distributed through the cell. Oxygen deprivation, X-irradiation, and other stresses cause the cell to be unable to use electrons to produce energy, and instead the electrons are available to react destructively with whatever may be available. While Nasonov showed that dyes and even particles enter energetically depleted cells, newer techniques are able to show that the leaky cells are structurally disrupted by the excessive reduction of their proteins, by excited electrons and free radicals.

In the 1970s, experimenters found that muscles from vitamin E deficient animals released their enzymes when washed in a saline solution, more easily than did the muscles from vitamin E replete animals. Other experiments around the same time showed that reducing the ATP of muscles caused a similar loss of their ability to retain their proteins.

Over the years, many experiments have established, both in vitro and in vivo, that fatigue, stress, aging, and inflammation cause cells to lose their normal constituents, but also to allow foreign materials to enter more easily.

When I was working on my thesis, around 1970, investigating the effects of aging on the metabolism of the uterus, I found that the changes occuring during aging were (in all the ways I tested) the same as those produced by X-irradiation, excess estrogen, oxygen deprivation, excess polyunsaturated fats, and vitamin E deficiency.

Although everyone working in the lab was familiar with the appearance of the uterus from old hamsters (they are typically large, stiff, and bluish), everyone was surprised when I suggested that the aged uteri seemed to function as if they were under the influence of a considerable amount of estrogen. Everyone was familiar with the medical textbook doctrine that "menopause is caused by estrogen deficiency." In humans, gynecologists know about "Chadwick's sign," the fact that the uterine cervix turns blue or purple during pregnancy, and everyone knows that blood is blue when it's deprived of oxygen, so it's surprising that estrogen's effect on tissue oxygenation isn't widely recognized.

When estrogen is given to an animal, it almost instantly causes capillaries to become leaky, allowing water to move out of the blood stream, and at the same time, estrogen causes cells to take up water. Both of these processes are the same as the early effects of oxygen deprivation. In the normal reproductive cycle, the surge of estrogen lasts only a few hours, and normal permeability is quickly restored by increasing progesterone. During those intermittent short exposures to estrogen, there isn't a massive leakage of serum proteins into the tissues. During the time of estrogenic influence, all kinds of cells are influenced, with the excitatory equilibrium of nerve cells, glandular cells, and immune system cells being shifted, lowering the threshold of excitation, or prolonging the excited state.

Anything that causes inflammation causes a similar loss of water from the blood, as it is taken up by swelling cells. If inflammation is generalized, it causes circulatory shock, because the volume of the blood has become insufficient to serve the organism's needs. One of Hans Selye's earliest observations of the effect of an overdose of estrogen was that it causes shock.

Although water loss causes the blood to become more viscous under the influence of estrogen, the plasma becomes hypotonic, meaning that it contains fewer osmotically active solutes than normal; some of the sodium that helps to maintain the blood's osmotic balance is lost through the kidneys, and some is taken up by the red blood cells and other cells. The osmotic imbalance of the blood causes tissue cells to take up more water, contributing to their increased excitability. In many cases, the vascular leakage of inflammation and shock can be corrected by using osmotically active substances, such as starch solutions, gelatin, or concentrated sodium chloride.

The tissue water retention caused by estrogen, hypoxia, and stress is analogous to the swelling of gels and colloids, that is, it's governed by the state of the electrons and counterions in the system. Excitation, fatigue, or injury can cause a shift of pH toward alkalinity, causing water uptake and swelling.

The blue color of the pregnant cervix, or of the uterus in an animal given an overdose of estrogen, indicates that the tissue isn't sufficiently oxygenated to maintain its normal red color, even though the flow of blood is increased. Some experimenters have noticed that newborn animals sometimes have the postural reflex (lordosis) that indicates an estrogenic state, and that suffocation can produce the same reflex. Irradiating animals with x-rays will also produce the whole range of estrogenic effects.

One of the features of the aged uterus that I studied was the age pigment, lipofuscin, a brown waxy material that accumulates in old or stressed tissues. Prolonged dosage with estrogen accelerates the formation of this pigment, which is largely derived from oxidized polyunsaturated fatty acids. Increased amounts of those fats in the diet, or a deficiency of vitamin E, or exposure to ionizing radiation, or oxygen deprivation, can also accelerate the formation of the age pigment. The presence of the pigment intensifies the effect of estrogen, since the pigment wastes oxygen by functioning as an oxidase enzyme.

Other tests that I did on aged, or estrogenized, uterine tissue indicated that several oxidative systems were activated; for example, the tissues showed an extremely high activity of the enzyme peroxidase, and a very intense reduction of a chemical dye (tetrazolium/formazan) that indicates the presence of reductive and oxidative activity, of the sorts caused by radiation and oxygen deprivation. These reductive and oxidative processes include the production of some free radicals that are capable of reacting randomly with polyunsaturated fatty acids.

The interactions between estrogen and the polyunsaturated fats are now coming to be more widely recognized as important factors in the inflammatory/hyperpermeable conditions that contribute to the development of heart and blood vessel disease, hypertension, cancer, autoimmune diseases, dementia, and other less common degenerative conditions.

Estrogen increases lipid peroxidation, and maintains a chronically high circulating level of free fatty acids, mainly PUFA, activates the phospholipases that release arachidonic acid from cells leading to formation of prostaglandins and isoprostanes, and increases the enzymes that form the inflammation-promoting platelet activating factor (PAF) while suppressing the enzymes that destroy it, and increases a broad range of other inflammatory mediators, interleukins, and NF-kappa B.

The leakage of enzymes out of cells and into the blood stream is recognized medically as evidence of damage to the organ that is losing them. Different combinations of enzymes are commonly considered to be evidence of a heart attack, or skeletal muscle damage, or liver disease, pancreatitis, prostate cancer, etc. But often the reason for the leakage isn't understood. Hypothyroidism, for example, causes leakage of enzymes, possibly mainly from the liver, but also from other organs. Excess estrogen, intense exercise, starvation, anything that increases lipid peroxidation and free radical production, such as drinking alcohol when the tissues contain polyunsaturated fats, can cause organs such as heart and liver to leak their components.

The loss of enzymes increases the energy needed to stay alive, but it doesn't necessarily change the basic functions of the cell. (Though when mitochondrial enzymes leak out into the cytoplasm, the cell's energy metabolism is impaired, at least temporarily.) But the entry of catalytic materials from other tissues changes the organization of a cell, giving it conflicting instructions. In many situations, as L.V. Polezhaev and V. Filatov demonstrated, the substances released during stress and degeneration serve to stimulate healing and regeneration. But when the resources aren't available for full repair or regeneration, only a scar, or atrophic fibrosis, or a tumor will be formed.

In severe stress, intracellular fibrin deposits have been found in the heart and other organs, including the prostate gland. Deficiency of testosterone causes vascular leakage into the prostate. Fibrin promotes tumor growth, partly by serving as a matrix, partly by releasing stimulatory peptides.

Kidney disease, diabetes, pregnancy toxemia and retinal degeneration are probably the best known problems involving vascular leakage, but increasingly, cancer and heart disease are being recognized as consequences of prolonged permeability defects. Congestive heart failure and pulmonary hypertension commonly cause leakage of fluid into the lungs, and shock of any sort causes the lung to get "wet," a waterlogged condition called "shock lung." Simply hyperventilating for a couple of minutes will increase leakage from the blood into the lungs; hyperventilation decreases carbon dioxide, and increases serotonin and histamine. Hyperoxia itself contributes to lung injury, and exacerbates emphysema, though it is common to see patients breathing a high concentration of oxygen. Emphysema (which can be caused by hypothyroidism or hyper-estrogenism, and often can be cured by thyroid or progesterone) and many other respiratory problems are associated with capillary leakage. Cells of the lung and intestine are able to synthesize their own fibrin, apparently because of their special problems in preventing leakage. Prolonged systemic inflammation can lead to lung fibrosis, and fibrosis increases the likelihood of lung cancer.

The inflammatory state that causes exaggerated cellular permeability is very closely related to "hyperventilation," the loss of too much carbon dioxide. The release of serotonin during hyperventilation isn't the only cause of vascular leakage; the carbon dioxide itself is an essential factor in regulating the state of cellular electrons and in maintaining cellular integrity. Hyperventilation, like the shift from oxidative to glycolytic energy production that typifies estrogenized or stressed cells or cancer, raises intracellular pH. In the case of mast cells, increasing alkalinity causes them to release histamine (Alfonso, et al., 2005), but similar "alkaline-induced exocytosis" seems to occur in all stressed tissues.

The blood platelets that become incontinent and leak serotonin in the absence of carbon dioxide are undergoing the same structural stresses experience by endothelial cells, smooth muscle cells, mast cells and all other cells when carbon dioxide is depleted. Although it has been about 70 years since Yandell Henderson made it clear that supplemental oxygen should be combined with carbon dioxide, mechanical ventilation in hospitals is still causing lung injury resulting from hyperventilation, i.e., the absence of carbon dioxide. A similar misunderstanding of biology was involved in the use of dialysis to treat kidney disease. Until recently, commercial dialysis fluids contained acetate and/or racemic lactate instead of bicarbonate, because of the difficulty of preparing bicarbonate solutions, and the result was that very prolonged dialysis would damage the brain and other organs. (Veech and Gitomer, 1988, Veech and Fowler, 1987.) Dialysis has been seen to increase lung permeability Bell, et al., 1988).

Amyloidosis produced by chronic dialysis affects all organs, but its effects are best known in the brain, heart, kidneys, and lungs. Serum amyloid-A is one of the acute phase proteins, like C-reactive protein (CRP), that are produced by inflammation. Estrogen, radiation and other stresses increase those pro-inflammatory acute phase proteins, and decrease protective albumin, which is called a "negative acute phase protein," since it decreases when the other acute phase proteins increase. The liver is the major source of the acute phase proteins, and it is constantly burdened by toxins absorbed from the bowel; disinfection of the bowel is known to accelerate recovery from stress.

Seen from the perspective of the stress-leakage syndrome, any serious injury or sickness damages all organs. The exhaled breath is being used to diagnose inflammatory lung disease, since so many of the mediators of inflammation are volatile, but systemic diseases such as cancer and arthritis, and relatively minor stress can be detected by changes in the chemicals found in the breath. Polyunsaturated fats and their breakdown products--aldehydes, prostaglandins, isoprostanes, hydrocarbons, and free radicals--and carbon monoxide, nitric oxide, nitrite, and hydrogen peroxide are increased in the breath by most stresses. Both proline and glycine (which are major amino acids in gelatin) are very protective for the liver, increasing albumin, and stopping oxidative damage.

Saturated fats are protective against free radical damage and can reverse liver fibrosis. Thyroid hormone protects against excess estrogen, and can prevent or reverse fibrosis of the heart. Antiestrogens are widely effective against vascular leakage. Thyroid, progesterone, and testosterone are among the most effective natural antiestrogens, and they are curative in many conditions that involve vascular leakage. Progesterone and pregnenolone have been called the antifibromatic steroids, and it has been used to treat many inflammatory and fibrotic diseases, including cancer.

The antiserotonin drugs are being increasingly used to treat fibrotic diseases, and other problems related to vascular leakage.

Antiinflammatory and anticoagulant things, especially aspirin and vitamin E, protect against the accelerated turnover of fibrinogen/fibrin caused by estrogen and the various inflammatory states.

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<span class="koboSpan" id="kobo.1.1">Menopause and its causes</span> A R T I C L E

Menopause and its causes

When I was in graduate school at the University of Oregon, everyone in our lab was working on the problem of reproductive aging. Previously, people in the lab had established that the ovaries didn't "run out of eggs." There was never really any basis for that ridiculous belief. Many people just said it, the way they said "old eggs" (but never old sperms) were responsible for birth defects, or that "estrogen is the female hormone," a deficiency of which is the cause of menopausal infertility. (Old sperms have been implicated in some birth defects. People who are newly married, for example, were found to have children with fewer birth defects than people of the same age who had been married a long time, suggesting that more frequent intercourse involves fresher sperms.) When ovaries have been treated with x-rays to destroy their ability to ovulate, they have been found to produce more estrogen than before. Ovulation is one thing, and the production of hormones is another thing. You can't determine whether ovulation has occurred by measuring the hormones.

Knowing the large amount of work that has gone into our understanding of the age-related decline in fertility, it is disturbing to see people on television and in popular health books saying that menopause occurs when the "ovaries run out of eggs."

Around 1970, many people were saying that aging was caused by the loss of brain cells. There is a glimmer of truth in that silly idea, just as there would be in saying that "aging is caused by the death of skin cells," making the skin thinner and drier and less elastic. Both the brain and the skin are sources of steroid hormones, and it is possible that the death of skin cells and neurons is one factor in the age-related decline in the "sex steroids." An organism would be an easier thing to understand if cells just did their job for a certain period of time, and then died. A man named Hayflick has given people some publications to cite, when they want to simplify things by saying that aging occurs when cells have used up their quota of 50 divisions, but there are many more studies that clearly show that Hayflick's limit is nothing but a product of the cells' environment. The cell's environment, the signals and substances and energy it receives, is complex, but real progress is being made in understanding the things involved in the aging process. Luckily, the infinite complexity of the environment is channeled into an understandable array of processes by the cell's systematic ways of responding.

I knew, from talking with L. C. Strong,1 that early reproductive maturity was associated with early death; in his strains of cancer-prone mice, he showed that high estrogen was the cause of early puberty, a high cancer incidence, and a relatively short life. D. A. Snowdon, et al., showed that the occurrence of menopause at an early age in women is associated with a greater risk of death from all causes, including strokes and coronary heart disease.2 (They saw ovarian aging as an indicator of general aging.) P. W. F. Wilson, et al., reported that postmenopausal estrogen use was associated with an increased incidence of heart disease and stroke.3 P. M. Wise showed that estrogen accelerates aging of the central nervous system, destroying the nerves which regulate the pituitary gonadotropins, and causing ovarian failure and infertility.4 Many other studies of particular tissues show that estrogen accelerates the rate of aging.

In my work with hamsters, I found that the infertility that developed at middle age was caused by a high rate of oxygen consumption in the uterus, causing the oxygen needed by the developing embryo to be consumed by uterine tissues, and causing suffocation of the embryo. This is the central mechanism by which the estrogen-containing contraceptives work: at any stage of pregnancy, a sufficient dose of estrogen kills the embryo.

Polvani and Nencioni,5 among others, found that in women, the onset of menopause (the first missed period, suddenly increased bone loss, nervous symptoms such as depression, insomnia, and flushing) corresponds to the failure to produce progesterone, while estrogen is produced at normal levels. This results in a great functional excess of estrogen, because it is no longer opposed by progesterone. Typically, it takes about four years for the monthly estrogen excess to disappear. They suggested that the bone loss sets in immediately when progesterone fails because cortisol then is able to dominate, causing bone catabolism; progesterone normally protects against cortisol. Other researchers have pointed out that estrogen dominance promotes mitosis of the prolactin-secreting cells of the pituitary, and that prolactin causes osteoporosis; by age 50, most people have some degree of tumefaction of the prolactin-secreting part of the pituitary. But estrogen dominance (or progesterone deficiency) also clearly obstructs thyroid secretion, and thyroid governs the rate of bone metabolism and repair. Correcting the thyroid and progesterone should take care of the cortisol/prolactin/osteo- porosis problem.

P. M. Wise4 has demonstrated that the "menopausal" pituitary hormones, high levels of LH and FSH, are produced because the regulatory nerves in the hypothalamus have lost their sensitivity to estrogen, not because estrogen is deficient. In fact, he showed that the nerves are desensitized precisely by their cumulative exposure to estrogen. If an animal's ovaries are removed when it is young, the regulatory nerves do not atrophy, and if ovaries are transplanted into these animals at the normally infertile age, they are fertile. But if animals are given larger doses of estrogen during youth, those nerves atrophy prematurely, and they become prematurely infertile.

The mechanism by which estrogen desensitizes and kills brain cells is now recognized as the "excitotoxic" process, in which the excitatory transmitter glutamic acid is allowed to exhaust the nerve cells. (This explains the older observations that glutamic acid, or aspartic acid, or aspartame, can cause brain damage and reproductive failure.) Cortisol also activates the excitotoxic system, in other brain cells, causing stress-induced atrophy of those cells.6 Progesterone and pregnenolone are recognized as inhibitors of this excitotoxic process.

Besides estrogen's promotion of excitotoxic cell death, leading to the failure of the gonadotropin regulatory system, estrogen's stress-mimicking action probably tends to increase the secretion of LH, in ways that can be corrected by supplementing progesterone and thyroid. Since Selye's work, it has been known that estrogen creates the same conditions as occur in the shock phase of the stress reaction. (And shock, in a potential vicious circle, can increase the level of estrogen.7) It has recently been demonstrated that estrogen stimulates the adrenal glands, independently of the pituitary's ACTH. This can increase the production of adrenal androgens, leading to hirsutism, and other male traits, including anabolic effects.8

It was established in the 1950s that estrogen "erases" memories in well trained animals. I suppose that acute effect is related to the chronic toxicity that leads to cell death. (In the 1940s, DES was sold to prevent miscarriages, though it was already known that it caused them; then there was the argument that it slowed aging of the skin, despite the Revlon studies at the University of Pennsylvania showing that it accelerates all aspects of skin aging; lately there has been talk of promoting estrogen to improve memory.)

Estrogen's nerve-exciting action is known to lower seizure thresholds; premenstrual epilepsy is probably another acute sign of the neurotoxicity of estrogen.

When fatigue and lethargy are associated with aging, the brain stimulating action of estrogen can make a woman feel that she has more energy. (Large doses given to rats will make them run compulsively; running wheels with odometers have shown that they will run over 30 miles a day from the influence of estrogen.) Estrogen inhibits one of the enzymic routes for inactivating brain amines, and so it has more general effects on the brain than just the glutamate system. This generalized effect on brain amines is more like the effects of cocaine or amphetamine. If that is a woman's basis for wanting to use estrogen, a monoamine oxidase inhibitor would be safer.

The reason for the menopausal progesterone deficiency is a complex of stress-related causes. Free-radicals (for example, from iron in the corpus luteum) interfere with progesterone synthesis, as do prolactin, ACTH, estrogen, cortisol, carotene, and an imbalance of gonadotropins. A deficiency of thyroid, vitamin A, and LDL-cholesterol can also prevent the synthesis of progesterone. Several of the things which cause early puberty and high estrogen, also tend to work against progesterone synthesis. The effect of an intra-uterine irritant is to signal the ovary to suppress progesterone production, to prevent pregnancy while there is a problem in the uterus. The logic by which ACTH suppresses progesterone synthesis is similar, to prevent pregnancy during stress. Since progesterone and pregnenolone protect brain cells against the excitotoxins, anything that chronically lowers the body's progesterone level tends to accelerate the estrogen-induced excitotoxic death of brain cells.

Since progesterone and pregnenolone protect brain cells against the excitotoxins, anything that chronically lowers the body's progesterone level tends to accelerate the estrogen-induced excitotoxic death of brain cells.

Chronic constipation, and anxiety which decreases blood circulation in the intestine, can increase the liver's exposure to endotoxin. Endotoxin (like intense physical activity) causes the estrogen concentration of the blood to rise. Diets that speed intestinal peristalsis might be expected to postpone menopause. Penicillin treatment, probably by lowering endotoxin production, is known to decrease estrogen and cortisone, while increasing progesterone. The same effect can be achieved by eating raw carrots (especially with coconut oil/olive oil dressing) every day, to reduce the amount of bacterial toxins absorbed, and to help in the excretion of estrogen. Finally, long hours of daylight are known to increase progesterone production, and long hours of darkness are stressful. Annually, our total hours of day and night are the same regardless of latitude, but different ways of living, levels of artificial illumination, etc., have a strong influence on our hormones. In some animal experiments, prolonged exposure to light has delayed some aspects of aging.

General aging contributes to the specific changes that lead to menopause, but the animal experiments show that fertility can be prolonged to a much greater age by preventing excitotoxic exhaustion of the hypothalamic nerves. The question that still needs to be more clearly answered is, to what extent can general aging be prevented or delayed by protecting against the excitotoxins? Minimizing estrogen (and cortisone) with optimal thyroid activity, and maximizing pregnenolone and progesterone to prevent excitotoxic cell fatigue, can be done easily. A diet low in iron and unsaturated fats protects the respiratory apparatus from the damaging effects of excessive excitation, and--since pregnenolone is formed in the mitochondrion--also helps to prevent the loss of these hormones.

Copyright: Raymond Peat, PhD 1997

REFERENCES

1. L. C. Strong, Biological Aspects of Cancer and Aging, Pergamon Press, 1968.

2. D. A. Snowdon, et al., "Is early natural menopause a biologic marker of health and aging? Am. J. Public Health 79, 709-714, 1989.

3. P. W. F. Wilson, et al. [The Framingham Study], N. E. J. M. 313(17), 1038-1043, 1985

4. P. M. Wise, "Influence of estrogen on aging of the central nervous system: Its role in declining female reproductive function," in Menopause: Evaluation, Treatment, and Health Concerns, pages 53-70, 1989.

5. Nencioni, T., and F. Polvani, Calcitonin, p. 297-305, A. Pecile, editor, Elsevier, N.Y., 1985.

6. T. I. Belova, "Structural damage to the mesencephalic reticular formation induced by immobilization stress," Bull. Exp. Biol. & Med. 108(7), 126030, 1989.

7. F. Fourrier, et al., "Sex steroid hormones in circulatory shock, sepsis syndrome, and septic shock," Circ. Shock 43(4), 171-178, 1994.

8. E. C. Ditkoff, et al., "The impact of estrogen on adrenal androgen sensitivity and secretion in polycystic ovary syndrome," J. Clin. Endocrinol. Metab. 80(2), 603-607, 1995.

9. C. Bain, et al., "Use of postmenopausal hormones and risk of myocardial infarction," Circulation 64, 42-46, 1981.

10. T. L. Bush, et al., "Estrogen use and all-cause mortality: Preliminary results from the Lipid Research Clinics Program follow-up study," JAMA 249, 903-906, 1983.

11. M. S. Hunter and K. L. M. Liao, "Intentions to use hormone replacement therapy in a community sample of 45-year-old women," Maturitas 20(1), 13-23, 1994. (Women who expressed an intention to use hormone replacement therapy at menopause reported significantly lower self-esteem, more depressed mood, anxiety, and negative attitudes toward menopause. The also expressed stronger beliefs in their doctors' ability--as opposed to their own--to control their menopause experience.)

12. L. Dennerstein, et al., "Psychological well-being, mid-life and the menopause," Maturitas 20(1), 1-11, 1994.

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<span class="koboSpan" id="kobo.1.1">Oils in Context</span> A R T I C L E

Oils in Context

An oil researcher[0] spent 100 days eating what he considered to be the "Eskimo diet," seal blubber and mackerel paste. He observed that his blood lipid peroxides (measured as malondialdehyde, MDA) reached a level 50 times higher than normal, and although MDA is teratogenic, he said he wasn't worried about fathering deformed children, because his sperm count had gone to zero. Evidently, he didn't have a very thorough understanding of the Eskimo way of life. In most traditional cultures, the whole animal is used for food, including the brain and the endocrine glands. Since unsaturated fats inhibit thyroid function, and since Eskimos usually have a high caloric intake but are not typically obese, it seems that` their metabolic rate is being promoted by something in their diet, which might also be responsible for protecting them from the effects experienced by the oil researcher. (According to G. W. Crile, the basal metabolic rate of Eskimos was 125% of that of people in the United States.)

People who eat fish heads (or other animal heads) generally consume the thyroid gland, as well as the brain. The brain is the body's richest source of cholesterol, which, with adequate thyroid hormone and vitamin A, is converted into the steroid hormones pregnenolone, progesterone, and DHEA, in proportion to the quantity circulating in blood in low-density lipoproteins. The brain is also the richest source of these very water-insoluble (hydrophobic) steroid hormones; it has a concentration about 20 times higher than the serum, for example. The active thyroid hormone is also concentrated many-fold in the brain.

DHEA (dehydroepiandrosterone) is known to be low in people who are susceptible to heart disease [1] or cancer, and all three of these steroids have a broad spectrum of protective actions. Thyroid hormone, vitamin A, and cholesterol, which are used to produce the protective steroids, have been found to have a similarly broad range of protective effects, even when used singly. For example, according to MacCallum,

It has been shown that certain lipoid substances, especially cholesterine, can act as inhibiting or neutralizing agents toward such haemolytic poisons as saponin, cobra poison, etc., through forming with them an innocuous compound. Hanes showed that the relative immunity of puppies from chloroform poisoning is due to the large amount of cholesterin esters in their tissues. When artificially introduced into the tissues of adult animals a similar protection is conferred.[2]

A high level of serum cholesterol is practically diagnostic of hypothyroidism, and can be seen as an adaptive attempt to maintain adequate production of the protective steroids. Broda Barnes' work clearly showed that hypothyroid populations are susceptible to infections, heart disease, and cancer. [3]

In the 1940s, some of the toxic effects of fish oil (such as testicular degeneration, softening of the brain, muscle damage, and spontaneous cancer) were found to result from an induced vitamin E deficiency. Unfortunately, there isn't much reason to think that just supplementing vitamin E will provide general protection against the unsaturated fats. The half-life of fats in human adipose tissue is about 600 days, meaning that significant amounts of previously consumed oils will still be present up to four years after they have been removed from the diet. [4] According to Draper, et al., [5]

, , , enrichment of the tissues with highly unsaturated fatty acids results in an increase in lipid peroxidation in vivo even in the presence of normal concentrations of vitamin E. Fasting for more than 24 hours also results in an increase in MDA excretion, implying that lipolysis is associated with peroxidation of the fatty acids released.

According to Lemeshko, et al., it seems that this effect increases with the age of the animal. [6]

Commercial advertising (including medical conferences sponsored by pharmaceutical companies) and commercially sponsored research are creating some false impressions about the role of unsaturated oils in the diet. Like the man who poisoned himself with the "Eskimo diet," many people focus so intently on avoiding one problem that they create other problems. Since I have discussed the association of unsaturated fats with aging, lipofuscin, and estrogen elsewhere, I will outline some of the other problems associated with the oils, especially as they relate to hormones.

Mechanisms and Essentiality: When something is unavoidable, in ordinary life, talking about "essentiality," or the minimum amount required for life or for optimal health, is more important as an exploration into the nature of our life than as a practical health issue. For example, how much oxygen, how many germs (of what kinds), how many cosmic rays (of what kinds), would produce the nicest human beings? The fact that we have adapted to something---oxygen at sea level, microbes, or vegetable fats, for example--doesn't mean that we are normally exposed to it in ideal amounts.

Animals contain desaturase enzymes, and are able to produce specific unsaturated fats (from oleic and palmitoleic acids) when deprived of the ordinary "essential fatty acids," [7] so it can be assumed that these enzymes have a vital purpose. The high concentration of unsaturated fats in mitochondria--the respiratory organelles where it seems that these lipids present a special danger of destructive oxidation--suggests that they are required for mitochondrial structure, or function, or regulation, or reproduction. Unsaturated fats have special properties of adsorption, [8] and are more soluble in water than are saturated fats. The movement and modulation of proteins and nucleic acids might require these special properties. As the main site of ATP production, I suspect that their water-retaining property might be crucial. When a protein solution (even egg-white) is poured into a high concentration of ATP, it contracts or "superprecipitates." This condensing, water-expelling property of ATP in protein solutions is similar to the effect of certain concentrations of salts on any polymer. It would seem appropriate to have a substance to oppose this condensing effect, to stimulate swelling [9, 10] and the uptake of precursor substances. Something that has an intrinsic structure-loosening or water-retaining effect would be needed. The ideas of "chaotropic agents" and "structural antioxidants" have been proposed by Vladimirov [11] to bring generality into our understanding of the mitochondria. Lipid peroxides are among the chaotropic agents, and thyroxin is among the structural antioxidants. The known oxygen-sparing effects of progesterone [12, 13] would make it appropriate to include it among the structural antioxidants. The incorporation of the wrong unsaturated fats into mitochondria would be expected to damage the vital respiratory functions.

Some insects that have been studied have been found not to require the essential fatty acids. [14]* According to reviewers, hogs and humans have not been shown to require the "essential" fatty acids. [15] In vitro studies indicate that they are not required for human diploid cells to continue dividing in culture. [16] According to Guarnieri, [17] EFA-deficient animals don't die from their deficiency. The early studies showing "essentiality" of unsaturated fats, by producing skin problems and an increased metabolic rate, have been criticized [18] in the light of better nutritional information, e.g., pointing out that the diets might have been deficient in vitamin B6 and/or biotin. The similar skin condition produced by vitamin B6 deficiency was found to be improved by adding unsaturated fats to the diet. A fat-free liver extract cured the "EFA deficiency." I think it would be reasonable to investigate the question of the increased metabolic rate produced by a diet lacking unsaturated fats (which inhibit both thyroid function and protein metabolism) in relation to the biological changes that have been observed. Since diets rich in protein are known to increase the requirement for vitamin B6 [19] (which is a co-factor of transaminases, for example), the increased rate of energy production and improved digestibility of dietary protein on a diet lacking unsaturated fats would certainly make it reasonable to provide the experimental animals with increased amount of other nutrients. With increasing knowledge, the old experiments indicating the "essentiality" of certain oils have lost their ability to convince, and they haven't been replaced by new and meaningful demonstrations. In the present state of knowledge, I don't think it would be unreasonable to suggest that the optional dietary level of the "essential fatty acids" might be close to zero, if other dietary factors were also optimized. The practical question, though, has to do with the dietary choices that can be made at the present time.

*If we followed Linus Pauling's reasoning in determining optimal vitamin C intake, this study of the linoleic acid content of the tissues of an animal which can synthesize it would suggest that we are eating about 100 times more "EFA" than we should.

In evaluating dietary fat, it is too often forgotten that the animals' diet (and other factors, including temperature) affect the degree of saturation of fats in its tissues, or its milk, or eggs. The fat of wild rabbits or summer-grazing horses, for example, can contain 40% linolenic acid, about the same as linseed oil. Hogs fed soybeans can have fat containing over 30% linoleic acid. [20] Considering that most of our food animals are fed large amounts of grains and soybeans, it isn't accurate to speak of their fats as "animal fats." And, considering the vegetable oil contained in our milk, eggs, and meat, it would seem logical to select other foods that are not rich in unsaturated oils.

Temperature and Fat: The fact that saturated fats are dominant in tropical plants and in warm-blooded animals relates to the stability of these oils at high temperatures. Coconut oil which had been stored at room temperature for a year was found to have no measurable rancidity. Since growing coconuts often experience temperatures around 100 degrees Fahrenheit, ordinary room temperature isn't an oxidative challenge. Fish oil or safflower oil, though, can't be stored long at room temperature, and at 98 degrees F, the spontaneous oxidation is very fast.

Bacteria vary the kind of fat they synthesize, according to temperature, forming more saturated fats at higher temperatures.[21] The same thing has been observed in seed oil plants. [22] Although sheep have highly saturated fat, the superficial fat near their skin is relatively unsaturated; it would obviously be inconvenient for the sheep if their surface fat hardened in cool weather, when their skin temperature drops considerably. Pigs wearing sweaters were found to have more saturated fat than other pigs.[23] Fish, which often live in water which is only a few degrees above freezing, couldn't function with hardened fat. At temperatures which are normal for fish, and for seeds which germinate in the cold northern springtime, rancidity of fats isn't a problem, but rigidity would be.

Unsaturated Fats Are Essentially Involved In Heart Damage: The toxicity of unsaturated oils for the heart is well established, [24, 25, 26] though not well known by the public.

In 1962, it was found that unsaturated fatty acids are directly toxic to mitochondria. [27] Since stress increases the amount of free fatty acids circulating in the blood (as well as lipid peroxides), and since lack of oxygen increases the intracellular concentration of free fatty acids, stored unsaturated fats would seem to represent a special danger to the stressed organism. Meerson and his colleagues [18] have demonstrated that stress liberates even local tissue fats in the heart during stress, and that systematic drug treatment, including antioxidants, can stop the enlargement of stress-induced infarctions. Recently, it was found that the cardiac necrosis caused by unsaturated fats (linolenic acid, in particular) could be prevented by a cocoa butter supplement. [29] The author suggests that this is evidence for the "essentiality" of saturated fats, but points out that animals normally can produce enough saturated fat from dietary carbohydrate or protein, to prevent cardiac necrosis, unless the diet provides too much unsaturated fat. A certain proportion of saturated fat appears to be necessary for stability of the mitochondria. Several other recent studies show that the "essential" fatty acids decrease the P/O ratio, or the phosphorylation efficiency, [30] the amount of usable energy produced by cellular respiration.

There has been some publicity about a certain unsaturated fat, eicosapentaenoic acid, or EPA, which can have some apparently protective and anti-inflammatory effects. A study in which butter was added to the animals' diet found that serum EPA was elevated by the butter. The investigator pointed out that other studies had been able to show increased serum EPA from an EPA supplement only when the animals had previously been fed butter. [31]

Intense lobbying by the soybean oil industry has created the widespread belief that "tropical oils" cause heart disease. In a comparison of many kinds of oil, including linseed oil, olive oil, whale oil, etc., palm oil appeared to be the most protective. The same researcher [32] more recently studied palm oil's antithrombotic effect, in relation to platelet aggregation. It was found that platelet aggregation was enhanced by sunflowerseed oil, but that palm oil tended to decrease it.

Much current research has concentrated on the factors involved in arterial clotting. Since the blood moves quickly through the arteries, rapid processes are of most interest to those workers, though some people do remember to think in terms of an equilibrium between formation and removal of clot material. For about 25 years there was interest in the ability of vitamin E to facilitate clot removal, apparently by activating proteolytic enzymes.[33] Unsaturated fats' ability to inhibit proteolytic enzymes in the blood has occasionally been discussed, but seldom in the U.S. The equilibrium between clotting and clot dissolution is especially important in the veins, where blood moves more slowly, and spends more time.

. . . the slower blood flows the greater its predisposition to clotting. However, this intrinsic process, leading to fibrin production, is slow, taking up to a minute or more to occur. Thrombosis as a result of stasis, therefore, occurs in the venous circulation; typically in the legs wherevenous return is slowest. In fact, many thousands of small thrombi are formed each day in the lower body. These pass via the vena cava into the lungs where thrombolysis occurs, this being a normal metabolic function of the organ. [34]

In the Shutes' research in the 1930s and 1040s, vitamin E and estrogen acted in opposite directions on the clot-removing enzymes.[33] Since estrogen increases blood lipids, and increases the incidence of strokes and heart attacks, it would be interesting to expand the Shutes' work by considering the degree of saturation of blood lipids in relation to the effects of vitamin E and estrogen on clot removal. Estrogen's effect on clotting is very complex, since it increases the ratio of unsaturated to saturated fatty acids in the body, and increases the tendency of blood to pool in the large veins, in addition to its direct effects on the clotting factors.

Immunodeficiency and Unsaturated Fats: Intravenous feeding with unsaturated fats is powerfully immunosuppressive [35] (though it often was used to give more calories to cancer patients) and is now advocated as a way to prevent graft rejection. The deadly effect of the long-chain unsaturated fats on the immune system has led to the development of new products containing short and medium-chain saturated fats for intravenous feeding. [36] It was recently reported that the anti-inflammatory effect of n-3 fatty acids (fish oil) might be related to the observed suppression of interleukin-1 and tumor necrosis factor by those fats. [37] The suppression of these anti-tumor immune factors persists after the fish oil treatment is stopped.

As mentioned above, stress and hypoxia can cause cells to take up large amounts of fatty acids. Cortisol's ability to kill white blood cells (which can be inhibited by extra glucose) is undoubtedly an important part of its immunosuppressive effect, and this killing is mediated by causing the cells to take up unsaturated fats. [38]

Several aspects of the immune system are improved by short-chain saturated fats. Their anti-histamine action [39] is probably important, because of histamine's immunosuppressive effects.[40] Unsaturated fats have been found to cause degranulation of mast cells.[41] The short-chain fatty acids normally produced by bacteria in the bowel apparently have a local anti-inflammatory action.[42]

A recent discussion of "tissue destruction by neutrophils" mentions "a fascinating series of experiments performed between 1888 and 1906," in which "German and American scientists established the importance of neutrophil proteinases and plasma antiproteinases in the evolution of tissue damage in vivo." [43] MacCallum's Pathology described some related work:

. . . Jobling has shown that the decomposition products of some fats--unsaturated fatty acids and their soaps--have the most decisive inhibiting action upon proteolytic ferments, their power being in a sense proportional to the degree of unsaturation of the fatty acid. So universally is it true that such unsaturated fatty acids can impede the action of proteolytic ferments that many pathological conditions (such as the persistence of caseous tuberculous material in its solid form) can be shown to be due to their presence. If they are rendered impotent by saturation of their unsaturated group with iodine, the proteolysis goes on rapidly and the caseous tubercle or gumma rapidly softens.[44]

Another comment by MacCallum suggests one way in which unsaturated fats could block the action of cytotoxic cells:

This function of the wandering cells is, of course, of immediate importance in connection with their task of cleaning up the injured area to prepare it for repair. While the proteases thus produced are active in the solution of undesirable material, their unbridled action might be detrimental. As a matter of fact, it is shown by Jobling and Petersen that the anti-ferment known to be present in the serum and to restrict the action of the ferment is a recognizable chemical substance, usually a soap or other combination of an unsaturated fatty acid. It is possible to remove or decompose this substance or to saturate the fatty acid with iodine and thus release the ferment to its full activity. [45]

Unsaturated Fats Are Essential For Cancer: The inhibition of proteolytic enzymes by unsaturated fats will act at many sites: digestion of protein, "digestion" of clots, "digestion" of the colloid in the thyroid gland which releases the hormones, the activity of white cells mentioned above, and the normal "digestion" of cytoplasmic proteins involved in maintaining a steady state as new proteins are formed and added to the cytoplasm. It has been suggested that inhibition of the destruction of intracellular proteins would shift the balance toward growth.[46] Cancer cells are known to have a high level of unsaturated fats,[47] yet they have a low level of lipid peroxidation;[48] lipid peroxidation inhibits growth, and is often mentioned as a normal growth restraining factor.[49]

In 1927, it was observed that a diet lacking fats prevented the development of spontaneous tumors.[50] Many subsequent investigators have observed that the unsaturated fats are essential for the development of tumors. [51, 52, 53] Tumors secrete a factor which mobilizes fats from storage, [54] presumably guaranteeing their supply in abundance until the adipose tissues are depleted. Saturated fats--coconut oil and butter, for example--do not promote tumor growth.[55] Olive oil is not a strong tumor promoter, but in some experiments it does have a slightly permissive effect on tumor growth. [56, 57] In some experiments, the carcinogenic action of unsaturated fats could be offset by added thyroid, [57] an observation which might suggest that at least part of the effect of the oil is to inhibit thyroid. Adding cystine to the diet (cysteine, the reduced form of cystine, is a thyroid antagonist) also increases the tumor incidence.[58] In a hyperthyroid state, the ability to quickly oxidize larger amounts of the toxic oils would very likely have a protective effect, preventing storage and subsequent peroxidation, and reducing the oils' ability to synergize with estrogen.

Consumption of unsaturated fat has been associated with both skin aging and with the sensitivity of the skin to ultraviolet damage, Ultraviolet light-induced skin cancer seems to be mediated by unsaturated fats and lipid peroxidation.[59]

In a detailed study of the carcinogenicity of different quantities of unsaturated fat, Ip, et al., tested levels ranging from 0.5% to 10%, and found that the cancer incidence varied with the amount of "essential oils" in the diet. Some of their graphs make the point very clearly: [52}

This suggests that the optimal EFA intake might be 0.5% or less.

Butter and coconut oil contain significant amounts of the short and medium-chain saturated fatty acids, which are very easily metabolized,[60] inhibit the release of histamine,[39] promote differentiation of cancer cells,[61] tend to counteract the stress-induced proteins,[62] decrease the expression of prolactin receptors, and promote the expression of the T3 (thyroid) receptor. [63] (A defect of the thyroid receptor molecule has been identified as an "oncogene," responsible for some cancers, as has a defect in the progesterone receptor.)

Besides inhibiting the thyroid gland, the unsaturated fats impair intercellular communication,[64] suppress several immune functions that relate to cancer, and are present at high concentrations in cancer cells, where their antiproteolytic action would be expected to interfere with the proteolytic enzymes and to shift the equilibrium toward growth. In the free fatty acid form, the unsaturated fats are toxic to the mitochondria, but cancer cells are famous for their compensatory glycolysis.

By using lethargic connective tissue cells known to have a very low propensity to take up unsaturated fats [65] as controls in comparison with, e.g., breast cancer cells, with a high affinity for fats, it is possible to show a "selective" toxicity of oils for cancer cells. However, an in vivo test of an alph-linolenic acid ester showed it to have a stimulating effect on breast cancer.[66] Given a choice, skin fibroblasts demonstrate a very specific preference for oleic acid, over a polyunsaturated fat.[67]

Even if unsaturated fats were (contrary to the best evidence) selectively toxic for cancer cells, their use in cancer chemotherapy would have to deal with the issues of their tendency to cause pulmonary embolism,their suppression of immunity including factors specifically involved in cancer resistance, and their carcinogenicity.

Brain Damage And Lipid Peroxidation: When pregnant mice were fed either coconut oil or unsaturated seed oil, the mice that got coconut oil had babies with normal brains and intelligence, but the mice exposed to the unsaturated oil had smaller brains, and had inferior intelligence. In another experiment, radioactively labeled soy oil was given to nursing rats, and it was shown to be massively incorporated into brain cells, and to cause visible structural changes in the cells. In 1980, shortly after this study was published in Europe, the U.S. Department of Agriculture issued a recommendation against the use of soy oil in infant formulas. More recently, [68] pregnant rats and their offspring were given soy lecithin with their food, and the exposed offspring developed sensorimotor defects.

Many other studies have demonstrated that excessive unsaturated dietary fats interfere with learning and behavior, [70, 71] and the fact that some of the effects can be reduced with antioxidants suggests that lipid peroxidation causes some of the damage. Other studies are investigating the involvement of lipid peroxidation in seizures.[72]

The past use of soy oil in artificial milk (and in maternal diets) has probably caused some brain damage. The high incidence of neurological defects (e.g., 90%) that has been found among violent criminals suggests that it might be worthwhile to look for unusual patterns of brain lipids in violent people.

There have been a series of claims that babies' brains or eyes develop better when their diets are supplemented with certain unsaturated oils, based on the idea that diets may be deficient in certain types of oil, Some experimenters claim that the supplements have improved the mental development of babies, but other researchers find that the supplemented babies have poorer mental development. But the oils that are added to the babies' diets are derived from fish or algae, and contain a great variety of substances (such as vitamins) other than the unsaturated fatty acids, and the researchers consistently fail to control for the effects of such substances.

It has shown that it is probably impossible to experience a detectable deficiency of linoleic acid outside of the laboratory setting,[69] but the real issue is probably whether the amount in the normal diet is harmful to development. Until the research with animals has produced a better understanding of the effects of unsaturated oils, experimenting on human babies seems hard to justify.

Marion Diamond, who has studied the improved brain growth in rats given a stimulating environment (which, like prenatal progesterone, produced improved intelligence and larger brains), observed that in old age the "enriched" rats' brains contained less lipofuscin (age pigment).[73] It is generally agreed that the unsaturated oils promote the formation of age pigment. The discovery that stress or additional cortisone (which, by blocking the use of glucose, forces cells to take up more fat) causes accelerated aging of the brain[74] should provide new motivation to investigate the antistress properties of substances such as the protective steroids mentioned above, and the short-chain saturated fats.

Essential for Liver Damage: Both experimental and epidemiological studies have shown that dietary linoleic acid is required for the development of alcoholic liver damage.[75] Animals fed tallow and ethanol had no liver injury, but even 0.7% or 2.5% linoleic acid with ethanol caused fatty liver, necrosis, and inflammation. Dietary cholesterol at a level of 2% was found to cause no harm,[76] but omitting it entirely from the diet caused leakage of amino-transferase enzymes. This effect of the absence of cholesterol was very similar to the effects of the presence of linoleic acid with ethanol.

Obesity: For many years studies have been demonstrating that dietary coconut oil causes decreased fat synthesis and storage, when compared with diets containing unsaturated fats. More recently, this effect has been discussed as a possible treatment for obesity.[77] The short-chain fats in coconut oil probably improve tissue response to the thyroid hormone (T3), and its low content of unsaturated fats might allow a more nearly optimal function of the thyroid gland and of mitochondria. A survey of other tropical fruits' content of short and medium chain fatty acids might be useful, to find lower calorie foods which contain significant amounts of the shorter-chain fats.

Other Problem Areas: The presence of palmitate in the lung surfactant phospholipids[78] suggests that maternal overload with unsaturated fats might interfere with the formation of these important substances, causing breathing problems in the newborn. The bone-calcium mobilizing effect of prostaglandins suggests that dietary fats might affect osteoporosis; the absence of osteoporosis in some tropical populations might relate to their consumption of coconut oil and other saturated tropical oils. The steroids which occur in association with some seed oils might be nutritionally significant, in the way animal hormones in foods undoubtedly are. For example, soy steroids can be converted by bowel bacteria into estrogens. R. Marker, et al., found diosgenin (the material in the Mexican yam from which progesterone, etc., are derived) in a palm kernel, Balanites aegyptica (Wall).[79] Another palm fruit also contains sterols with anti-androgenic and anti-edematous actions.[80, 81]

If the amount of ingested unsaturated fats (inhibitors of protein digestion) were lower, protein requirements might be lower.

The similar effects of estrogen and of polyunsaturated fats (PUFA) are numerous. They include antagonism to vitamin E and thyroid, to respiration and proteolysis; promotion of lipofuscin formation and of clot formation, promotion of seizure activity, impairment of brain development and learning; and involvement in positive or negative regulation of cell division, depending on cell type.

These parallels suggest that the role of PUFA in reproduction might be similar to that of estrogen, namely, the promotion of uterine and breast cell proliferation, water uptake, etc. Such parallels should be a caution in generalizing from the conditions which are essential for reproduction to the conditions which are compatible with full development and full functional capacity. If a certain small amount of dietary PUFA is essential for reproduction, but for no other life function, then it is analogous to the brief "estrogen surge," which must quickly be balanced by opposing hormones. The present approach to contraception through estrogen-induced miscarriage might give way to fertility regulation by diet. A self-actualizing pro-longevity diet, low in PUFA, might prolong our characteristically human condition of delayed reproductive maturity, and, if PUFA are really essential for reproduction, unsaturated vegetable oils could temporarily be added to the diet when reproduction is desired.

Conclusions: Polyunsaturated fats are nearly ubiquitous, but if they are "essential nutrients," in the way vitamin A, or lysine, is essential, that has not been demonstrated. It seems clear that they are essential for cancer, and that they have other properties which cause them to be toxic at certain levels. It might be time to direct research toward determining whether there is a threshold of toxicity, or whether they are, like ionizing radiation, toxic at any level.

Note:

A possible mitochondrial site for toxicity: In 1971 I was trying to combine some of the ideas of Albert Szent-Gyorgyi, Otto Warburg, W. F. Koch, and L. C. Strong. I was interested in the role of ubiquinone in mitochondrial respiration. In one experiment, I was using paper chromatography to compare oils that I had extracted from liver with vitamin E and with commercially purified ubiquinone. Besides using the pure substances, I decided to combine vitamin E with ubiquinone for another test spot. As soon as I combined the two oils, their amber and orange colors turned to an inky, greenish black color. I tested both bacterial and mammalian ubiquinone, and benzoquinone, and they all produced similar colors with vitamin E. When I ran the solvent up the paper, the vitamin E and the ubiquinone traveled at slightly different speeds. The black spot, containing the mixture, also moved, but each substance moved at its own speed, and as the materials separated, their original lighter colors reappeared. Charge-transfer bonds, which characteristically produce dark colors, are very weak bonds. I think this must have been that kind of bond. Years later, I tried to repeat the experiment, using "ubiquinone" from various capsules that were sold for medical use. Instead of the waxy yellow-orange material I had used before, these capsules contained a liquid oil with a somewhat yellow color. Very likely, the ubiquinone was dissolved in vegetable oil. At the time, I was puzzled that the color reaction didn't occur, but later I realized that a solvent containing double bonds (e.g., soy oil or other oil containing PUFA) would very likely prevent the close association between vitamin E and ubiquinone which is necessary for charge-transfer to occur. Since I think Koch and Szent-Gyorgyi were right in believing that electronic activation is the most important feature of the living state, I think the very specific electronic interaction between vitamin E and ubiquinone must play an important role in the respiratory function of ubiquinone. Ubiquinone is known to be a part of the electron transport chain which can leak electrons, so this might be one of the ways in which vitamin E can prevent the formation of toxic free-radicals. If it can prevent the "leakage" of electrons, then this in itself would improve respiratory efficiency. If unsaturated oils interfere with this very specific but delicate bond, then this could explain, at least partly, their toxicity for mitochondria. ["Electron leak" reference: B. Halliwell, in Age Pigments (R. S. Sohal, ed.), pp. 1-62, Elsevier, Amsterdam, 1981.]

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<span class="koboSpan" id="kobo.1.1">Osteoporosis, harmful calcification, and nerve/muscle malfunctions</span> A R T I C L E

Osteoporosis, harmful calcification, and nerve/muscle malfunctions

During pregnancy, a woman's ability to retain dietary calcium and iron increases, and the baby seems to be susceptible to overloading. A normal baby doesn't need dietary iron for several months, as it uses the iron stored in its tissue, and recently it has been reported that normal fetuses and babies may have calcified pituitary glands. Pituitary cell death is sometimes seen with the concretions. (Groisman, et al.) Presumably, the calcification is resorbed as the baby grows. This is reminiscent of the "age pigment" that can be found in newborns, representing fetal stress from hypoxia, since that too disappears shortly after birth. Iron overload, age pigment, and calcification of soft tissues are so commonly associated with old age, that it is important to recognize that the same cluster occurs at the other extreme of (young) age, and that respiratory limitations characterize both of these periods of life.

Calcium is probably the most popular element in physiological research, since it functions as a regulatory trigger in many cell processes, including cell stimulation and cell death. Its tendency to be deposited with iron in damaged tissue has often been mentioned. In hot weather, chickens pant to cool themselves, and this can lead to the production of thin egg shells. Carbonated water provides enough carbon dioxide to replace that lost in panting, and allows normal calcification of the shells. [Science 82, May, 1982] The deposition of calcium is the last phase of the "tertiary coat" of the egg, to which the oviduct glands successively add albumin, "egg membrane," and the shell, containing matrix proteins (including some albumin; Hincke, 1995) and calcium crystals. Albumin is the best understood of these layers, but it is still complex and mysterious; its unusual affinity for metal ions has invited comparisons with proteins of the immune system. It is known to be able to bind iron strongly, and this is considered to have an "immunological" function, preventing the invasion of organisms that depend on iron. Maria de Sousa ("Iron and the lymphomyeloid system: A growing knowledge," Iron in Immunity, Cancer and Inflammation, ed. by M. de Sousa and J. H. Brock, Wiley & Sons, 1989) has argued that the oxygen delivery system and the immune system evolved together, recycling iron in a tightly controlled system.

The role of macrophages in the massive turnover of hemoglobin, and as osteoclasts, gives us a perspective in which iron and calcium are handled in analogous ways. Mechnikov's view of the immune system, growing from his observations of the "phagocytes," similarly gave it a central role in the organism as a form-giving/ nutrition-related process. In a family with "marble-bone disease," or osteopetrosis, it was found that their red blood cells lacked one form of the carbonic anhydrase enzyme, and that as a result, their body fluids retained abnormally high concentrations of carbon dioxide. Until these people were studied, it had been assumed that an excess of carbon dioxide would have the opposite effect, dissolving bones and causing osteoporosis or osteopenia, instead of osteopetrosis. The thyroid hormone is responsible for the carbon dioxide produced in respiration. Chronic hypothyroidism causes osteopenia, and in this connection, it is significant that women (as a result of estrogen's effects on the thyroid) are much more likely than men to be hypothyroid, and that, relative to men, women in general are "osteopenic," that is, they have more delicate skeletons than men do.

In an experiment, rats were given a standard diet, to which had been added 1% Armour thyroid, that is, they were made extremely hyperthyroid. Since their diet was inadequate (later experiments showed that this amount of thyroid didn't cause growth retardation when liver was added to the diet) for their high metabolic rate, they died prematurely, in an apparently undernourished state, weighing much less than normal rats. Their bones, however, were larger and heavier than the bones of normal rats. A few incompetent medical "studies" have made people fear that "taking thyroid can cause osteoporosis." Recognizing that hypothyroid women are likely to have small bones and excessive cortisol production, the inadequate treatment of hypothyroidism with thyroxin (the thyroid-suppressive precursor material), is likely to be associated with relative osteoporosis, simply because it doesn't correct hypothyroidism. Similar misinterpretations have led people to see an association between "thyroid use" (generally thyroxin) and breast cancer--hypothyroid women are likely to have cancer, osteoporosis, obesity, etc., and are also likely to have been inadequately treated for hypothyroidism. T3, the active form of thyroid hormone, does contribute to bone formation. (For example, M. Alini, et al.)

Around the same time (early 1940s) that the effects of thyroid on bone development were being demonstrated, progesterone was found to prevent age-related changes in bones, and "excessive" seeming doses of thyroid were found to prevent age-related joint diseases in rats.

A logical course of events, building on these and subsequent discoveries, would have been to observe that the glucocorticoids cause a negative calcium balance, leading to osteoporosis, and that thyroid and progesterone oppose those hormones, protecting against osteoporosis. But the drug industry had discovered the profits in estrogen ("the female hormone") and the cortisone-class of drugs. Estrogen was promoted to prevent miscarriages, to stop girls (and boys) from growing too tall, to cure prostate and breast cancer, to remedy baldness, and 200 other absurdities. As all of those frauds gradually became untenable, even in the commercial medical culture, the estrogen industry began to concentrate on osteoporosis and femininity. Heart disease and Alzheimer's disease back those up.

"If estrogen causes arthritis, prescribe prednisone for the inflammation. If prednisone causes osteoporosis, increase the dose of estrogen to retard the bone-loss. People are tough, and physiological therapies aren't very profitable."

Fifteen years ago I noted in a newsletter that hip fractures most often occur in frail, underweight old women, and that heavier, more robust women seem to be able to bear more weight with less risk of fracture. Although I hadn't read it at the time, a 1980 article (Weiss, et al.) compared patients with a broken hip or arm with a control group made up of hospitalized orthopedic patients with problems other than hip or arm fractures. The fracture cases' weight averaged 19 pounds lighter than that of the other patients. They were more than 3.6 times as likely to be alcoholic or epileptic. It would be fair to describe them as a less robust group.

Since the use of estrogen has become so common in the U.S., it is reasonable to ask whether the incidence of hip fractures in women over 70 has declined in recent decades. If estrogen protects against hip fractures, then we should see a large decrease in their incidence in the relevant population.

Hip fractures, like cancer, strokes, and heart disease, are strongly associated with old age. Because of the baby-boom, 1945 to 1960, our population has a bulge, a disproportion in people between the ages of 35 and 50, and those older. Increasingly, we will be exposed to publicity about the declining incidence of disease, fraudulently derived from the actually declining proportion of old people. For example, analyzing claims based on the pretense that the population bulge doesn't exist, I have seen great publicity given to studies that would imply that our life-expectancy is now 100 years, or more.

Comparing the number of hip fractures, per 1000 75 year old women, in 1996, with the rate in 1950, we would have a basis for judging whether estrogen is having the effect claimed for it.

The x-ray data seem to convince many people estrogen is improving bone health, by comparing measurements in the same person before and after treatment. Does estrogen cause water retention? Yes. Does tissue water content increase measured bone density? Yes. Are patients informed that their "bone scans" don't have a scientific basis? No. The calcification of soft tissues under the influence of estrogen must also be taken into account in interpreting x-ray evidence. (Hoshino, 1996) Granted that woman who are overweight have fewer hip fractures (and more cancer and diabetes), what factors are involved? Insulin is the main factor promoting fat storage, and it is anabolic for bone. (Rude and Singer, "Hormonal modifiers of mineral metabolism.") The greatest decrease in bone mass resulting from insulin deficiency was seen in white females, and after five years of insulin treatment, there was a lower incidence of decreased bone mass (Rosenbloom, et al., 1977). McNair, et al. (1978 and 1979) found that the loss of bone mass coincided with the onset of clinical diabetes. Since excess cortisol can cause both high blood sugar and bone loss, when diabetes is defined on the basis of high blood sugar, it will often involve high blood sugar caused by excess cortisol, and there will be calcium loss. Elsewhere, I have pointed out some of the similarities between menopause and Cushing's syndrome; a deficiency of thyroid and progesterone can account for many of these changes. Nencioni and Polvani have observed the onset of progesterone deficiency coinciding with bone loss, and have emphasized the importance of progesterone's antagonism to cortisol.

Johnston (1979) found that progesterone (but not estrone, estradiol, testosterone, or androstenedione) was significantly lower in those losing bone mass most rapidly.

Around the age of 50, when bone loss is increasing, progesterone and thyroid are likely to be deficient, and cortisol and prolactin are likely to be increased. Prolactin contributes directly to bone loss, and is likely to be one of the factors that contributes to decreased progesterone production.

Estrogen tends to cause increased secretion of prolactin and the glucocorticoids, which cause bone loss, but it also promotes insulin secretion, which tends to prevent bone loss. All of these factors are associated with increased cancer risk.

Thyroid and progesterone, unlike estrogen, stimulate bone-building, and are associated with a decreased risk of cancer. It seems sensible to use thyroid and progesterone for their general anti-degenerative effects, protecting the bones, joints, brain, immune system, heart, blood vessels, breasts, etc.

But the issue of calcification/decalcification is so general, we mustn't lose interest just because the practical problem of osteoporosis is approaching solution.

For example, healthy high energy metabolism requires the exclusion of most calcium from cells, and when calcium enters the stimulated or deenergized cell, it is likely to trigger a series of reactions that lower energy production, interfering with oxidative metabolism. During aging, both calcium and iron tend to accumulate and they both seem to have an affinity for similar locations, and they both tend to displace copper. (Compare K. Sato, et al., on the calcification of copper-containing paints.) Elastin is a protein, the units of which are probably bound together by copper atoms. In old age, elastin is one of the first substances to calcify, for example in the elastic layers of arteries, causing them to lose elasticity, and to harden into almost bone-like tubes. In the heart and kidneys, the mitochondria (rich in copper-enzymes) are often the location showing the earliest calcification, for example when magnesium is deficient.

Obviously, certain proteins have higher than average affinity for copper, iron, and calcium. For example, egg-white's unusual behavior with copper can be seen if you make a meringue in a copper pan--the froth is unusually firm. My guess is that copper atoms bind the protein molecules into relatively elastic systems. In many systems, calcium forms the link between adhesive proteins.

In brain degeneration, the regions that sometimes accumulate aluminum, will accumulate other metals instead, if they predominate in the environment; calcium is found in this part of the brain in some of the Pacific regions studied by Gajdusek. Certain cells in the brain used to be called "metalophils," because they could be stained intensely with silver and other metals; I suppose these are part of the immune system, handling iron as described by Maria de Sousa. Macrophages have been proposed as an important factor in producing atherosclerotic plaques (Carpenter, et al.). There is evidence that they (and not smooth muscle cells) are the characteristic foam cells, and their conversion of polyunsaturated oils into age pigment accounts for the depletion of those fats in the plaques. The same evidence could be interpreted as a defensive reaction, binding iron and destroying unsaturated fatty acids, and by this detoxifying action, possibly protecting against calcification and destruction of elastin. (This isn't the first suggestion that atherosclerosis might represent a protective process; see S. M. Plotnikov, et al., 1994.)

Since carbon dioxide and bicarbonate are formed in the mitochondria, it is reasonable to suppose that the steady outward flow of the bicarbonate anion would facilitate the elimination of calcium from the mitochondria. Since damaged mitochondria are known to start the process of pathological calcification in the heart and kidneys, it probably occurs in other tissues that are respiratorily stressed. And if healthy respiration, producing carbon dioxide, is needed to keep calcium outside the cell, an efficient defense system could also facilitate the deposition of calcium in suitable places--depending on specific protein binding. The over-grown bones in the hyperthyroid rats and the women with osteopetrosis suggest that an abundance of carbon dioxide facilitates bone formation. Since no ordinary inorganic process of precipitation/crystallization has been identified that could account for this, we should consider the possibility that the protein matrix is regulated in a way that promotes (or resists) calcification. The affinity of carbon dioxide for the amine groups on proteins (as in the formation of carbamino hemoglobin, which changes the shape of the protein) could change the affinity of collagen or other proteins for calcium. Normally, ATP is considered to be the most important substance governing such changes of protein conformation or binding properties, but ordinarily, ATP and CO2 are closely associated, because both are produced in respiration. Gilbert Ling has suggested that hormones such as progesterone also act as cardinal adsorbants, regulating the affinity of proteins for salts and other molecules.

Cells have many proteins with variable affinity for calcium; for example in muscle, a system called the endoplasmic reticulum, releases and then sequesters calcium to control contraction and relaxation. (This calcium-binding system is backed up by--and is spatially in close association with--that of the mitochondrion.) Ion-exchange resins can be chemically modified to change their affinity for specific ions, and molecules capable of reacting strongly with proteins can change the affinities of the proteins for minerals. What evidence is there that carbon dioxide could influence calcium binding? The earliest deposition of crystals on implanted material is calcium carbonate. (J. Vuola, et al, 1996.) In newly formed bone, the phosphate content is low, and increases with maturity. While mature bone has an apatite-like ratio of calcium and phosphate, newly calcified bone is very deficient in phosphate (according to Dallemagne, the initial calcium to phosphorus ratio is 1.29, and it increases to 2.20.) (G. Bourne, 1972; Dallemagne.)

The carbonate content of bone is often ignored, but in newly formed bone, it is probably the pioneer. Normally, "nucleation" of crystals is thought of as a physical event in a supersaturated solution, but the chemical interaction between carbon dioxide and amino groups (amino acids, protein, or ammonia, for example) removes the carbon dioxide from solution, and the carbamino acid formed becomes a bound anion with which calcium can form a salt. With normal physiological buffering, the divalent calcium (Ca2+) should form a link between the monovalent carbamino acid and another anion. Linking with carbonate (CO32-), one valence would be free to continue the salt-chain. This sort of chemistry is compatible with the known conditions of bone formation.

Klein, et al. (1996), think of uncoupled oxidative phosphorylation in terms of "subtle thermogenesis," which isn't demonstrated in their experiment, but their experiment actually suggests that stimulated production of carbon dioxide is the factor that stimulates calcification. Their experiment seems to be the in vitro equivalent of the various observations mentioned above. DHEA, which powerfully stimulates bone formation, is (like thyroid and progesterone) thermogenic, but in these cases, the relevant event is probably the stimulation of respiration, not the heat production. In pigs (Landrace strain) susceptible to malignant hyperthermia, there is slow removal of calcium from the contractile apparatus of their muscles. Recent evidence shows that an extramitochondrial NADH-oxidase is functioning. This indicates that carbon dioxide production is limited. I think this is responsible for the cells' sluggishness in expelling calcium.

Stress-susceptible pigs show abnormalities of muscle metabolism (e.g., high lactate formation) that are consistent with hypothyroidism. (T. E. Nelson, et al., "Porcine malignant hyperthermia: Observations on the occurrence of pale, soft, exudative musculature among susceptible pigs," Am. J. Vet. Res. 35, 347-350, 1974; M. D. Judge, et al., "Adrenal and thyroid function in stress-susceptible pigs (Sus domesticus)," Am. J. Physiol. 214(1), 146-151, 1968.)

Malignant hyperthermia during surgery is usually blamed on genetic susceptibility and sensitivity to anesthetics. (R. D. Wilson, et al., "Malignant hyperpyrexia with anesthesia," JAMA 202, 183-186, 1967; B.A Britt and W. Kalow, "Malignant hyperthermia: aetiology unknown," Canad. Anaesth. Soc. J. 17, 316-330, 1970.) Hypertonicity of muscles, various degrees of myopathy and rigidity, and uncoupling of oxidative phosphorylation occur in these people, as in pigs. Lactic acidosis suggests that mitochondrial respiration is defective in the people, as in the pigs. Besides the sensitivity to anesthetics, the muscles of these people are abnormally sensitive to caffeine and elevated extracellular potassium. During surgery, artificial ventilation, combined with stress, toxic anesthetics, and any extramitochondrial oxidation that might be occurring (such as NADH-oxidase, which produces no CO2), make relative hyperventilation a plausible explanation for the development of hyperthermia. Hyperventilation can cause muscle contraction. Panting causes a tendency for fingers and toes to cramp. Free intracellular calcium is the trigger for muscle contraction (and magnesium is an important factor in relaxation.) Capillary tone, similarly, is increased by hyperventilation, and relaxed by carbon dioxide. The muscle-relaxing effect of carbon dioxide shows that the binding of intracellular calcium is promoted by carbon dioxide, as well as by ATP. The binding of calcium in a way that makes it unable to interfere with cellular metabolism is, in a sense, a variant of simple extrusion of calcium, and the binding of calcium to extracellular materials. A relaxed muscle and a strong bone are characterized by bound calcium.

Activation of the sympathetic nervous system promotes hyperventilation. This means that hypothyroidism, with high adrenalin (resulting from a tendency toward hypoglycemia because of inefficient use of glucose and oxygen), predisposes to hyperventilation.

Muscle stiffness, muscle soreness and weakness, and osteoporosis all seem to be consequences of inadequate respiration, allowing lactic acid to be produced instead of carbon dioxide. Insomnia, hyperactivity, anxiety, and many chronic brain conditions also show evidence of defective respiration, for example, either slow consumption of glucose or the formation of lactic acid, both of which are common consequences of low thyroid function. Several studies (e.g., Jacono and Robertson, 1987) suggest that abnormal calcium regulation is involved in epilepsy. The combination of supplements of thyroid (emphasizing T3), magnesium, progesterone and pregnenolone can usually restore normal respiration, and it seems clear that this should normalize calcium metabolism, decreasing the calcification of soft tissues, increasing the calcification of bones, and improving the efficiency of muscles and nerves. (Magnesium, like carbonate, is a component of newly formed bone.) The avoidance of polyunsaturated vegetable oils is important for protecting respiration; some of the prostaglandins they produce have been implicated in osteoporosis, but more generally, they antagonize thyroid function and they can interfere with calcium control. The presence of the "Mead acid" (the omega-9 unsaturated fat our enzymes synthesize) in cartilage suggests a new line of investigation regarding the bone-toxicity of the polyunsaturated dietary oils.

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J. Pearson, et al, Osteoporosis 5, 174-184, 1995 J. Dequeker, et al, "Dual X-ray absorptiometry--cross-calibration and normative reference ranges for the spine," Bone 17(3), 247-254, 1995 ("...there is no uniformity in reporting results and in presenting reference data." "It is...crucially important to select appropriate reference data in clinical and epidemiological studies.") T.M. Hangartner and C. C. Johnston, "Influence of fat on bone measurements with dual-energy absorptionmetry," Bone Miner 9, 71-81, 1990. R. Valkema, et al., "Limited precision of lumbar spine dual photon absorptiometry by variations in the soft-tissue background," J. Nucl. Med. 31, 1774-1781, 1990.

M. Silberberg and R. Silberberg, Arch. Path. 31(1), 85-92, 1941. (Progesterone counteracts aging of bone in guinea pig.) M. Silberberg and R. Silberberg, Growth 4(3), 1305-14, 1940. (Decreased severity and incidence of old-age changes in the joints of normal mice.) G. Coryn, "Recherche experimentale sur l'influence des glands endocrines sur l'histologie du cartilage de conjugaison," Annales d'anatomie pathol. 16, 27, 1939.

O. Rahn, "Protozoa need carbon dioxide for growth," Growth 5, 197-199, 1941. "On page 113 of this volume, the statement of Valley and Rettger that all bacteria need carbon dioxide for growth had been shown to apply to young as well as old cells." "...it is possible...to remove it as rapidly as it is produced, and under these circumstances, bacteria cannot multiply." K. L. H. Carpenter, et al., "Production of ceroid and oxidised lipids by macrophages in vitro," Lipofuscin--1987: State of the Art, I. Zs.-Nagy, editor, pp. 245-268, 1988.

A. Schlemmer, et al., "Posture, age, menopause, and osteopenia do not influence the circadian variation in the urinary excretion of pyridinium crosslinks," J. Bone Miner. Res. 9(12), 1883-1888, 1994. N. S. Weiss, et al., "Decreased risk of fractures of the hip and lower forearm with postmenopausal use of estrogen,:" N. Engl. J. Med. 303, 1195-1198, 1980.

S. M. Plotnikov, et al., "Anxiety, atherogenesis, and antioxidant protection: Clinico-pathogenetic relationships," Bull. Exp. Biol. & Medicine 117(2), 221, 1994.

G. M. Groisman, et al., "Calcified concretions in the anterior pituitary gland of the fetus and the newborn: A light and electron microscopic study," Human Pathology 27(11), 1139-1143, 1996. (...calcified concretions represent a normal finding in the anterior pituitary gland of fetuses and young infants.")

K. S. G. Jie. "Vitamin K status and bone mass in women with and without aortic atherosclerosis: A population-based study," Calc. Tiss. Intern. 59(5), 352-356, 1996. ("The finding that in atherosclerotic women vitamin K status is associated with bone mass supports our hypothesis that vitamin K status affects the mineralization processes in both bone and in atherosclerotic plaques."

B. Y. Klein, et al., "Cell-mediated mineralization in culture at low temperature associated with subtle thermogenic response," J. of Cellular Biochemistry 63(2), 229-238, 1996. "...cell-mediated mineralization is preceded by characteristics of anaerobic and low efficiency energy metabolism." "Modulation of mitochondrial membrane potential and energy metabolism could be linked to regulation of mineralization by the uncoupling of oxidative phosphorylation. This uncoupling should be associated with thermogenesis in cells that induce mineralization." C. R. Heath, B.S.C. Leadbeater, and M. E. Callow, "The control of calcification of antifouling paints in hard waters using a phosphonate inhibitor," Biofouling 9(4), 317-325, 1996. ("All paints contained cuprous oxide....)

C. D. Yee, et al., "The relationship of nutritional copper to the development of postmenopausal osteoporosis in rats," Biol. Trace Element Res. 48(1), 1-11, 1995.

H Hoshino, et al., "The influence of aortic calcification on spinal bone mineral density in vitro," Calc. Tiss. Intern 59(1), 21-23, 1996. ("...changes over time in a patient could falsely elevate values.") E. Toussirot, et , "Giant calcification in soft tissue after shoulder corticosteroid injection, J. of Rheumatology 23(1), 181-182, 1996, "Such periarticular calcifications are rarely observed and generally after triamcinolone hexacetonide injection."

M. Alini, et al., "In serum-free culture thyroid hormones can induce full expression of chondrocyte hypertrophy leading to matrix calcification," J. of Bone and Mineral Res. 11(1), 105-113, 1996. ("...we compared the capacity of T3 with T4 to stimulate expression of the hypertrophic phenotype and matrix calcification in three . . . prehypertrophic chondrocyte subpopulations." "...T3 was at least 50-fold more potent than T4. The effects of T3 were most pronounced with the most immature cells." "...matrix calcification, measured by the incorporation of Ca45(2+) into the cell layer, always occurred earlier in cells cultured with T3 compared with T4."

M. T. Hincke, "Ovalbumin is a component of the chicken eggshell matrix," Connective Tissue Research 31(3), 227-233, 1995. (Immunochemically demonstrated in the mammillary bodies of decalcified shell. "These results indicate that ovalbumin is present during the initial phase of shell formation and becomes incorporated into the protein matrix of the mammillary bodies.")

A. L. Boskey, et al., "Persistence of complexed acidic phospholipids in rapidly mineralizing tissues is due to affinity for mineral and resistance to hydrolytic attack: In vitro data," Calc. Tiss. Intern. 58(1), 45-51, 1996. (Complexed acidic phospholipids may persist in the growth plate and facilitate initial mineral deposition.)

A.L. Boskey, et al., "Viable cells are a requirement for in vitro cartilage calcification," Calc. Tiss. Intern. 58(3), 177-185, 1996. (Challenges dogma that chondrocyte death must precede calcification in the growth plate.) K. Sekino, et , role of coccoliths in the utilization of inorganic carbon by a marine unicellular coccolithophorid, Plant and Cell Physiol 37(2), 123-127, 1996.

Y. Seyama, et al., "Effect of vitamin K2 on experimental calcinosis induced by vitamin D2 in rat soft tissue," Intern. J. for Vitamin and Nutr. Res. 66(1), 36-38, 1996.

R. Danielsen, et, "Predominance of aortic calcification as an atherosclerotic manifestation in women: The Reykjavik study," J. of Clin. Epidemiology 49(3), 383-387, 1996. (...a potential relation to pulse pressure; associated with blood sugar, use of antidiabetic drugs, serum cholesterol, smoking; much more frequent in women.) F. Etcharry, et al., Fahr's disease and mitochondrial myopathy," Revue Neurologique 151(12), 731-733, 1995. (Calcification of the basal ganglia, Fahr's disease, associated with mitochondrial myopathy.) J. J. Jacono and J. M. Robertson, "The effects of estrogen, progesterone, and ionized calcium on seizures during the menstrual cycle of epileptic women," Epilepsia 28(5), 571-577, 1987.

J. E. Sojka and C. M. Weaver, "Magnesium supplementation and osteoporosis," Nutrition Reviews 53(3), 71-74, 1995. ("...magnesium therapy appears to have prevented fractures and resulted in a significant increase in bone density.")

R. Eastell, "Management of corticosteroid-induced osteoporosis," J. Internal Medicine 237(5), 439-447, 1995. "Corticosteroid therapy results in osteoporosis." "The most important mechanism for the bone loss is a decrease in osteoblastic activity."

J. P. Bonjour and R. Rizzoli, "Inadequate protein intake and osteoporosis: Possible involvement of the IGF system,:" Nutritional Aspects of Osteoporosis '84, Challenges of Mod. Med. 7, 399-406, 1995. H. Pedersen, et al, "Skin thickness in patients with osteoporosis..." Skin Pharmacology 8(4), 207-210, 1995.

K. E. Schaefer, et al., "Phasic changes in bone CO2 fractions, calcium, and phosphorus during chronic hypercapnia," J. Applied Physiol. 48(5), 802-811, 1980.

F. C. Driessens, "Probable phase composition of the mineral in bone," Z. Naturforsch (C) 35(5-6), 357-362, 1980.

G. R. Sauer, et al., "A facilitative role for carbonic anhydrase activity in matrix vesicle mineralization," Bone Miner. 26(1), 69-71, 1994, E. Reichart, et al., "CO2 storage in various organs during chronic experimental hypercapnia," Bull. Eur. Physiopathol. Respir. 12(1), 19-32, 1976. ("During a four week hypercapnia, this CO2 increase is very inmportant in bone and brain compared with that of other organs.... ...the bone CO2 content is still increasing after four weeks.") H. Nitta, et al., "Effects of hot environments and carbonated drinking water on bone characteristics of eight-week-old broiler chicks," Poult. Sci. 65(3), 469-473, 1986.

W. G. Bottje and P. C. Harrison, "Effect of carbonated water on growth performance of cockerels subjected to constant and cyclic heat stress termperatures," Poult. Sci. 64(7), 1285-92, 1985. P. Quint, et al., "Characteristic molar ratios of magnesium, carbon dioxide, calcium and phosphorus in the mineralizing fracture callus and predentine," Calcif. Tissue Int.32(3), 257-261, 1980. ("It was found that the Mg and CO2-contents are high in relation to Ca and P values during the prestages and early stages of mineralization.") M. F. Gulyi, "Role of carbonic acid and ammonium nitrogen in regulation of metabolism and physiological function in heterotrophic organisms," Ukr. Biokhim. Zh. 52(2), 141-145, 1980.

K. E. Schaefer, et al., "Effect of intermittent exposure to 3% CO2 on respiration, acid-base balance, and calcium-phosphorus metabolism," Undersea Biomed. Res. 6 Suppl, S115-34, 1979. ("The known renal response to hypercapnia, consisting of an increased excretion of titratable acidity, ammonia, and hydrogen ion excretion, occurred but was interrupted after the first day....")

U. F. Rasmussen, et al., "Characterization of mitochondria from pig muscle:

Higher activity of exo-NADH-oxidase in animals suffering from malignant hyperthermia," Biochem. J. 315(Pt. 2), 659-663, 1996. R. K. Rude and F. R. Singer, "Hormone modifiers of mineral metabolism," in Disorders of Mineral Metabolism, vol. II: Calcium Physiology, Ed. by F. Bronner and J. W. Coburn, Academic Press, 1982.

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<span class="koboSpan" id="kobo.1.1">Progesterone Pregnenolone & DHEA - Three Youth-Associated Hormones</span> A R T I C L E

Progesterone Pregnenolone & DHEA - Three Youth-Associated Hormones

PROGESTERONE INFORMATION

Raymond Peat, MA, PhD (Univ. of Oregon)

Endocrine Physiologist, specializing in hormonal changes in stress and aging

Sixty years ago, progesterone was found to be the main hormone produced by the ovaries. Since it was necessary for fertility and for maintaining a healthy pregnancy, it was called the "pro-gestational hormone," and its name sometimes leads people to think that it isn't needed when you don't want to get pregnant. In fact, it is the most protective hormone the body produces, and the large amounts that are produced during pregnancy result from the developing baby's need for protection from the stressful environment. Normally, the brain contains a very high concentration of progesterone, reflecting its protective function for that most important organ. The thymus gland, the key organ of our immune system, is also profoundly dependent on progesterone.

In experiments, progesterone was found to be the basic hormone of adaptation and of resistance to stress. The adrenal glands use it to produce their anti-stress hormones, and when there is enough progesterone, they don't have to produce the potentially harmful cortisone. In a progesterone deficiency, we produce too much cortisone, and excessive cortisone causes osteoporosis, aging of the skin, damage to brain cells, and the accumulation of fat, especially on the back and abdomen.

Experiments have shown that progesterone relieves anxiety, improves memory, protects brain cells, and even prevents epileptic seizures. It promotes respiration, and has been used to correct emphysema. In the circulatory system, it prevents bulging veins by increasing the tone of blood vessels, and improves the efficiency of the heart. It reverses many of the signs of aging in the skin, and promotes healthy bone growth. It can relieve many types of arthritis, and helps a variety of immunological problems.

If progesterone is taken dissolved in vitamin E, it is absorbed very efficiently, and distributed quickly to all of the tissues. If a woman has ovaries, progesterone helps them to produce both progesterone and estrogen as needed, and also helps to restore normal functioning of the thyroid and other glands. If her ovaries have been removed, progesterone should be taken consistently to replace the lost supply. A progesterone deficiency has often been associated with increased susceptibility to cancer, and progesterone has been used to treat some types of cancer.

It is important to emphasize that progesterone is not just the hormone of pregnancy. To use it only "to protect the uterus" would be like telling a man he doesn't need testosterone if he doesn't plan to father children, except that progesterone is of far greater and more basic significance than testosterone. While men do naturally produce progesterone, and can sometimes benefit from using it, it is not a male hormone. Some people get that impression, because some physicians recommend combining estrogen with either testosterone or progesterone, to protect against some of estrogen's side effects, but progesterone is the body's natural complement to estrogen. Used alone, progesterone often makes it unnecessary to use estrogen for hot flashes or insomnia, or other symptoms of menopause.

When dissolved in vitamin E, progesterone begins entering the blood stream almost as soon as it contacts any membrane, such as the lips, tongue, gums, or palate, but when it is swallowed, it continues to be absorbed as part of the digestive process. When taken with food, its absorption occurs at the same rate as the digestion and absorption of the food.

PREGNENOLONE

Pregnenolone, which is the raw material for producing many of the hormones of stress and adaptation, was known as early as 1934, but for several years it was considered to be an "inert" substance. A reason for this belief is that it was first tested on healthy young animals. Since these animals were already producing large amounts of pregnenolone (in the brain, adrenal glands, and gonads), additional pregnenolone had no effect.

In the 1940s, pregnenolone was tested in people who were sick or under stress, and it was found to have a wide range of beneficial actions, but the drug industry never had much interest in it. Its very generality made it seem unlike a drug, and its natural occurrence made it impossible to patent. Thus, many synthetic variants, each with a more specialized action and some serious side effects, came to be patented and promoted for use in treating specific conditions. The drug companies created an atmosphere in which many people felt that each disease should have a drug, and each drug, a disease. The side effects of some of those synthetic hormones were so awful that many people came to fear them. For example, synthetic varieties of "cortisone" can destroy immunity, and can cause osteoporosis, diabetes, and rapid aging, with loss of pigment in the skin and hair, and extreme thinning of the skin.

Natural pregnenolone is present in young people of both sexes at a very high concentration, and one reason for the large amount produced in youth is that it is one of our basic defenses against the harmful side effects that an imbalance of even our natural hormones can produce. In excess, natural cortisone or estrogen can be dangerous, but when there is an abundance of pregnenolone, their side effects are prevented or minimized.

In a healthy young person or animal, taking even a large dose of pregnenolone has no hormone-like or drug-like action at all. It is unique in this way. But if the animal or person is under stress, and producing more cortisone than usual, taking pregnenolone causes the cortisone to come down to the normal level. After the age of 40 or 45, it seems that everyone lives in a state of continuous "stress," just as a normal part of aging. This coincides with the body's decreased ability to produce an abundance of pregnenolone.

When aging rats are given a supplement of pregnenolone, it immediately improves their memory and general performance. Human studies, as early as the 1940s, have also demonstrated improved performance of ordinary tasks. It is now known that pregnenolone is one of the major hormones in the brain. It is produced by certain brain cells, as well as being absorbed into the brain from the blood. It protects brain cells from injury caused by fatigue, and an adequate amount has a calming effect on the emotions, which is part of the reason that it protects us from the stress response that leads to an excessive production of cortisone. People feel a mood of resilience and an ability to confront challenges.

Many people have noticed that pregnenolone has a "face-lifting" action. This effect seems to be produced by improved circulation to the skin, and by an actual contraction of some muscle-like cells in the skin. A similar effect can improve joint mobility in arthritis, tissue elasticity in the lungs, and even eyesight. Many studies have shown it to be protective of "fibrous tissues" in general, and in this connection it was proven to prevent the tumors that can be caused by estrogen.

Pregnenolone is largely converted into two other "youth-associated" protective hormones, progesterone and DHEA. At the age of 30, both men and women produce roughly 30 to 50 mg. of pregnenolone daily. When taken orally, even in the powdered form, it is absorbed fairly well. One dose of approximately 300 mg (the size of an aspirin tablet) keeps acting for about a week, as absorption continues along the intestine, and as it is "recycled" in the body. Part of this long lasting effect is because it improves the body's ability to produce its own pregnenolone. It tends to improve function of the thyroid and other glands, and this "normalizing" effect on the other glands helps to account for its wide range of beneficial effects.

DHEA: ANOTHER YOUTH-ASSOCIATED HORMONE

Raymond Peat, MA, PhD (Univ. of Oregon)

Endocrine Physiologist

DHEA (dehydroepiandrosterone) has a technical-sounding name because it has never been identified with a single dominant function, in spite of its abundance in the body. Many researchers still think of it as a substance produced by the adrenal glands, but experiments show that animals without adrenals are able to produce it in normal amounts. Much of it is formed in the brain (from pregnenolone), but it is probably produced in other organs, including the skin. The brain contains a much higher concentration of DHEA than the blood does.

In old age, we produce only about 5% as much as we do in youth. This is about the same decrease that occurs with progesterone and pregnenolone. The other hormones (for example, cortisone) do not decrease so much; as a result, our balance shifts continually during aging toward dominance by hormones such as cortisone, which use up more and more body substance, without rebuilding it. Protection against the toxic actions of these specialized hormones is a major function of DHEA and the other youth-associated hormones.

For example, starvation, aging, and stress cause the skin to become thin and fragile. An excess of cortisone--whether it is from medical treatment, or from stress, aging, or malnutrition--does the same thing. Material from the skin is dissolved to provide nutrition for the more essential organs. Other organs, such as the muscles and bones, dissolve more slowly, but just as destructively, under the continued influence of cortisone. DHEA blocks these destructive effects of cortisone, and actively restores the normal growth and repair processes to those organs, strengthening the skin and bones and other organs. Stimulation of bone-growth by DHEA has been demonstrated in vitro (in laboratory tests), and it has been used to relieve many symptoms caused by osteoporosis and arthritis, even when applied topically in an oily solution.

Estrogen is known to produce a great variety of immunological defects, and DHEA, apparently by its balancing and restorative actions, is able to correct some of those immunological defects, including some "autoimmune" diseases.

It is established that DHEA protects against cancer, but it isn't yet understood how it does this. It appears to protect against the toxic cancer-producing effects of excess estrogen, but its anti-cancer properties probably involve many other functions.

Diabetes can be produced experimentally by certain poisons which kill the insulin-producing cells in the pancreas. Rabbits were experimentally made diabetic, and when treated with DHEA their diabetes was cured. It was found that the insulin-producing cells had regenerated. Many people with diabetes have used brewer's yeast and DHEA to improve their sugar metabolism. In diabetes, very little sugar enters the cells, so fatigue is a problem. DHEA stimulates cells to absorb sugar and to burn it, so it increases our general energy level and helps to prevent obesity.

Young people produce about 12 to 15 milligrams of DHEA per day, and that amount decreases by about 2 mg. per day for every decade after the age of 30. This is one of the reasons that young people eat more without getting fat, and tolerate cold weather better: DHEA, like the thyroid hormone, increases our heat production and ability to burn calories. At the age of 50, about 4 mg. of DHEA per day will usually restore the level of DHEA in the blood to a youthful level. It is important to avoid taking more than needed, since some people (especially if they are deficient in progesterone, pregnenolone, or thyroid) can turn the excess into estrogen or testosterone, and large amounts of those sex hormones can disturb the function of the thymus gland and the liver.

People who have taken an excess of DHEA have been found to have abnormally high estrogen levels, and this can cause the liver to enlarge, and the thymus to shrink.

One study has found that the only hormone abnormality in a groupt of Alzheimers patients' brains was an excess of DHEA. In cell culture, DHEA can cause changes in glial cells resembling those seen in the aging brain. These observations suggest that DHEA should be used with caution. Supplements of pregnenolone and thyroid seem to be the safest way to optimize DHEA production.

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Progesterone, not estrogen, is the coronary protection factor of women.

In the 1940s, around the time that Hans Selye was reporting that estrogen causes shock, and that progesterone protects against many stress-related problems, the anthropologist Ashley Montague published The Natural Superiority of Women. Later, as I looked at the history of endocrine research, it seemed apparent that progesterone was responsible for many of the biological advantages of females, such as a longer average life-span, while testosterone was responsible for men’s advantage in muscular strength.

Although evidence of estrogen’s toxicity had been accumulating for decades, pharmaceutical promotion was finding hundreds of things to treat with estrogen, which they called “the female hormone.” By the 1940s, it was known to produce excessive blood clotting, miscarriage, cancer, age-like changes in connective tissue, premenstrual syndrome, varicose veins, orthostatic hypotension, etc., but, as Mark Twain said, a lie can run around the world before the truth gets its boots on.

After the DES fiasco, in which “the female hormone” which had been sold to prevent miscarriages was proven to cause them, the estrogen industry decided to offer men the protection against heart attacks that women supposedly got from their estrogen. The men who received estrogen in the study had an increased incidence of heart attacks, so that campaign was postponed for about 30 years.

The Shutes used vitamin E to treat the excessive blood clotting caused by estrogen, and vitamin E was considered to be an estrogen antagonist. Estrogen affected the liver’s production of clot-regulating proteins, and it also relaxed large veins, allowing blood pooling that slowed the blood sufficiently to give it time to form clots before returning to the lungs. Early in the century, unsaturated fats were found to inactivate the proteolytic enzymes that dissolve clots, and vitamin E was known, by the 1940s, to provide protection against the toxicity of the unsaturated fats. The toxic synergy of estrogen and unsaturated fats had already been recognized.

But in the 1950s, the seed oil industry, ignoring the toxic, carcinogenic effects of the unsaturated oils, began intensified promotion of their products as beneficial foods. (Decades earlier, Mark Twain had reported on the plans of the cottonseed industry to make people eat their by-product instead of butter.)

While estrogen was being offered as the hormone that protects against heart attacks, the liquid vegetable oils were being advertised as the food that would prevent heart attacks. Just a few years after the estrogen industry suffered the setbacks of the DES and heart attack publicity, the oil industry cancelled some tests of the “heart protective diet,” because it was causing both more heart attacks and more cancer deaths.

Somehow, these two fetid streams converged: Estrogen, like the unsaturated oils, lowered the amount of cholesterol in the blood, and an excess of blood cholesterol was said to cause heart attacks. (And, more recently, the estrogenic effects of the seed oils are claimed to offer protection against cancer.)

The ability to lower the cholesterol “risk factor” for heart attacks became a cultural icon, so that the contribution of estrogen and unsaturated oils to the pathologies of clotting could be ignored. Likewise, the contribution of unsaturated fats’ lipid peroxidation to the development of atherosclerotic plaques was simply ignored. But one of estrogen’s long established toxic effects, the reduction of tone in veins, was turned into something like a “negative risk factor”: The relaxation of blood vessels would prevent high blood pressure and its consequences, in this new upside down paradigm. This vein-dilating effect of estrogen has been seen to play a role in the development of varicose veins, in orthostatic hypotension, and in the formation of blood clots in the slow-moving blood in the large leg veins.

When it was discovered that the endothelial relaxing factor was nitric oxide, a new drug business came into being. Nitroglycerine had been in use for decades to open blood vessels, and, ignoring the role of nitrite vasodilators in the acquired immunodeficiency syndrome, new drugs were developed to increase the production of nitric oxide. The estrogen industry began directing research toward the idea that estrogen works through nitric oxide to “improve” the function of blood vessels and the heart.

(Besides the argument based on “risk factors,” many people cite the published observations that “women who take estrogen are healthier” than women who don’t use it. But studies show that their “control groups” consisted of women who weren’t as healthy to begin with.)

In the 1970s, after reading Szent-Gyorgyi’s description of the antagonistic effect of progesterone and estrogen on the heart, I reviewed the studies that showed that progesterone protects against estrogen’s clotting effect. I experimented with progesterone, showing that it increases the muscle tone in the walls of veins, which is very closely related to the effects Szent-Gyorgyi described in the heart. And progesterone opposes estrogen’s ability to increase the amount of free fatty acids circulating in the blood.

More recently, it has been discovered that progesterone inhibits the expression of the enzyme nitric oxide synthase, while estrogen stimulates its expression. At the time of ovulation, when estrogen is high, a woman breathes out 50% more nitric oxide (“NO”) than men do, but at other times, under the influence of increased progesterone and thyroid, and reduced estrogen, women exhale much less NO than men do. (Nitric oxide is a free radical, and it decomposes into other toxic compounds, including the free radical peroxynitrile, which damages cells, including the blood vessels. brain, and heart. Carbon dioxide tends to inhibit the production of peroxynitrile.)

If nitric oxide produced under the influence of estrogen were important in preventing cardiovascular disease, then men’s larger production of nitric oxide would give them greater protection than women have.

From more realistic perspectives, nitric oxide is being considered as a cause of aging, especially brain aging. Nitric oxide interacts with unsaturated fats to reduce oxygen use, damage mitochondria, and cause edema.

I think we can begin to see that the various “heart protective” ideas that have been promoted to the public for fifty years are coming to a dead end, and that a new look at the fundamental problems involved in heart disease would be appropriate. Basic principles that make heart disease more understandable will also be useful for understanding shock, edema, panic attacks, high altitude sickness, high blood pressure, kidney disease, some lung diseases, MS, multiple organ failure, and excitotoxicity or “programmed” cell death of the sort that causes degenerative nerve diseases and deterioration of other tissues.

The research supporting this view is remarkably clear, but it isn’t generally known because of the powerful propaganda coming from the drug and oil industries and their public servants.

Broda Barnes was right when he said that the “riddle of heart attacks” was solved when he demonstrated that hypothyroidism caused heart attacks, and that they were prevented by correcting hypothyroidism. He also observed that correcting hypothyroidism prevented the degenerative conditions (including heart disease) that so often occur in diabetics. Since hypothyroidism and diabetes are far more frequent in women, who have fewer heart attacks than men, it is appropriate to wonder why women tolerate hypothyroidism better than men.

In hypothyroidism and diabetes, respiration is impaired, and lactic acid is formed even at rest, and relatively little carbon dioxide is produced. To compensate for the metabolic inefficiency of hypothyroidism, adrenalin and noradrenalin are secreted in very large amounts. Adrenalin causes free fatty acids to circulate at much higher levels, and the lactic acid, adrenalin, and free fatty acids all stimulate hyperventilation. The already deficient carbon dioxide is reduced even more, producing respiratory alkalosis. Free fatty acids, especially unsaturated fats, increase permeability of blood vessels, allowing proteins and fats to enter the endothelium and smooth muscle cells of the blood vessels. Lactic acid itself promotes an inflammatory state, and in combination with reduced CO2 and respiratory alkalosis, contributes to the hyponatremia (sodium deficiency) that is characteristic of hypothyroidism. This sodium deficiency and osmotic dilution causes cells to take up water, increasing their volume.

In hyperventilation, the heart’s ability to work is decreased, and the work it has to do is increased, because peripheral resistance is increased, raising blood pressure. One component of peripheral resistance is the narrowing of the channels in blood vessels caused by endothelial swelling. In the heart, a similarly waterlogged state makes complete contraction and complete relaxation impossible.

Estrogen itself intensifies all of these changes of hypothyroidism, increasing perrmeability and edema, and decreasing the force of the heart-beat, impairing the diastolic relaxation. Besides its direct actions, and synergism with hypothyroidism, estrogen also chronically increases growth hormone, which causes chronic exposure of the blood vessels to higher levels of free fatty acids (with a bias toward unsaturated fatty acids), and promotes edema and vascular leakage. Hyperestrogenism, like hypothyroidism, tends to produce dilution of the body fluids, and is associated with increased bowel permeability, leading to endotoxemia; both dilution of the plasma and endotoxemia impair heart function.

Progesterone’s effects are antagonistic to estrogen’s:. Progesterone decreases the formation of nitric oxide, decreasing edema; it strengthens the heart beat, by improving venous return and increasing stroke volume, but at the same time it reduces peripheral resistance by relaxing arteries (by inhibiting calcium entry but also by other effects, and independently of the endothelium) and decreasing edematous swelling.

The effects of progesterone on the heart and blood vessels are paralleled by those of carbon dioxide: Increased carbon dioxide increases perfusion of the heart muscle, increases its stroke volume, and reduces peripheral resistance. The physical and chemical properties of carbon dioxide that I have written about previously include protective anti-excitatory and energy-sustaining functions that explain these effects. Since these effects have been known for many years, I think it is obvious that the obsessive interest in explaining these functions in terms of other molecules, such as nitric oxide, is motivated by the desire for new drugs, not by a desire to understand the physiology with which the researchers are pretending to deal.

Although women, because of estrogen’s antithyroid actions, are much more likely to suffer from hypothyroidism than men are, until menopause they have much higher levels of progesterone than men do. The effects of hyperestrogenism and hypothyroidism, with lower carbon dioxide production, are offset by high levels of progesterone. After menopause, women begin to have heart attacks at a rapidly increasing rate.

During the years that men are beginning to have a considerable risk of heart attacks, with declining thyroid function indicated by lower T3, their testosterone and progesterone are declining, while their estrogen is rising. Men who have heart attacks have much higher levels of estrogen than men at the same age who haven’t had a heart attack.

Whether the issue is free radical damage, vascular permeability with fat deposition, vascular spasm, edema, decreased heart efficiency, or blood clotting, the effects of chronic estrogen exposure are counter-adaptive. Progesterone, by opposing estrogen, is universally protective against vascular and heart disease.

So far, the rule in most estrogen/progesterone research has been to devise experiments so that claims of benefit can be made for estrogen, with the expectation that they will meet an uncritical audience. In some studies, it’s hard to tell whether idiocy or subterfuge is responsible for the way the experiment was designed and described, for example when synthetic chemicals with anti-progesterone activity are described as “progesterone.” Since one estrogen-funded researcher who supposedly found progesterone to be ineffective as treatment for premenstrual syndrome practically admitted to me in conversation an intent to mislead, I think it is reasonable to discount idiocy as the explanation for the tremendous bias in published research. With the vastly increased resources in the estrogen industry, resulting from the product promotion “for the prevention of heart disease,” I think we should expect the research fraud to become increasingly blatant.

Rather than being “heart protective,” estrogen is highly heart-toxic, and it is this that makes its most important antagonist, progesterone, so important in protecting the heart and circulatory system.

REFERENCES

JAMA 1998 Aug 19;280(7):605-13. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E University of California, San Francisco 94143, USA. CONTEXT: Observational studies have found lower rates of coronary heart disease (CHD) in postmenopausal women who take estrogen than in women who do not, but this potential benefit has not been confirmed in clinical trials. OBJECTIVE: To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease. DESIGN: Randomized, blinded, placebo-controlled secondary prevention trial. SETTING: Outpatient and community settings at 20 US clinical centers. PARTICIPANTS: A total of 2763 women with coronary disease, younger than 80 years, and postmenopausal with an intact uterus. Mean age was 66.7 years. INTERVENTION: Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily (n = 1380) or a placebo of identical appearance (n = 1383). Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were taking it at the end of 1 year, and 75% at the end of 3 years. MAIN OUTCOME MEASURES: The primary outcome was the occurrence of nonfatal myocardial infarction (MI) or CHD death. Secondary cardiovascular outcomes included coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke or transient ischemic attack, and peripheral arterial disease. All-cause mortality was also considered. RESULTS: Overall, there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes: 172 women in the hormone group and 176 women in the placebo group had MI or CHD death (relative hazard [RH], 0.99; 95% confidence interval [CI], 0.80-1.22). The lack of an overall effect occurred despite a net 11% lower low-density lipoprotein cholesterol level and 10% higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group (each P<.001). Within the overall null effect, there was a statistically significant time trend, with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5. More women in the hormone group than in the placebo group experienced venous thromboembolic events (34 vs 12; RH, 2.89; 95% CI, 1.50-5.58) and gallbladder disease (84 vs 62; RH, 1.38; 95% CI, 1.00-1.92). There were no significant differences in several other end points for which power was limited, including fracture, cancer, and total mortality (131 vs 123 deaths; RH, 1.08; 95% CI, 0.84-1.38). CONCLUSIONS: During an average follow-up of 4.1 years, treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease. The treatment did increase the rate of thromboembolic events and gallbladder disease. Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, we do not recommend starting this treatment for the purpose of secondary prevention of CHD. However, given the favorable pattern of CHD

Am J Med 1982 Dec;73(6):872-81. Serum estrogen levels in men with acute myocardial infarction. Klaiber EL, Broverman DM, Haffajee CI, Hochman JS, Sacks GM, Dalen JE Serum estradiol and serum estrone levels were assessed in 29 men in 14 men in whom myocardial infarction was ruled out; in 12 men without apparent coronary heart disease but hospitalized in an intensive care unit; and in 28 men who were not hospitalized and who acted as control subjects. (The 12 men who were hospitalized but who did not have coronary heart disease were included to control for physical and emotional stress of a severe medical illness.) Ages ranged from 21 to 56 years. Age, height, and weight did not differ significantly among groups. Blood samples were obtained in the patient groups on each of the first three days of hospitalization. The serum estrone level was significantly elevated in all four patient groups when compared with that in the control group. Estrone level, then, did not differentiate patients with and without coronary heart disease. Serum estradiol levels were significantly elevated in the groups with myocardial infarction, unstable angina, and in the group in whom myocardial infarction was ruled out. However, estradiol levels were not significantly elevated in the group in the intensive care unit without coronary heart disease when compared to the level in the normal control group. Serum estradiol levels, then, were elevated in men with confirmed or suspected coronary heart disease but were not elevated in men without coronary heart disease even under the stressful conditions found in an intensive care unit. Serum estradiol levels were significantly and positively correlated (p less than 0.03) with serum total creatine phosphokinase levels in the patients with myocardial infarction. The five patients with myocardial infarction who died within 10 days of admission had markedly elevated serum estradiol levels. The potential significance of these serum estradiol elevations is discussed in terms of estradiol's ability to enhance adrenergic neural activity and the resultant increase in myocardial oxygen demand.

JAMA 1978 Apr 3;239(14):1407-9. Noncontraceptive estrogens and nonfatal myocardial infarction. Jick H, Dinan B, Rothman KJ We obtained information on 107 women younger than 46 years discharged from a hospital with a diagnosis of acute myocardial infarction. In the series there were 17 women aged 39 to 45 years who were otherwise apparently healthy and had had a natural menopause, hysterectomy, or tubal ligation or whose spouse had had a vasectomy. Among them, nine (53%) were taking noncontraceptive estrogens just prior to admission. Among 34 control women, four (12%) were taking estrogens. The relative risk estimate, comparing estrogen users with nonusers, is 7.5, with 90% confidence limits of 2.4 and 24. All but one of the 17 ml subjects were cigarette smokers. While this illness is rare in most healthy young women, the risk in women older than about 38 years who both smoke and take estrogens appears to be substantial.

JAMA 1978 Apr 3;239(14):1403-6. Oral contraceptives and nonfatal myocardial infarction. Jick H, Dinan B, Rothman KJ We obtained information on 107 women younger than 46 years who were discharged from a hospital with a diagnosis of acute myocardial infarction. In the series 26 women were otherwise apparently healthy and potentially childbearing. Among these 26 women, 20 (77%) were taking oral contraceptives just prior to admission, and one was taking conjugated estrogens. Among 59 control women, 14 (24%) were taking oral contraceptives and one was taking conjugated estrogens. The relative risk estimate, comparing oral contraceptive users with nonusers, is 14 with 90% confidence limits of 5.5 and 37. All but two of the 26 women were cigarette smokers. While this illness is rare in most healthy young women, the risk in women older than about 37 years who both smoke and take oral contraceptive appears to be high.

M. Karmazyn, et al., "Changes in coronary vascular resistance associated with prolonged hypoxia in isolated rat hearts: A possible role of prostaglandins,"Life Sciences 25, 1991-1999, 1979. "if...hypoxic perfusion is prolonged, the initial dilatation passes off and an intense vasoconstriction results." "The constriction could be prevented by progesterone but not by estradiol or testosterone." "There is increasing evidence that angina pectoris and myocardiaol infarction may often be due to active caronary constriction." "Inhibitors of PG synthesis at high concentrations prevented or reversed the constriction." (Besides aspirin) "Chloroquine, procaine and propranolol can all behave as PG antagonists...." "The failure of estradiol or testosterone to have any effect and the complete prevention of the constriction by physiological levels of progesterone suggest that more attention should be paid to this last steroid." "...hypoxia can cause coronary constriction and...the effect does not occur in young or progesterone-treated hearts...."

Am J Epidemiol 1996 May 15;143(10):971-8. Prior to use of estrogen replacement therapy, are users healthier than nonusers? Matthews KA, Kuller LH, Wing RR, Meilahn EN, Plantinga P. Observational studies have demonstrated that women who have used postmenopausal estrogen replacement therapy (ERT) are at reduced risk of coronary heart disease. The authors examined whether premenopausal women who subsequently elected to use ERT during menopause had a better cardiovascular risk factor profile prior to use than did nonusers. A total of 541 premenopausal women had their cardiovascular risk factors and psychosocial characteristics evaluated at study entry. After approximately 8 years, 355 women had become postmenopausal, and 157 women reported ERT use during the follow-up period (mean = 93.4 months). The authors compared the premenopausal characteristics of users with those of nonusers. Relative to nonusers, ERT users were better educated (63 vs. 81% with at least some college), and prior to the use of ERT had higher levels of high density lipoprotein (HDL) cholesterol (1.49 vs. 1.59 mmol/liter), HDL2 (0.50 vs. 0.57 mmol/liter), HDL3 (0.98 vs. 1.02 mmol/liter), leisure physical activity (5, 122 vs. 7,158 Kjoules), and alcohol intake (7.5 vs. 9.7 g/day), and lower levels of apolipoprotein B (0.97 vs. 0.90g/liter), systolic blood pressure (112.1 vs. 107.1 mmHg) and diastolic blood pressure (73.8 vs. 71.4 mmHg), weight (68.5 vs. 64.2 kg), and fasting insulin (9.10 vs. 7.66 microU/liter). Prior to use of ERT, in comparison with nonusers, subsequent users reported on standardized questionnaires that they often exhibited Type A behavior, more aware of their feelings, motives, and symptoms, and had more symptoms of stress. Women who elect to use ERT have a better cardiovascular risk factor profile prior to the use of ERT than do women who subsequently do not use this treatment during the menopause, which supports the hypothesis that part of the apparent benefit associated with the use of ERT is due to preexisting characteristics of women who use ERT. This study underscores the widely recognized importance of randomized clinical trials to estimate the direct benefit of postmenopausal ERT for protecting women from cardiovascular disease.

"Effects of androgens on haemostasis," Winkler UH, Maturitas, 1996 Jul, 24:3, 147-55. "Androgen deficiency is associated with an increased incidence of cardiovascular disease. There is evidence that thromboembolic disease as well as myocardial infarction in hypogonadic males are mediated by low baseline fibrinolytic activity. Hypogonadism in males is associated with an enhancement of fibrinolytic inhibition via increased synthesis of the plasminogen activator inhibitor PAI 1.”

M. Mabry White, et al., “Estrogen, progesterone, and vascular reactivity: Potential cellular mechanisms," Endocrine Reviews 16(6), 739, 1995. "Female hormones are broadly recognized as affecting susceptibility to vascular disease...." Migraines, Raynaud's phenomena, primary pulmonary hypertension are mentioned as vascular disorders with a female predominance.

J. Boczkowski, et al., "Induction of diaphragmatic nitric oxide synthase after endotoxin administration in rats; role on diaphragmatic contractile dysfunction," J. Clin. Invest. 98, 1550-1559, 1996. "We conclude that iNOS [inducible nitric oxide synthase] was induced..." by endotoxin.

Arch Int Pharmacodyn Ther 1986 May;281(1):57-65. Effects of 17 beta-estradiol on the isolated rabbit heart. Raddino R, Manca C, Poli E, Bolognesi R, Visioli O. We have studied the effects of 17 beta-estradiol on the left ventricular pressure and on the coronary perfusion pressure in isolated rabbit heart, in order to evaluate the action of this hormone on the myocardial contractility and on the coronary resistances. 17 beta-Estradiol has induced a negative inotropic effect starting from a concentration of 10(-6) M and a vasodilation starting from 10(-7) M when administered on a vasopressin-induced coronary spasm. These effects are not related to sex or to alpha-, beta-adrenergic, histaminergic, anaesthetic-like mechanisms, but seem to interfere with calcium transport.

Med Hypotheses 1997 Aug;49(2):183-5. Coronary artery spasm: a hypothesis on prevention by progesterone. Kanda I, Endo M. Department of Surgery, Heart Institute of Japan, Tokyo Women's Medical College, Japan. The mechanism of coronary artery spasm has been hypothesized as follows: the dormant gene of the smooth muscle of the human coronary artery is identical or similar to the active gene of the smooth muscle of ductus arteriosus, but can be activated by estrogen. The activation could be preventable by progesterone. The prevention is due to the reduction of the number of estrogen receptors of the smooth muscle of the coronary artery.

J. Bolanos, et al., "Nitric oxide-mediated inhibition of the mitochondrial respiratory chain in cultured astrocytes," J. Neurochem. 63, 910-916, 1994.

M. Cleeter, et al., "Reversible inhibition of cytochrome C oxidase, the terminal enzyme of the mitochondrial respiratory chain, by nitric oxide," FEBS Lett. 345, 50-54, 1994.

Ann Thorac Surg 1999 Sep;68(3):925-30. Coronary perfusate composition influences diastolic properties, myocardial water content, and histologic characteristics of the rat left ventricle. Starr JP, Jia CX, Amirhamzeh MM, Rabkin DG, Hart JP, Hsu DT, Fisher PE, Szabolcs M, Spotnitz HM. “Recent studies found that edema, histology, and left ventricular diastolic compliance exhibit quantitative relationships in rats. Edema due to low osmolarity coronary perfusates increases myocardial water content and histologic edema score and decreases left ventricular filling. The present study examined effects of perfusate osmolarity and chemical composition on rat hearts.” “Myocardial water content reflected perfusate osmolarity, being lowest in Stanford and University of Wisconsin solutions (p<0.05 versus other groups) and highest in dilute Plegisol (p<0.05). Left ventricular filling volumes were smallest in dilute Plegisol and Plegisol (p<0.05).” “Perfusate osmolarity determined myocardial water content and left ventricular filling volume. However, perfusate chemical composition influenced the histologic appearance of edema. Pathologic grading of edema can be influenced by factors other than osmolarity alone.”

Progesterone inhibits inducible nitric oxide synthase gene expression and nitric oxide production in murine macrophages. Miller L; et al J Leukoc Biol, 59(3):442-50 1996 Mar. The purpose of this study was to determine whether the female hormones estradiol-l7 beta (E2) and progesterone (P4) influence inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) by interferon gamma (IFN-gamma) and lipopolysaccharide (LPS)-activated mouse macrophages. Treatment with P4 alone caused a time- and dose-dependent inhibition of NO production by macrophage cell lines (RAW 264.7, J774) and mouse bone marrow culture-derived macrophages as assessed by nitrite accumulation. RAW 264.7 cells transiently transfected with an iNOS gene promoter/luciferase reporter-gene construct that were stimulated with IFN-gamma/LPS in the presence of P4 displayed reduced luciferase activity and NO production. Analysis of RAW 264.7 cells by Northern blot hybridization revealed concurrent P4-mediated reduction in iNOS mRNA. These observations suggest that P4-mediated inhibition of NO may be an important gender-based difference within females and males that relates to macrophage-mediated host defense.

Testosterone relaxes rabbit coronary arteries and aorta. Yue P; Chatterjee K; Beale C; Poole-Wilson PA; Collins P Department of Cardiac Medicine, National Heart and Lung Institute, London, UK. Circulation, 1995 Feb 15, 91:4, 1154-60 “Testosterone induces endothelium-independent relaxation in isolated rabbit coronary artery and aorta, which is neither mediated by prostaglandin I2 or cyclic GMP. Potassium conductance and potassium channels but not ATP-sensitive potassium channels may be involved partially in the mechanism of testosterone-induced relaxation. The in vitro relaxation is independent of sex and of a classic receptor. The coronary artery is significantly more sensitive to relaxation by testosterone than the aorta. Testosterone is a more potent relaxing agent of rabbit coronary artery than other testosterone analogues.”

J. Nakamura, et al., "Estrogen regulates vascular endothelial growth permeability factor expression in 7,12-dimethyl- benz(a)anthracene-induced rat mammary tumors," Endocrinology 137(12_, 5589-5596, 1996. ("...one mechanism by which estrogen acts as a mammary tumor promotor is by stimulating VEG/PF, leading to increased tumor angiogenesis and/or permeability of the microvessels to allow tumor cell migration.")

D. A. Barber, et al., "Endothelin receptors are modulated in association with endogenous fluctuations in estrogen," Amer. J. of Physiology--Heart and Circulatory Physiology 40(5), H1999-H2006, 1996. ("...contractions to endothelin-1 but not endothelin-3 or sarafotoxin S6c were significantly greater in coronary arterial rings from female comparred with male pigs...." "In addition, independent of endogenous estrogen status, coronary arteries from female pigs generate significantly greater contractions to endothelin-1 compared with male pigs. This phenomenon occurs at the level of smooth muscle and is not dependent on the endothelium or synthesis of nitric oide or prostaglandins."

T. M. Chou, et al, "Testosterone induces dilation of canine coronary conductance and resistance arteries in vivo," Circulation 94(10), 2614-2619, 1996.

K. Sudhir, et al., "Estrogen enhances basal nitric oxide release in the forearm vasculature in perimenopausal women," Hypertension 28(3), 330-334, 1996.

G. Sitzler, et al., "Investigation of the negative inotropic effects of 17-beta-oestradiol in human isolated myocardial tissues," British J. of Pharmacology 119(1), 43-48, 1996.

S. M. Hyder, et al., "Uterine expression of vascular endothelial growth factor is increased by estradiol and tamoxifen," Cancer Research 56(17), 3954-3960, 1996. ("These findings raise the possibility that estrogen and antiestrogen effects on uterine edema, proliferation, and tumor incidence may involve local increases in tissue VEGF production.")

N. Ferrara and T. Davis-Smyth, "The biology of vascular endothelial growth factor," Endocrine Reviews 18(1), 4-19,? 1997. "...induces vasodilatation in vitro in a dose-dependent fashion and produces transient tachycardia, hypotension, and a decrease in cardiac output when injected intravenously in conscious...rats. Such effects appear to be caused by a decrease in venous return, mediated primarily by endothelial cell-derived nitric oxide...." "Recently, elevation of VEGF in the peritoneal fluid of patients with endometriosis has been reported.""...it has been suggested that VEGF up-regulation plays a pathogenic role in the capillary hyperpermeability that characterizes ovarian hyperstimulation syndrome as well as in the dysfunctional endothelium of preeclampsia."

B. Jilma, et al, "Sex differences in concentrtions of exhaled nitric oxide and plasma nitrate," Life Sciences 58*6), 469-476, 1996. ("Nitric oxide is generally considered as an endogenous vasoprotective agent." "...men exhaled 50% more NO and had 99% higher (nitrate) NO3 levels than women."

Progesterone inhibits inducible nitric oxide synthase gene expression and nitric oxide production in murine macrophages. Miller L; et al J Leukoc Biol, 59(3):442-50 1996 Mar. “Treatment with P4 alone caused a time- and dose-dependent inhibition of NO production by macrophage cell lines (RAW 264.7, J774) and mouse bone marrow culture-derived macrophages as assessed by nitrite accumulation. RAW 264.7 cells transiently transfected with an iNOS gene promoter/luciferase reporter-gene construct that were stimulated with IFN-gamma/LPS in the presence of P4 displayed reduced luciferase activity and NO production. Analysis of RAW 264.7 cells by Northern blot hybridization revealed concurrent P4-mediated reduction in iNOS mRNA. These observations suggest that P4-mediated inhibition of NO may be an important gender-based difference within females and males that relates to macrophage-mediated host defense.”

Int J Epidemiol 1990 Jun;19(2):297-302. Relationship of menopausal status and sex hormones to serum lipids and blood pressure. Wu ZY, Wu XK, Zhang YW. “Conditional logistic regression analysis found that progesterone is a protective factor only and testosterone is one of the risk factors for hypertension.”

Pharmacol Biochem Behav 1990 Oct;37(2):325-7. Steroid sex hormones and cardiovascular function in healthy males and females: a correlational study. Lundberg U, Wallin L, Lindstedt G, Frankenhaeuser M Department of Psychiatry and Psychology, Karolinska Institutet, Sweden. “The relationship of serum estradiol and testosterone levels to systolic (SBP) and diastolic blood pressure (DBP) and heart rate (HR) was examined in healthy nonsmoking males (n = 30) and females (n = 22), 30-50 years of age (mean age for men = 41.2, women = 39.9). Postmenopausal women and women taking oral contraceptives had been excluded. Testosterone levels in women were positively correlated with SBP, DBP and HR, after removing the effects of age and body mass. Positive correlations were also found between estradiol and SBP and HR in women.”

Scand J Clin Lab Invest 1993 Jul;53(4):353-8. Effects of ovarian stimulation on blood pressure and plasma catecholamine levels. Tollan A, Oian P, Kjeldsen SE, Holst N, Eide I. “After stimulation a positive correlation was observed between systolic blood pressure and arterial adrenaline (r = 0.73, p = 0.027), and between systolic blood pressure and the arterial-venous difference for adrenaline (r = 0.81, p = 0.007). The increased venous noradrenaline levels may be a reflex-mediated activation of the sympathetic nervous tone due to a decrease in blood pressure, or may indicate reduced neuronal re-uptake of released noradrenaline. The mechanisms behind the strong correlation between adrenaline and blood pressure are unclear, but may be induced by the supraphysiological oestradiol levels.”

J Mol Cell Cardiol 1986 Dec;18(12):1207-18. Post-ischemic cardiac chamber stiffness and coronary vasomotion: the role of edema and effects of dextran. Vogel WM, Cerel AW, Apstein CS. “Contributions of edema to left ventricular (LV) chamber stiffness and coronary resistance after ischemia were studied in isolated buffer-perfused rabbit hearts, with constant LV chamber volume, subjected to 30 min global ischemia and 60 min reperfusion. During reperfusion hearts were perfused with standard buffer or with 3% dextran to increase oncotic pressure and decrease water content.” “Coronary resistance in untreated ischemic hearts increased by 26% from 2.0 +/- 0.06 to 2.6 +/- 0.06 mmHg/ml/min after 60 min reperfusion. In treated hearts coronary resistance increased by 16% from 1.9 +/- 0.09 to 2.2 +/- 0.09 mm/Hg/ml/min (P less than 0.01 v. untreated ischemic). To determine whether the decrease in coronary resistance with dextran could be ascribed to active vasodilation, dilator responses to 2 min hypoxia or 10(-4)M adenosine were tested in nonischemic and reperfused ischemic hearts. Dilator responses were stable in nonischemic hearts or hearts reperfused after 15 min ischemia but after 30 min ischemia the dilator response to hypoxia was reduced by 72% (P less than 0.025) and the dilator response to adenosine was eliminated (P less than 0.02). Thus the response to dextran was unlike that of a direct vasodilator. These data suggest that myocardial edema plays a significant role in maintaining increased ventricular chamber stiffness and coronary resistance during reperfusion after ischemia.”

Experientia 1980 Dec 15;36(12):1402-3. Bilinear correlation between tissue water content and diastolic stiffness of the ventricular myocardium. Pogatsa G. In oedematous and dehydrated canine hearts a close bilinear correlation was demonstrated between myocardial water content and diastolic stiffness (characterized by the passive elastic modulus) with an optimal minimum of stiffness at normal myocardial water content.

S Afr Med J 1975 Dec 27;49(55):2251-4. Effect of natural oestrogens on blood pressure and weight in postmenopausal women. Notelovitz M. “An investigation of the effect of conjugated oestorgens (USP) on the blood pressure and weight gain of postmenopausal women was undertaken. Fifty-one unselected women were treated for one year with cyclically administered conjugated oestrogen. Both the mean systolic and diastolic blood pressures of those in the group increased, but only the diastolic was significantly elevated.” “The significance of the change in blood pressure is commented upon, and the recommendation that postmenopausal women on oestrogen replacement therapy should have their blood pressure measured every 6 months is made.”

Am J Hypertens 1995 Mar;8(3):249-53. Ambulatory blood pressure in mild hypertensive women taking oral contraceptives. A case-control study. Narkiewicz K, Graniero GR, D'Este D, Mattarei M, Zonzin P, Palatini P. “Both daytime and nighttime systolic blood pressure values were significantly higher in oral contraceptive users. There was an average 8.3 mm Hg difference (95% confidence interval, 3.0 to 13.7 mm Hg; P = .003) for the daytime and 6.1 mm Hg difference (95% confidence interval, 0.4 to 11.8 mm Hg; P = .04) for the nighttime.” “Our results support the opinion that alternative methods of contraception should be considered for hypertensive women in place of oral contraceptives.”

Am J Surg Pathol 1995 Apr;19(4):454-62. Reversible ischemic colitis in young women. Association with oral contraceptive use. Deana DG, Dean PJ. .”Ischemic colitis, a condition of middle-aged to elderly patients, occurs uncommonly in younger persons.” “Ten women (59%) were using low-dose estrogenic oral contraceptive agents, compared with the 1988 national average of 18.5% oral contraceptive users among females aged 15 to 44 years. The calculated odds ratio yielded a greater than sixfold relative risk for the occurrence of ischemic colitis among oral contraceptive users. In addition, four women not currently on hormonal contraceptive therapy had a past history of oral contraceptive use; the three remaining women were taking estrogen as replacement therapy after oophorectomy. In one patient, documented reversible ischemic colitis recurred on resumption of oral contraceptive use....” “...spontaneous ischemic colitis is a disorder found almost exclusively in women and is associated with the clinical use of exogenous estrogenic agents.”

J Clin Endocrinol Metab 1993 Jun;76(6):1542-7. Differential changes in serum concentrations of androgens and estrogens (in relation with cortisol) in postmenopausal women with acute illness. Spratt DI, Longcope C, Cox PM, Bigos ST, Wilbur-Welling C. “We evaluated relationships between changes in serum levels of cortisol (F), androgens, estrogens, and gonadotropins in 20 postmenopausal women with acute critical illness to determine if changes in adrenal androgens and estrogens paralleled gonadal axis suppression or adrenal stimulation. Two patterns of changes in sex steroids were observed. Admission serum levels of androstenedione (delta 4-A), estradiol, and estrone, like F, were increased compared to healthy controls (P < 0.0001). delta 4-A and estrone then decreased toward normal by day 5 in parallel with cortisol (r = 0.56 and 0.60).” “The decreased serum T levels suggest inhibition of 17 beta-OH-dehydrogenase and/or increased aromatization to estradiol.The marked increase in serum estrogen levels also suggests increased aromatization. The absence of increases in DHEA and DHEA-S suggest enhanced activity of 3 beta-hydroxysteroid dehydrogenase and/or inhibition of C17,20-lyase activity of P-450c17.”.

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<span class="koboSpan" id="kobo.1.1">Thyroid: Therapies, Confusion, and Fraud</span> A R T I C L E

Thyroid: Therapies, Confusion, and Fraud

I. Respiratory-metabolic defect

II. 50 years of commercially motivated fraud

III. Tests and the "free hormone hypothesis"

IV. Events in the tissues

V. Therapies

VI. Diagnosis

I. Respiratory defect

Broda Barnes, more than 60 years ago, summed up the major effects of hypothyroidism on health very neatly when he pointed out that if hypothyroid people don't die young from infectious diseases, such as tuberculosis, they die a little later from cancer or heart disease. He did his PhD research at the University of Chicago, just a few years after Otto Warburg, in Germany, had demonstrated the role of a "respiratory defect" in cancer. At the time Barnes was doing his research, hypothyroidism was diagnosed on the basis of a low basal metabolic rate, meaning that only a small amount of oxygen was needed to sustain life. This deficiency of oxygen consumption involved the same enzyme system that Warburg was studying in cancer cells.

Barnes experimented on rabbits, and found that when their thyroid glands were removed, they developed atherosclerosis, just as hypothyroid people did. By the mid-1930s, it was generally known that hypothyroidism causes the cholesterol level in the blood to increase; hypercholesterolemia was a diagnostic sign of hypothyroidism. Administering a thyroid supplement, blood cholesterol came down to normal exactly as the basal metabolic rate came up to the normal rate. The biology of atherosclerotic heart disease was basically solved before the second world war.

Many other diseases are now known to be caused by respiratory defects. Inflammation, stress, immunodeficiency, autoimmunity, developmental and degenerative diseases, and aging, all involve significantly abnormal oxidative processes. Just brief oxygen deprivation triggers processes that lead to lipid peroxidation, producing a chain of other oxidative reactions when oxygen is restored. The only effective way to stop lipid peroxidation is to restore normal respiration.

Now that dozens of diseases are known to involve defective respiration, the idea of thyroid's extremely broad range of actions is becoming easier to accept.

II. 50 years of fraud

Until the second world war, hypothyroidism was diagnosed on the basis of BMR (basal metabolic rate) and a large group of signs and symptoms. In the late 1940s, promotion of the (biologically inappropriate) PBI (protein-bound iodine) blood test in the U.S. led to the concept that only 5% of the population were hypothyroid, and that the 40% identified by "obsolete" methods were either normal, or suffered from other problems such as sloth and gluttony, or "genetic susceptibility" to disease. During the same period, thyroxine became available, and in healthy young men it acted "like the thyroid hormone." Older practitioners recognized that it was not metabolically the same as the traditional thyroid substance, especially for women and seriously hypothyroid patients, but marketing, and its influence on medical education, led to the false idea that the standard Armour thyroid USP wasn't properly standardized, and that certain thyroxine products were; despite the fact that both of these were shown to be false.

By the 1960s, the PBI test was proven to be irrelevant to the diagnosis of hypothyroidism, but the doctrine of 5% hypothyroidism in the populaton became the basis for establishing the norms for biologically meaningful tests when they were introduced.

Meanwhile, the practice of measuring serum iodine, and equating it with "thyroxine the thyroid hormone," led to the practice of examining only the iodine content of the putative glandular material that was offered for sale as thyroid USP. This led to the substitution of materials such as iodinated casein for desiccated thyroid in the products sold as thyroid USP. The US FDA refused to take action, because they held that a material's iodine content was enough to identify it as "thyroid USP." In this culture of misunderstanding and misrepresentation, the mistaken idea of hypothyroidism's low incidence in the population led to the acceptance of dangerously high TSH (thyroid stimulating hormone) activity as "normal." Just as excessive FSH (follicle stimulating hormone) has been shown to have a role in ovarian cancer, excessive stimulation by TSH produces disorganization in the thyroid gland.

III. Tests & the "free hormone hypothesis"

After radioactive iodine became available, many physicians would administer a dose, and then scan the body with a Geiger counter, to see if it was being concentrated in the thyroid gland. If a person had been eating iodine-rich food (and iodine was used in bread as a preservative/dough condition, and was present in other foods as an accidental contaminant), they would already be over saturated with iodine, and the gland would fail to concentrate the iodine. The test can find some types of metastatic thyroid cancer, but the test generally wasn't used for that purpose. Another expensive and entertaining test has been the thyrotropin release hormone (TRH) test, to see if the pituitary responds to it by increasing TSH production. A recent study concluded that "TRH test gives many misleading results and has an elevated cost/benefit ratio as compared with the characteristic combination of low thyroxinemia and non-elevated TSH." (Bakiri, Ann. Endocr (Paris) 1999), but the technological drama, cost, and danger (Dokmetas, et al., J Endocrinol Invest 1999 Oct; 22(9): 698-700) of this test is going to make it stay popular for a long time. If the special value of the test is to diagnose a pituitary abnormality, it seems intuitively obvious that overstimulating the pituitary might not be a good idea (e.g., it could cause a tumor to grow).

Everything else being equal, as they say, looking at the amount of thyroxine and TSH in the blood can be informative. The problem is that it's just a matter of faith that "everything else" is going to be equal. The exceptions to the "rule" regarding normal ranges for thyroxine and TSH have formed the basis for some theories about "the genetics of thyroid resistance," but others have pointed out that, when a few other things are taken into account, abnormal numbers for T4, T3, TSH, can be variously explained.

The actual quantity of T3, the active thyroid hormone, in the blood can be measured with reasonable accuracy (using radioimmunoassay, RIA), and this single test corresponds better to the metabolic rate and other meaningful biological responses than other standard tests do. But still, this is only a statistical correspondence, and it doesn't indicate that any particular number is right for a particular individual.

Sometimes, a test called the RT3U, or resin T3 uptake, is used, along with a measurement of thyroxine. A certain amount of radioactive T3 is added to a sample of serum, and then an adsorbent material is exposed to the mixture of serum and radioactive T3. The amount of radioactivity that sticks to the resin is called the T3 uptake. The lab report then gives a number called T7, or free thyroxine index. The closer this procedure is examined, the sillier it looks, and it looks pretty silly on its face.. The idea that the added radioactive T3 that sticks to a piece of resin will correspond to "free thyroxine," is in itself odd, but the really interesting question is, what do they mean by "free thyroxine"? Thyroxine is a fairly hydrophobic (insoluble in water) substance, that will associate with proteins, cells, and lipoproteins in the blood, rather than dissolving in the water. Although the Merck Index describes it as "insoluble in water," it does contain some polar groups that, in the right (industrial or laboratory) conditions, can make it slightly water soluble. This makes it a little different from progesterone, which is simply and thoroughly insoluble in water, though the term "free hormone" is often applied to progesterone, as it is to thyroid. In the case of progesterone, the term "free progesterone" can be traced to experiments in which serum containing progesterone (bound to proteins) is separated by a (dialysis) membrane from a solution of similar proteins which contain no progesterone. Progesterone "dissolves in" the substance of the membrane, and the serum proteins, which also tend to associate with the membrane, are so large that they don't pass through it. On the other side, proteins coming in contact with the membrane pick up some progesterone. The progesterone that passes through is called "free progesterone," but from that experiment, which gives no information on the nature of the interactions between progesterone and the dialysis membrane, or about its interactions with the proteins, or the proteins' interactions with the membrane, nothing is revealed about the reasons for the transmission or exchange of a certain amount of progesterone. Nevertheless, that type of experiment is used to interpret what happens in the body, where there is nothing that corresponds to the experimental set-up, except that some progesterone is associated with some protein.

The idea that the "free hormone" is the active form has been tested in a few situations, and in the case of the thyroid hormone, it is clearly not true for the brain, and some other organs. The protein-bound hormone is, in these cases, the active form; the associations between the "free hormone" and the biological processes and diseases will be completely false, if they are ignoring the active forms of the hormone in favor of the less active forms. The conclusions will be false, as they are when T4 is measured, and T3 ignored. Thyroid-dependent processes will appear to be independent of the level of thyroid hormone; hypothyroidism could be caller hyperthyroidism.

Although progesterone is more fat soluble than cortisol and the thyroid hormones, the behavior of progesterone in the blood illustrates some of the problems that have to be considered for interpreting thyroid physiology. When red cells are broken up, they are found to contain progesterone at about twice the concentration of the serum. In the serum, 40 to 80% of the progesterone is probably carried on albumin. (Albumin easily delivers its progesterone load into tissues.) Progesterone, like cholesterol, can be carried on/in the lipoproteins, in moderate quantities. This leaves a very small fraction to be bound to the "steroid binding globulin." Anyone who has tried to dissolve progesterone in various solvents and mixtures knows that it takes just a tiny amount of water in a solvent to make progesterone precipitate from solution as crystals; its solubility in water is essentially zero. "Free" progesterone would seem to mean progesterone not attached to proteins or dissolved in red blood cells or lipoproteins, and this would be zero. The tests that purport to measure free progesterone are measuring something, but not the progesterone in the watery fraction of the serum.

The thyroid hormones associate with three types of simple proteins in the serum: Transthyretin (prealbumin), thyroid binding globulin, and albumin. A very significant amount is also associated with various serum lipoproteins, including HDL, LDL, and VLDL (very low density lipoproteins). A very large portion of the thyroid in the blood is associated with the red blood cells. When red cells were incubated in a medium containing serum albumin, with the cells at roughly the concentration found in the blood, they retained T3 at a concentration 13.5 times higher than that of the medium. In a larger amount of medium, their concentration of T3 was 50 times higher than the medium's. When laboratories measure the hormones in the serum only, they have already thrown out about 95% of the thyroid hormone that the blood contained.

The T3 was found to be strongly associated with the cells' cytoplasmic proteins, but to move rapidly between the proteins inside the cells and other proteins outside the cells.

When people speak of hormones travelling "on" the red blood cells, rather than "in" them, it is a concession to the doctrine of the impenetrable membrane barrier.

Much more T3 bound to albumin is taken up by the liver than the small amount identified in vitro as free T3 (Terasaki, et al., 1987). The specific binding of T3 to albumin alters the protein's electrical properties, changing the way the albumin interacts with cells and other proteins. (Albumin becomes electrically more positive when it binds the hormone; this would make the albumin enter cells more easily. Giving up its T3 to the cell, it would become more negative, making it tend to leave the cell.) This active role of albumin in helping cells take up T3 might account for its increased uptake by the red cells when there were fewer cells in proportion to the albumin medium. This could also account for the favorable prognosis associated with higher levels of serum albumin in various sicknesses.

When T3 is attached chemically (covalently, permanently) to the outside of red blood cells, apparently preventing its entry into other cells, the presence of these red cells produces reactions in other cells that are the same as some of those produced by the supposedly "free hormone." If T3 attached to whole cells can exert its hormonal action, why should we think of the hormone bound to proteins as being unable to affect cells? The idea of measuring the "free hormone" is that it supposedly represents the biologically active hormone, but in fact it is easier to measure the biological effects than it is to measure this hypothetical entity. Who cares how many angels might be dancing on the head of a pin, if the pin is effective in keeping your shirt closed?

IV. Events in the tissues

Besides the effects of commercial deception, confusion about thyroid has resulted from some biological clichés. The idea of a "barrier membrane" around cells is an assumption that has affected most people studying cell physiology, and its effects can be seen in nearly all of the thousands of publications on the functions of thyroid hormones. According to this idea, people have described a cell as resembling a droplet of a watery solution, enclosed in an oily bag which separates the internal solution from the external watery solution. The cliché is sustained only by neglecting the fact that proteins have a great affinity for fats, and fats for proteins; even soluble proteins, such as serum albumin, often have interiors that are extremely fat-loving. Since the structural proteins that make up the framework of a cell aren't "dissolved in water" (they used to be called "the insoluble proteins"), the lipophilic phase isn't limited to an ultramicroscopically thin surface, but actually constitutes the bulk of the cell.

Molecular geneticists like to trace their science from a 1944 experiment that was done by Avery., et al. Avery's group knew about an earlier experiment, that had demonstrated that when dead bacteria were added to living bacteria, the traits of the dead bacteria appeared in the living bacteria. Avery's group extracted DNA from the dead bacteria, and showed that adding it to living bacteria transferred the traits of the dead organisms to the living.

In the 1930s and 1940s, the movement of huge molecules such as proteins and nucleic acids into cells and out of cells wasn't a big deal; people observed it happening, and wrote about it. But in the 1940s the idea of the barrier membrane began gaining strength, and by the 1960s nothing was able to get into cells without authorization. At present, I doubt that any molecular geneticist would dream of doing a gene transplant without a "vector" to carry it across the membrane barrier.

Since big molecules are supposed to be excluded from cells, it's only the "free hormone" which can find its specific port of entry into the cell, where another cliché says it must travel into the nucleus, to react with a specific site to activate the specific genes through which its effects will be expressed.

I don't know of any hormone that acts that way. Thyroid, progesterone, and estrogen have many immediate effects that change the cell's functions long before genes could be activated.

Transthyretin, carrying the thyroid hormone, enters the cell's mitochondria and nucleus (Azimova, et al., 1984, 1985). In the nucleus, it immediately causes generalized changes in the structure of chromosomes, as if preparing the cell for major adaptive changes. Respiratory activation is immediate in the mitochondria, but as respiration is stimulated, everything in the cell responds, including the genes that support respiratory metabolism. When the membrane people have to talk about the entry of large molecules into cells, they use terms such as "endocytosis" and "translocases," that incorporate the assumption of the barrier. But people who actually investigate the problem generally find that "diffusion," "codiffusion," and absorption describe the situation adequately (e.g., B.A. Luxon, 1997; McLeese and Eales, 1996). "Active transport" and "membrane pumps" are ideas that seem necessary to people who haven't studied the complex forces that operate at phase boundaries, such as the boundary between a cell and its environment.

V. Therapy

Years ago it was reported that Armour thyroid, U.S.P., released T3 and T4, when digested, in a ratio of 1:3, and that people who used it had much higher ratios of T3 to T4 in their serum, than people who took only thyroxine. The argument was made that thyroxine was superior to thyroid U.S.P., without explaining the significance of the fact that healthy people who weren't taking any thyroid supplement had higher T3:T4 ratios than the people who took thyroxine, or that our own thyroid gland releases a high ratio of T3 to T4. The fact that the T3 is being used faster than T4, removing it from the blood more quickly than it enters from the thyroid gland itself, hasn't been discussed in the journals, possibly because it would support the view that a natural glandular balance was more appropriate to supplement than pure thyroxine.

The serum's high ratio of T4 to T3 is a pitifully poor argument to justify the use of thyroxine instead of a product that resembles the proportion of these substances secreted by a healthy thyroid gland, or maintained inside cells. About 30 years ago, when many people still thought of thyroxine as "the thryoid hormone," someone was making the argument that "the thyroid hormone" must work exclusively as an activator of genes, since most of the organ slices he tested didn't increase their oxygen consumption when it was added. In fact, the addition of thyroxine to brain slices suppressed their respiration by 6% during the experiment. Since most T3 is produced from T4 in the liver, not in the brain, I think that experiment had great significance, despite the ignorant interpretation of the author. An excess of thyroxine, in a tissue that doesn't convert it rapidly to T3, has an antithyroid action. (See Goumaz, et al, 1987.) This happens in many women who are given thyroxine; as their dose is increased, their symptoms get worse.

The brain concentrates T3 from the serum, and may have a concentration 6 times higher than the serum (Goumaz, et al., 1987), and it can achieve a higher concentration of T3 than T4. It takes up and concentrates T3, while tending to expel T4. Reverse T3 (rT3) doesn't have much ability to enter the brain, but increased T4 can cause it to be produced in the brain. These observations suggest to me that the blood's T3:T4 ratio would be very "brain favorable" if it approached more closely to the ratio formed in the thyroid gland, and secreted into the blood. Although most synthetic combination thyroid products now use a ratio of four T4 to one T3, many people feel that their memory and thinking are clearer when they take a ratio of about three to one. More active metabolism probably keeps the blood ratio of T3 to T4 relatively high, with the liver consuming T4 at about the same rate that T3 is used.

Since T3 has a short half life, it should be taken frequently. If the liver isn't producing a noticeable amount of T3, it is usually helpful to take a few micorgrams per hour. Since it restores respiration and metabolic efficiency very quickly, it isn't usually necessary to take it every hour or two, but until normal temperature and pulse have been achieved and stabilized, sometimes it's necessary to take it four or more times during the day. T4 acts by being changed to T3, so it tends to accumulate in the body, and on a given dose, usually reaches a steady concentration after about two weeks.

An effective way to use supplements is to take a combination T4-T3 dose, e.g., 40 mcg of T4 and 10 mcg of T3 once a day, and to use a few mcg of T3 at other times in the day. Keeping a 14-day chart of pulse rate and temperature allows you to see whether the dose is producing the desired response. If the figures aren't increasing at all after a few days, the dose can be increased, until a gradual daily increment can be seen, moving toward the goal at the rate of about 1/14 per day

VI. Diagnosis

In the absence of commercial techniques that reflect thyroid physiology realistically, there is no valid alternative to diagnosis based on the known physiological indicators of hypothyroidism and hyperthyroidism. The failure to treat sick people because of one or another blood test that indicates "normal thyroid function," or the destruction of patients' healthy thyroid glands because one of the tests indicates hyperthyroidism, isn't acceptable just because it's the professional standard, and is enforced by benighted state licensing boards.

Toward the end of the twentieth century, there has been considerable discussion of "evidence-based medicine." Good judgment requires good information, but there are forces that would over-rule individual judgment as to whether published information is applicable to certain patients. In an atmosphere that sanctions prescribing estrogen or insulin without evidence of an estrogen deficiency or insulin deficiency, but that penalizes practitioners who prescribe thyroid to correct symptoms, the published "evidence" is necessarily heavily biased. In this context, "meta-analysis" becomes a tool of authoritarianism, replacing the use of judgment with the improper use of statistical analysis.

Unless someone can demonstrate the scientific invalidity of the methods used to diagnose hypothyroidism up to 1945, then they constitute the best present evidence for evaluating hypothyroidism, because all of the blood tests that have been used since 1950 have been.shown to be, at best, very crude and conceptually inappropriate methods.

Thomas H. McGavack's 1951 book, The Thyroid, was representative of the earlier approach to the study of thyroid physiology. Familiarity with the different effects of abnormal thyroid function under different conditions, at different ages, and the effects of gender, were standard parts of medical education that had disappeared by the end of the century. Arthritis, irregularities of growth, wasting, obesity, a variety of abnormalities of the hair and skin, carotenemia, amenorrhea, tendency to miscarry, infertility in males and females, insomnia or somnolence, emphysema, various heart diseases, psychosis, dementia, poor memory, anxiety, cold extremities, anemia, and many other problems were known reasons to suspect hypothyroidism. If the physician didn't have a device for measuring oxygen consumption, estimated calorie intake could provide supporting evidence. The Achilles' tendon reflex was another simple objective measurement with a very strong correlation to the basal metabolic rate. Skin electrical resistance, or whole body impedance wasn't widely accepted, though it had considerable scientific validity.

A therapeutic trial was the final test of the validity of the diagnosis: If the patient's symptoms disappeared as his temperature and pulse rate and food intake were normalized, the diagnostic hypothesis was confirmed. It was common to begin therapy with one or two grains of thyroid, and to adjust the dose according to the patient's response. Whatever objective indicator was used, whether it was basal metabolic rate, or serum cholesterol. or core temperature, or reflex relaxation rate, a simple chart would graphically indicate the rate of recovery toward normal health.

REFERENCES

McGavack, Thomas Hodge.: The thyroid,: St. Louis, Mosby, 1951. 646 p. ill.Several chapters contributed by various authors.Call Numbers WK200 M145t 1951 (Rare Book).

Endocrinology 1979 Sep; 105(3): 605-12. Carrier-mediated transport of thyroid hormones through the rat blood-brain barrier: primary role of albumin-bound hormone. Pardridge WM.

Endocrinology 1987 Apr;120(4):1590-6. Brain cortex reverse triiodothyronine (rT3) and triiodothyronine concentrations under steady state infusions of thyroxine and rT3. Goumaz MO, Kaiser CA, Burger A.G.

J Clin Invest 1984 Sep;74(3):745-52. Tracer kinetic model of blood-brain barrier transport of plasma protein-bound ligands. Empiric testing of the free hormone hypothesis. Pardridge WM, Landaw EM. Previous studies have shown that the fraction of hormone or drug that is plasma protein bound is readily available for transport through the brain endothelial wall, i.e., the blood-brain barrier (BBB). To test whether these observations are reconcilable with the free-hormone hypothesis, a tracer-kinetic model is used Endocrinology 113(1), 391-8, 1983, Stimulation of sugar transport in cultured heart cells by triiodothyronine (T2) covalently bound to red blood cells and by T3 in the presence of serum, Dickstein Y, Schwartz H, Gross J, Gordon A.

Endocrinology 1987 Sep; 121(3): 1185-91. Stereospecificity of triiodothyronine transport into brain, liver, and salivary gland: role of carrier- and plasma protein-mediated transport. Terasaki T, Pardridge WM. J. Neurophysiol 1994 Jul;72(1):380-91. Film autoradiography identifies unique features of [125I]3,3'5'-(reverse) triiodothyronine transport from blood to brain. Cheng LY, Outterbridge LV, Covatta ND, Martens DA, Gordon JT, Dratman MB

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Mech Ageing Dev 1990 Mar 15;52(2-3):141-7. Blood-brain transport of triiodothyronine is reduced in aged rats. Mooradian AD Geriatrics Section, Tucson VA Medical Center, AZ.

Endocrinology 1987 Sep;121(3):1185-91. Stereospecificity of triiodothyronine transport into brain, liver, and salivary gland: role of carrier- and plasma protein-mediated transport. Terasaki T, Pardridge WM. J Clin Invest 1984 Sep;74(3):745-52. Tracer kinetic model of blood-brain barrier transport of plasma protein-bound ligands. Empiric testing of the free hormone hypothesis. Pardridge WM, Landaw EM.

Endocrinology 1980 Dec;107(6):1705-10. Transport of thyroid and steroid hormones through the blood-brain barrier of the newborn rabbit: primary role of protein-bound hormone. Pardridge WM, Mietus LJ. Endocrinology 1979 Sep; 105(3): 605-12. Carrier-mediated transport of thyroid hormones through the rat blood-brain barrier: primary role of albumin-bound hormone. Pardridge WM.

Endocrinology 1975 Jun;96(6):1357-65. Triiodothyronine binding in rat anterior pituitary, posterior pituitary, median eminence and brain. Gordon A, Spira O.

Endocr Rev 1989 Aug;10(3):232-74. The free hormone hypothesis: a physiologically based mathematical model. Mendel CM. Biochim Biophys Acta 1991 Mar 4;1073(2):275-84. Transport of steroid hormones facilitated by serum proteins. Watanabe S, Tani T, Watanabe S, Seno M Kanagawa.

D Novitzky, H Fontanet, M Snyder, N Coblio, D Smith, V Parsonnet, Impact of triiodothyronine on the survival of high-risk patients undergoing open heart surgery, Cardiology, 1996, Vol 87, Iss 6, pp 509-515. Biochim Biophys Acta 1997. Jan 16;1318(1-2):173-83 Regulation of the energy coupling in mitochondria by some steroid and thyroid hormones. Starkov AA, Simonyan RA, Dedukhova VI, Mansurova SE, Palamarchuk LA, Skulachev VP

Thyroid 1996 Oct;6(5):531-6. Novel actions of thyroid hormone: the role of triiodothyronine in cardiac transplantation. Novitzky D. Rev Med Chil 1996 Oct;124(10):1248-50. [Severe cardiac failure as complication of primary hypothyroidism]. Novik V, Cardenas IE, Gonzalez R, Pena M, Lopez Moreno JM.

Cardiology 1996 Nov-Dec;87(6):509-15. Impact of triiodothyronine on the survival of high-risk patients undergoing open heart surgery. Novitzky D, Fontanet H, Snyder M, Coblio N, Smith D, Parsonnet V Curr Opin Cardiol 1996 Nov;11(6):603-9. The use of thyroid hormone in cardiac surgery. Dyke C

N Koibuchi, S Matsuzaki, K Ichimura, H Ohtake, S Yamaoka. Ontogenic changes in the expression of cytochrome c oxidase subunit I gene in the cerebellar cortex of the perinatal hypothyroid rat. Endocrinology, 1996, Vol 137, Iss 11, pp 5096-5108.

Biokhimiia 1984 Aug;49(8):1350-6. [The nature of thyroid hormone receptors. Translocation of thyroid hormones through plasma membranes]. [Article in Russian] Azimova ShS, Umarova GD, Petrova OS, Tukhtaev KR, Abdukarimov A. The in vivo translocation of thyroxine-binding blood serum prealbumin (TBPA) was studied. It was found that the TBPA-hormone complex penetrates-through the plasma membrane into the cytoplasm of target cells. Electron microscopic autoradiography revealed that blood serum TBPA is localized in ribosomes of target cells as well as in mitochondria, lipid droplets and Golgi complex. Negligible amounts of the translocated TBPA is localized in lysosomes of the cells insensitive to thyroid hormones (spleen macrophages). Study of T4- and T3-binding proteins from rat liver cytoplasm demonstrated that one of them has the antigenic determinants common with those of TBPA. It was shown autoimmunoradiographically that the structure of TBPA is not altered during its translocation.

Am J Physiol 1997 Sep;273(3 Pt 1):C859-67. Cytoplasmic codiffusion of fatty acids is not specific for fatty acid binding protein. Luxon BA, Milliano MT [The nature of thyroid hormone receptors. Intracellular functions of thyroxine-binding prealbumin] Azimova ShS; Normatov K; Umarova GD; Kalontarov AI; Makhmudova AA, Biokhimiia 1985 Nov;50(11):1926-32. The effect of tyroxin-binding prealbumin (TBPA) of blood serum on the template activity of chromatin was studied. It was found that the values of binding constants of TBPA for T3 and T4 are 2 X 10(-11) M and 5 X 10(-10) M, respectively. The receptors isolated from 0.4 M KCl extract of chromatin and mitochondria as well as hormone-bound TBPA cause similar effects on the template activity of chromatin. Based on experimental results and the previously published comparative data on the structure of TBPA, nuclear, cytoplasmic and mitochondrial receptors of thyroid hormones as well as on translocation across the plasma membrane and intracellular transport of TBPA, a conclusion was drawn, which suggested that TBPA is the "core" of the true thyroid hormone receptor. It was shown that T3-bound TBPA caused histone H1-dependent conformational changes in chromatin. Based on the studies with the interaction of the TBPA-T3 complex with spin-labeled chromatin, a scheme of functioning of the thyroid hormone nuclear receptor was proposed.

[The nature of thyroid hormone receptors. Thyroxine- and triiodothyronine-binding proteins of mitochondria] Azimova ShS; Umarova GD; Petrova OS; Tukhtaev KR; Abdukarimov A. Biokhimiia 1984 Sep;49(9):1478-85. T4- and T3-binding proteins of rat liver were studied. It was found that the external mitochondrial membranes and matrix contain a protein whose electrophoretic mobility is similar to that of thyroxine-binding blood serum prealbumin (TBPA) and which binds either T4 or T3. This protein is precipitated by monospecific antibodies against TBPA. The internal mitochondrial membrane has two proteins able to bind thyroid hormones, one of which is localized in the cathode part of the gel and binds only T3, while the second one capable of binding T4 rather than T3 and possessing the electrophoretic mobility similar to that of TBPA.

Radioimmunoprecipitation with monospecific antibodies against TBPA revealed that this protein also the antigenic determinants common with those of TBPA. The in vivo translocation of 125I-TBPA into submitochondrial fractions was studied. The analysis of densitograms of submitochondrial protein fraction showed that both TBPA and hormones are localized in the same protein fractions. Electron microscopic autoradiography demonstrated that 125I-TBPA enters the cytoplasm through the external membrane and is localized on the internal mitochondrial membrane and matrix.

[The nature of thyroid hormone receptors. Translocation of thyroid hormones through plasma membranes]. Azimova ShS; Umarova GD; Petrova OS; Tukhtaev KR; Abdukarimov A. Biokhimiia 1984 Aug;49(8):1350-6.. The in vivo translocation of thyroxine- binding blood serum prealbumin (TBPA) was studied. It was found that the TBPA-hormone complex penetrates-through the plasma membrane into the cytoplasm of target cells. Electron microscopic autoradiography revealed that blood serum TBPA is localized in ribosomes of target cells as well as in mitochondria, lipid droplets and Golgi complex. Negligible amounts of the translocated TBPA is localized in lysosomes of the cells insensitive to thyroid hormones (spleen macrophages). Study of T4- and T3-binding proteins from rat liver cytoplasm demonstrated that one of them has the antigenic determinants common with those of TBPA. It was shown autoimmunoradiographically that the structure of TBPA is not altered during its translocation. Endocrinology 1987 Apr;120(4):1590-6 Brain cortex reverse triiodothyronine (rT3) and triiodothyronine concentrations under steady state infusions of thyroxine and rT3. Goumaz MO, Kaiser CA, Burger AG.

Gen Comp Endocrinol 1996 Aug;103(2):200-8 Characteristics of the uptake of 3,5,3'-triiodo-L-thyronine and L-thyroxine into red blood cells of rainbow trout (Oncorhynchus mykiss). McLeese JM, Eales JG.

Prog Neuropsychopharmacol Biol Psychiatry 1998 Feb;22(2):293-310. Increase in red blood cell triiodothyronine uptake in untreated unipolar major depressed patients compared to healthy volunteers. Moreau X, Azorin JM, Maurel M, Jeanningros R.

Prog Neuropsychopharmacol Biol Psychiatry 1998 Feb;22(2):293-310. Increase in red blood cell triiodothyronine uptake in untreated unipolar major depressed patients compared to healthy volunteers. Moreau X, Azorin JM, Maurel M, Jeanningros R.

Biochem J 1982 Oct 15;208(1):27-34. Evidence that the uptake of tri-iodo-L-thyronine by human erythrocytes is carrier-mediated but not energy-dependent. Docter R, Krenning EP, Bos G, Fekkes DF, Hennemann G. J Clin Endocrinol Metab 1990 Dec;71(6):1589-95. Transport of thyroid hormones by human erythrocytes: kinetic characterization in adults and newborns. Osty J, Valensi P, Samson M, Francon J, Blondeau JP. J Endocrinol Invest 1999 Apr;22(4):257-61. Kinetics of red blood cell T3 uptake in hypothyroidism with or without hormonal replacement, in the rat. Moreau X, Lejeune PJ, Jeanningros R.

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<span class="koboSpan" id="kobo.1.1">The transparency of life: Cataracts as a model of age-related disease</span> A R T I C L E

The transparency of life: Cataracts as a model of age-related disease

Cataracts can disappear when the eye's metabolic condition is corrected. A supply of energy is essential to maintain the transparent structure.

Lactic acid increases as carbon dioxide decreases, during a typical energy deficiency. Deficient thyroid, and the resulting excess of cortisol relative to pregnenolone and progesterone, define the energy deficiency.

Increased lactate relative to CO2 in the cell alters cell pH and electrical charge, causing swelling. Swelling and increased water content characterize the cataract.

High altitude is inversely related to cataracts, despite the known role of sunlight in causing cataracts; this is a strong confirmation of the protective role of carbon dioxide.

In the markets around Lake Patzcuaro, they sell green transparent fish, about 6 inches long. When cooked, the meat is white, like ordinary fish. Most fish filets are a little translucent, but are at least cloudy, and usually pink by transmitted light. I dont know how the transparent fish work, because it seems that the blood and the network of blood vessels needed to sustain muscle activity would diffuse the light. Anyway, cooking disrupts the mysteriously ordered state of water and proteins that makes them transparent, roughly the way egg-white loses its transparency when it is cooked. I have never heard a convincing explanation for the opacity of cooked egg-white, either, but anything that disrupts the original structuring of the protein-water interaction will destroy the transparency.

Around 1970, I used a technique called nuclear magnetic resonance (NMR), which is the basis for the procedure known as MRI (magnetic resonance imaging), to compare the state of water in old (uterine) tissue and young tissue. Old tissue predictably contains less water than young tissue, but I found that the water in the old tissue was in a relatively free and uncontrolled state. When tissue swells and takes up water, more of the water is likely to be in this uncontrolled state, and this is one of the things that makes MRI so useful, because tumors, for example, show up vividly because of their large amount of uncontrolled (unbound) water. I suspect that the measurements I made on uterine tissue showed a localized effect, that opposed the general trend toward increased dryness with aging. In the case of cataracts, this is clearly the case: Most of the lens becomes drier with age, but at a certain point there is a reversal, and some of the tissue takes up too much water. Thats why I refer to cataracts as a model of age-related disease, rather than as a model of aging. In this sense, I am including them among the inflammatory diseases of aging--colitis, arthritis, and cancer, for example. MRI now can show developing cataracts before they are visible, because of increased water content in the area.

The lens of the eye is a fairly dense, tough, transparent living structure, which can develop opaque areas, cataracts, as a result of old age, poisoning, radiation, disease, or trauma. The varieties of cataract relate to the causes. Most of the oxidative metabolism of the lens is in or near the epithelial layer that surrounds it. Old-age cataracts most often begin in this region.

Although the efficient oxidative energy metabolism occurs near the surface of the lens, there is a constant flow of fluid through the lens, entering it mainly in the front and back, and leaving on its sides or equator (considering the front and back as the poles, the direction light passes through). Oxygen and nutrients are supplied to the lens by way of this circulation of fluid, entering mostly from the aqueous humor in front (which also supplies the cornea), but also from the vitreous humor behind the lens.

When the flow of nutrients and energy is impaired, the organized state of the protein and water system in the cell is damaged, and an excess of water is taken up by the cells, as the protein content decreases. The loss of organization causes light to be dispersed, with a loss of transparency.

The lens of the eye is usually treated as something so specialized that it is hardly considered to be part of our living substance, just as dentistry has tended to treat teeth as inert things to be approached mechanically, rather than physiologically. The lenss circulatory system is very interesting, because of what it says about the nature of living substance. In the absence of blood vessels, it provides its own flow of nutrients. This flow is reminiscent of the flow of substances through the dentine channels of the teeth, through the axons of nerves (two-way transport in a very narrow channel), and, in some ways recalls the flow of fluids in plants, called guttation (drop formation), which is disturbing to botanists, because it is contrary to the textbook descriptions of proper physiology.

The flow of material through lens cells, dentine canals, and nerve axons should allow us to gain a perspective in which these observable processes become a model for other biological situations in which transport occurs: Kidney, intestine, or the skin of frogs, for example, in which water, ions, and other solutes are moved in considerable quantities.

When cells metabolize, they create gradients. In the cell, electrical, chemical, osmotic, and thermal gradients, for example, are constantly being produced or maintained. The whole substance of the cell is involved in its life processes. Because of prejudices introduced 200 years ago, the life of the cell has been relegated to its membrane (where hypothetical membrane pumps reside) and its nucleus. When the term cell (hollow space) came into use instead of corpuscle (little body), a mind-set came into existence that discounted the importance of most of the living material, and claimed that it was a mere random solution. Random solutions dont do much. The wonderful membrane, under the direction of the nucleus (and its set of instructions), took care of everything.

Whenever assimilation or excretion took place, it was explained by inventing a property possessed by the cell membranes. Therefore, we have physiology textbooks that have an unfounded explanation for everything. Before Copernicus, planetary movements were described as arbitrary "epicycles." They didn't make sense, but people studied them and felt that they were important. "Membrane physiology" is the modern equivalent of the Ptolemaic epicycles.

We know that glucose can be metabolized into pyruvic acid, which, in the presence of oxygen, can be metabolized into carbon dioxide. Without oxygen, pyruvic acid can be converted into lactic acid. The production of lactic acid tends to increase the pH inside the cell, and its excretion can lower the pH outside the cell.

The decrease of carbon dioxide that generally accompanies increased lactic acid, corresponds to increased intracellular pH. Carbon dioxide binds to many types of protein, for example by forming carbamino groups, changing the protein conformation, as well as its electrical properties, such as its isoelectric point. With increased pH, cell proteins become more strongly ionized, tending to separate, allowing water to enter the spaces, in the same way a gel swells in an alkaline solution.

The Bohr-Haldane effect describes the fact that hemoglobin releases oxygen in the presence of carbon dioxide, and releases carbon dioxide in the presence of oxygen. When oxygen is too abundant, it makes breathing more difficult, and one of its effects is to cause carbon dioxide to be lost rapidly. At high altitude, more carbon dioxide is retained, and this makes cellular respiration more efficient.

The importance of carbon dioxide to cell control process, and to the structure of the cell and the structure of proteins in general suggested that degenerative diseases would be less common at high altitude. Wounds and broken bones heal faster at high altitude, but the available statistics are especially impressive in two of the major degenerative conditions, cancer and cataracts.

The two biggest studies of altitude and cataracts (involving 12,217 patients in one study, and 30,565 lifelong residents in a national survey in Nepal) showed a negative correlation between altitude and the incidence of cataract. At high altitude, cataracts appeared at a later age. In Nepal, an increase of a few thousand feet in elevation decreased the incidence of cataracts by 2.7 times. At the same time, it was found that exposure to sunlight increased the incidence of cataracts, and since the intensity of ultraviolet radiation is increased with altitude, this makes the decreased incidence of cataracts even more important.

All of the typical causes of cataracts, aging, poisons, and radiation, decrease the formation of carbon dioxide, and tend to increase the formation of lactic acid. Lactic acid excess is typically found in eyes with cataracts.

The electrical charge on the structural proteins will tend to increase in the presence of lactic acid or the deficiency of carbon dioxide, and the increase of charge will tend to increase the absorption of water.

The lens can survive for a considerable length of time in vitro (since it has its own circulatory system), so it has been possible to demonstrate that changes in the composition of the fluid can cause opacities to form, or to disappear.

Oxidants, including hydrogen peroxide which occurs naturally in the aqueous humor, can cause opacities to form quickly, but they will also disappear quickly in a solution that restores metabolic energy. The lens regulates itself powerfully; for example, it will swell when put into a hypotonic solution, but will quickly adapt, returning to approximately its normal size.

Several years ago, I saw what appeared to be oxidant-induced cataracts. Two women had a very sudden onset of cataracts, and I asked about their diet and supplements; it turned out that one of them had begun taking 500 mg of zinc daily a few months earlier, and the other had begun taking 600 mg of zinc and 250 mg of iron, on her doctors recommendation, just a couple of months before the cataracts appeared.

For some reason, there have been many nutritional supplements sold as cataract remedies in the form of eye drops. I suppose a trace of the material could diffuse through the cornea into the aqueous humor, where it might make a difference in the lenss nutrient supply, but it seems more reasonable to treat the body as a whole, nourishing every part in a balanced way.

Besides living at a high elevation or breathing extra carbon dioxide, the most certain way to increase the amount of carbon dioxide in the eye, and to prevent an excess of lactic acid, is to make sure that your thyroid function is adequate.

One man who took thyroid, USP, and vitamin E told me that his cataracts had regressed, but I havent known other people who tried this.

If a person already has distinct cataracts, it might be worthwhile to experiment with a relatively high degree of hypercapnia, for example, breathing a 5% mixture of CO2 in air.

Carbon dioxide, at higher levels than are normal at sea level, has a profound effect on free radicals, reducing the free radical activity in the blood to approximately zero, before reaching the level that produces acidosis.

There are several situations in which carbon dioxide affects the hydration, water content, of biological materials, that I think give an insight into its effects on the lens. Hydrophilic glycoproteins are involved in each case. These are proteins with attached chains of sugar molecules that make them associate with a large amount of water. In the cornea, increased carbon dioxide strongly protects against swelling. The bulk of the cornea is a connective tissue that is relatively simple and passive compared to the compact cellular structure of the lens, and it is conventional to describe the thin layers of cells on the inside and outside of the cornea as being responsible for the water content of the underlying substance. However, even when the epithelial cells are removed, it has been demonstrated that carbon dioxide is able to prevent corneal swelling. (M.V. Riley, et al., The roles of bicarbonate and CO2 in transendothelial fluid movement and control of corneal thickness," Invest. Ophthalmol. Vis. Sci. 36(1), 103-112, 1995.)

Bronchial mucous secretions are an even simpler system, so it is very interesting that carbon dioxide is recognized as the most powerful regulator of their behavior. (This has important implications for cystic fibrosis, or mucoviscidosis.) Goodman and Gilman (page 1068, Pharmacological Basis of Therapeutics, 2nd Edition, Macmillan Co., 1956), say

"Among inhalants, steam and carbon dioxide have been found to be excellent expectorants. Relative humidity above 85 per cent liquefies sputum, decreases its viscosity...." "Carbon dioxide is the most effective agent of all. It not only lowers the viscosity of tenacious sputum, thereby facilitating expectoration, but it decreases the volume of sputum by promoting its active resorption by bronchial mucosa." "A five to ten per cent concentration of carbon dioxide is adequate and well tolerated if administered at intervals." "Oxygen has been shown to be an antiexpectorant and has effects opposite to those of carbon"

Oxygen tends to displace carbon dioxide from tissue, and is a source of free radicals.

One of the best-known free radical scavenging substances that has been widely used as a drug is iodide. It has been used to treat asthma, parasites, syphilis, cancer, Graves disease, periodontal disease, and arteriosclerosis. Diseases that produce tissue overgrowth associated with inflammation--granulomas--have been treated with iodides, and although the iodide doesnt necessarily kill the germ, it does help to break down and remove the granuloma. Leprosy and syphilis were among the diseases involving granulomas* that were treated in this way. In the case of tuberculosis, it has been suggested that iodides combine with unsaturated fatty acids which inhibit proteolytic enzymes, and thus allow for the removal of the abnormal tissue.

In experimental animals, iodide clearly delays the appearance of cataracts. (Buchberger, et al., 199l.)

Inflammation, edema, and free radical production are closely linked, and are produced by most things that interfere with energy production.

Endotoxin, produced by bacteria, mainly in the intestine, disrupts energy production, and promotes maladaptive inflammation. The wide spectrum of benefit that iodide has, especially in diseases with an inflammatory component, suggests first that it protects tissue by blocking free radical damage, but it also suggests the possibility that it might specifically protect against endotoxin.

There are subtler differences in transparence that probably have a variety of causes, but differences in water content or hydration might be involved in the lower transparency that has been seen in women's lenses. Estrogen, which tends to produce edema and hypotonic body fluids, also increases prolactin production. Prolactin is involved in water and electrolyte regulation, and it has been found to accelerate the development of experimental cataracts. (M. C. Ng, et al, 1987.) These hormones are associated with the calcification of soft tissues, and cataracts contain very high levels of calcium. (Avarachan and Rawal, 1987; Hightower and Reddy, 1982.)

Estrogen is strongly associated with free radical processes, calcium mobilization, and acetylcholine release, all of which are involved in the process of excitoxicity. Alvarez, et al., (1996) have shown a possible involvement of acetylcholine in calcium mobilization in the lens.

Serotonin is another regulatory substance strongly associated with prolactin and estrogen, and it also can be involved in disrupting the metabolism of the lens. This is one of the potential dangers in using supplemental tryptophan. (Candia, et al., 1980.)

Old age commonly involves some changes in the color of tissues--loss of pigment from hair and skin, with appearance of new pigment (age pigment, lipofuscin), which may appear as liver spots. But there is also a tendency of the toenails, fingernails, teeth, and lenses to turn yellow or brown. Some of this dark material seems to be age pigment, derived from unsaturated fatty acids, but other components have been identified, for example, tryptophan from damaged proteins. The Maillard reaction (similar to the browning that occurs in bread crust) has often been mentioned in relation to aging, and involves the combination of protein amino groups with sugars. But the browning of the lens tends to be associated with the general age related drying of the lens, it isnt irregularly distributed, and it doesnt significantly harm vision.

When I first heard about the age-related browning of the lens, I thought that the experience of colors would be affected, so I devised a test in which the relative darkness of blue and yellow could be judged in comparison with a graded strip of shades of grey.

After people of ages ranging from 10 to 80 had given exactly the same matches, I realized that the nervous system probably corrects for the yellow filter effect of the brown lens.

The browning of tissues will be the subject of another newsletter.

Among the interesting causes of cataracts: Tamoxifen and hypotonic fluids, sodium deficiency; toxicity of tryptophan; oxidants (metals, hydrogen peroxide, PUFA); diabetes, photosensitizers and sunlight; excess calcium, deficient magnesium. Excess cortisol. Radiation. Arachidonic and linoleic acids in other situations have been found to block cells' regulation of their water content. Hypothyroidism tends to increase the activity of serotonin, estrogen, prolactin, calcium, and the tendency of tissues to retain water, and to decrease the level of ATP.

Among the factors that probably have a role in preventing cataracts: Thyroid, progesterone, pregnenolone, vitamin E, iodide, pyruvate. Increasing the carbon dioxide lowers the cells pH, and tends to resist swelling. Palmitic acid (a saturated fat that can be synthesized by our tissues) is normally oxidized by the lens. Calcium blockers experimentally prevent cataracts, suggesting that magnesium and thyroid (which also act to exclude calcium from cells) would have the same effect.

Thyroid hormone is essential for maintaining adequate carbon dioxide production, for minimizing lactic acid, cortisol and prolactin, for regulating calcium and magnesium, for avoiding hypotonicity of the body fluids, and for improving the ratio of palmitic acid to linoleic acid.

.

REFERENCES

Inhibition of ionic transport and ATPase activities by serotonin analogues in the isolated toad lens, Candia OA; Lanzetta PA; Alvarez LJ; Gaines W, Biochim Biophys Acta (602)2, 389-400, 1980. Tryptamine, 5-methyltryptamine and 5-methoxytryptamine had dual effects: 1 mM in the posterior bathing solution depressed the potential difference of the posterior face of the lens, which resulted in an increase in the translenticular potential difference and short-circuit current; 1 mM in the anterior solution (in contact with the lens epithelium) produced a quick and pronounced reduction of the potential difference of the anterior face. This resulted in a 90-100% decline of the translenticular short-circuit current. Serotonin and tryptamine were then tested for their effect on the ATPases of lens epithelium. Both amines inhibited the enzymes with tryptamine at 5 mM completely inhibiting all ATPase activity. Since tryptophan is transported from the aqueous humor into the lens and may be converted by lens enzymes to serotonin and tryptamine, these findings may have physiological implications in cataractogenesis.

Effects of Ca2+ on rabbit translens short-circuit current: evidence for a Ca2+ inhibitable K+ conductance," Alvarez LJ; Candia OA; Zamudio AC, Curr Eye Res, 1996 Dec, 15:12, 1198-207. PURPOSE: To characterize the effects of medium Ca2+ levels on rabbit lens electrical properties. Overall, these results suggest that lens Ca2(+)-mobilizing agents (e.g. acetylcholine) could trigger the inhibition of epithelial K+ conductance(s) by the direct action of Ca2+ on K+ channels."

Effects of Ca2+ on rabbit translens short-circuit current: evidence for a Ca2+ inhibitable K+ conductance, Alvarez LJ; Candia OA; Zamudio AC, Curr Eye Res, 1996 Dec, 15:12, 1198-207. PURPOSE: To characterize the effects of medium Ca2+ levels on rabbit lens electrical properties. Overall, these results suggest that lens Ca2(+)-mobilizing agents (e.g. acetylcholine) could trigger the inhibition of epithelial K+ conductance(s) by the direct action of Ca2+ on K+ channels.

D600 increases the resistance associated with the equatorial potassium current of the lens, Walsh SP; Patterson JW, Exp Eye Res, 1992 Jul, 55:1, 81-5 This effect is similar to that produced by quinine and by a calcium-free medium, and is attributed to the prevention of an increase in the calcium-dependent conductance produced by pCMPS.

Effects of hydrogen peroxide oxidation and calcium channel blockers on the equatorial potassium current of the frog lens, Walsh SP; Patterson JW, Exp Eye Res, 1994 Mar, 58:3, 257-65. Hydrogen peroxide, in concentrations of 10-1000 microM, produces two major changes in the current-voltage relationships associated with the equatorial potassium current of the lens. First, the resting and reversal potentials become more negative than they were prior to treatment with hydrogen peroxide and second, the membrane resistance related to the equatorial current is decreased. The shift in the resting and reversal potentials is in the opposite direction from that produced by ouabain. Based on the Nernst equation, the shift in the reversal potential suggests that there is an increase in the concentration of potassium in the lens. The 86Rb uptake and efflux are increased. These observations suggest that hydrogen peroxide stimulates the Na,K-pump. The decrease in membrane resistance is inhibited by 100 microM of quinine, a calcium-dependent potassium channel blocker, and does not decrease in a calcium-free medium. This suggests that the decrease in resistance may be secondary to an increase in lenticular calcium. These effects of hydrogen peroxide are similar to those of p-chloromercuriphenylsulfonate (pCMPS), a nearly impermeant sulfhydryl binding agent, and suggest that permeant hydrogen peroxide may increase calcium influx by acting on sulfhydryl groups on the outer surface of lens membranes. Verapamil, a calcium channel blocker, is reported to prevent cataract formation.

Effect of prolactin on galactose cataractogenesis, Ng MC; Tsui JY; Merola LO; Unakar NJ phthalmic Res 19:2, 82-94, 1987. Prolactin has been known to affect the water and electrolyte balance. Because increased lens hydration has been shown to be a common phenomenon in most, if not all types of cataracts, we have been interested in investigating a possible role of prolactin in sugar cataract induction and progression. For this study, we have used morphological and biochemical approaches. The prolactin delivery method involved intraperitoneal implantation of one or more pellets in Sprague-Dawley female rats. Following implantation of the desired number of prolactin or control (nonprolactin) pellets, animals were either fed galactose and lab chow, or lab chow diet. Gross morphological observations of whole lenses, slit-lamp examination of lenses and light microscopic analysis of lens sections showed that in the galactose-fed prolactin group, galactose associated alteration progressed faster and total opacification (mature cataract development) was achieved earlier than in the nonprolactin group. The levels of galactose and dulcitol were higher in the lenses of galactose-fed prolactin treated rats as compared to lenses from nonprolactin (control) rats. No significant difference in lens Na+-K+ ATPase activity between the prolactin and nonprolactin group was observed. Our results indicate that prolactin accelerates galactose-induced cataractogenesis in rats."

"A hypothetical mechanism for toxic cataract due to oxidative damage to the lens epithelial membrane," Bender CJ Med Hypotheses, 1994 Nov, 43:5, 307-11 Lenticular opacities can be induced by numerous external agents that coincide with those that catalyze oxidative damage to lipids. One of the consequences of lipid peroxidation is that the affected membrane is rendered more permeable to protons. A proton leak in the tight epithelium of lens would uncouple the Na+/K(+)-ATPases that regulate the water and ionic content of the bounded tissue. Once regulatory control of the osmotic pressure is lost, the phase state of the cell's soluble proteins would change, leading to refractive changes or, in extreme cases, precipitation. The same does not occur in cornea because the stroma is an extracellular polymer blend rather than solution of soluble polymers. Polymeric phase transitions in the cornea require that divalent cations pass the epithelial membrane, which can occur only through the action of ionophores.

Tsubota K; Laing RA; Kenyon KR Invest Ophthalmol Vis Sci, 1987 May, 28:5, 785-9, Abnormalities in glucose metabolism are thought to be among the main causes of cataract formation. The authors have made noninvasive biochemical measurements of the lens that provide information concerning glucose metabolism in the lens epithelium. The autofluorescence of reduced pyridine nucleotides (PN) and oxidized flavoproteins (Fp) within the rabbit lens were noninvasively measured as a function of depth using redox fluorometry. The peak of the autofluorescence at 440 nm (excited at 360 nm) and 540 nm (excited at 460 nm) were determined at the lens epithelium. When 8 mM sodium pentobarbital, a known inhibitor of mitochondrial respiration, was applied to the lens, the autofluorescence peak at 440 nm increased and that at 540 nm decreased. The 440 nm autofluorescence is thought to be from reduced pyridine nucleotides, whereas the 540 nm autofluorescence is from the oxidized flavoprotein. Blocking lens respiration with pentobarbital caused an increase in the PN/Fp ratio by a factor of 3 within 3.5 hr after pentobarbital application.

[Use of pyrimidine bases and ATP for conservative treatment of early cataracts] Larionov LN Oftalmol Zh, 1977, 32:3, 221-2

Concentrations of some ribonucleotides, L-lactate, and pyruvate in human senile cataractous lenses with special reference to anterior capsular/subcapsular opacity, Laursen AB Acta Ophthalmol (Copenh), 1976 Dec, 54:6, 677-92 The concentrations of some ribonucleoside tri- and diphosphates, adenosine-5'-monophosphate, L-lactate and pyruvate were determined in human senile cataractous lenses removed during cataract operations. Pyruvate concentrations were found to be negligible (median = 56 mumol/kg lens wet weight) in 15 human senile cataractous lenses. On the basis of correlations between the biomicroscopic appearances of the senile cataractous lenses (N = 80) and the concentrations and ratios of the metabolites in question, the following classification was found to be justified: 1. Immature cataractous lenses without anterior capsular/subcapsular opacity: high levels of ribonucleoside triphosphates (RTP), high sums of RTP, ribonucleoside diphosphates (RDP), and adenosine 5'-monophosphate (AMP) as well as high levels of L-lactate and high ratios of L-lactate in the lens/L-lactate in the aqueous. 2. Immature cataractous lenses with anterior capsular/subcapsular opacity; intermediate levels of RTP, intermediate values for the sums of RTP, RDP, and AMP, high L-lactate levels, and intermediate values of the ratios of L-lactate in the lens/L-lactate in the aqueous.

Sulochana KN; Ramakrishnan S; Vasanthi SB; Madhavan HN; Arunagiri K; Punitham R, First report of congenital or infantile cataract in deranged proteoglycan metabolism with released xylose, Br J Ophthalmol, 1997 Apr, 81:4, 319-23." "Of 220 children of both sexes below 12 years of age, with congenital or infantile cataract treated in Sankara Nethralaya, Madras, India, during a period of 2 years, 145 excreted fragments of GAG (heparan and chondroitin sulphates) in their urine. There was no such excretion among the control group of 50 children. The same was found accumulated in the blood and lenses of affected children. In addition, xylose was present in small amounts in the urine and blood and xylitol was present in the lens. There was a significant elevation in the activity of beta glucuronidase in lymphocytes and urine, when compared with normals. All the above findings suggest deranged proteoglycan metabolism. As the urine contained mostly GAG fragments and very little xylose, Benedict's reagent was not reduced. This ruled out galactosaemia.CONCLUSION: An increase of beta glucuronidase activity might have caused extensive fragmentation of GAG with resultant accumulation in the blood and lens and excretion in urine. Small amounts of xylose may have come from xylose links between GAG and core protein of proteoglycans. Owing to their polyanionic nature, GAG fragments in the lens might abstract sodium, and with it water, thereby increasing the hydration of the lens. Excessive hydration and the osmotic effect of xylitol from xylose might cause cataract. While corneal clouding has been reported in inborn acid mucopolysaccharidosis, congenital or infantile cataract with deranged metabolism of proteoglycans (acid mucopolysaccharide-xylose-protein complex) is reported in children for the first time."

"State of electrolytes, osmotic balance and the activity of ATPase in the lenses of selenite--induced cataracts," Avarachan PJ; Rawal UM Indian J Ophthalmol, 1987, 35:5-6, 210-3. "Selenite-cataracts incorporated many morphological characteristics observed in human senile catracts. Progressive elevation of sodium, marked loss of potassium, several fold increment of calcium; considerable loss of magnesium levels, a dose-response reduction of total-ATPase activity and significant hydration are the important features observed in the lens during the progressive treatment of selenite. The sodium-potassium imbalance is found to be a secondary effect during the development of cataract and is suggested to bring about by an abnormal accumulation of calcium ions and inactivation of transport enzyme. The calcium activated proteases could be the promoting factor for the proteolysis and insolubilization of lens proteins in the inducement of selenite cataract. The impact of selenite on the SH containing ATPase anzymes could be the cause of impairment in energy metabolism, derangement of electrolytes and osmotic imbalance which, in turn, accelerate the cortical involvement of lens opacities."

"Glucose metabolism by human cataracts in culture," Wolfe JK; Chylack LT Jr Exp Eye Res 43:2, 243-9, 1986. Metabolism in human senile cataracts has been studied using uniformly labeled [14C]glucose. Intracapsularly extracted lenses were cultured in TC-199 media with a glucose concentration of 5.5 mM. Results show that lactate production accounts for 97% of the glucose metabolized. Under these standard incubation conditions there is negligible accumulation of alpha-glycerol phosphate, glucose-6-phosphate, and sorbitol. The rate of lactate production was found to be relatively uniform over a range of cataract severities which were determined from the CCRG classification. The effects of several perturbants in the medium were measured. An ATP concentration of 3 mM was found to inhibit lactate production."

M. V. Riley, et al., "The roles of bicarbonate and CO2 in transendothelial fluid movement and control of corneal thickness," Invest. Ophthalmol. Vis. Sci. 36(1), 103-112, 1995. "The equilibrium thickness of deepithelialized corneas swollen with HCO-/CO2 on both surfaces was 35 microns less than that of corneas swollen in HPO4-." "Normal corneal thickness can be maintained in vitro only in media that contain HCO3- at concentrations of more than 20 mM."

"The effect of X-irradiation on the sodium-potassium-activated adenosine triphosphatase (Na-K-ATPase) activity in the epithelium of the rat lens. A histochemical and biochemical study," Palva M Acta Ophthalmol (Copenh), 1978 Jun, 56:3, 431-8. "The epithelial Na-K-ATPase activity of the rat lens was studied after X-irradiation at intervals of three to ninety days. The enzyme was demonstrated histochemically by light microscopy and it was measured biochemically by a fluorometric method. Neither histochemical nor biochemical changes of Na-K-ATPase content of the lens epithelium were observed during the development of cataract. In whole-mount preparations the enzyme activity was localized in the cell membranes. However, one month after radiation a few peripheral cells had in addition a precipitated over the whole cell. The unaltered Na-K-ATPase content in the epithelium suggests that the hydration of the lens after X-irradiation is primarily caused by changes in the passive permeability properties of the cell membranes and not by a decreased capacity of the activity cation pump."

McNamara NA; Polse KA; Bonanno JA Stromal acidosis modulates corneal swelling. Invest Ophthalmol Vis Sci, 1994 Mar, 35:3, 846-50 "PURPOSE. Studies have shown that stromal acidosis reduces the rate of corneal thickness recovery after induced edema, providing the first human in vivo evidence that corneal pH can influence corneal hydration control. This finding raises the question of the possible effect that pH may have on induced corneal swelling. To explore this question, the corneal swelling response to hypoxia was measured while stromal pH was controlled. METHODS. Corneal edema and stromal acidosis was induced in ten subjects by passing a mixture of nitrogen and carbon dioxide gas across the eyes through tight-fitting goggles. One eye of each subject received 100% N2, whereas the contralateral eye received a mixture of 95% N2 and 5% CO2. Exposures of 95% N2 + 5% CO2 lower pH on average to 7.16 versus 7.34 for 100% N2 alone. Before and after 2.5 hours of gas exposure, central corneal thickness (CCT) was measured. RESULTS. Eyes exposed to the lower pH environment (eg, N2 + CO2) developed less change in CCT compared to the eyes receiving N2 alone. Overall increase in CCT was 29.9 +/- 5.3 microns for eyes exposed to the 95% N2 + 5% CO2 gas mixture, versus 37.1 +/- 4.8 microns for 100% N2 eyes (P < 0.0001). CONCLUSIONS. The corneal swelling response to hypoxia can be reduced by lowering stromal pH. Because changes in corneal pH alone have not been found to alter steady-state CCT, it is proposed that pH exerts its effect only under non-steady-state conditions (ie, corneal swelling and deswelling). This suggests that acidosis may produce changes in the rate of lactate metabolism or alter endothelial hydraulic conductivity."

Buchberger W; Winkler R; Moser M; Rieger G, "Influence of iodide on cataractogenesis in Emory mice," Ophthalmic Res, 1991, 23:6, 303-8. Cataract development was studied in two groups of Emory mice by periodical biomicroscopic examinations (beginning at 5 weeks of age) and by a final evaluation of water-soluble SH groups in the lenses. The experimental group was given 256 micrograms iodide/kg body weight with the drinking water throughout the study. The untreated control group received tap water. Iodide treatment induced a delay of cataract formation...." "A still significant difference in the degree of cataract was also found between the two groups at week 47 of age. No difference was found in the content of water-soluble SH groups. The results are discussed in relation to the known antioxidant and .OH-scavenging effect of iodide and to the oxidative changes in the lens occurring during progression of cataract development."

"[The chemical nature of the fluorescing products accumulating in the lipids of the crystalline lenses of mice with hereditary cataract]," Shvedova AA; Platonov ES; Polianskii NB; Babizhaev MA; Kagan VE Biull Eksp Biol Med, 1987 Mar, 103:3, 301-4. "The content of diene conjugates (lipid hydroperoxides) was shown to be significantly higher in lipids extracted from the lenses of mice with hereditary cataract than in the controls. The same holds true for characteristics of fluorescence of the end-product of lipid peroxidation." "It was established that high-molecular weight fluorescent fractions corresponded to lipid components of lipofuscin-like pigments. NMR and mass spectrometry of low-molecular weight fractions suggested that they contained predominantly products of free radical oxidation of long chain polyunsaturated fatty acids (C22:6). "

"Formation of N'-formylkynurenine in proteins from lens and other sources by exposure to sunlight," Pirie A Biochem J, 1971 Nov, 125:1, 203-8.

"Lipid fluorophores of the human crystalline lens with cataract." Babizhayev MA Graefes Arch Clin Exp Ophthalmol, 1989, 227:4, 384-91 "It has been established that the development of cataract is accompanied by the formation of various fluorophores in the lipid fraction of the lens. These lipid-fluorescing products have been separated chromatographically according to polarity and molecular weight. It is shown that the initial stages of the development of cataract are characterized by the appearance of lipid fluorophores in the near ultraviolet and violet regions of the spectrum (excitation maximum 302-330 nm, emission maximum 411 nm) with low polarity and a small molecular weight; the maturing of the cataract is characterized by an increase in the intensity of the long-wave fluorescence of the lipids in the blue-green region (430-480 nm) and by the formation of polymeric high-molecular-weight fluorescing lipid products with high polarity. It has been demonstrated that the appearance of lipid fluorophores in the crystalline lens is associated with the free radical oxidative modification of the phospholipids and fatty acids in cataract."

"Incidence of cataracts in the mobile eye hospitals of Nepal," Brandt F; Malla OK; Pradhan YM; Prasad LN; Rai NC; Pokharel RP; Lakhe S, Graefes Arch Clin Exp Ophthalmol, 1982, 218:1, 25-7 The incidence of cataract in Nepal was determined from data collected in 14 mobile eye hospitals (called 'eye camps'). Of a total of 12,217 patients examined in the out-patient department (OPD), cataract surgery was performed on 2,163. The percentage of cataract patients in the OPD was less in the mountains (13.8%) than in the Tarai plains (19.8%). In the inhabitants of the mountains, the majority of whom belong to the Tibeto-Birman race, cataracts appeared at a significantly later age in both males and females compared to the people of the plains, who are mostly Indo-Aryan. Cataracts were discovered in both groups at a younger age in women than in men."

"Associations among cataract prevalence, sunlight hours, and altitude in the Himalayas." Brilliant LB; Grasset NC; Pokhrel RP; Kolstad A; Lepkowski JM; Brilliant GE; Hawks WN; Pararajasegaram R., Am J Epidemiol 118:2, 250-64 1983. "The relationship between cataract prevalence, altitude, and sunlight hours was investigated in a large national probability sample survey of 105 sites in the Himalayan kingdom of Nepal, December 1980 through April 1981. Cataract of senile or unknown etiology was diagnosed by ophthalmologists in 873 of 30,565 full-time life-long residents of survey sites. Simultaneously, the altitude of sites was measured using a standard mountain altimeter. Seasonally adjusted average daily duration of sunlight exposure for each site was calculated by a method which took into account latitude and obstructions along the skyline. Age- and sex-standardized cataract prevalence was 2.7 times higher in sites at an altitude of 185 meters or less than in sites over 1000 meters. Cataract prevalence was negatively correlated with altitude (r = -0.533, p less than 0.0001). However, a positive correlation between cataract prevalence and sunlight was observed (r = 0.563, p less than 0.0001). Sites with an average of 12 hours of sunlight exposure had 3.8 times as much cataract as sites with an average of only seven hours of exposure. Sunlight was blocked from reaching certain high altitude sites by tall neighboring mountains. "

"The untenability of the sunlight hypothesis of cataractogenesis," Harding JJ Doc Ophthalmol 88:3-4, 345-9, 1994-95. "The excess prevalence of cataract in third world countries led early this century to the hypothesis that sunlight causes cataract. The hypothesis, which ignored differences in diet, culture, poverty and prevalence of other diseases such as diarrhoea, received little support until about thirty years ago when biochemical studies were set up to explore the browning of lens proteins, which is a common feature of cataract on the Indian subcontinent. Initially these studies were encouraging in that exposure to sunlight caused some changes seen in cataractous lenses, but eventually the hypothesis was rejected because the first change in the laboratory was the destruction of tryptophan, but this was not found in brown cataract lenses. A brown nuclear cataract could not be produced artificially in the laboratory using sunlight or UV exposure. Exposure of laboratory animals has produced lens opacities, but in most experiments the doses required have also caused keratitis, conjunctivitis, iritis and inflammation. The cornea seems more sensitive than the lens, which is not surprising, as it gets the first chance to absorb damaging UV. The biochemical rejection of the hypothesis coincided with the re-start of the epidemiological studies. Most of these are simply latitude studies and are no more than a repeat of what was available sixty years ago. They do not help to find a cause. Two studies showed that cataract was less common at higher altitude in the Himalayas, but unfortunately led to opposing conclusions. On the basis of common knowledge that UV exposure was greater at higher altitude, the first altitude study led to the rejection of the sunlight hypothesis."

"Anticataract action of vitamin E: its estimation using an in vitro steroid cataract model," Ohta Y; Okada H; Majima Y; Ishiguro I Ophthalmic Res, 1996, 28 Suppl 2:, 16-25 The aim of this study was to estimate the anticataract action of vitamin E using an in vitro methylprednisolone (MP)-induced cataract model. The same severity of early cortical cataract was induced in lenses isolated from male Wistar rats aged 6 weeks by incubation with MP (1.5 mg/ml) in TC-199 medium. The cataractous lenses showed slight increases in lipid peroxide (LPO) content and Na+/K+ ratio and slight decreases in reduced glutathione (GSH) content and glyceraldehyde-3-phosphate dehydrogenase (GAP-DH), a sensitive index of oxidative stress, and Na+,K(+)-ATPase activities. When the cataractous lenses were further incubated in TC-199 medium with and without vitamin E (250 micrograms/ml) for 48 h, the progression of cataract was prevented in the vitamin E-treated lenses, but not in the vitamin E-untreated lenses. The vitamin E-untreated lenses showed a decrease in vitamin E content and an increase in water content in addition to further increases in LPO content and Na+/K+ ratio and further decreases in GSH content and GAP-DH and Na+,K(+)-ATPase activities. In contrast, the changes of these components and enzymes except for GSH were attenuated in the vitamin E-treated lenses. From these results, it can be estimated that vitamin E prevents in vitro cataractogenesis in rat lenses treated with MP by protecting the lenses against oxidative damage and loss of membrane function. "

"Prevention of oxidative damage to rat lens by pyruvate in vitro: possible attenuation in vivo," Varma SD; Ramachandran S; Devamanoharan PS; Morris SM; Ali AH,.Curr Eye Res, 1995 Aug, 14:8, 643-9 Studies have been conducted to assess the possible preventive effect of pyruvate against lens protein oxidation and consequent denaturation and insolubilization. Rat lens organ culture system was used for these studies. The content of water insoluble proteins (urea soluble) increased if the lenses were cultured in medium containing hydrogen peroxide. Incorporation of pyruvate in the medium prevented such insolubilization. The insolubilization was associated primarily with loss of gamma crystallin fraction of the soluble proteins. PAGE analysis demonstrated that insolubilization is related to -S-S- bond formation which was preventable by pyruvate. Since pyruvate is a normal tissue metabolite the findings are considered pathophysiologically significant against cataract formation. This was apparent by the prevention of selenite cataract in vivo by intraperitoneal administration of pyruvate.

"Glucocorticoid-induced cataract in chick embryo monitored by Raman spectroscopy," Mizuno A; Nishigori H; Iwatsuru M Invest Ophthalmol Vis Sci, 30:1, 132-7, 1989. Glucocorticoid-induced cataract lens in chick embryo was monitored by laser Raman spectroscopy. The lens opacity that appeared in chick embryo is a reversible one. Raman spectra show no significant change in the relative content of water or secondary structure of the proteins upon lens opacification. The intensity ratios of tyrosine doublet bands in Raman spectra between clear and opaque lens portions are changes. This change is reversible, and is interpreted as a protein-water phase separation that occurred during lens opacification.

[NMR study of the state of water in the human lens during cataract development] Babizhaev MA; Deev AI; Nikolaev GM, Biofizika 30:4, 671-4,1985. Water proton spin-spin relaxation times (T2) and the content of bound, "non-freezable" at -9 degrees C water in both normal human lenses and human lenses of different stages of cataract progression (cataracta incipiens, nondum matura, mature hypermatura) were measured by NMR spin echoes method. By the stage of cataracta nondum matura, increase of bound water content and simultaneous, almost half decrease of the relaxation time (T2), were observed. However, on the following stages of cataract evaluation (almost mature, mature cataracts) a gradual decrease of bound water content is noted, but only for the mature cataract stage the water content significantly differs from that of the normal one. On the stage of hypermature cataract the presence of two unexchanged with each other fractions of water is found. The obtained data are explained by lens protein reconstructions during the cataract progression.

Hightower KR; Reddy VN Ca++-induced cataract. Invest Ophthalmol Vis Sci, 1982 Feb, 22:2, 263-7 Cataracts in cultured rabbit lenses were produced by elevation of internal calcium. Experimental procedures were successful in increasing levels of total and bound Ca++, often without significant changes in sodium, potassium, or water content. Although the excess in calcium was predominantly associated with water-soluble proteins and was freely diffusible, a significant amount was bound to membranes and cytosol water-insoluble proteins. Thus, in lenses with a 10-fold increase in total Ca++, the bound Ca++ increased twofold, nearly 35% of which remained fixed to water-insoluble and membrane proteins after exhaustive (72 hr) dialysis. In contrast, over 95% of the Ca++ in water-soluble protein fractions was removed by dialysis.

[Use of pyrimidine bases and ATP for conservative treatment of early cataracts] Larionov LN Oftalmol Zh, 1977, 32:3, 221-2.

"Noninvasive measurements of pyridine nucleotide and flavoprotein in the lens," Tsubota K; Laing RA; Kenyon KR Invest Ophthalmol Vis Sci 28:5, 785-9, 1987. "Abnormalities in glucose metabolism are thought to be among the main causes of cataract formation. The authors have made noninvasive biochemical measurements of the lens that provide information concerning glucose metabolism in the lens epithelium. The autofluorescence of reduced pyridine nucleotides (PN) and oxidized flavoproteins (Fp) within the rabbit lens were noninvasively measured as a function of depth using redox fluorometry. The peak of the autofluorescence at 440 nm (excited at 360 nm) and 540 nm (excited at 460 nm) were determined at the lens epithelium. When 8 mM sodium pentobarbital, a known inhibitor of mitochondrial respiration, was applied to the lens, the autofluorescence peak at 440 nm increased and that at 540 nm decreased. The 440 nm autofluorescence is thought to be from reduced pyridine nucleotides, whereas the 540 nm autofluorescence is from the oxidized flavoprotein. Blocking lens respiration with pentobarbital caused an increase in the PN/Fp ratio by a factor of 3 within 3.5 hr after pentobarbital application."

"Concentrations of some ribonucleotides, L-lactate, and pyruvate in human senile cataractous lenses with special reference to anterior capsular/subcapsular opacity," Laursen AB Acta Ophthalmol (Copenh) 54:6, 677-92,1976. The concentrations of some ribonucleoside tri- and diphosphates, adenosine-5'-monophosphate, L-lactate and pyruvate were determined in human senile cataractous lenses removed during cataract operations. Pyruvate concentrations were found to be negligible (median = 56 mumol/kg lens wet weight) in 15 human senile cataractous lenses. On the basis of correlations between the biomicroscopic appearances of the senile cataractous lenses (N = 80) and the concentrations and ratios of the metabolites in question, the following classification was found to be justified: 1. Immature cataractous lenses without anterior capsular/subcapsular opacity: high levels of ribonucleoside triphosphates (RTP), high sums of RTP, ribonucleoside diphosphates (RDP), and adenosine 5'-monophosphate (AMP) as well as high levels of L-lactate and high ratios of L-lactate in the lens/L-lactate in the aqueous. 2. Immature cataractous lenses with anterior capsular/subcapsular opacity; intermediate levels of RTP, intermediate values for the sums of RTP, RDP, and AMP, high L-lactate levels, and intermediate values of the ratios of L-lactate in the lens/L-lactate in the aqueous."

"Lipid fluorophores of the human crystalline lens with cataract," Babizhayev MA Graefes Arch Clin Exp Ophthalmol, 1989, 227:4, 384-91. [Initial stages of cataracts are characterized by the fluorescence of the products of fatty acid free radical oxidation.]

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Tryptophan, serotonin, and aging

Beginning with the industrial production of glutamic acid (sold as MSG, monosodium glutamate), the public has been systematically misinformed about the effects of amino acids in the diet. The FDA has been industry's powerful ally in misleading the public. Despite research that clearly showed that adults assimilate whole proteins more effectively than free amino acids, much of the public has been led to believe that predigested hydrolized protein and manufactured free amino acids are more easily assimilated than real proteins, and that they are not toxic. Even if free amino acids could be produced industrially without introducing toxins and allergens, they wouldn't be appropriate for nutritional use.

Although some research shows that babies up to the age of 18 months can assimilate free amino acids, a baby formula containing hydrolyzed protein was associated with decreased serum albumin, which suggests that it interfered with protein synthesis.

The myth that free amino acids are natural nutritional substances has been used to promote the use of many products besides MSG, including aspartame, chelated minerals, and tryptophan.

Although several amino acids can be acutely or chronically toxic, even lethal, when too much is eaten, tryptophan is the only amino acid that is also carcinogenic. (It can also produce a variety of toxic metabolites, and it is very susceptible to damage by radiation.) Since tryptophan is the precursor of serotonin, the amount of tryptophan in the diet can have important effects on the way the organism responds to stress, and the way it develops, adapts, and ages.

When an inflammatory disease (eosinophilia-myalgia syndrome) was noticed in people using tryptophan tablets (1989-90), there was an intense campaign to exonerate the tryptophan itself by blaming the reaction on an impurity in one company's product. But the syndrome didn't occur only in the people who used that company's product, and similar changes can be produced by a high-tryptophan diet (Gross, et al., 1999).

There are people who advocate the use of tryptophan supplementation or other means to increase serotonin in the tissues as a treatment for the fibromyalgia syndrome, but the evidence increasingly suggests that excessive serotonin, interfering with muscle mitochondria, is a major factor in the development of that syndrome.

In 1965, Hans Selye showed that the injection of serotonin caused muscular dystrophy. Subsequent studies suggest that serotonin excess is involved in both muscular and nervous dystrophy or degeneration. (O'Steen, 1967; Narukami, et al., 1991; Hanna and Peat, 1989.)

The fatigue produced by over-training is probably produced by a tryptophan and serotonin overload, resulting from catabolism of muscle proteins and stress-induced increases in serotonin. Muscle catabolism also releases a large amount of cysteine, and cysteine, methionine, and tryptophan suppress thyroid function (Carvalho, et al., 2000). Stress also liberates free fatty acids from storage, and these fatty acids increase the uptake of tryptophan into the brain, increasing the formation of serotonin. Since serotonin increases ACTH and cortisol secretion, the catabolic state tends to be self-perpetuating. This process is probably a factor influencing the rate of aging, and contributing to the physiological peculiarities of aging and depression.

Malnutrition, and specifically protein deficiency, produces an inflammatory state that involves extreme serotonin dominance. Stress or malnutrition prenatally or in infancy leads to extreme serotonin dominance in adulthood. Other functions of tryptophan are reduced, as more of it is turned into serotonin.

Decreasing tryptophan or decreasing serotonin improves learning and alertness, while increased serotonin impairs learning.

Tryptophan is an essential amino acid for reproduction and growth of the young animal. Most research on the nutritional requirements for amino acids has been done on farm animals, because of the economic incentive to find the cheapest way to produce the fastest growth. Farmers aren't interested in the nutritional factors that would produce the longest-lived pigs. Some research has been done on the amino acid requirements of rats over a significant part of their short lifespans. In rats and farm animals, the amount of tryptophan required decreases with time as the rate of growth slows.

In some ways, rats never really mature, since they keep growing for nearly their whole lifespan. Their growth stops just a short time before they die, which is usually around the age of two or three years. (At this age, rats' cells still retain approximately the same high water content seen in the cells of a two year-old child.) They usually become infertile about half-way through their lifespan. If we try to draw conclusions about amino acid requirements from the rat studies, I think we would want to extrapolate the curve for the decreasing need for tryptophan, far beyond the point seen during the rat's short life. And those requirements were determined according to the amounts that produced a maximum rate of growth, using the index of the pig farmers, as if the rats were being studied for possible use as meat.

When rats were fed a diet completely lacking tryptophan for a short period, or a diet containing only one fourth of the normal amount for a more prolonged period, the results were surprising: They kept the ability to reproduce up to the age of 36 months (versus 17 months for the rats on the usual diet), and both their average longevity and their maximum longevity increased significantly. They looked and acted like younger rats. (A methionine-poor diet also has dramatic longevity-increasing effects.)

On the tryptophan-poor diet, the amount of serotonin in the brain decreased. When brain serotonin decreases, the level of testosterone in male animals increases. More than 20 years ago, a chemical (p-chlorophenylalanine) that inhibits serotonin synthesis was found to tremendously increase libido.

In old age, the amount of serotonin in the brain increases. This undoubtedly is closely related to the relative inability to turn off cortisol production that is characteristic of old age (Sapolsky and Donnelly, 1985). Hypothyroidism increases the formation of serotonin, as does cortisol (Henley, et al., 1997, 1998; Neckers and Sze, 1976).

In white hair, the amount of tryptophan is higher than in hair of any other color. Although serotonin and tryptophan are very important during rapid growth, their presence in senile tissues is probably closely associated with the processes of decline. The hair loss that occurs in hypothyroidism, postpartum syndrome, and with the use of drugs such as St. John's wort (which can also cause the serotonin syndrome) could be another effect of excess serotonin.

Serotonin stimulates cell division and tends to increase the formation of connective tissue, so its formation should be closely regulated once full growth is achieved. It contributes to the age- or stress-related thickening of blood vessels, and other fibrotic processes that impair organ function.

The metabolic rate (eating more without gaining extra weight) and ability to regulate body temperature are increased by early tryptophan deprivation. (Ashley and Curzon, 1981; Segall and Timiras, 1975.) The ability to oxidize sugar is impaired by serotonin, and several drugs with antiserotonin actions are being used to treat diabetes and its complications, such as hypertension, obesity, and foot ulcers.

An excess of tryptophan early in life, stress, or malnutrition, activates the system for converting tryptophan into serotonin, and that tendency persists into adulthood, modifying pituitary function, and increasing the incidence of pituitary and other cancers.

Serotonin's contribution to high blood pressure is well established. It activates the adrenal cortex both directly and through activation of the pituitary. It stimulates the production of both cortisol and aldosterone. It also activates aldosterone secretion by way of the renin-angiotensin system. Angiotensin is an important promoter of inflammation, and contributes to the degeneration of blood vessels with aging and stress. It can also promote estrogen production.

In the traditional diet, rather than just eating muscle meats, all the animal parts were used. Since collagen makes up about 50% of the protein in an animal, and is free of tryptophan, this means that people were getting about half as much tryptophan in proportion to other amino acids when they used foods such as head cheese, ox-tails, and chicken feet.

While some of the toxic effects of an excess of individual amino acids have been investigated, and some of the protective or harmful interactions resulting from changing the ratios of the amino acids have been observed, the fact that there are about 20 amino acids in our normal diet means that there is an enormous number of possibilities for harmful or beneficial interactions.

The optimal quantity of protein in the diet has traditionally been treated as if it were a matter that could be resolved just by observing the rate of growth when a certain protein is given in certain quantities, along with standard amounts of calories and other nutrients. This kind of research has been useful to farmers who want to find the cheapest foods that will produce the biggest animals in the shortest time. But that kind of research climate has spread a degraded concept of nutrition into the culture at large, influencing medical ideas of nutrition, the attitudes of consumers, and the policies of governmental regulatory agencies.

When synthetic amino acids are used to supplement natural proteins, they are usually chosen according to irrelevant models of the ideal protein's composition, and many toxic contaminants are invariably present in the synthetic free amino acids.

For the present, the important thing is to avoid the use of the least appropriate food products, while choosing natural foods that have historical, epidemiological, and biochemical justification.

Whey has been promoted as a protein supplement, but it contains a slightly higher proportion of tryptophan than milk does. Cheese (milk with the whey removed) contains less tryptophan. Some people have been encouraged to eat only the whites of eggs, to avoid cholesterol, but the egg albumin is rich in tryptophan.

The expensive tender cuts of meat contain excessive amounts of cysteine and tryptophan, but bone broth (gelatin) and the tougher cuts of meat contain more gelatin, which lacks those amino acids. Many fruits are deficient in tryptophan, yet have very significant quantities of the other amino acids. They also contain some of the carbon skeleton (keto-acid) equivalents of the essential amino acids, which can be converted to protein in the body.

Serotonin excess produces a broad range of harmful effects: Cancer, inflammation, fibrosis, neurological damage, shock, bronchoconstriction, and hypertension, for example. Increased serotonin impairs learning, serotonin antagonists improve it.

The simplest, nonessential, amino acid, glycine, has been found to protect against carcinogenesis, inflammation, fibrosis, neurological damage, shock, asthma, and hypertension. Increased glycine improves learning (Handlemann, et al., 1989; File, et al., 1999), glycine antagonists usually impair it. Its antitoxic and cytoprotective actions are remarkable. Collagen, besides being free of tryptophan, contains a large amount of glycine--32% of its amino acid units, 22% of its weight.

The varied antiinflammatory and protective effects of glycine can be thought of as an antiserotonin action. For example, serotonin increases the formation of TNF (tumor necrosis factor, also called cachectin), glycine inhibits it. In some situations, glycine is known to suppress the formation of serotonin. Antagonists of serotonin can potentiate glycine's effects (Chesnoy-Marchais, et al., 2000). People who ate traditional diets, besides getting a lower concentration of tryptophan, were getting a large amount of glycine in their gelatin-rich diet.

Gelatin, besides being a good source of glycine, also contains a large amount of proline, which has some antiexcitatory properties similar to glycine.

If a half-pound of steak is eaten, it would probably be reasonable to have about 20 grams of gelatin at approximately the same time. Even a higher ratio of gelatin to muscle meat might be preferable.

Carbon dioxide, high altitude, thyroid, progesterone, caffeine, aspirin, and decreased tryptophan consumption protect against excessive serotonin release. When sodium intake is restricted, there is a sharp increase in serotonin secretion. This accounts for some of the antiinflammatory and diuretic effects of increased sodium consumption--increasing sodium lowers both serotonin and adrenalin.

The polyunsaturated oils interact closely with serotonin and tryptophan, and the short and medium chain saturated fatty acids have antihistamine and antiserotonin actions. Serotonin liberates free fatty acids from the tissues, especially the polyunsaturated fats, and these in turn liberate serotonin from cells such as the platelets, and liberate tryptophan from serum albumin, increasing its uptake and the formation of serotonin in the brain. Saturated fats don't liberate serotonin, and some of them, such as capric acid found in coconut oil, relax blood vessels, while linoleic acid constricts blood vessels and promotes hypertension. Stress, exercise, and darkness, increase the release of free fatty acids, and so promote the liberation of tryptophan and formation of serotonin. Increased serum linoleic acid is specifically associated with serotonin-dependent disorders such as migraine.

Coconut oil, because of its saturated fatty acids of varied chain length, and its low linoleic acid content, should be considered as part of a protective diet.

In the collagen theory of aging, it is argued that changes in the extracellular matrix are responsible for isolating cells from their environment, reducing the availability of nutrients and oxygen, and reducing their ability to send and receive the chemical signals that are needed for correct adaptive functioning.

In diabetes, basement membranes are thickened, and in a given volume of tissue there are fewer capillaries. This effect probably involves excessive serotonin (Kasho, et al., 1998). Old animals contain a higher proportion of collagen. Old tendons (or tendons that have been exposed to excessive estrogen, which stimulates the formation of collagen) are more rigid, and behave almost as if they have been partly cooked. In diseases such as carcinoid, in which very large amounts of serotonin are released systemically, fibrosis is exaggerated, and may be the direct cause of death. Radiation and oxygen deprivation also lead to increased tissue fibrosis.

In specific fibrotic conditions, such as cirrhosis of the liver, it is known that glycine and saturated fats can reverse the fibrosis. In fibrosis of the heart, thyroid hormone is sometimes able to reverse the condition.

I think these facts imply that excessive tryptophan, estrogen, and polyunsaturated fats contribute significantly, maybe decisively, to the degenerative changes that occur in aging. Experiments have separately shown that reducing dietary tryptophan or unsaturated fats can extend the healthy lifespan, and several antiestrogenic interventions (removal of the pituitary, or supplementing with progesterone) can slow age-related changes and delay degenerative diseases. Since these factors interact, each tending to promote the others, and also interact with exogenous toxins, excess iron accumulation, and other stressors, it would be reasonable to expect greater results when several of the problems are corrected at the same time.

REFERENCES

Toxicol Pathol 1998 May-Jun;26(3):395-402. Glycine modulates the toxicity of benzyl acetate in F344 rats. Abdo KM, Wenk ML, Harry GJ, Mahler J, Goehl TJ, Irwin RD. These results suggest that the neurodegeneration induced by BA is mediated by a depletion of the glycine pool and the subsequent excitotoxicity.

Res Clin Stud Headache 1978;6:110-6. Role of individual free fatty acids in migraine. Anthony M Total plasma free fatty acids, platelet serotonin content and plasma stearic, palmitic, oleic and linoleic acids were estimated in 10 migraine patients before, during and after a migraine attack. Total and individual plasma free fatty acid levels rose and platelet serotonin content fell in most patients. The highest rise was observed in linoleic acid, which is known to be a potent liberator of platelet serotonin in vitro and is the only precursor of all prostaglandins in the body. It is suggested that the rise in plasma levels of linoleic acid in migraine could be responsible for the platelet serotonin release observed during the attack.

Clin Exp Neurol 1978;15:190-6. Individual free fatty acids and migraine. Anthony M Total plasma free fatty acids (FFAs), platelet serotonin content and plasma stearic, palmitic, oleic and linoleic acids were estimated in 10 migrainous patients before, during and after a migraine attack. Total and individual plasma FFA levels rose and platelet serotonin fell in most patients. Comparison of the pre-headache and headache mean values showed that of the FFAs linoleic acid rises most during headache. 10 non-migrainous controls had platelet serotonin content estimated before and after the ingestion of 20g linoleic acid. All showed a significant fall in platelet serotonin in the post-ingestion period. It is shown that linoleic acid releases platelet serotonin in vitro, and this study suggests that it has the same action in vivo. Further, it is the precursor of all prostaglandins in the body and its marked elevation during migraine may serve as a source of increased prostaglandin E1 (PGE1) synthesis. It is suggested that linoleic acid plays an important role in the biochemical process of the migraine attack, acting both as a serotonin releasing factor and a source of PGF1, the vasodilating action of which can aggravate the clinical symptoms of migraine.

J Appl Physiol 1993 Jun;74(6):3006-12. Neuroendocrine and substrate responses to altered brain 5-HT activity during prolonged exercise to fatigue. Bailey SP, Davis JM, Ahlborn EN. Pharmacological manipulation of brain serotonergic [5-hydroxytryptamine (5-HT)] activity affects run time to exhaustion in the rat. These effects may be mediated by neurochemical, hormonal, or substrate mechanisms. Groups of rats were decapitated during rest, after 1 h of treadmill running (20 m/min, 5% grade), and at exhaustion. Immediately before exercise rats were injected intraperitoneally with 1 mg/kg of quipazine dimaleate (QD; a 5-HT agonist), 1.5 mg/kg of LY 53857 (LY; a 5-HT antagonist), or the vehicle (V; 0.9% saline). LY increased and QD decreased time to exhaustion (approximately 28 and 32%, respectively; P < 0.05). Brain 5-HT and 5-hydroxyindole-3-acetic acid concentrations were higher at 1 h of exercise than at rest (P < 0.05), and the latter increased even further at fatigue in the midbrain and striatum (P < 0.05).

Neurochem Int 1993 Sep;23(3):269-83. Glutamate, GABA, glycine and taurine modulate serotonin synthesis and release in rostral and caudal rhombencephalic raphe cells in primary cultures. Becquet D, Hery M, Francois-Bellan AM, Giraud P, Deprez P, Faudon M, Fache MP, Hery F.

Acta Physiol Scand 2001 Oct;173(2):223-30. Exercise-induced changes in brain glucose and serotonin revealed by microdialysis in rat hippocampus: effect of glucose supplementation. Bequet F, Gomez-Merino D, Berthelot M, Guezennec CY.

Amino Acids 2001;20(1):25-34. Amino acids and central fatigue. Blomstrand E. There is an increasing interest in the mechanisms behind central fatigue, particularly in relation to changes in brain monoamine metabolism and the influence of specific amino acids on fatigue. When the 5-HT level was elevated in this way the performance was impaired in both rats and human subjects, and in accordance with this a decrease in the 5-HT level caused an improvement in running performance in rats. The precursor of 5-HT is the amino acid tryptophan and the synthesis of 5-HT in the brain is thought to be regulated by the blood supply of free tryptophan in relation to other large neutral amino acids (including the branched-chain amino acids, BCAA) since these compete with tryptophan for transport into the brain.

J Neurol Sci 1988 Apr;84(2-3):239-46. Increased platelet aggregation and release reaction in myotonic dystrophy. Bornstein NM, Zahavi M, Korczyn AD, Zahavi J.

Curr Med Chem 2001 Sep;8(11):1257-74. The inhibitory neural circuitry as target of antiepileptic drugs. Bohme I, Luddens H. Impairments and defects in the inhibitory neurotransmission in the CNS can contribute to various seizure disorders, i.e., gamma-aminobutyric acid (GABA) and glycine as the main inhibitory neurotransmitters in the brain play a crucial role in some forms of epilepsy.

Braz J Med Biol Res 2000 Mar;33(3):355-61. Thyroid peroxidase activity is inhibited by amino acids. Carvalho DP, Ferreira AC, Coelho SM, Moraes JM, Camacho MA, Rosenthal D

Q J Exp Psychol B 2000 Aug;53(3):225-38. Rapid visual learning in the rat: effects at the 5-HT1a receptor subtype. Cassaday HJ, Simpson EL, Gaffan EA. The 5-hydroxytryptamine1a (5-HT1a) receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 0.15 mg/kg) impaired rats' rapid visual learning on a computerized maze. This treatment also increased decision time (DT) but the learning impairment was not necessarily a side-effect of slower responding because, in this task, responses made at long DT are more accurate than those at short DT. Its reversal with WAY-100635 offers support to the hypothesis that 5-HT1a receptor antagonists could improve cognitive function, under conditions of pre-existing impairment due to overactive serotonergic inhibition, as is thought to occur in Alzheimer's disease.

Med Sci Sports Exerc 1997 Jan;29(1):58-62. Effects of acute physical exercise on central serotonergic systems. This paper reviews data concerning the effects of acute physical exercise (treadmill running) in trained rats. Works from the 1980's have established that acute running increases brain serotonin (5-hydroxytryptamine: 5-HT) synthesis in two ways. Lipolysis-elicited release of free fatty acids in the blood compartment displaces the binding of the essential amino acid tryptophan to albumin, thereby increasing the concentration of the so-called "free tryptophan" portion, and because exercise increases the ratio of circulating free tryptophan to the sum of the concentrations of the amino acids that compete with tryptophan for uptake at the blood-brain barrier level, tryptophan enters markedly in the brain compartment. However, this marked increase in central tryptophan levels increases only to a low extent brain 5-HT synthesis, as assessed by the analysis of 5-hydroxyindoleacetic acid levels, thereby suggesting that exercise promotes feedback regulatory mechanisms. Indirect indices of 5-HT functions open the possibility that acute exercise-induced increases in 5-HT biosynthesis are associated with (or lead to) increases in 5-HT release.

Int J Dev Neurosci 1997 Apr;15(2):257-63. Postnatal changes of brain monoamine levels in prenatally malnourished and control rats. Chen JC, Turiak G, Galler J, Volicer L.

Eur J Pharmacol 2000 Aug 25;402(3):205-13. Glycinergic potentiation by some 5-HT(3) receptor antagonists: insight into selectivity. Chesnoy-Marchais D, Levi S, Acher F.

Mech Ageing Dev 1986 Oct;36(2):161-71. Influence of low tryptophan diet on survival and organ growth in mice. De Marte ML, Enesco HE. Greater survival and reduced growth were found to characterize mice on a tryptophan deficient diet as compared to fully fed control mice. The 50% survival point was reached by the tryptophan restricted group at 683 days, and by the control group at 616 days. Measurements of body weight, organ weight, and DNA level were made at 8, 12, 24, 36, 52 and 78 weeks of age. Both whole body weight and organ weight of liver, kidney, heart and spleen were about 30% lower in the tryptophan restricted group as compared to the controls, so that the ratio of organ weight to body weight remained at a constant value for both groups. There was no significant change in cell number as determined by DNA measurements, as a result of the tryptophan restriction.

J Clin Psychopharmacol 1999 Dec;19(6):506-12. Beneficial effects of glycine (bioglycin) on memory and attention in young and middle-aged adults. File SE, Fluck E, Fernandes C. .The effects of Bioglycin(Konapharma, Pratteln, Switzerland), a biologically active form of the amino acid glycine, were . . . studied in healthy students (mean age, 20.7 years) and middle-aged men (mean age, 58.9 years) with tests that measured attention, memory and mood, using a double-blind, randomized, crossover design. Compared with the young group, the middle-aged group had significantly poorer verbal episodic memory, focused, divided, and sustained attention; they also differed in their subjective responses at the end of testing. Bioglycin significantly improved retrieval from episodic memory in both the young and the middle-aged groups, but it did not affect focused or divided attention. However, the middle-aged men significantly benefited from Bioglycin in the sustained-attention task. The effects of Bioglycin differed from those of other cognitive enhancers in that it was without stimulant properties or significant effects on mood, and it primarily improved memory rather than attention. It is likely to be of benefit in young or older people in situations where high retrieval of information is needed or when performance is impaired by jet lag, shift work, or disrupted sleep. It may also benefit the impaired retrieval shown in patients with schizophrenia, Parkinson's disease, and Huntington's disease.

Brain Res 1997 Sep 12;768(1-2):43-8. Mobilization of arachidonate and docosahexaenoate by stimulation of the 5-HT2A receptor in rat C6 glioma cells. Garcia MC, Kim HY Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD 20852, USA. In this study, we demonstrate that astroglial 5-HT2A receptors are linked to the mobilization of polyunsaturated fatty acids (PUFA). Stimulation of C6 glioma cells, prelabeled with [3H]arachidonate (AA, 20:4n6) and [14C]docosahexaenoate (DHA, 22:6n3), with serotonin and the 5-HT(2A/2C) receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) resulted in the mobilization of both [3H] and [14C] into the supernatant of the cell monolayers. The increased radioactivity in the supernatant was mainly associated with free fatty acids. These results indicate that the 5-HT2A receptor is coupled to the mobilization of PUFA.

Neurosci Lett 1995 May 5;190(2):143-5. Serotonin involvement in the spontaneous alternation ability: a behavioral study in tryptophan-restricted rats. Gonzalez-Burgos I, Olvera-Cortes E, Del Angel-Meza AR, Feria-Velasco A. Laboratorio de Psicobiologia, Centro de Investigacion Biomedica de Occidente, IMSS, Guadalajara, Jal., Mexico. Spontaneous alternation (SA) is controlled by septal cholinergic terminals in the hippocampus. Serotoninergic terminals end on cholinergic nerve endings in the hippocampus, and their possible role in SA was investigated in rats fed with a tryptophan-deficient diet, from weaning to 60 days of age. A T-maze was used for the test. At the age of 40 days, an increase in SA occurred in the tryptophan deficient rats, although this effect disappeared by 60 days of age. A modulatory role of serotonin in the psychoneural control of SA is suggested, and it may be through presynaptic inhibition of hippocampal cholinergic terminals.

Physiol Behav 1998 Jan;63(2):165-9. Effect of tryptophan restriction on short-term memory. Gonzalez-Burgos I, Perez-Vega MI, Del Angel-Meza AR, Feria-Velasco A. Centro de Investigacion Biomedica de Michoacan, Instituto Mexicano del Seguro Social, Morelia. Several brain regions are involved in the learning process that is integrated from sensorial inputs. It is thereafter consolidated in short- (STM) or long-term memory. Serotonin is strongly related to both types of memory, and particularly, to STM, however, its regulatory role is still unclear. In this study, the effects of tryptophan (TRY) restriction on learning and STM were evaluated. Ten Sprague-Dawley female rats were fed with a TRY-restricted diet (0.15g/100g) starting from postnatal Day 21. At 21, 40, and 60 days of age, 5 trials per animal were carried out in a "hard-floor"-Biel maze, after 24 h of water abstinence. The number of errors per trial were registered before reaching the goal. At both 40 and 60 days, experimental rats committed less errors than controls. Likewise, the TRY-restricted group learned the task from the second trial on, whereas controls did not solve it until the third trial. TRY restriction, and therefore brain serotonin reduction, could impair normal cholinergic activity in some areas such as the hippocampus and the cerebral cortex, where involvement in learning and memory is well documented. Morphological and neurochemical plastic events could also be related to the more efficient performance of the task by the TRY-restricted rats.

Am J Physiol 1997 Jul;273(1 Pt 2):R324-30. Mechanisms in the pressor effects of hepatic portal venous fatty acid infusion. Grekin RJ, Dumont CJ, Vollmer AP, Watts SW, Webb RC Portal venous infusion of oleate solution has pressor effects. We have examined efferent mechanisms, measured the response to sustained infusion, and determined the effect of linoleate. Eight conscious animals received concurrent infusions of prazosin or vehicle with portal venous infusion of oleate. Oleate alone increased mean arterial pressure from 109.0 +/- 4.1 to 123.0 +/- 5.8 mmHg (P = 0.02), whereas no increase in blood pressure occurred when oleate was infused with prazosin. In 10 rats, concurrent infusion of losartan had no effect on the pressor activity of portal oleate infusion. Twenty-two animals received portal oleate or vehicle as a continuous infusion for 7 days. Mean arterial pressure (126.1 +/- 2.0 vs. 107.8 +/- 2.6 mmHg, P < 0.001) and heart rate (383 +/- 5 vs. 366 +/- 5, P = 0.0257) were increased in oleate-infused animals. No differences in plasma fatty acids, glucose, insulin, pressor hormones, liver enzymes, or in vitro arterial pressor responsiveness were observed. Portal venous infusion of linoleate increased arterial pressure by 12.2 +/- 3.2 mmHg (P = 0.033). These results indicate that alpha-adrenergic activity is necessary for the acute pressor effects of portal oleate, that sustained portal oleate infusion results in persistent blood pressure elevation, and that other long-chain fatty acids besides oleate have pressor effects.

Adv Exp Med Biol 1999;467:507-16. Tryptophan toxicity--time and dose response in rats. Gross B, Ronen N, Honigman S, Livne E. During the past decade L-tryptophan (Trp) ingestion have been associated with a multisystemic syndrome, known as eosinophilia myalgia syndrome (EMS). Even though an epidemic studies indicated that a contaminant, 1,1'-ethylidene-bis-L-tryptophan was involved in EMS, abnormalities in metabolism of Trp have been reported in other similar clinical syndromes such as carcinoid syndrome, scleroderma or eosinophilic fasciitis. Increased amounts of connective tissue and induction of inflammatory cell proliferation were observed in lung, spleen and in gastrocnemia muscle of rats treated with higher dose of Trp for longer period. Induction of kynurenine pathway by injection of p-CPA caused more tissue damage. It is concluded that excessive Trp or elevation of its metabolites could play a role in amplifying some of pathological features of EMS. This pathological damage is further augmented by metabolites of the kynurenine pathway.

Zh Nevrol Psikhiatr Im S S Korsakova 1999;99(2):12-20. [Neuroprotective effects of glycine in the acute period of ischemic stroke.] [Article in Russian] Gusev EI, Skvortsova VI, Komissarova IA, Dambinova SA, Raevskii KS, Alekseev AA, Bashkatova VG, Kovalenko AV, Kudrin VS, Iakovleva EV.

Pharmacol Biochem Behav 1989 Dec;34(4):823-8. Milacemide, a glycine prodrug, enhances performance of learning tasks in normal and amnestic rodents. Handelmann GE, Nevins ME, Mueller LL, Arnolde SM, Cordi AA. Increasing glycine concentrations in the brain by administration of a glycine prodrug, milacemide, is shown here to enhance performance of a shock-motivated passive avoidance task in rats, and to reverse drug-induced amnesia in a spontaneous alternation paradigm in mice. These studies indicate a role of glycinergic neurotransmission in memory processes, and support the therapeutic potential of glycinergic drugs in memory impairment.

Pain 1989 Aug;38(2):145-50. Ketanserin in reflex sympathetic dystrophy. A double-blind placebo controlled cross-over trial. Hanna MH, Peat SJ.

Synapse 1997 Sep;27(1):36-44. Thyroid hormones and the treatment of depression: an examination of basic hormonal actions in the mature mammalian brain. Henley WN, Koehnle TJ. The lack of mechanistic insight reflects, in large part, a longstanding bias that the mature mammalian central nervous system is not an important target site for thyroid hormones.

Am J Physiol 1997 Feb;272(2 Pt 2):H894-903. Hypothyroid-induced changes in autonomic control have a central serotonergic component. Henley WN, Vladic F. Three experiments were conducted in unanesthetized rats made hypothyroid (Hypo) or maintained as euthyroid controls (Eu) to examine general cardiovascular responsiveness [experiment I (Exp I)]; responsiveness to a serotonin (5-HT2) agonist, dl-2,5-dimethoxy-4-iodoamphetamine [DOI intracerebroventricularly; experiment II (Exp II)]; or responsiveness to a 5-HT(1A) agonist dl-8-hydroxydipropyl-aminotetralin hydrobromide [8-OH-DPAT intracerebroventricularly; experiment III (Exp III)]. In Exp I, intravenous infusions of phenylephrine and nitroprusside provided little evidence that findings in Exp II and III were caused by generalized impairment in cardiovascular responsiveness in Hypo. In Exp II and III, Eu and Hypo were given either intra-arterial atropine or vehicle. Atropine significantly elevated heart rate (Exp II and III) and mean arterial pressure (Exp II) in Eu only. When compared with Eu, Hypo had a reduced pressor response (5.2 vs. 20.1%), an attenuated pulse pressure response (19.3 vs. 35.4%), and a more robust bradycardia (-17.7 vs. -7.0%) in response to DOI. These differences were atropine sensitive. In Exp III, Hypo had larger decrements in mean arterial pressure (-9.0 vs. -5.1%), heart rate ( -13.9 vs. - 7.7%), and body temperature (-4.5 vs. -2.7%) in response to 8-OH-DPAT in comparison to Eu. Parasympathetic involvement in the differential responses to 8-OH-DPAT was less clear than with DOI. Deranged autonomic control in hypothyroidism may be caused, in part, by changes in central serotonergic activity.

Brain Res 1986 Mar;390(2):221-6. Brain serotonin synthesis and Na+,K+-ATPase activity are increased postnatally after prenatal administration of L-tryptophan. Hernandez-Rodriguez J, Chagoya G. The effect of prenatal L-tryptophan supplementation on the serotonin (5-HT) synthesis and the activity of Na+,K+-ATPase in the cerebral cortex was studied during postnatal development, from birth up to day 30. A parallel and significant elevation of the serotonin content and the activity of tryptophan-5-hydroxylase was observed in the brain of infant rats born to mothers treated with L-tryptophan, as related to non-treated controls. The activity of Na+,K+-ATPase was also significantly elevated at the different ages studied throughout the developmental period, as related to controls. These results suggest an important role of L-tryptophan in the early regulation of the serotonin-synthesizing machinery, which lasts postnatally. Elevation of ATPase activity seems to be associated to the elevation in the activity of the 5-HT system.

Brain Res 1977 Mar 4;123(1):137-45. Daily variations of various parameters of serotonin metabolism in the rat brain. II. Circadian variations in serum and cerebral tryptophan levels: lack of correlation with 5-HT turnover. Hery F, Chouvet G, Kan JP, Pujol JF, Glowinski J Significant circadian variations in 5-HT and 5-HIAA levels were found in cerebral tissues. Important significant circadian variations in free and total serum tryptophan levels were also observed. In both cases, the maximal levels were found during the middle of the dark phase after the peak of 5-HIAA levels. The diurnal changes in tryptophan content in cerebral tissues seemed thus related to those found in serum.

Kidney Int 1998 Oct;54(4):1083-92. Serotonin enhances the production of type IV collagen by human mesangial cells. Kasho M, Sakai M, Sasahara T, Anami Y, Matsumura T, Takemura T, Matsuda H, Kobori S, Shichiri M.

Pharmacol Biochem Behav 1977 Sep;7(3):245-52. Fatty acid and tryptophan changes on disturbing groups of rats and caging them singly. Knott PJ, Hutson PH, Curzon G The effects of disturbing groups of 24 hr fasted rats on plasma unesterified fatty acid (UFA) and tryptophan concentrations and brain tryptophan concentrations were investigated. Removing rats from cages rapidly increased plasma UFA and corticosterone and decreased plasma and whole blood tryptophan of cage mates. The disturbance also appeared to influence biochemical values of rats in other cages within the same chamber. Effects specific to individual cages were also suggested. In subsequent experiments 24 fasting rats caged together were rapidly transferred to 24 separate cages and killed at intervals. Plasma UFA rose to a maximum by 12 min and then fell toward initial values. Plasma total tryptophan concurrently fell then rose. Its percentage in the free (ultrafilterable) state, and in some experiments the absolute values of free tryptophan rose then fell. When the latter rise was marked then brain tryptophan and the 5-HT metabolite 5-hydroxyindoleacetic acid rose. Tyrosine changes were negligible. Thus altered brain tryptophan level and 5-HT metabolism may be associated with plasma tryptophan changes caused by brief environmental disturbance.

J Insect Physiol 2000 May 1;46(5):793-801. Effect of an amino acid on feeding preferences and learning behavior in the honey bee, Apis mellifera. Kim YS, Smith BH. Subjects preferred to feed on a sucrose stimulus that contained glycine, and the highest relative preference was recorded for the highest concentration of glycine. All concentrations of glycine enhanced the rate and magnitude of a conditioned response to an odor . . . .

Eur J Pharmacol 1981 May 22;71(4):495-8. Antagonism of L-glycine to seizures induced by L-kynurenine, quinolinic acid and strychnine in mice. Lapin IP.

Int J Circumpolar Health 1998;57 Suppl 1:386-8. Seasonal variation of the amino acid, L-tryptophan, in interior Alaska. Levine ME, Duffy LK. The seasonal pattern of L-tryptophan was studied in a Fairbanks, Alaska, population that was unadapted to the extreme light variations of the North. Previously, this population was shown to exhibit seasonal behavior effects such as increases in fatigue and sleep duration, as well as endocrine effects such as increases in melatonin levels and phase shifting. Prominent results included finding increased levels in the winter at several different diurnal time points. These findings support hypotheses which relate underlying physiological adaptations to the North to the increased incidence of behavioral disorders such as depression and alcoholism.

Infect Immun 2001 Sep;69(9):5883-91. Dietary glycine prevents peptidoglycan polysaccharide-induced reactive arthritis in the rat: role for glycine-gated chloride channel. Li X, Bradford BU, Wheeler MD, Stimpson SA, Pink HM, Brodie TA, Schwab JH, Thurman RG.

J Neurol Sci 1989 Jan;89(1):27-35. Polyamine biosynthetic decarboxylases in muscles of rats with different experimental myopathies. Lorenzini EC, Colombo B, Ferioli ME, Scalabrino G, Canal N.

Int J Dev Neurosci 1996 Aug;14(5):641-8. Nutritional recovery does not reverse the activation of brain serotonin synthesis in the ontogenetically malnourished rat. Manjarrez GG, Magdaleno VM, Chagoya G, Hernandez J Coordinacion de Investigacion Biomedica del Centro Medico Nacional, I.M.S.S. Mexico, D.F. In the present work we confirm that gestational malnutrition effects body and brain composition and results in an activation of the synthesis of the brain neurotransmitter 5-hydroxytryptamine. These results also demonstrate more activity of the rate-limiting enzyme tryptophan hydroxylase in the malnourished fetal and postnatal brain. However, the activity of this enzyme remains increased in the brain of nutritionally recovered animals accompanied by an increase in the synthesis of 5-hydroxytryptamine. We therefore suggest that, in the nutritionally recovered animal, the mechanism of activation of this biosynthetic path in the brain may be not dependent on the increased availability of free L-tryptophan observed in malnourished animals, but might be due to a specific change in the enzyme complex itself. This hypothesis is supported by the fact that plasma free and brain L-tryptophan return to normal in the recovered animal.

Brain Res 1997 Nov 7;774(1-2):265-8. Tryptophan ingestion by gestant mothers alters prolactin and luteinizing hormone release in the adult male offspring. Martin L, Rodriguez Diaz M, Santana-Herrera C, Milena A, Santana C.

Rev Esp Fisiol 1984 Jun;40(2):213-9. [Lipolytic effect of serotonin in vitro]. [Article in Spanish] Martinez-Conde A, Mayor de la Torre P, Tamarit-Torres J The lipolytic action of serotonin on isolated adipocytes from the adipose tissue of rats has been studied. The adipocytes were incubated in serotonin 10(-6) M. Changes both in concentration and composition of the free intra and extracellular fatty acids as well as diacylglycerides through liquid gas chromatography were evaluated at different intervals. A lower concentration of free fatty acids and diacylglycerides is produced during the first minutes of incubation as well as a subsequent increase in the concentration of both, which becomes greatest after 20-30 minutes. The composition of both lipidic fractions (FFA and DAG) into fatty acids at 5, 10, 20 and 30 minutes, is related to the composition of the triacylglycerides (TAG), since during the esterification process a decline in the DAG of linoleic and palmitoleic acid is observed, both acids arranging themselves preferably in the TAG 2 position. Whereas the inverse process occurs during lipolysis; i.e. an increase in the proportion of the acids in the 2 position. In the FFA fraction, a higher proportion of fatty acids, preferential by arranged in positions 1 + 3 of the TAG's is observed. Similarly a decrease is observed in the extracellular concentration of FFA in the presence of serotonin with respect to the controls, a fact which has been described by other authors. An analysis of the present data leads us to revise the possible role of "Cahill's cycle" (simultaneous activation of the DAG-acyl-transferase and the HSL-TAG-lipase) in the action of serotonin and other hormones.

Nahrung 1991;35(9):961-7. [The effect of different protein diets on longevity and various biochemical parameters of aged rats]. Medovar BJa, Petzke KJ, Semesko TG, Albrecht V, Grigorov JuG Institut fur Gerontologie, AMW, UdSSR, Kiev. In this work 23 month old rats were fed for 200 days with different protein diets (NT-diet: 19% protein, 72% of animal origin and LP-diet: 8.8% protein exclusively of vegetable origin). Some metabolic parameters and lifespan (on the base of a 50% death-rate) were determined. The relations of the liver free amino acids glycine + alanine and tyrosine + phenylalanine + branched chain amino acids and the ratio of phenylalanine/tyrosine were determined to be higher in the LP-group. Phenylalanine in liver and urea concentrations in liver and serum were lower in the LP-group. Furthermore the dopamine or serotonin levels were significantly lower in lateral and medial or lateral regions of the hypothalamus respectively in LP-diet fed rats. The norepinephrine content was not modified by the diets. The median lifespan of 23 month old rats was higher by 24% following LP-treatment. These results suggest that the protein component (amino acids) of different diets may modify metabolic parameters and lifespan of animals by mechanisms in which the central regulation may be involved.

J Neurol Sci 1976 May;28(1):41-56. Skeletal muscle necrosis following membrane-active drugs plus serotonin. Meltzer HY.

Brain Res Bull 1977 Sep-Oct;2(5):347-53. Effects of developmental protein malnutrition on tryptophan utilization in brain and peripheral tissues. Miller M, Leahy JP, McConville F, Morgane PJ, Resnick O.

Exp Neurol 1977 Oct;57(1):142-57. Tryptophan availability: relation to elevated brain serotonin in developmentally protein-malnourished rats. Miller M, Leahy JP, Stern WC, Morgane PJ, Resnick O.

Synapse 1990;6(4):338-43. Age-related changes of strychnine-insensitive glycine receptors in rat brain as studied by in vitro autoradiography. Miyoshi R, Kito S, Doudou N, Nomoto T. 3H-glycine binding sites were most concentrated in the hippocampus, cerebral cortex, and olfactory tubercle, and moderate densities of binding sites were located in the striatum, nucleus accumbens, amygdala, and certain thalamic nuclei. In aged animals, severe decline of 3H-glycine binding sites was observed in the telencephalic regions including the hippocampus and cerebral cortex. These results suggest that the decrease of glycine receptors in particular brain regions has some relation with changes of neuronal functions associated with aging process in these areas.

Enzyme 1976;21(6):481-7. Inhibition of actomyosin ATPase by high concentrations of 5-hydroxytryptamine. Possible basis of lesion in 5HT-induced experimental myopathy. Mothersill C, Heffron JJ, McLoughlin JV.

Brain Res 1975 Jul 25;93(1):123-32. Regulation of 5-hydroxytryptamine metabolism in mouse brain by adrenal glucocorticoids. Neckers L, Sze PY A single injection of hydrocortisone acetate (HCA; 20 mg/kg, i.p.) accelerated the accumulation of 5-HT in whole brain after inhibition of monoamine oxidase activity by paragyline. The hormone did not appear to change brain tryptophan hydroxylase or 5-hydroxytryptophan decarboxylase activity. However, tryptophan levels in brain were elevated by 50% within 1 h after treatment with HCA.

Proc Soc Exp Biol Med 1967 Nov;126(2):579-83. Serotonin antagonist increases longevity in mice with hereditary muscular dystrophy. O'Steen WK.

Mech Ageing Dev 1988 Apr;43(1):79-98. Histology and survival in age-delayed low-tryptophan-fed rats. Ooka H, Segall PE, Timiras PS. Diets containing tryptophan in concentrations 30 and 40 percent of those fed to controls from weaning to 24-30 months or more, can delay aging in Long-Evans female rats. Mortality among low-tryptophan-fed rats was greater in the juvenile period, but substantially less than controls at late ages. Histological biomarkers of aging were also delayed after tryptophan restriction in some organs (liver, heart, uterus, ovary, adrenal and spleen) but not in others (kidney, lung, aorta). Brain serotonin levels were low in tryptophan-deficient rats but showed remarkable capacity for rehabilitation. Effects on early and late mortality and brain levels of serotonin were proportional to the severity of the restriction.

Age Ageing 1985 Mar;14(2):71-5. Plasma tryptophan, age and depression. Phipps DA, Powell C. Plasma, obtained from 131 nondepressed, otherwise healthy subjects aged from 17 to 102 years, and 22 depressed subjects aged over 70 years, was analysed for total and free tryptophan. Variation with age was found in total tryptophan. This association has not been described hitherto. There was a significant increase in total tryptophan and a non-significant increase in free tryptophan with depression. This is in contrast to some studies in younger people showing a decline in plasma tryptophan in depressed subjects.

Bratisl Lek Listy 1975 Jul;64(1):58-63. [The effect of serotonin on the release of free fatty acids from human and rat adipose tissue (author's transl)]. [Article in Czech] Rath R, Kujalova V.

Adv Exp Med Biol 1999;467:497-505. Oxidative damage in rat tissue following excessive L-tryptophan and atherogenic diets. Ronen N, Livne E, Gross B.

FASEB J 1994 Dec;8(15):1302-7. Methionine restriction increases blood glutathione and longevity in F344 rats. Richie JP Jr, Leutzinger Y, Parthasarathy S, Malloy V, Orentreich N, Zimmerman JA Met restriction resulted in a 42% increase in mean and 44% increase in maximum life span, and in 43% lower body weight compared to controls (P < 0.001). Increases in blood GSH levels of 81% and 164% were observed in mature and old Met-restricted animals, respectively (P < 0.001).

Carcinogenesis 1999 Nov;20(11):2075-81. Dietary glycine prevents the development of liver tumors caused by the peroxisome proliferator WY-14,643. Rose ML, Cattley RC, Dunn C, Wong V, Li X, Thurman RG.

Mech Ageing Dev 1983 Nov-Dec; 23(3-4):245-52. Low tryptophan diets delay reproductive aging. Segall PE, Timiras PS, Walton JR. Newly weaned female rats fed diets severely deficient in the essential amino acid tryptophan show marked delays in reproductive aging, with conception and delivery occurring as late as 36 months. The rate of aging in these rats seems inversely related to both their early growth rates and the accessibility of brain tryptophan. The subsequent age retardation may depend on a reduction in both early cell loss and rate of brain maturation.

Mech Ageing Dev 1978 Jan;7(1):1-17. Neural and endocrine development after chronic tryptophan deficiency in rats: I. Brain monoamine and pituitary responses. Segall PE, Ooka H, Rose K, Timiras PS. Caloric restriction and tryptophan deficient diets have been shown to delay aging in the immature laboratory rat. Another group of animals, in which growth and maturation was delayed by feeding d,1-parachlorophenylalanine (PCPA) showed decreases in serotonin, norepinephrine and dopamine concentrations in all brain regions investigated. All treatments employed to arrest growth and maturation resulted in pituitary alterations manifested by gross, histological and ultrastructural changes. It is postulated that there maturation- and age-retarding treatments delay the development of the central nervous system resulting in postponed maturation of the neuroendocrine axis, with consequent hypoactivity of certain pituitary functions and a resultant delay in the onset of maturation and senescence.

Aktuelle Gerontol 1977 Oct;7(10):535-8. Long-term tryptophan restriction and aging in the rat. Segall P. Growth-retarded rats fed a tryptophan deficient diet at 21 days for periods of 6-22 months were shown to reach normal body weight when subsequently fed Purina Rat Chow. They demonstrated an increased ability over similar aged controls to recover from hypothermia induced by 3-minute whole-body ice water immersion, were able to bear litters at 17--28 months of age, showed a delay in the age of onset of visible tumors, and indicated an increase in their average lifespan at late ages. Animals fed on this diet from 3 months of age revealed a similar ability to reproduce at advanced ages, but not as marked as those placed on the diet earlier. The average lifespan (in months +/- the standard error of the mean) of the rats recovering from the long-term tryptophan-deficient diets was 36.31 +/- 2.26 while the control rats survived an average of 30.5 +/- 1.90 months. The last of 8 rats surviving the period of tryptophan-deficiency died at 45.50 months (1387 days) while the last of 14 control rats died at 41.75 months (1266 days). It is hypothesized that some kind of subtle mechanism exerts its influence on the rats during the period of tryptophan deficiency which caused an accelerated morbidity and mortality as they approached senescence approximately 1 to 2 years after refeeding. This is parallel to the situation with immature animals subjected to long-term caloric restriction and then fed on normal diets.

Mech Ageing Dev 1976 Mar-Apr;5(2):109-24. Patho-physiologic findings after chronic tryptophan deficiency in rats: a model for delayed growth and aging. Segall PE, Timiras PS. Long-Evans female rats three weeks, three months and 13-14 months of age were placed on tryptophan-deficient diets for periods ranging from a few months to nearly two years. Growth was interupted during the period of tryptophan-deficiency, but when the animals were returned to a complete diet, they gained weight and grew to normal size. Ability to reproduce, as indicated by litter production, was present at 17-28 months of age in rats which had been deprived of tryptophan, whereas no controls over 17 months of age produced any offspring. Other signs of delayed aging in the experimental group included, at advanced ages, greater longevity, as well as later onset in the appearance of obvious tumors, and better coat condition and hair regrowth. Many of these effects were also seen in pair-fed controls (fed a diet equal in amount to that eaten by the tryptophan-deprived rats, but with 1-tryptophan added). It is hypothesized that tryptophan deficiency delays growth, development and maturation of the central nervous system (CNS), in particular, by decreasing the levels of the neurotransmitter serotonin, for which tryptophan is the necessary precursor. In a parallel experiment, chronic treatment with d, 1-parachlorophenylalanine, an inhibitor of brain serotonin synthesis, from weaning until adulthood, also inhibited growth (body weight) and delayed sexual maturation (age of vaginal opening). These observations suggest that diets deficient in tryptophan or restricted in calories can affect maturation and aging by interfering with CNS protein synthesis, or neurotransmitter metabolism, or both.

Naturwissenschaften 1965 Sep;52(18):519. [Serotonin-caused muscular dystrophy]. [Article in German] Selye H.

Toxicology 1999 Feb 15;132(2-3):139-46. Protection against chronic cadmium toxicity by glycine. Shaikh ZA, Tang W

Biosci Biotechnol Biochem 1998 Mar;62(3):580-3. Increased conversion ratio of tryptophan to niacin in severe food restriction. Shibata K, Kondo T, Miki A.

Monogr Neural Sci 1976;3:94-101. Sex, migraine and serotonin interrelationships. Sicuteri F, Del Bene E, Fonda C. Sexual deficiency or frank impotence in man could be due to an imbalance of monoamines, particularly 5-HT, at the mating center level. An absolute or relative excess of 5-HT seems to antagonize testosterone at the level of the mating center receptors in the brain. Plasma testosterone levels in so-called psychological impotence are normal. When the 5-HT concentration in sexually deficient men is sufficiently decreased with parachlorophenylalanine (PCPA) treatment and testosterone levels increased following its administration, a vivid sexual stimulation appears in about half of the untractable cases. Yet the PCPA-MAOI treatment avoids the prostate carcinogenic risk of testosterone administration in aging males, and seems to have euphorizing effects stronger than those expected only from MAOI therapy. Because of the several side effects of PCPA-MAOI testosterone, the present experiments should be interpreted very cautiously.

Hepatology 1999 Mar;29(3):737-45. Glycine and uridine prevent D-galactosamine hepatotoxicity in the rat: role of Kupffer cells. Stachlewitz RF, Seabra V, Bradford B, Bradham CA, Rusyn I, Germolec D, Thurman RG.

Eur J Appl Physiol Occup Physiol 1999 Mar;79(4):318-24. Effect of acute and chronic exercise on plasma amino acids and prolactin concentrations and on [3H]ketanserin binding to serotonin2A receptors on human platelets. Struder HK, Hollmann W, Platen P, Wostmann R, Weicker H, Molderings GJ. The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has been shown to modulate various physiological and psychological functions such as fatigue. Altered regulation of the serotonergic system has been suggested to play a role in response to exercise stress. The present results support the hypothesis that acute endurance exercise may increase 5-HT availability. This was reflected in the periphery by increased concentration of the 5-HT precursor free TRP, by increased plasma PRL concentration, and by a reduction of 5-HT2A receptors on platelets.

Epilepsy Res 1999 Jan;33(1):11-21. Pharmacokinetic analysis and anticonvulsant activity of glycine and glycinamide derivatives. Sussan S, Dagan A, Bialer M.

Adv Biochem Psychopharmacol 1976; 15:251-65. Glucocorticoid regulation of the serotonergic system of the brain. Sze PY. Glucorticoids at concentrations above 10(-7) M stimulate the uptake of tryptophan by brain synaptosomes.

Neurobiol Aging 1984 Fall;5(3):235-42. Lifetime brain serotonin: regional effects of age and precursor availability. Timiras PS, Hudson DB, Segall PE. In the rat, regional brain serotonin levels which do not change from 2-30 months of age are increased at 36 months. Impaired brain serotonin levels recover moderately but remain lower than controls as late as 36 months, growth is never completely compensated, and norepinephrine levels show a rebound increase.

Kidney Int 1996 Feb;49(2):449-60. Cytoprotection of kidney epithelial cells by compounds that target amino acid gated chloride channels. Venkatachalam MA, Weinberg JM, Patel Y, Saikumar P, Dong Z

Am J Physiol Lung Cell Mol Physiol 2000 Aug;279(2):L390-8. Dietary glycine blunts lung inflammatory cell influx following acute endotoxin. Wheeler MD, Rose ML, Yamashima S, Enomoto N, Seabra V, Madren J, Thurman RG.

Am J Physiol 1999 Nov;277(5 Pt 1):L952-9. Production of superoxide and TNF-alpha from alveolar macrophages is blunted by glycine. Wheeler MD, Thurman RG.

Stroke 1991 Apr;22(4):469-76. Identification of capric acid as a potent vasorelaxant of human basilar arteries. White RP, Ricca GF, el-Bauomy AM, Robertson JT To determine whether naturally occurring fatty acids, especially saturated ones, might act directly as vasodilators, segments of human basilar arteries and umbilical arteries were precontracted submaximally with prostaglandin F2 alpha and then exposed to different saturated fatty acids (C4 through C16) or unsaturated fatty acids (C14:1, C18:1, C18:2, and C18:3) at concentrations from 4 microM to 4 mM. The results showed caprate (C10) to be the most potent vasorelaxant and basilar arteries to be more responsive (EC50 = 63 microM) than umbilical arteries (EC50 = 780 microM). Caprate also inhibited contractions elicited by KCl, serotonin, and the thromboxane analogue U46619.

Neurochem Res 1978 Jun;3(3):295-311. Adaptive changes induced by high altitude in the development of brain monoamine enzymes. Vaccari A, Brotman S, Cimino J, Timiras PS.

Growth Dev Aging 1991 Winter; 55(4):275-83. Effect of aging and diet restriction on monoamines and amino acids in cerebral cortex of Fischer-344 rats. Yeung JM, Friedman E.

Proc Natl Acad Sci U S A 1992 Jul 15;89(14):6443-6. Platelet activation by simultaneous actions of diacylglycerol and unsaturated fatty acids. Yoshida K, Asaoka Y, Nishizuka Y Several cis-unsaturated fatty acids such as oleic, linoleic, linolenic, eicosapentaenoic, and docosahexaenoic acids added directly to intact human platelets greatly enhance protein kinase C activation as judged by the phosphorylation of its specific endogenous substrate, a 47-kDa protein. In the presence of ionomycin and either 1,2-dioctanoylglycerol or phorbol 12-myristate 13-acetate, the release of serotonin from the platelets is also remarkably increased by cis-unsaturated fatty acids. The effect of these fatty acids is observed at concentrations less than 50 microM. Saturated fatty acids and trans-unsaturated fatty acids are inactive. . . . cis-unsaturated fatty acids increase an apparent sensitivity of the platelet response to Ca2+. The results suggest that cis-unsaturated fatty acids, which are presumably produced from phosphatidylcholine by signal-dependent activation of phospholipase A2, may take part directly in cell signaling through the protein kinase C pathway.

Jpn J Physiol 1969 Apr 15;19(2):176-86. Lipolytic action of serotonin in brown adipose tissue in vitro. Yoshimura K, Hiroshige T, Itoh S

Hepatology 2000 Sep;32(3):542-6. Glycine prevents apoptosis of rat sinusoidal endothelial cells caused by deprivation of vascular endothelial growth factor. Zhang Y, Ikejima K, Honda H, Kitamura T, Takei Y, Sato N

Mol Pharmacol 1999 Sep;56(3):455-63. Dietary glycine and renal denervation prevents cyclosporin A-induced hydroxyl radical production in rat kidney. Zhong Z, Connor HD, Yin M, Moss N, Mason RP, Bunzendahl H, Forman DT, Thurman RG

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<span class="koboSpan" id="kobo.1.1">Unsaturated Vegetable Oils: Toxic</span> A R T I C L E

Unsaturated Vegetable Oils: Toxic

GLOSSARY:

Immunodeficiency (weakness of the immune system) can take many forms. AIDS, for example, refers to an immunodeficiency which is "acquired," rather than "inborn." Radiation and vegetable oils can cause "acquired immunodeficiency." Unsaturated oils, especially polyunsaturates, weaken the immune system's function in ways that are similar to the damage caused by radiation, hormone imbalance, cancer, aging, or viral infections. The media discuss sexually transmitted and drug-induced immunodeficiency, but it isn't yet considered polite to discuss vegetable oil-induced immunodeficiency.

Unsaturated oils: When an oil is saturated, that means that the molecule has all the hydrogen atoms it can hold. Unsaturation means that some hydrogen atoms have been removed, and this opens the structure of the molecule in a way that makes it susceptible to attack by free radicals.

Free radicals are reactive molecular fragments that occur even in healthy cells, and can damage the cell. When unsaturated oils are exposed to free radicals they can create chain reactions of free radicals that spread the damage in the cell, and contribute to the cell's aging.

Rancidity of oils occurs when they are exposed to oxygen, in the body just as in the bottle. Harmful free radicals are formed, and oxygen is used up.

Essential fatty acids (EFA) are, according to the textbooks, linoleic acid and linolenic acid, and they are supposed to have the status of "vitamins," which must be taken in the diet to make life possible. However, we are able to synthesize our own unsaturated fats when we don't eat the "EFA," so they are not "essential." The term thus appears to be a misnomer. [M. E. Hanke, "Biochemistry," Encycl. Brit. Book of the Year, 1948.]

Q: You say vegetable oils are hazardous to your health. What vegetable oils are you talking about?

Mainly, I'm referring to soybean oil, corn oil, safflower oil, canola, sesame oil, sunflower seed oil, palm oil, and any others that are labeled as "unsaturated" or "polyunsaturated." Almond oil, which is used in many cosmetics, is very unsaturated.

Chemically, the material that makes these oils very toxic is the polyunsaturated fat itself. These unsaturated oils are found in very high concentrations in many seeds, and in the fats of animals that have eaten a diet containing them. The fresh oils, whether cold pressed or consumed as part of the living plant material, are intrinsically toxic, and it is not any special industrial treatment that makes them toxic. Since these oils occur in other parts of plants at lower concentration, and in the animals which eat the plants, it is impossible to eat a diet which lacks them, unless special foods are prepared in the laboratory.

These toxic oils are sometimes called the "essential fatty acids" or "vitamin F," but this concept of the oils as essential nutrients was clearly disproved over 50 years ago.

Linoleic and linolenic acids, the "essential fatty acids," and other polyunsaturated fatty acids, which are now fed to pigs to fatten them, in the form of corn and soy beans, cause the animals' fat to be chemically equivalent to vegetable oil. In the late 1940s, chemical toxins were used to suppress the thyroid function of pigs, to make them get fatter while consuming less food. When that was found to be carcinogenic, it was then found that corn and soy beans had the same antithyroid effect, causing the animals to be fattened at low cost. The animals' fat becomes chemically similar to the fats in their food, causing it to be equally toxic, and equally fattening.

These oils are derived from seeds, but their abundance in some meat has led to a lot of confusion about "animal fats." Many researchers still refer to lard as a "saturated fat," but this is simply incorrect when pigs are fed soybeans and corn.

Q: How are these oils hazardous to your health?

Ultimately, all systems of the body are harmed by an excess of these oils. There are two reasons for this. One is that the plants produce the oils for protection, not only to store energy for the germination of the seed. To defend the seeds from the animals that would eat them, the oils block the digestive enzymes in the animals' stomachs. Digestion is one of our most basic functions, and evolution has built many other systems by using variations of that system; as a result, all of these systems are damaged by the substances which damage the digestive system.

The other reason is that the seeds are designed to germinate in early spring, so their energy stores must be accessible when the temperatures are cool, and they normally don't have to remain viable through the hot summer months. Unsaturated oils are liquid when they are cold, and this is necessary for any organism that lives at low temperatures. For example, fish in cold water would be stiff if they contained saturated fats. These oils easily get rancid (spontaneously oxidizing) when they are warm and exposed to oxygen. Seeds contain a small amount of vitamin E to delay rancidity. When the oils are stored in our tissues, they are much warmer, and more directly exposed to oxygen, than they would be in the seeds, and so their tendency to oxidize is very great. These oxidative processes can damage enzymes and other parts of cells, and especially their ability to produce energy.

The enzymes which break down proteins are inhibited by unsaturated fats, and these enzymes are needed not only for digestion, but also for production of thyroid hormones, clot removal, immunity, and the general adaptability of cells. The risks of abnormal blood clotting, inflammation, immune deficiency, shock, aging, obesity, and cancer are increased. Thyroid and progesterone are decreased. Since the unsaturated oils block protein digestion in the stomach, we can be malnourished even while "eating well."

Plants produce many protective substances to repel or injure insects and other animals that eat them. They produce their own pesticides. The oils in seeds have this function. On top of this natural toxicity, the plants are sprayed with industrial pesticides, which can concentrate in the seed oils.

It isn't the quantity of these polyunsaturated oils which governs the harm they do, but the relationship between them and the saturated fats. Obesity, free radical production, the formation of age pigment, blood clotting, inflammation, immunity, and energy production are all responsive to the ratio of unsaturated fats to saturated fats, and the higher this ratio is, the greater the probability of harm there is.

There are interesting interactions between these oils and estrogen. For example, puberty occurs at an earlier age if estrogen is high, or if these oils are more abundant in the diet. This is probably a factor in the development of cancer.

All systems of the body are harmed by an excess of these oils. There are three main kinds of damage: one, hormonal imbalances, two, damage to the immune system, and three, oxidative damage.

Q: How do they cause hormonal imbalances?

There are many changes in hormones caused by unsaturated fats. Their best understood effect is their interference with the function of the thyroid gland. Unsaturated oils block thyroid hormone secretion, its movement in the circulatory system, and the response of tissues to the hormone. When the thyroid hormone is deficient, the body is generally exposed to increased levels of estrogen. The thyroid hormone is essential for making the "protective hormones" progesterone and pregnenolone, so these hormones are lowered when anything interferes with the function of the thyroid. The thyroid hormone is required for using and eliminating cholesterol, so cholesterol is likely to be raised by anything which blocks the thyroid function. [B. Barnes and L. Galton, Hypothyroidism, 1976, and 1994 references.]

Q: How do they damage the immune system?

Vegetable oil is recognized as a drug for knocking out the immune system. Vegetable oil emulsions were used to nourish cancer patients, but it was discovered that the unsaturated oils were suppressing their immune systems. The same products, in which vegetable oil is emulsified with water for intravenous injection, are now marketed specifically for the purpose of suppressing immunity in patients who have had organ transplants. Using the oils in foods has the same harmful effect on the immune system. [E. A. Mascioli, et al.,Lipids 22(6) 421, 1987.] Unsaturated fats directly kill white blood cells. [C. J. Meade and J. Martin, Adv. Lipid Res., 127, 1978.]

Q: How do they cause oxidative damage?

Unsaturated oils get rancid when exposed to air; that is called oxidation, and it is the same process that occurs when oil paint "dries." Free radicals are produced in the process.

This process is accelerated at higher temperatures. The free radicals produced in this process react with parts of cells, such as molecules of DNA and protein and may become attached to those molecules, causing abnormalities of structure and function.

Q: What if I eat only organically grown vegetable oils?

Even without the addition of agricultural chemicals, an excess of unsaturated vegetable oils damages the human body. Cancer can't occur, unless there are unsaturated oils in the diet. [C. Ip, et al., Cancer Res. 45, 1985.] Alcoholic cirrhosis of the liver cannot occur unless there are unsaturated oils in the diet. [Nanji and French, Life Sciences. 44, 1989.] Heart disease can be produced by unsaturated oils, and prevented by adding saturated oils to the diet. [J. K. G. Kramer, et al., Lipids 17, 372, 1983.]

Q. What oils are safe?

Coconut and olive oil are the only vegetable oils that are really safe, but butter and lamb fat, which are highly saturated, are generally very safe (except when the animals have been poisoned). Coconut oil is unique in its ability to prevent weight-gain or cure obesity, by stimulating metabolism. It is quickly metabolized, and functions in some ways as an antioxidant. Olive oil, though it is somewhat fattening, is less fattening than corn or soy oil, and contains an

antioxidant which makes it protective against heart disease and cancer.

Israel had the world's highest incidence of breast cancer when they allowed the insecticide lindane to be used in dairies, and the cancer rate decreased immediately after the government prohibited its use. The United States has fairly good laws to control the use of cancer-causing agents in the food supply, but they are not vigorously enforced. Certain cancers are several times more common among corn farmers than among other farmers, presumably because corn "requires" the use of more pesticides. This probably makes corn oil's toxicity greater than it would be otherwise, but even the pure, organically grown material is toxic, because of its intrinsic unsaturation.

In the United States, lard is toxic because the pigs are fed large quantities of corn and soy beans. Besides the intrinsic toxicity of the seed oils, they are contaminated with agricultural chemicals. Corn farmers have a very high incidence of cancer, presumably because of the pesticides they use on their crop.

Q: But aren't "tropical oils" bad for us?

In general, tropical oils are much more healthful than oils produced in a cold climate. This is because tropical plants live at a temperature that is close to our natural body temperature. Tropical oils are stable at high temperatures. When we eat tropical oils, they don't get rancid in our tissues as the cold-climate seed oils, such as corn oil, safflower oil and soy oil, do. [R.B. Wolf, J. Am. Oil Chem. Soc. 59, 230, 1982; R. Wolfe, Chem 121, Univ. of Oregon, 1986.]

When added to a balanced diet, coconut oil slightly lowers the cholesterol level, which is exactly what is expected when a dietary change raises thyroid function. This same increase in thyroid function and metabolic rate explains why people and animals that regularly eat coconut oil are lean, and remarkably free of heart disease and cancer.

Although I don't recommend "palm oil" as a food, because I think it is less stable than coconut oil, some studies show that it contains valuable nutrients. For example, it contains antioxidants similar to vitamin E, which lowers both LDL cholesterol and a platelet clotting factor. [B. A. Bradlow, University of Illinois, Chicago; Science News 139, 268, 1991.] Coconut oil and other tropical oils also contain some hormones that are related to pregnenolone or progesterone.

Q: Isn't coconut oil fattening?

Coconut oil is the least fattening of all the oils. Pig farmers tried to use it to fatten their animals, but when it was added to the animal feed, coconut oil made the pigs lean [See Encycl. Brit. Book of the Year, 1946].

Q: What about olive oil? Isn't it more fattening than other vegetable oils?

In this case, as with coconut oil, "fattening" has more to do with your ability to burn calories than with the caloric value of the oil. Olive oil has a few more calories per quart than corn or soy oil, but since it doesn't damage our ability to burn calories as much as the unsaturated oils do, it is less fattening. Extra virgin olive oil is the best grade, and contains an antioxidant that protects against cancer and heart disease. [1994, Curr. Conts.]

Q: Is "light" olive oil okay?

No. Now and then someone learns how to make a profit from waste material. "Knotty pine" boards were changed from a discarded material to a valued decorative material by a little marketing skill. Light olive oil is a low grade material which sometimes has a rancid smell and probably shouldn't be used as food.

Q: Is margarine okay?

There are several problems with margarine. The manufacturing process introduces some toxins, including a unique type of fat which has been associated with heart disease. [Sci. News, 1974; 1991.] There are likely to be dyes and preservatives added to margarine. And newer products contain new chemicals that haven't been in use long enough to know whether they are safe.

However, the basic hardening process, hydrogenation of the oils, has been found to make the oils less likely to cause cancer. If I had to choose between eating ordinary corn oil or corn oil that was 100% saturated, to make a hard margarine, I would choose the hard margarine, because it resists oxidation, isn't suppressive to the thyroid gland, and doesn't cause cancer.

Q: What about butter?

Butter contains natural vitamin A and D and some beneficial natural hormones. It is less fattening than the unsaturated oils. There is much less cholesterol in an ounce of butter than in a lean chicken breast [about 1/5 as much cholesterol in fat as in lean meat on a calorie basis, according to R. Reiser of Texas A & M Univ., 1979.].

Q: Are fish oils good for you?

Some of the unsaturated fats in fish are definitely less toxic than those in corn oil or soy oil, but that doesn't mean they are safe. Fifty years ago, it was found that a large amount of cod liver oil in dogs' diet increased their death rate from cancer by 20 times, from the usual 5% to 100%. A diet rich in fish oil causes intense production of toxic lipid peroxides, and has been observed to reduce a man's sperm count to zero. [H. Sinclair, Prog. Lipid Res. 25, 667, 1989.]

Q: What about lard?

In this country, lard is toxic beause the pigs are fed large quantities of corn and soy beans. Besides the natural toxicity of the seed oils, the oils are contaminated with agricultural chemicals. Corn farmers have a very high incidence of cancer, presumably because corn "requires" the use of more pesticides. This probably makes corn oil's toxicity greater than it would be otherwise. but even the pure, organically grown material is toxic, because of its unsaturation.

Women with breast cancer have very high levels of agricultural pesticides in their breasts [See Science News, 1992, 1994].

Israel had the world's highest incidence of breast cancer when they allowed the insecticide lindane to be used in dairies, and the cancer rate decreased immediately after the government prohibited its use. The United States has fairly good laws to control the use of cancer-causing agents in the food supply, but they are not vigorously enforced. [World Incid. of Cancer, 1992]

Q: I have no control over oils when eating out. What can I do to offset the harmful effects of polyunsaturated oils?

A small amount of these oils won't kill you. It is the proportion of them in your diet that matters. A little extra vitamin E (such as 100 units per day) will take care of an occasional American restaurant meal. Based on animal studies, it would take a teaspoonful per day of corn or soy oil added to a fat-free diet to significantly increase our risk of cancer. Unfortunately, it is impossible to devise a fat-free diet outside of a laboratory. Vegetables, grains, nuts, fish and meats all naturally contain large amounts of these oils, and the extra oil used in cooking becomes a more serious problem.

Q Why are the unsaturated oils so popular if they are dangerous?

It's a whole system of promotion, advertising, and profitability.

50 years ago, paints and varnishes were made of soy oil, safflower oil, and linseed (flax seed) oil. Then chemists learned how to make paint from petroleum, which was much cheaper. As a result, the huge seed oil industry found its crop increasingly hard to sell. Around the same time, farmers were experimenting with poisons to make their pigs get fatter with less food, and they discovered that corn and soy beans served the purpose, in a legal way. The crops that had been grown for the paint industry came to be used for animal food. Then these foods that made animals get fat cheaply came to be promoted as foods for humans, but they had to direct attention away from the fact that they are very fattening. The "cholesterol" focus was just one of the marketing tools used by the oil industry. Unfortunately it is the one that has lasted the longest, even after the unsaturated oils were proven to cause heart disease as well as cancer. [Study at L.A. Veterans Hospital, 1971.]

I use some of these oils (walnut oil is very nice, but safflower oil is cheaper) for oil painting, but I am careful to wash my hands thoroughly after I touch them, because they can be absorbed through the skin.

SUMMARY

Unsaturated fats cause aging, clotting, inflammation, cancer, and weight gain.

Avoid foods which contain the polyunsaturated oils, such as corn, soy, safflower, flax, cottonseed, canola, peanut, and sesame oil.

Mayonnaise, pastries, even candies may contain these oils; check the labels for ingredients.

Pork is now fed corn and soy beans, so lard is usually as toxic as those oils; use only lean pork.

Fish oils are usually highly unsaturated; "dry" types of fish, and shellfish, used once or twice a week, are good. Avoid cod liver oil.

Use vitamin E.

Use coconut oil, butter, and olive oil.

Unsaturated fats intensify estrogen's harmful effects.

REFERENCES

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2. J. M. Bell and P. K. Lundberg, "Effects of a commercial soy lecithin preparation on development of sensorimotor behavior & brain biochemicals in the rat," Dev. Psychobiol. 8(1), 59-66, 1985.

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4. M. S. Brown, et al., "Receptor mediated uptake of lipoprotein-cholesterol and its utilization for steroid synthesis," Recent Progress in Hormone Res. 35, 315-257, 1979.

5. P. A. Cerutti, "Oxy-radicals and cancer," Lancet 455(8926), 862-863, 1994.

6. I. Davies and A. P. Fotheringham, "Lipofuscin--Does it affect cellular performance?" Exp. Gerontol. 16, 119-125, 1981.

7. K. L. Erickson, et al., "Dietary lipid modulation of immune responsiveness," Lipids 18, 468-74, 1983.

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10. M. C. Galli, et al., "Peroxidation potential of rat thymus during development and involution," Comp. Biochem. Physiol (C) 107(3), 435-440, 1994.

11. J. M. Gaziano, et al., "Supplementation with beta-carotene in vivo and in vitro does not inhibit low density lipoprotein oxidation," Atherosclerosis 112(2), 187-195, 1995.

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H. R. Hirsch, "The waste-product theory of aging: Cell division rate as a function of waste volume," Mech. Ageing Dev. 36, 95-107, 1986.

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18. Clement Ip, et al., "Requirement of essential fatty acids for mammary tumorigenesis," Cancer Res. 45(5), 1997-2001, 1985.

19. P. V. Johnston, "Dietary fat, eicosanoids, and immunity," Adv. in Lipid Res. 21, 103-41, 1985.

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21. H. A. Kleinveld, et al., "Vitamin E and fatty acid intervention does not attenuate the progression of atherosclerosis in watanabe heritable hyperlipidemic rabbits," Arterioscler. Thromb. Vasc. Biol. 15(2), 290-297, 1995.

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Essential Fatty Acids ("EFA"): A Technical Point

Those fatty acids, such as linoleic acid and linolenic acid, which are found in linseed oil, soy oil, walnut oil, almond oil, corn oil, etc., are essential for the spontaneous development of cancer, and also appear to be decisive factors in the development of age pigment, alcoholic cirrhosis of the liver, diabetes, obesity, stress-induced immunodeficiency, some aspects of the shock reaction, epilepsy, brain swelling, congenital retardation, hardening of the arteries, cataracts, and other degenerative conditions. They are possibly the most important toxin for animals.

The suppression of an enzyme system is characteristic of toxins. The "EFA" powerfully, almost absolutely, inhibit the enzyme systems--desaturases and elongases--which make our native unsaturated fatty acids.

After weaning, these native fats gradually disappear from the tissues and are replaced by the EFA and their derivatives. The age-related decline in our ability to use oxygen and to produce energy corresponds closely to the substitution of linoleic acid for the endogenous fats, in cardiolipin, which regulates the crucial respiratory enzyme, cytochrome oxidase.

Although the fish oils are less effective inhibitors of the enzymes, they are generally similar to the seed oils in their ability to promote cancer, age-pigment formation, free radical damage, etc. Their only special nutritional value seems to be their vitamin A and vitamin D content. Since vitamin A is important in the development of the eye, it is interesting that claims are being made for the essentiality of some of the fatty acid components of fish oil, in relation to the development of the eye.

The polyunsaturated oils from seeds are recommended for use in paints and varnishes, but skin contact with these substances should be avoided.

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<span class="koboSpan" id="kobo.1.1">Vegetables, etc.Who Defines Food?</span> A R T I C L E

Vegetables, etc.Who Defines Food?

Since bacteria in the rumens of cows destroy unsaturated fatty acids, but don't harm vitamin E, it seems reasonable to suppose that beef and milk would have a better ratio of vitamin E to unsaturated fats than do the plants eaten by the cows.

Toxic pesticides are found in higher concentrations in the urine and fat of slaughtered animals than in their livers, since the livers are detoxifying the chemicals and causing them to be excreted. Presumably, the animals' livers will perform the same detoxification reactions with the phytotoxicants that occur naturally in their diet.

Not long ago, breast feeding was socially unacceptable in the United States, and several manufacturers were teaching the worlds poorest women to use their baby-food formulas even when there was no clean water for its preparation. Industrialists have campaigned to convince the public that their by-products, from cotton-seed oil to shrimp shells, are health foods. In several parts of the world, desperately poor people sometimes eat clay, and even clay has been promoted as a health food. Almost anything becomes food, when people are under economic and social pressure. If these things arent acutely toxic, they can become part of our normal diet.

Our instincts give us a few clues about our nutritional needs, such as thirst, the hunger for salt, the pleasantness of sweet things, and the unpleasantness of certain odors or very acrid or bitter tastes. People who are constitutionally unable to taste certain bitter chemicals find certain vegetables less objectionable; their instinctive guidance has become less clear. But within the boundaries of cravings and disgust, habits and customs become the dominant forces in diet. "Professional dietitians" and other "experts" primarily function as enforcers of cultural prejudice.

The manufacturers of pureed vegetables for babies used to put large amounts of salt, sugar, and monosodium glutamate into their products, because the added chemicals served as instinctual signals that made the material somewhat acceptable to the babies. There was no scientific basis for providing these vegetables to babies in a form that they would accept, but it was a profitable practice that was compatible with the social pressure against prolonged breast feeding.

Poor people, especially in the spring when other foods were scarce, have sometimes subsisted on foliage such as collard and poke greens, usually made more palatable by cooking them with flavorings, such as a little bacon grease and lots of salt. Eventually, "famine foods" can be accepted as dietary staples. The fact that cows, sheep, goats and deer can thrive on a diet of foliage shows that leaves contain essential nutrients. Their minerals, vitamins, and amino acids are suitable for sustaining most animal life, if a sufficient quantity is eaten. But when people try to live primarily on foliage, as in famines, they soon suffer from a great variety of diseases. Various leaves contain antimetabolic substances that prevent the assimilation of the nutrients, and only very specifically adapted digestive systems (or technologies) can overcome those toxic effects.

Some plants have specific pests, such as insects, that have adapted to be resistant to that plants toxins, but if the plant and its predator are to survive, there has to be a balance between the plant tissues digestibility and its toxicity. Injury of a plant stimulates it to make increased amounts of its defensive chemicals. Plant toxins are known to be specific for animal tissues; for example, a toxin will inhibit the action of an enzyme from an animal, but a plant enzyme that catalyzes the same reaction wont be affected.

Plant defensive chemicals can have beneficial uses as drugs. Plants are important sources for chemicals used in chemotherapy of cancer, with the purpose of stopping cell division. Other plant drugs can stimulate cell division. The drug from one plant will sometimes protect cells against the toxic effects of another plant. The use of any drug that isnt a natural part of animal physiology will have many biological effects, so that a beneficial drug action will usually be accompanied by unwanted side-effects. An antioxidant may turn out to disrupt the endocrine system, an antiinflammatory drug may be mutagenic or carcinogenic.

A particular plant will have a variety of defensive chemicals, with specific functions. Underground, the plants roots and tubers are susceptible to attack by fungi and nematodes. The leaves, stems, and seeds are susceptible to attack by insects, birds, and grazing animals. Since the plants seeds are of unique importance to the plant, and contain a high concentration of nutrients, they must have special protection. Sometimes this consists of a hard shell, and sometimes of chemicals that inhibit the animals digestive enzymes. Many plants have evolved fruits that provide concentrated food for animals, and that serve to distribute the seeds widely, as when a bird eats a berry, and excretes the undigested seed at a great distance. If the fruit were poisonous, it wouldnt serve the plants purpose so well. In general, the plants most intense toxins are in its seeds, and the fruits, when mature, generally contain practically no toxins. Roots contain chemicals that inhibit microorganisms, but because they arent easily accessible by grazing animals and insects, they dont contain the digestive inhibitors that are more concentrated in the above-ground organs of the plant.

The toxins of plants include phenols, tannins, lectins/agglutinins, and trypsin-inhibitors, besides innumerable more specific metabolic inhibitors, including anti-vitamins. Unsaturated fats themselves are important defenses, since they inhibit trypsin and other proteolytic enzymes, preventing the assimilation of the proteins that are present in seeds and leaves, and disrupting all biological processes that depend on protein breakdown, such as the formation of thyroid hormone and the removal of blood clots.

Generally, fruits, roots, and tubers provide a high concentration of nutrients along with low concentrations of toxic antimetabolic substances.

While nutritional reference tables often show fruits and potatoes as having about 2% protein content, while nuts, grains, and legumes are shown with a high protein content, often in the range of 15% to 40%, they neglect to point out that fruits and potatoes have a very high water content, while that of the seeds is extremely low. The protein content of milk is about 3%, which according to the charts would suggest that it is inferior to beans and grains. In fact, the protein value of grain is negligible, mainly because seeds contain their protein in a storage form, that is extremely rich in nitrogen, but poor in essential amino acids. Special preparation is needed to reduce the toxicity of seeds, and in the case of beans, these methods are never very satisfactory.

Besides their specific defensive toxins and antimetabolites, plants are major sources of allergens. The allergenicity of a food depends on the sensitivity of the individual, as well as on the growth conditions of the plant. The use of extremely toxic pesticides has affected both the crops and the sensitivity of the human population to allergens. Sensitivities induced originally by toxic pesticides used on certain crops can probably persist after the industrial chemical has been eliminated, because the immune system is susceptible to conditioning.

Many types of phytochemicals are mutagenic, and some of those are carcinogenic. Bruce Ames, at the University of California, devised a method of screening for mutagens, using bacteria. One of his graduate students using the technique found that the flame retardants in children's pajamas and bedding were powerful mutagens, and were probably causing cancer. That event made Ames a celebrity, and in the 1980s he went on a lecture tour supported by the American Cancer Society. His lectures reflected the doctrine of the A.C.S., that industrial chemicals aren't responsible for cancer, but that individual actions, such as smoking or dietary choices, are the main causes of cancer. He used a fraudulently "age adjusted" graph of cancer mortality, that falsely showed that mortality from all types of cancer except lung cancer had leveled off after the A.C.S. came into existence. He described tests in which he had compared DDT to extracts of food herbs, and found DDT to be less mutagenic than several of the most commonly used flavoring herbs. His message, which was eagerly received by his audience of chemistry and biology professors, was that we should not worry about environmental pollution, because it's not as harmful as the things that we do to ourselves. He said that if everyone would eat more unsaturated vegetable oil, and didn't smoke, they wouldn't have anything to worry about.

For me, the significance of his experiment was that plants contain natural pesticides that should be taken more seriously, without taking industrial toxins less seriously.

Technologies have been invented to convert vegetation into digestible protein, but at our present scientific and technological level, its better to simply minimize our use of the more toxic foods, and to direct more effort toward the elimination of the conditions that produce famine.

Animal proteins, and fruits, because they contain the lowest levels of toxins, should form the basis of the diet. Not all fruits, of course, are perfectly safe--avocados, for example, contain so much unsaturated fat that they can be carcinogenic and hepatotoxic.

Protein deficiency itself contributes to the harm done by toxins, since the livers ability to detoxify them depends on adequate nutrition, especially good protein. In the 1940s, Biskinds experiments showed that protein deficiency leads to the accumulation of estrogen, because the liver normally inactivates all the estrogen in the blood as it passes through the liver. This applies to phytoestrogens and industrial estrogens as well as to the natural estrogens of the body. At a certain point, the increased estrogen and decreased thyroid and progesterone cause infertility, but before that point is reached, the hyperestrogenism causes a great variety of birth defects. Deformities of the male genitals, and later, testicular cancer in the sons and breast cancer in the daughters, are produced by the combination of toxins and nutritional deficiencies.

REFERENCES

Onderstepoort J Vet Res 1989 Jun;56(2):145-6. Thiaminase activities and thiamine content of Pteridium aquilinum, Equisetum ramosissimum, Malva parviflora, Pennisetum clandestinum and Medicago sativa. Meyer P Animal and Dairy Science Research Institute, Private Bag, Irene. Thiaminase type 1 and 2 activities and thiamine content of five plants were determined. Of these Pteridium aquilinum and Equisetum ramosissimum were found to have considerably more thiaminase activity and lower thiamine content than Malva parviflora, Pennisetum clandestinum and Medicago sativa.

Nature 1994 Apr 21;368(6473):683-4. Mystery of the poisoned expedition. Earl JW, McCleary BV Department of Biochemistry, Royal Alexandra Hospital for Children, Camperdown, Sydney, New South Wales, Australia. The Burke and Wills expedition through the interior of Australia in the nineteenth century ended in calamity. But the cause of death was more pernicious than anyone at the time had imagined: beriberi due to thiaminase poisoning.

Comment in: Nature 1994 Aug 11; 370(6489):408. Aust Vet J 1992 Jul;69(7):165-7. Mechanisms underlying Phalaris aquatica "sudden death" syndrome in sheep. Bourke CA, Carrigan MJ New South Wales Agriculture, Agricultural Research and Veterinary Centre, Orange. Twenty outbreaks of Phalaris aquatica "sudden death" syndrome in sheep were investigated between 1981 and 1991. Four were confirmed and one was suspected, to be a cardiac disorder; 5 were confirmed and 3 were suspected, to be a polioencephalomalacic disorder; the aetiology of the remaining 7 outbreaks could not be determined. Potentially toxic levels of hydrocyanic acid (20 to 36 mg/100 g) were measured in the 3 toxic phalaris pastures tested. The measurement of potentially toxic levels of nitrate nitrogen (2920 micrograms/g) in toxic phalaris pastures by others, was noted. It is suggested that phalaris "sudden death" syndrome could have as many as 4 different underlying mechanisms, and that these might reflect the presence in the plant of a cardio-respiratory toxin, a thiaminase and amine co-substate, cyanogenic compounds, and nitrate compounds.

Indian J Med Res 1991 Oct;94:378-83. Genotoxic effects of some foods & food components in Swiss mice. Balachandran B, Sivaswamy SN, Sivaramakrishnan VM Isotope Division, Cancer Institute, Madras. A number of commonly consumed foods and food components in south India were screened for their genotoxic effects on Swiss mice. Salted, sundried and oil fried vegetables and fishes induced chromosomal aberrations, sperm head abnormalities and micronuclei production, which were comparable to the effect of the positive control viz., 20-methylcholanthrene. Spices like Cissus quadrangularis (an indigenous herb used in certain south Indian dishes) and pyrolysed cumin and aniseeds showed moderate effects. Calamus oil, widely used in pharmaceuticals was highly effective. All the three parameters of genotoxicity gave similar results.

In Vivo 1998 Nov-Dec;12(6):675-89. Comparative anticancer effects of vaccination and dietary factors on experimentally-induced cancers. Zusman I Laboratory of Teratology and Experimental Oncology, Koret School of Veterinary Medicine, Faculty of Agriculture, Food and Environmental Quality Sciences, Hebrew University of Jerusalem, Rehovot, Israel. The role of two major factors were analyzed in the prevention of experimentally-induced cancers: a) vaccination of animals with polyclonal IgG generated against the soluble p53 antigen and b) feeding of animals with diets rich with dietary fibers or fat. a) In vaccination, a few attempts have been made to utilize p53 protein as a tumor suppressor. IgG generated against the cytoplasmic, soluble p53 antigen from tumor-bearing rats prevents the carcinogenic effect of 1,2-dimethylhydrazine (DMH) decreasing significantly the number of tumor-bearing rats in vaccinated group compared with non vaccinated controls and preventing benign tumors from becoming malignant. The antitumor effect of vaccination is accompanied by a significant increase in the serum-level of p53 antigen in vaccinated rats compared with non vaccinated controls. The immune response of a host to vaccination activates the lymph components of the spleen, and this activation is manifested by the multiplication of the number of lymphocytes which are generated against specific antigens. This multiplication is achieved by the higher division of the antigen-specific lymphoblasts with their subsequent transformation into plasma cells. These cells synthesize the specific protein (IgG). One such protein is the tumor-associated p53 protein, which is synthesized by rats against rabbit anti-p53 IgG. b) The role of dietary factors in the prevention of chemically induced cancer was reviewed on two models: the role of high fiber diets in prevention of colon cancer, and the role of high fat diets in the prevention of mammary gland cancer. Experiments in colon cancer showed that 20% cellulose decreased significantly tumor incidence caused by DMH. The tumor-preventive effect of a cellulose diet was accompanied by increased enzyme concentrations, such as ornithine decarboxylase, thymidine kinase and beta-glucuronidase. This effect was accompanied by activation of some cellular mechanisms, i.e. apoptosis, proliferating cell nuclear antigen (PCNA) and p53 protein synthesis. Experiments in mammary glands cancer showed that a 15% olive-oil diet reduced significantly the tumor incidence caused by 9,10-dimethyl-1,2-benzanthracene. The antitumor effect of the olive-oil diet was connected to its content of monounsaturated fatty acids, such as oleic and palmitic acids. The promotive tumorigenic effects of other high-fat diets (avocado, soybeans) were associated with high content of some polyunsaturated fatty acids (linoleic and alpha-linolenic). Different diets have different targets. The effect of the same diet depends on its anti-tumor substances content. CONCLUSIONS: Vaccination and some diets have similar mechanism in their tumor-preventive effects.

Ann Nutr Metab 1991;35(5):253-60. Effect of dietary avocado oils on hepatic collagen metabolism. Wermam MJ, Mokady S, Neeman I Department of Food Engineering and Biotechnology, Technion - Israel Institute of Technology, Haifa. The effect of various avocado and soybean oils on collagen metabolism in the liver was studied in growing female rats for 8 weeks and in day-old chicks for 1 week. In comparison with rats fed either refined avocado oil, refined or unrefined soybean oils, rats fed unrefined avocado oil showed a significant decrease in total collagen solubility in the liver, while there were no changes in total collagen, protein and moisture content. Chicks fed unrefined avocado oil as compared to those fed refined avocado oil also showed a decrease in hepatic total soluble collagen while hepatic total collagen remained unaffected. Electron micrographs and light-microscope examinations of rats' liver revealed collagen accumulation in the periportal location. This is suggestive of the early stages of fibrosis.

Life Sci 1997;60(19):1635-41. L-canaline: a potent antimetabolite and anti-cancer agent from leguminous plants. Rosenthal GA Laboratory of Biochemical Ecology, University of Kentucky, Lexington 40506, USA. garose@ukcc.uky.edu L-Canaline, the L-2-amino-4-(aminooxy)butyric acid structural analog of L-ornithine' is a powerful antimetabolite stored in many leguminous plants. This nonprotein amino acid reacts vigorously with the pyridoxal phosphate moiety of vitamin B6-containing enzymes to form a covalently-bound oxime that inactivates, often irreversibly, the enzyme. Canaline is not only capable of inhibiting ornithine-dependent enzymic activity, but it also can function as a lysine antagonist. Recently, this natural product was found to possess significant antineoplastic in vitro activity against human pancreatic cancer cells.

Food Chem Toxicol 1999 May;37(5):481-91. Occurrence of emodin, chrysophanol and physcion in vegetables, herbs and liquors. Genotoxicity and anti-genotoxicity of the anthraquinones and of the whole plants. Mueller SO, Schmitt M, Dekant W, Stopper H, Schlatter J, Schreier P, Lutz WK Department of Toxicology, University of Wurzburg, Germany. 1,8-Dihydroxyanthraquinones, present in laxatives, fungi imperfecti, Chinese herbs and possibly vegetables, are in debate as human carcinogens. We screened a variety of vegetables (cabbage lettuce, beans, peas), some herbs and herbal-flavoured liquors for their content of the 'free' anthraquinones emodin, chrysophanol and physcion. For qualitative and quantitative analysis, reversed-phase HPLC (RP-LC), gas chromatography-mass spectrometry (GC-MS) and RP-LC-MS were used. The vegetables showed a large batch-to-batch variability, from 0.04 to 3.6, 5.9 and 36 mg total anthraquinone per kg fresh weight in peas, cabbage lettuce, and beans, respectively. Physcion predominated in all vegetables. In the herbs grape vine leaves, couch grass root and plantain herb, anthraquinones were above the limit of detection. Contents ranged below 1 mg/kg (dry weight). All three anthraquinones were also found in seven of 11 herbal-flavoured liquors, in a range of 0.05 mg/kg to 7.6 mg/kg. The genotoxicity of the analysed anthraquinones was investigated in the comet assay, the micronucleus test and the mutation assay in mouse lymphoma L5178Y tk+/- cells. Emodin was genotoxic, whereas chrysophanol and physcion showed no effects. Complete vegetable extract on its own did not show any effect in the micronucleus test. A lettuce extract completely abolished the induction of micronuclei by the genotoxic anthraquinone danthron. Taking into consideration the measured concentrations of anthraquinones, estimated daily intakes, the genotoxic potency, as well as protective effects of the food matrix, the analysed constituents do not represent a high priority genotoxic risk in a balanced human diet.

Int J Food Sci Nutr 1998 Sep;49(5):343-52. Lipid content and fatty acid composition in foods commonly consumed by nursing Congolese women: incidences on their essential fatty acid intakes and breast milk fatty acids. Rocquelin G, Tapsoba S, Mbemba F, Gallon G, Picq C Tropical Nutrition Unit, ORSTOM, Montpellier, France. The fat content and fatty acid (FA) composition of nearly 40 foods, currently consumed by 102 nursing Congolese mothers living in Brazzaville, were determined to assess their impact on mothers' essential fatty acid (EFA) intakes and breast milk FA. Data on mothers' milk FA and dietary habits which allowed food selection were recently published (Rocquelin et al., 1998). Most foods were locally produced. Food samples were collected at local markets, bleached if necessary to avoid microbial degradation, and stored at +4 degrees C or -20 degrees C. They were lyophilized upon their arrival in the laboratory before lipid analyses. FA composition of food lipids was determined by capillary gas chromatography. Staple diets included low-fat, high-carbohydrate foods (processed cassava roots, wheat bread) and high-polyunsaturated fatty acid (PUFA) foods: soybean oil (high in 18 : 2 n-6 and alpha-18 : 3 n-3), bushbutter (dacryodes edulis), peanuts, avocado (high in fat and 18 : 2 n-6), freshwater and salt-water fish (high in LC n-3 and/or n-6 PUFA), and leafy green vegetables (low in fat but very high in alpha-18 : 3 n-3). Their frequent consumption by nursing mothers provided enough EFA to meet requirements due to lactation. It also explains why mothers' breast milk was rich in C8-C14 saturated FA (26% of total FA) and in n-6, n-3 PUFA (respectively 15.0% and 2.4% of total FA) highly profitable for breastfed infants' development. From this point of view, dietary habits of Congolese mothers have to be sustained for they are more adequate than most Western-type diets.

Med Oncol Tumor Pharmacother 1990;7(2-3):69-85. Dietary carcinogens, environmental pollution, and cancer: some misconceptions. Ames BN, Gold LS Division of Biochemistry and Molecular Biology, University of California, Berkeley 94720. Various misconceptions about dietary carcinogens, pesticide residues, and cancer causation are discussed. The pesticides in our diet are 99.99% natural, since plants make an enormous variety of toxins against fungi, insects, and animal predators. Although only 50 of these natural pesticides have been tested in animal cancer tests, about half of them are carcinogens. About half of all chemicals tested in animal cancer tests are positive. The proportion of natural pesticides positive in animal tests of clastogenicity is also the same as for synthetic chemicals. It is argued that testing chemicals in animals at the maximum tolerated dose primarily measures chronic cell proliferation, a threshold process. Cell proliferation is mutagenic in several ways, including inducing mitotic recombination, and therefore chronic induction of cell proliferation is a risk factor for cancer.

Proc Natl Acad Sci U S A 1980 Aug;77(8):4961-5. Fecalase: a model for activation of dietary glycosides to mutagens by intestinal flora. Tamura G, Gold C, Ferro-Luzzi A, Ames BN Many substances in the plant kingdom and in man's diet occur as glycosides. Recent studies have indicated that many glycosides that are not mutagenic in tests such as the Salmonella test become mutagenic upon hydrolysis of the glycosidic linkages. The Salmonella test utilizes a liver homogenate to approximate mammalian metabolism but does not provide a source of the enzymes present in intestinal bacterial flora that hydrolyze the wide variety of glycosides present in nature. We describe a stable cell-free extract of human feces, fecalase, which is shown to contain various glycosidases that allow the in vitro activation of many natural glycosides to mutagens in the Salmonella/liver homogenate test. Many beverages, such as red wine (but apparently not white wine) and tea, contain glycosides of the mutagne quercetin. Red wine, red grape juice, and tea were mutagenic in the test when fecalase was added, and red wine contained considerable direct mutagenic activity in the absence of fecalase. The implications of quercetin mutagenicity and carcinogenicity are discussed.

Br J Rheumatol 1994 Aug;33(8):790-1. Even garlic. Sweetman BJ

Nutr Cancer 1988;11(4):251-7. Cytotoxicity of extracts of spices to cultured cells. Unnikrishnan MC, Kuttan R Amala Cancer Research Centre, Kerala, India. The cytotoxicity of the extracts from eight different spices used in the Indian diet was determined using Dalton's lymphoma ascites tumor cells and human lymphocytes in vitro and Chinese Hamster Ovary cells and Vero cells in tissue culture. Alcoholic extracts of the spices were found to be more cytotoxic to these cells than their aqueous extracts. Alcoholic extracts of several spices inhibited cell growth at concentrations of 0.2-1 mg/ml in vitro and 0.12-0.3 mg/ml in tissue culture. Ginger, pippali (native to India; also called dried catkins), pepper, and garlic showed the highest activity followed by asafetida, mustard, and horse-gram (native to India). These extracts also inhibited the thymidine uptake into DNA.

J Toxicol Sci 1984 Feb;9(1):77-86. [Mutagenicity and cytotoxicity tests of garlic]. [Article in Japanese] Yoshida S, Hirao Y, Nakagawa S Mutagenicity and cytotoxicity of fresh juice and alcohol extract from garlic were studied by Ames' test, Rec assay, Micronucleus test and the check of the influence to HEp 2 and chinese hamster embryo (CHE) primary cultured cells. No evidence of mutagenicity of these samples were observed in Ames' test and Rec assay, while there was dose dependent increase of micronucleated cells and polychromatocytes on the bone marrow cells of mice and chinese hamsters treated with garlic juice. There were severe damages, e.g. growth inhibition and morphological changes of both cultured cells due to garlic juice, but no or slightly cytotoxic signs were observed even in high concentration of garlic extract. A higher sensitivity to the cytotoxic effects of garlic was seen by the present findings with CHE primary cells than HEp 2 cell line.

Chung Hua Chung Liu Tsa Chih 1985 Mar;7(2):103-5 [Comparison of the cytotoxic effect of fresh garlic, diallyl trisulfide, 5-fluorouracil (5-FU), mitomycin C (MMC) and Cis-DDP on two lines of gastric cancer cells]. [Article in Chinese] Pan XY Teratog Carcinog Mutagen 1998; 18(6):293-302 In vitro and in vivo study of the clastogenicity of the flavone cirsitakaoside extracted from Scoparia dulcis L. (Scrophulariaceae). Pereira-Martins SR, Takahashi CS, Tavares DC, Torres LM Department of Biology, Federal University of Maranhao, Sao Luis, MA. Brazil. smartins@rgm.fmrp.usp.br The mutagenic effect of the flavone cirsitakaoside extracted from the medicinal herb Scoparia dulcis was evaluated in vitro by using human peripheral blood cultures treated with doses of 5, 10, and 15 microg of the flavone/ml culture medium for 48 h. The compound proved to be mutagenic at the highest concentration tested (15 microg/ml). Furthermore, the proliferative index was significantly reduced in all cultures treated with the flavone, although the mitotic index was not reduced. However, the clastogenic activity of the flavone cirsitakaoside was not observed when Swiss mice were treated orally with doses of 10, 20, and 30 mg/animal for 24 h.

Proc Nutr Soc 1977 Sep;36(2):51A.Attempts to overcome anti-nutritive factors in field beans (Vicia faba L) and field peas (Pisum sativum) fed in diets to laying hens. Davidson J

Am J Clin Nutr 1995 Sep;62(3):506-11. The influence of genetic taste markers on food acceptance. Drewnowski A, Rock CL Human Nutrition Program, School of Public Health, University of Michigan, Ann Arbor 48109-2029, USA. Genetically mediated sensitivity to the bitter taste of phenylthiocarbamide (PTC) and 6-n-propylthiouracil (Prop) has long been associated with enhanced sensitivity to other sweet and bitter compounds. New studies suggest that tasters and supertasters of Prop may also differ from notasters in their taste preferences and in their patterns of food rejection and food acceptance. One question is whether the acceptability of bitter-tasting vegetables is influenced by Prop taster status. Cruciferous vegetables are among the major dietary sources of potentially chemoprotective agents in cancer control, and their consumption is reported to alter cancer risk. Strategies aimed at dietary change in individuals or groups should consider the role of genetic taste markers and their potential influences on food preferences and dietary habits.

J Environ Sci Health B 1999 Jul;34(4):681-708. Accumulation of potentially toxic elements in plants and their transfer to human food chain. Dudka S, Miller WP University of Georgia, Department of Crop and Soil Sciences, Athens 30602-2727, USA. Contaminated soils can be a source for crop plants of such elements like As, Cd, Cr, Cu, Ni, Pb, and Zn. The excessive transfer of As, Cu, Ni, and Zn to the food chain is controlled by a "soil-plant barrier"; however, for some elements, including Cd, the soil-plant barrier fails. The level of Cd ingested by average person in USA is about 12 micrograms/day, which is relatively low comparing to Risk Reference Dose (70 micrograms Cd/day) established by USEPA. Food of plant origin is a main source of Cd intake by modern society. Fish and shellfish may be a dominant dietary sources of Hg for some human populations. About half of human Pb intake is through food, of which more than half originates from plants. Dietary intake of Cd and Pb may be increased by application of sludges on cropland with already high levels of these metals. Soils amended with sludges in the USA will be permitted (by USEPA-503 regulations) to accumulate Cr, Cd, Cu, Pb, Hg, Ni, and Se, and Zn to levels from 10 to 100 times the present baseline concentrations. These levels are very permissive by international standards. Because of the limited supply of toxicity data obtained from metals applied in sewage sludge, predictions as to the new regulations will protect crop plants from metal toxicities, and food chain from contamination, are difficult to make.

BJU Int 2000 Jan;85(1):107-13. A maternal vegetarian diet in pregnancy is associated with hypospadias. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. North K, Golding J Unit of Paediatric and Perinatal Epidemiology, Division of Child Health, University of Bristol, UK. OBJECTIVE: To investigate the possible role of the maternal diet, particularly vegetarianism and consumption of phytoestrogens, in the origin of hypospadias, which is reported to be increasing in prevalence. SUBJECTS AND METHODS: Detailed information was obtained prospectively from mothers, including previous obstetric history, lifestyle and dietary practices, using structured self-completed questionnaires during pregnancy. Previously recognized associations with environmental and parental factors were examined, focusing particularly on the hypothesized hormonal link. Multivariate logistic regression was used to identify independent associations. RESULTS: Of 7928 boys born to mothers taking part in the Avon Longitudinal Study of Pregnancy and Childhood, 51 hypospadias cases were identified. There were no significant differences in the proportion of hypospadias cases among mothers who smoked, consumed alcohol or for any aspect of their previous reproductive history (including the number of previous pregnancies, number of miscarriages, use of the contraceptive pill, time to conception and age at menarche). Significant differences were detected for some aspects of the maternal diet, i.e. vegetarianism and iron supplementation in the first half of pregnancy. Mothers who were vegetarian in pregnancy had an adjusted odds ratio (OR) of 4.99 (95% confidence interval, CI, 2.10-11.88) of giving birth to a boy with hypospadias, compared with omnivores who did not supplement their diet with iron. Omnivores who supplemented their diet with iron had an adjusted OR of 2.07 (95% CI, 1.00-4.32). The only other statistically significant association for hypospadias was with influenza in the first 3 months of pregnancy (adjusted OR 3.19, 95% CI 1.50-6.78). CONCLUSION: As vegetarians have a greater exposure to phytoestrogens than do omnivores, these results support the possibility that phytoestrogens have a deleterious effect on the developing male reproductive system.

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<span class="koboSpan" id="kobo.1.1">Vitamin E: Estrogen antagonist, energy promoter, and anti-inflammatory</span> A R T I C L E

Vitamin E: Estrogen antagonist, energy promoter, and anti-inflammatory

Vitamin E, like progesterone and aspirin, acts within the cellular regulatory systems, to prevent inflammation and inappropriate excitation. Since uncontrolled excitation causes destructive oxidations, these substances prevent those forms of oxidation.

Molecules that can easily be oxidized and reduced can function as antioxidants, and vitamin E does function as that kind of antioxidant in many chemical environments. But it is highly misleading to consider that as the explanation for its many beneficial biological effects. That kind of reasoning contributed to the use of the antioxidant carcinogens BHT and BHA as food additives and "antiaging" supplements, and many other chemicals are being promoted on the basis of their abstract antioxidant function.

Becoming aware of the real value of vitamin E will have far reaching implications in nutrition and medicine.

In determining criminal or civil legal responsibility, the concept "should have known" is recognized and used. In science, which is all about knowing, there is certainly a responsibility to be informed when the subject involves the life and health of millions of people. The science establishment of government and industry should be held responsible for the information it hides, destroys, or ignores for its own benefit. The US government has an agency for prosecuting research fraud, but the concept is applied so narrowly as to be meaningless, when deception has become the rule. And since it controls the court system, govenment agencies and their functionaries won't be prosecuted, even when their crimes become well known.

"Vitamin E was advocated as an effective treatment for heart disease by Dr. Evan Shute of London, Ontario more than 50 years ago. His pioneering claims, which were unacceptable to the medical community at large, have been confirmed by recent findings from epidemiologic studies and clinical trials."

Political scientists have recognized the process in which big corporations "capture" the governmental agencies that were created to regulate them. The editorial boards of professional journals can be captured even more cheaply than the agencies of government, and their influence can be even more valuable to industry.

If science impinges upon the plans of an industry, it can be managed into compliance, when the industry controls the journals and the agencies that fund research.

In the 1940s, it had already become clear to the estrogen industry that vitamin E research was impinging on its vital interests.

The Manhattan Project, that created the atomic bomb, also created a generation of scientific and bureaucratic zealots who ignored public health and safety to advance their projects and their careers, and changed the way science was done. At exactly the same time, the pharmaceutical industry was using its financial and political power to change the way medicine was practiced and taught, and the consequences for world health rivalled those of the nuclear industry.

In 1933 the physician R.J. Shute was aware of the problems associated with toxemia of pregnancy or preeclampsia. Especially among poorly nourished women, many pregnancies were complicated by circulatory problems, including cyclic bleeding, thrombosis, stroke, and hypertension, and these difficult pregnancies often ended in miscarriage or premature delivery, resulting in many serious health problems among the babies that survived.

At that time, both estrogen and vitamin E were being widely studied, though the exact structure of the tocopherol molecule wasn't defined until 1936-37. Vitamin E had been found to improve fertility of both male and female animals, and to prevent intrauterine death of the embryo or fetus, so it was called the "antisterility vitamin." Using it to prevent women from having miscarriages must have occurred to many people.

Animal research in the 1930s was also showing that estrogen had many toxic effects, including causing infertility or intrauterine death, connective tissue abnormalities, and excessive blood clotting. Dr. Shute and his sons, Wilfred and Evan, were among those who considered vitamin E to be an antiestrogen. They found that it was very effective in preventing the clotting diseases of pregnancy.

Other researchers, who knew that progesterone protected against the toxic effects of estrogen, described vitamin E as the "progesterone-sparing agent," since so many of its antiestrogenic effects resembled those of progesterone.

The Shute brothers began using vitamin E to treat circulatory diseases in general, rather than just in pregnant women--blood clots, phlebitis, hypertension, heart disease, and diabetes all responded well to treatment with large doses.

Vitamin E, as its name indicates, was the fifth type of "vitamin" factor to be identified, and it received its name in 1922, even though its chemical structure hadn't been identified. The public quickly understood and accepted that certain substances in food were essential for life and health, so by 1940 practically all physicians were recommending the use of nutritional supplements.

If vitamin E was essential for human health, and achieved at least some of its amazing effects by opposing estrogen, then the synthetic estrogen industry had a problem.

Edward L. Bernays had already been in business for decades, teaching corporations and governments how to "engineer consent." After his work for the government to engineer support for entering the first world war, Bernays' next big job was for the tobacco industry. To convince women to smoke cigarettes, to achieve equality with men, he organized an Easter parade, Torches of Freedom, in which thousands of women marched smoking their freedom torches. In association with the American Medical Association (the editor of JAMA actually helped the tobacco industry design its campaigns), Bernays ran a campaign to convince Americans that smoking was good for the health.

The drug industry began using his techniques in sometimes crude but always effective ways. Estrogen was named "the female hormone;" natural hormones, including estrogen and progesterone, were claimed, without any research, to be inactive when taken orally. Physician-shills were created to claim wonderful effects for estrogen. The vitamin status of the tocopherols was denied; as recently as the 1970s (and maybe later), university professors of dietetics were flatly saying "no one needs vitamin E."

Very little research showing the curative effects of vitamin E in human diseases was allowed to be published, so it was only occasionally necessary to openly denounce vitamin E as worthless or dangerous. In 1981, the journal of the AMA published an article reviewing the "toxic" effects of vitamin E. Since I had read all of the articles cited, I realized that the author was claiming that whenever vitamin E changed something, the change was harmful, even though the original publication had described the effect as beneficial.

Although JAMA was eventually forced to give up its revenue from cigarette advertising, it didn't suffer at all, because of the vast advertising campaigns of the estrogen industry. JAMA obviously wouldn't want to publish anything suggesting that vitamin E, or progesterone, or thyroid, might be beneficial because of its antagonism of the harmful effects of estrogen.

Estrogen causes changes in the uterus that prevent implantation of the embryo, and that impair support for its development if it has already implanted. It decreases the availability of oxygen to the embryo, while vitamin E increases it.

My dissertation adviser, A.L. Soderwall, did a series of experiments in which he showed that providing hamsters with extra vitamin E postponed the onset of infertility in middle age. In my experiments, vitamin E increased the amount of oxygen in the uterus, correcting an oxygen deficiency produced either by supplemental estrogen or by old age. Progesterone has similar effects on the delivery of oxygen to the uterus.

In the 1940s, the official definition of vitamin E's activity was changed. Instead of its effectiveness in preventing the death and resorption of embryos, or the degeneration of the testicles or brain or muscles, it was redefined as an antioxidant, preventing the oxidation of unsaturated oils.

Although some people continued to think of it as a protective factor against thrombosis, heart attacks, diabetes, and infertility, the medical establishment claimed that the prevention or cure of diseases in animals wasn't relevant to humans, and that a mere antioxidant couldn't prevent or cure any human disease.

The experiments that led to the identification of vitamin E involved feeding rats a diet containing rancid lard and, as a vitamin A supplement, cod liver oil. Both of these contained large amounts of polyunsaturated oils.

From 1929 to the early 1930s, other researchers were claiming to have demonstrated that the polyunsaturated fatty acids were nutritionally essential. These experiments, like the vitamin E experiments, were done on rats, but the medical establishment was satisfied that rat experiments proved that humans need linoleic or linolenic acid, while they refused to accept that vitamin E was essential for humans. When, in the 1940s, a group of vitamin B6 researchers showed that the supposed "essential fatty acid deficiency" could be cured by a supplement of vitamin B6, it became apparent that the polyunsaturated fatty acids slowed metabolism, and reduced all nutritional needs. The thyroid hormone was powerfully suppressed by the "essential" fatty acids.

When we consider the two sets of experiments together, their outstanding feature is the toxicity of the polyunsaturated oils, which in one kind of experiment suppressed metabolism, and in the other kind of experiment created a variety of degenerative conditions.

By the late 1940s and early 1950s, estrogens of various sorts had been synthesized from hydrocarbons, and were being recommended to prevent miscarriages, because "estrogen is the female hormone." The meat industry had found that the polyunsaturated oils were valuable in animal feed, since they suppressed metabolism and made it cheaper to fatten the animals, and these antithyroid oils were next marketed as "heart protective" human foods, though by suppressing the thyroid and destroying vitamin E, they actually contributed to both heart disease and cancer. (Giving estrogen to livestock to improve their feed efficiency, and to people "to prevent heart attacks," was an interesting parallel to the oil promotional campaigns.)

The influence of the food oil industry kept researchers away from the idea that these oils were not safe for food use, and instead tended to support the idea that vitamin E is just an antioxidant, and that the seed oils were the best way to get vitamin E in the diet.

The antifertility effects of the polyunsaturated oils, demonstrated in the vitamin E experiments, weren't at the time understood to have anything to do with estrogen's antifertility effects. But to understand vitamin E, I think we have to consider the close interactions between estrogen and the polyunsatured fatty acids (PUFA). Their actions are closely intertwined, and are antagonized by a variety of energizing and stabiliizing substances, including saturated fats, progesterone, thyroid, vitamin E, and aspirin.

Generally, chemicals that inhibit enzymes are toxic, producing some sort of symptom or deterioration. But a group of enzymes related to estrogen and PUFA are inhibited by these protective substances. Although under our present diet, these enzymes metabolize the PUFA, in the fetus and newborn they act on our endogenous fats, the series related to the Mead acids. The Mead acid is antiinflammatory, and broadly protective. The dietary PUFA interfere with these natural protective substances,

The enzymes that, if we didnt eat PUFA, would be regulating the Mead series, being activated in response to stress, would be producing antistress substances, which would limit the stress reaction. But as we become increasingly saturated with the anti-vitamin E fats, these enzymes, instead of stopping inflammation, promote it and cause tissue injury. The remaining stress limiting factors, such as progesterone, by correcting the distortions caused by stress, tend to eliminate the conditions which activated the enzymes--in a very indirect form of inhibition.

Many of the events involved in inflammation are increased by estrogen, and decreased by vitamin E. Estrogen causes capillaries to become leaky; vitamin E does the opposite. Estrogen increases platelet aggregation, and decreases a factor that inhibits platelet aggregation; vitamin E does the opposite.

Excess clotting is known to be caused by too much estrogen, and also by a vitamin E deficiency.

Clotting leads to fibrosis, and there is clear evidence that vitamin E prevents and cures fibrotic diseases, but this still isn't generally accepted by the powerful medical institutions. Estrogen and polyunsaturated fats increase fibrosis.

Estrogen increases progstaglandin synthesis, vitamin E decreases their synthesis; estrogen increases the activity of the enzymes COX and LOX, vitamin E decreases their activitiy. (Jiang, et al., 2000; Ali, et al., 1980; Parkhomets, et al., 2001.) Estrogen releases enzymes from lysosomes, vitamin E inhibits their release. Beta-glucuronidase, one of these enzymes, can release estrogen at the site of an inflammation.

Estrogen often increases intracellular calcium and protein kinase C, vitamin E has generally opposite effects.

The polyunsaturated fatty acids and their derivatives, the prostaglandins, act as effectors, or amplifiers, of estrogen's actions.

If vitamin E is acting as a protectant against the polyunsaturated fatty acids, that in itself would account for at least some of its antiestrogenic effects.

Besides antagonizing some of the end effects of the toxic fatty acids, vitamin E inhibits lipolysis, lowering the concentration of free fatty acids (the opposite of estrogens effect), and it also binds to, and inactivates, free fatty acids. The long saturated carbon chain is very important for its full functioning, and this saturated chain might allow it to serve as a substitute for the omega -9 fats, from which the Mead acid is formed. The unsaturated tocotrienols have hardly been tested for the spectrum of true vitamin E activity, and animal studies have suggested that it may be toxic, since it caused liver enlargement.

One possibly crucial protective effect of vitamin E against the polyunsaturated fatty acids that hasn't been explored is the direct destruction of linolenic and linoleic acid. It is known that bacterial vitamin E is involved in the saturation of unsaturated fatty acids, and it is also known that intestinal bacteria turn linoleic and linolenic acids into the fully saturated stearic acid.

"No metabolic function is known for alpha-tocopherolquinol or its quinone other than as a cofactor in the biohydrogenation of unsaturated fatty acids that can be carried out by only a few organisms."

P.E. Hughes and S.B. Tove, 1982.

Linoleic acid was significantly decreased (P < 0.001) and there was a significant rise (P < 0.05) in its hydrogenation product, stearic acid. Linolenic acid was also significantly decreased. . . . The study provides evidence that bacteria from the human colon can hydrogenate C18 essential polyunsaturated fatty acids.

F.A. Howard & C. Henderson, 1999

Because of the way in which the decision to call vitamin E a simple antioxidant was conditioned by the historical setting, there has been a reluctance, until recently, to give much weight to the pathogenicity of lipid peroxidation and free radicals, partly because lipid peroxidation is only a minor part of the toxicity of the polyunsaturated oils, and there was little support for the investigation of the real nature of their toxicity. This environment has even distorted the actual antioxidant value of the various forms of vitamin E. (For example, see Chen, et al., 2002.)

The people who say that vitamin E is nothing but an antioxidant sometimes take other antioxidants, with, or instead of, vitamin E. BHT, BHA, and many natural compounds (derived from industrial and agricultural wastes) are often said to be "better than vitamin E" as antioxidants. Anything that can be oxidized and reduced (melatonin, estrogen, tryptophan, carotene, etc.) will function as an antioxidant in some system, but in other circumstances, it can be a pro-oxidant.

The people who think there is benefit in the abstract "antioxidant" function seem to be thinking in terms of something that will, like a ubiquitous fire department, put out every little fire as soon as it starts. I think it's more appropriate to think of the biological antioxidant systems as programs for controlling the arsonists before they can set the fires.

Since the requirement for vitamin E decreases as the consumption of unsaturated fats decreases, the requirement, if any, would be very small if we didn't eat significant quantities of those fats.

In the years since the tocopherols were identified as vitamin E, the material sold for research and for use as a nutritional supplement has changed drastically several times, even when it has been given a specific chemical identity, such as mixed tocopherols or d-alpha tocopherol. Variations in viscosity and color, caused by changes in the impurities, have undoubtedly influenced its biological effects, but the ideology about its antioxidant value has kept researchers from finding out what a particular batch of it really is and what it really does.

"We compared the effect of a mixed tocopherol preparation with that of alpha-tocopherol alone on superoxide dismutase (SOD) activity and iNOS expression in cultured myocytes exposed to H-R." "Both tocopherol preparations attenuated cell injury. . . . However, mixed-tocopherol preparation was much superior to alpha-tocopherol in terms of myocyte protection. . . . Lack of efficacy of commercial tocopherol preparations in clinical trials may reflect absence of gamma- and delta-tocopherols."

Chen H, Li D, Saldeen T, Romeo F, Mehta JL,Biochem Biophys Res Commun 2002 "Mixed tocopherol preparation is superior to alpha-tocopherol alone against hypoxia-reoxygenation injury."

Keeping our diet as free as possible of the polyunsaturated fats, to create something like the "deficiency" state that is so protective (against cancer, trauma, poison, shock, inflammation, infection, etc.) in the animal experiments, seems preferable to trying to saturate ourselves with antioxidants, considering the imperfectly defined nature of the vitamin E products, and the known toxicity of many of the other antioxidants on the market.

The carcinogenic properties of the polyunsaturated fats have been known for more than 50 years, as has the principle of extending the life span by restricted feeding. More recently several studies have demonstrated that the long lived species contain fewer highly unsaturated fats than the short lived species. Restriction of calories prevents the lipids in the brain, heart, and liver from becoming more unsaturated with aging. (Lee, et al., 1999; Laganiere, et al., 1993; Tacconi, et al., 1991; R. Patzelt-Wenczler, 1981.)

When cells are grown in tissue culture without the essential fatty acids, they become deficient, and in that state are very resistant to chemical injury, and can be grown indefinitely. Besides being a simple demonstration of the way in which the polyunsaturated fats sensitize cells to injury (Wey, et al., 1993), these experiments must be an embarrassment to the people who base their argument for the oils essentiality on a supposed requirement for making cell membranes. Since the cells can multiply nicely in their deficient state, we have to conclude that the oils arent needed for membranes, or maybe that cells resist injury better without membranes.

In the opposite direction, an excess of insulin or prolactin, or a deficiency of vitamin E, increases the activity of the enzymes that convert linoleic acid into the more highly unsaturated fatty acids. Excess insulin and prolactin are crucially involved in many degenerative diseases.

The highly unsaturated fats suppress respiration in many ways, and these trends toward increased unsaturation with aging, endocrine stress, and vitamin E deficiency parallel the life-long trend toward lower energy production from respiration. Many studies show that vitamin E can protect and improve mitochondrial energy production. (Kikuchi, et al., 1991; Donchenko, et al., 1990, 1983; Guarnieri, et al., 1981, 1982.) But the state of so-called essential fatty acid deficiency not only makes mitochondria very resistant to injury, it greatly intensifies their energy production. Vitamin E supplementation is seldom as effective as the absence of the toxic oils.

Many nutrition charts no longer list liver as a good source of vitamin E, but a large portion of an animals vitamin E is in its liver. This bias in the dietetic literature can be traced to various sources, but a major influence was the campaign in the 1970s by the drug companies that had patented new forms of synthetic vitamin A. They had physicians and professors fabricate stories about the great toxicity of natural vitamin A, and placed the stories in national magazines, to clear the field for their supposedly non-toxic products, which have turned out to be disastrously toxic. The result is that many people have fearfully stopped eating liver, because of its vitamin A. The other vitamins in liver, including vitamin K, function very closely with vitamin E, and the stably stored forms of vitamin E are likely to be a good approximation for our needs.

There is still a strong division between what people can say in their professional publications, and what they believe. A man who was influential in designating vitamin E as an antioxidant, M.K. Horwitt, complained when the government raised its recommended vitamin E intake by 50%, because it wasnt supported by new data, and because millions of people get only ten milligrams per day and are healthy. But he has been taking 200 mg daily (plus aspirin) for many years. He apparently doesn't have very much confidence in the ideas he advocates publicly.

REFERENCES

Prostaglandins Med 1980 Feb;4(2):79-85. Inhibition of human platelet cyclooxygenase by alpha-tocopherol. Ali M, Gudbranson CG, McDonald JW. Alpha-tocopherol, an inhibitor of platelet aggregation, was evaluated for its effects on the synthesis of thromboxane and prostaglandins. A dose-dependent reduction in thromboxane B2 and prostaglandin D2 synthesis was observed with approximately 60% inhibition at 5.0 IU or alpha-tocopherol. Alpha-tocopherol produced a time-dependent, irreversible inhibition.

Int J Vitam Nutr Res 2001 Jan;71(1):18-24. Vitamin E and the prevention of atherosclerosis. Bron D, Asmis R. Recent new findings have shed new light on the physiological role of vitamin E and suggest that it has a much broader array of biological activities than originally expected. In addition to its well described role as an antioxidant, it is becoming evident that vitamin E also can modulate the immune system, suppress local and chronic inflammation, reduce blood coagulation and thrombus formation, and enhance cell function and survival.

Plast Reconstr Surg 1981 Nov;68(5):696-9. The effectiveness of alpha-tocopherol (vitamin E) in reducing the incidence of spherical contracture around breast implants. Baker JL Jr. Vitamin E appears to be a safe, simple, and inexpensive means of reducing the number of postoperative capsular contractures following breast augmentation. The synthetic form of vitamin E (alpha-tocopherol) is recommended to avoid nausea or skin eruptions in patients with oily skin, which are frequently encountered when the natural form is taken. No harmful side effects have been noted in any of the patients to date. Vitamin E has no effect on coagulation systems and does not cause excessive bleeding either during or after surgery. The recommended dosage of synthetic vitamin E is 1000 IU, b.i.d., for 2 years beginning 1 week before surgery. If no contracture exists at that time, the dosage may be reduced to 1000 IU daily thereafter.

Carcinogenesis 1999 Jun;20(6):1019-24. Decrease in linoleic acid metabolites as a potential mechanism in cancer risk reduction by conjugated linoleic acid. Banni S, Angioni E, Casu V, Melis MP, Carta G, Corongiu FP, Thompson H, Ip C.

Mech Ageing Dev 1978 Nov;8(5):311-28. Anomalous vitamin E effects in mitochondrial oxidative metabolism. Baumgartner WA, Hill VA, Wright ET. Three different vitamin E effects, suggestive of specific antioxidant effects, were discovered in the protective action of vitamin E against respiratory decline (a decrease in mitochondrial respiration attributed to a "leakage" of electron transport radicals). No correlation was found between respiraotry decline and random lipid peroxidation. The mechanisms behind two of the three atypical vitamin E effects were defined. Both involve an artifact in the TBA assay for lipid peroxidation. This artifact occurs when TBA assays are carried out in the presence of sucrose and acetaldehyde; the latter is produced from ethanol, the solvent used to add vitamin E to preparations. The artifact in the TBA assay for peroxidations appears also to be responsible for differing interpretations of the hepatotoxic effect of ethanol.

Eur J Biochem 1990 Mar 10;188(2):327-32. Polychlorinated biphenyls increase fatty acid desaturation in the proliferating endoplasmic reticulum of pigeon and rat livers. Borlakoglu JT, Edwards-Webb JD, Dils RR.

Nutr Cancer 2000;38(1):87-97. Effects of topical and oral vitamin E on pigmentation and skin cancer induced by ultraviolet irradiation in Skh:2 hairless mice. Burke KE, Clive J, Combs GF Jr, Commisso J, Keen CL, Nakamura RM. Results showed that the skin concentrations of Eol, as well as levels in the adipose tissue, were increased after topical application. Mice treated with each form of vitamin E showed no signs of toxicity and had significantly less acute and chronic skin damage induced by UV irradiation, as indicated by reduced inflammation and pigmentation and by later onset and lesser incidence of skin cancer.

Am J Physiol 1991 Jun;260(6 Pt 2):R1235-40. Acute phase response in exercise. II. Associations between vitamin E, cytokines, and muscle proteolysis. Cannon JG, Meydani SN, Fielding RA, Fiatarone MA, Meydani M, Farhangmehr M, Orencole SF, Blumberg JB, Evans WJ.

Vrach Delo 1990 Dec;(12):6-8. [The effect of tocopherol and nicotinic acid on the microcirculation and blood coagulability in patients with ischemic heart disease] Chernomorets NN, Kotlubei GV, Vatutin NT, Zhivotovskaia IA, Gnilitskaia VB, Alifanova RE, Lobach EIa, Mal'tseva NV, Mitrofanov AN. Complex treatment using tocopherol acetate produced a positive effect on the coagulation properties of the blood and did essentially influence the fibrinolytic activity and microcirculation. Tocopherol plus nicotinic acid resulted in normalization of the blood coagulation process, favoured activation of fibrinolysis and improvement of the microcirculatory bed.

Free Radic Biol Med 1991;10(5):325-38. Oxidative status and oral contraceptive. Its relevance to platelet abnormalities and cardiovascular risk. Ciavatti M, Renaud S. INSERM Unit 63, Bron, France. Oral contraceptive (OC) use is a risk for thrombogenic events. From these data we conclude that: 1. OC use modifies slightly but significantly the oxidative status in women and in animals by decreasing in plasma and blood cells the antioxidant defenses (vitamins and enzymes). 2. The changes in the oxidative status are related to an increase in plasma lipid peroxides apparently responsible for the hyperaggregability and possibly the imbalance in clotting factors associated with the OC-induced prethrombotic state. 3. These effects of OC appear to be increased by a high intake of polyunsaturated fat and counteracted by supplements of vitamin E. 4. The risk factors acting synergistically with OC, have all been shown to increase platelet reactivity.

Bol Med Hosp Infant Mex 1980 May-Jun;37(3):457-67. [Jaundice caused by microangiopathic hemolysis associated to septicemia in the newborn] Covarrubias Espinoza G, Lepe Zuniga JL. These infants with over 3% fragmented cells were found to have a significant association with: sepsis, jaundice, crenated RBC's, low levels of hemoglobin, increased reticulocyte count, and low vitamin E levels.

Endocrinology 1992 Nov;131(5):2482-4. Vitamin E protects hypothalamic beta-endorphin neurons from estradiol neurotoxicity. Desjardins GC, Beaudet A, Schipper HM, Brawer JR. Estradiol valerate (EV) treatment has been shown to result in the destruction of 60% of beta-endorphin neurons in the hypothalamic arcuate nucleus. Evidence suggests that the mechanism of EV-induced neurotoxicity involves the conversion of estradiol to catechol estrogen and subsequent oxidation to free radicals in local peroxidase-positive astrocytes. In this study, we examined whether treatment with the antioxidant, vitamin E, protects beta-endorphin neurons from the neurotoxic action of estradiol. Our results demonstrate that chronic vitamin E treatment prevents the decrement in hypothalamic beta-endorphin concentrations resulting from arcuate beta-endorphin cell loss, suggesting that the latter is mediated by free radicals. Vitamin E treatment also prevented the onset of persistent vaginal cornification and polycystic ovarian condition which have been shown to result from the EV-induced hypothalamic pathology.

Free Radic Biol Med 2000 Dec 15;29(12):1302-6. Hyperinsulinemia: the missing link among oxidative stress and age-related diseases? Facchini FS, Hua NW, Reaven GM, Stoohs RA. Other proaging effects of insulin involve the inhibition of proteasome and the stimulation of polyunsaturated fatty acid (PUFA) synthesis and of nitric oxide (NO). The hypothesis that hyperinsulinemia accelerates aging also offers a metabolic explanation for the life-prolonging effect of calorie restriction and of mutations decreasing the overall activity of insulin-like receptors in the nematode Caenorhabditis elegans.

J Bacteriol 1982 Sep;151(3):1397-402. Occurrence of alpha-tocopherolquinone and alpha-tocopherolquinol in microorganisms. Hughes PE, Tove SB. Both alpha-tocopherolquinol and alpha-tocopherolquinone were found in 56 of 93 strains of microorganisms examined. Those microorganisms that did not contain alpha-tocopherolquinol or alpha-tocopherolquinone tended to fall into two groups. One group consisted of gram-positive, anaerobic or facultative bacteria with a low content of guanine and cytosine, and the second group encompassed all of the filamentous microorganisms studied. "No metabolic function is known for alpha-tocopherolquinol or its quinone other than as a cofactor in the biohydrogenation of unsaturated fatty acids that can be carried out by only a few organisms."

J Biol Chem 1980 Dec 25;255(24):11802-6. Identification of deoxy-alpha-tocopherolquinol as another endogenous electron donor for biohydrogenation. Hughes PE, Tove SB.

J Biol Chem 1980 May 25;255(10):4447-52. Identification of an endogenous electron donor for biohydrogenation as alpha-tocopherolquinol. Hughes PE, Tove SB. The ratio of alpha-tocopherolquinone produced to fatty acid reduced was 2:1 when the tocopherol derivatives were extracted aerobically. When the extraction was carried out anaerobically, the ratio was 1. It is suggested that the oxidation of 2 molecules of alpha-tocopherolquinol, each to the semiquinone, provides the electrons required for the reduction of the cis-bond of the conjugated dienoic fatty acid.

Lett Appl Microbiol 1999 Sep;29(3):193-6. Hydrogenation of polyunsaturated fatty acids by human colonic bacteria. Howard FA, Henderson C. Emulsions of the fatty acids linoleic (C18:2 n-6), alpha-linolenic (C18:3 n-3) and arachidonic acid (C20:4 n-6) were incubated for 4 h under anaerobic conditions with human faecal suspensions. Linoleic acid was significantly decreased (P < 0.001) and there was a significant rise (P < 0.05) in its hydrogenation product, stearic acid. Linolenic acid was also significantly decreased (P < 0.01), and significant increases in C18:3 cis-trans isomers (P < 0.01) and linoleic acid (P < 0.05) were seen. With each acid, there were non-significant increases in acids considered to be intermediates in biohydrogenation. The study provides evidence that bacteria from the human colon can hydrogenate C18 essential polyunsaturated fatty acids. However, with arachidonic acid there was no evidence of hydrogenation.

Prostaglandins Leukot Essent Fatty Acids 1998 Dec;59(6):395-400. Modulation of rat liver lipid metabolism by prolactin. Igal RA, de Gomez Dumm IN, Goya RG.

Clin Chim Acta 1994 Mar;225(2):97-103. Vitamin E and the hypercoagulability of neonatal blood. Jain SK, McCoy B, Wise R. There was a significant correlation between plasma vitamin E and whole blood clotting time (r = 0.54, P < 0.04) of cord blood. The addition of standard vitamin E to cord blood in vitro resulted in prolongation of whole blood clotting time. This suggests that a deficiency of plasma vitamin E can shorten whole blood clotting time in newborns, which may have a role in the disseminated intravascular coagulation frequently experienced by newborn infants.

Proc Natl Acad Sci U S A 2000 Oct 10;97(21):11494-9. gamma-tocopherol and its major metabolite, in contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells. Jiang Q, Elson-Schwab I, Courtemanche C, Ames BN. Cyclooxygenase-2 (COX-2)-catalyzed synthesis of prostaglandin E(2) (PGE(2)) plays a key role in inflammation and its associated diseases, such as cancer and vascular heart disease. Here we report that gamma-tocopherol (gammaT) reduced PGE(2) synthesis in both lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and IL-1beta-treated A549 human epithelial cells with an apparent IC(50) of 7.5 and 4 microM, respectively. The inhibitory effects of gammaT and gamma-CEHC stemmed from their inhibition of COX-2 activity, rather than affecting protein expression or substrate availability, and appeared to be independent of antioxidant activity. The inhibitory potency of gammaT and gamma-CEHC was diminished by an increase in AA concentration, suggesting that they might compete with AA at the active site of COX-2. We also observed a moderate reduction of nitrite accumulation and suppression of inducible nitric oxide synthase expression by gammaT in lipopolysaccharide-treated macrophages. These findings indicate that gammaT and its major metabolite possess anti-inflammatory activity and that gammaT at physiological concentrations may be important in human disease prevention.

Biosci Biotechnol Biochem 1992 Sep;56(9):1420-3. Effects of alpha-tocopherol and tocotrienols on blood pressure and linoleic acid metabolism in the spontaneously hypertensive rat (SHR). Koba K, Abe K, Ikeda I, Sugano M. Both alpha-tocopherol and a 1:1.7 mixture of alpha-tocopherol and tocotrienols at a 0.2% dietary level significantly depressed the age-related increase in the systolic blood pressure of spontaneously hypertensive rats (SHRs) after 3 weeks of feeding. The aortic production of prostacyclin was increased 1.5 times both by alpha-tocopherol and a tocotrienol mixture, suggesting a possible relevance to their hypotensive effect. These vitamins did not influence the delta 6- and delta 5-desaturase activities of liver microsomes, but fatty acid profiles of the liver phospholipids predicted a reduction of linoleic acid desaturation. These effects were in general more clear with tocotrienols than with alpha-tocopherol. Platelet aggregation by 5 microM ADP remained uninfluenced. Thus, tocotrienols may have effects on various lipid parameters somewhat different from those of alpha-tocopherol.

Gerontology 1993;39(1):7-18. Modulation of membrane phospholipid fatty acid composition by age and food restriction. Laganiere S, Yu BP. H.M. Phospholipids from liver mitochondrial and microsomal membrane preparations were analyzed to further assess the effects of age and lifelong calorie restriction on membrane lipid composition. The data revealed characteristic patterns of age-related changes in ad libitum (AL) fed rats: membrane levels of long-chain polyunsaturated fatty acids, 22:4 and 22:5, increased progressively, while membrane linoleic acid (18:2) decreased steadily with age. Levels of 18:2 fell by approximately 40%, and 22:5 content almost doubled making the peroxidizability index increase with age. We concluded that the membrane-stabilizing action of long-term calorie restriction relates to the selective modification of membrane long-chain polyunsaturated fatty acids during aging.

Free Radic Biol Med 1999 Feb;26(3-4):260-5. Modulation of cardiac mitochondrial membrane fluidity by age and calorie intake. Lee J, Yu BP, Herlihy JT. The fatty acid composition of the mitochondrial membranes of the two ad lib fed groups differed: the long-chain polyunsaturated 22:4 fatty acid was higher in the older group, although linoleic acid (18:2) was lower. DR eliminated the differences. Considered together, these results suggest that DR maintains the integrity of the cardiac mitochondrial membrane fluidity by minimizing membrane damage through modulation of membrane fatty acid profile.

Lipids 2001 Jun;36(6):589-93. Effect of dietary restriction on age-related increase of liver susceptibility to peroxidation in rats. Leon TI, Lim BO, Yu BP, Lim Y, Jeon EJ, Park DK.

Jpn J Pharmacol 1979 Apr;29(2):179-86. Effect of linoleic acid hydroperoxide on liver microsomal enzymes in vitro. Masuda Y, Murano T. Rat liver microsomes incubated with linoleic acid hydroperoxide (LAHPO) lost cytochrome P-450 specifically among the enzymes of microsomal electron transport systems. The loss of cytochrome P-450 content and glucose-6-phosphatase activity by LAHPO was accompanied by an increase in malondialdehyde (MDA) production. These results suggest the possibility that the loss of microsomal enzyme activities during lipid peroxidation may be attributed largely to a direct attack on enzyme proteins by lipid peroxides rather than indirectly to a structural damage of microsomal membranes resulting from peroxidative breakdown of membrane lipids.

Ukr Biokhim Zh 2001 Jan-Feb;73(1):43-7. [Effect of alpha-tocopherol, tocopheryl quinone and other complexes with tocopherol-binding proteins on the activity of enzymes metabolizing arachidonic acid] Parkhomets' VP, Silonov SB, Donchenko HV. Palladin Institute of Biochemistry, National Academy of Science of Ukraine, Kyiv. alpha-Tocopherol, tocopherylquinon jointly with the proteins tocopherol acceptors from cytosole were identified to inhibit the activity of 5-lipoxigenase and so the synthesis of leukotriene A4 at the early stages providing for A4 hydrolase activation and C4 synthesase, as well as accelerate leukotrienes B4 and C4 synthesis at the further stages respectively changing the final spectrum of leukotriens in the organism tissues. Firstly, the leading role of proteins complexes capable to strengthen the effect of alpha-tocopherol and tocopherylquinon on arachidonic acid oxidative metabolism was determined.

Int J Vitam Nutr Res 1981;51(1):26-33. [Effect of vitamin E on the synthesis of polyunsaturated fatty acids] Patzelt-Wenczler R. The formation of polyunsaturated fatty acids is influenced by vitamin E. The enzyme of the endoplasmic reticulum isolated from rat liver responsible for chain elongation and desaturation showed higher activity under vitamin E-deficiency. The activity was raised both per mg protein and per mg DNA. The application of alpha-Tocopherol to the vitamin E-deficient animals caused the normalization of the enzyme activity within 48 hours. This indicates a regulatory function of alpha-Tocopherol in the process of oxidation.

Lipids 2001 May;36(5):491-8. Correlation of fatty acid unsaturation of the major liver mitochondrial phospholipid classes in mammals to their maximum life span potential. Portero-Otin M, Bellmunt MJ, Ruiz MC, Barja G, Pamplona R.

Free Radic Biol Med 1999 Oct;27(7-8):729-37. Age-dependent increase of collagenase expression can be reduced by alpha-tocopherol via protein kinase C inhibition. Ricciarelli R, Maroni P, Ozer N, Zingg JM, Azzi A. Our in vitro experiments with skin fibroblasts suggest that alpha-tocopherol may protect against skin aging by decreasing the level of collagenase expression, which is induced by environmental insults and by aging.

Prostaglandins Leukot Essent Fatty Acids 1991 Oct;44(2):89-92. Inhibition of PGE2 production in macrophages from vitamin E-treated rats. Sakamoto W, Fujie K, Nishihira J, Mino M, Morita I, Murota S.

Int J Vitam Nutr Res 1990;60(1):26-34. The influence of vitamin E on rheological parameters in high altitude mountaineers. Simon-Schnass I, Korniszewski L. The erythrocyte filterability was unaltered in the vitamin E group in comparison with baseline but was significantly impaired in the control group.

Neurobiol Aging 1991 Jan-Feb;12(1):55-9. Aging and food restriction: effect on lipids of cerebral cortex. Tacconi MT, Lligona L, Salmona M, Pitsikas N, Algeri S. In experimental animals dietary restriction reduces the body weight increase due to aging, increases longevity and delays the onset of age-related physiological deterioration, including age-related changes in serum lipids. Little is known about the influence of food restriction on brain lipids, whose concentration and composition have been shown to change with age. We studied whether some biochemical and biophysical parameters of rat brain membranes, known to be modified with age, were affected by a diet low in calories, in which 50% of lipids and 35% of carbohydrates have been replaced by fibers. The diet was started at weaning and maintained throughout the animal's entire life span. Animals fed the low calorie diet survived longer and gained less body weight than standard diet fed rats. Age-related increases in microviscosity, cholesterol/phospholipid and sphingomyelin/phosphatidylcholine ratios were reduced or restored to the levels of young animals in cortex membranes of 32 old rats fed the low calorie diet, while the age-related increase in mono- to polyunsaturated fatty acid ratios in phospholipids was further raised. In conclusion we have shown that a diet low in calories and high in fibers affects lipid composition in the rat brain, in a direction opposite to that normally believed to reduce age-related deterioration of brain functions.

Toxicol Appl Pharmacol 1993 May;120(1):72-9. Essential fatty acid deficiency in cultured human keratinocytes attenuates toxicity due to lipid peroxidation. Wey HE, Pyron L, Human keratinocytes are commonly grown in culture with a serum-free medium. Under these conditions, keratinocytes become essential fatty acid deficient (EFAD), as determined by gas chromatographic analysis of cell phospholipid fatty acid composition. Exposure of EFAD keratinocytes for 2 hr to concentrations of t-butyl hydroperoxide (tBHP) up to 2 mM did not result in toxicity assessed by lactate dehydrogenase (LDH) release and only a small indication of lipid peroxidation assessed by the release of thiobarbituric acid-reactive substances (TBARS). Addition of 10 microM linoleic acid (LA) to serum-free medium alleviated the EFAD condition by increasing the phospholipid content of LA and its elongation and desaturation products, arachidonic acid and docosatetraenoic acid. Exposure of LA-supplemented keratinocytes to tBHP resulted in significant LDH (at 1 and 2 mM tBHP) and TBARS (tBHP concentration dependent) release. TBARS release was also significantly elevated in unexposed LA-supplemented keratinocytes (basal release). Co-supplementation with the antioxidant, alpha-tocopherol succinate (TS) prevented tBHP (1 mM)-induced LDH release in LA-supplemented cultures. TS supplementation also attenuated the effect of tBHP on TBARS release, but when compared to TS-supplemented EFAD cultures, LA supplementation still led to increased tBHP-induced TBARS release. Keratinocyte cultures are potentially useful as an alternative to animals in toxicology research and testing. It is important, however, that the cell model provide a response to toxic insult similar to that experienced in vivo. Our results suggest that fatty acid and antioxidant nutrition of cultured keratinocytes are important parameters in mediating the toxic effects of lipid peroxidation.

Cancer Lett 1997 Jan 1;111(1-2):179-85. Subcutaneous, omentum and tumor fatty acid composition, and serum insulin status in patients with benign or cancerous ovarian or endometrial tumors. Do tumors preferentially utilize polyunsaturated fatty acids? Yam D, Ben-Hur H, Dgani R, Fink A, Shani A, Berry EM.

AC Chan, J. of Nutrition, 1998
"The response-to-injury hypothesis explains atherosclerosis as a chronic inflammatory response to injury of the endothelium, which leads to complex cellular and molecular interactions among cells derived from the endothelium, smooth muscle and several blood cell components. Inflammatory and other stimuli trigger an overproduction of free radicals, which promote peroxidation of lipids in LDL trapped in the subendothelial space. Products of LDL oxidation are bioactive, and they induce endothelial expression and secretion of cytokines, growth factors and several cell surface adhesion molecules. The last-mentioned are capable of recruiting circulating monocytes and T lymphocytes into the intima where monocytes are differentiated into macrophages, the precursor of foam cells. In response to the growth factors and cytokines, smooth muscle cells proliferate in the intima, resulting in the narrowing of the lumen. Oxidized LDL can also inhibit endothelial production of prostacyclin and nitric oxide, two potent autacoids that are vasodilators and inhibitors of platelet aggregation. Evidence is presented that vitamin E is protective against the development of atherosclerosis. Vitamin E enrichment has been shown to retard LDL oxidation, inhibit the proliferation of smooth muscle cells, inhibit platelet adhesion and aggregation, inhibit the expression and function of adhesion molecules, attenuate the synthesis of leukotrienes and potentiate the release of prostacyclin through up-regulating the expression of cytosolic phospholipase A2 and cyclooxygenase. Collectively, these biological functions of vitamin E may account for its protection against the development of atherosclerosis."

6: Early Hum Dev 1994 Nov 18;39(3):177-88
Vitamin A and related essential nutrients in cord blood: relationships with anthropometric measurements at birth. Ghebremeskel K, Burns L, Burden TJ, Harbige L, Costeloe K, Powell JJ, Crawford M. Institute of Brain Chemistry and Human Nutrition, Queen Elizabeth Hospital for Children, London, UK. Following the advice given by the Department of Health to women who are, or may become pregnant, not to eat liver and liver products because of the risk of vitamin A toxicity, the concentrations of vitamins A and E, and copper, magnesium and zinc in cord blood were investigated. The study was conducted in Hackney, an inner city area of London. Esters of vitamin A were not detected in any of the samples, indicating that there was no biochemical evidence of a risk of toxicity. Indeed, vitamin A correlated significantly with birthweight, head circumference, length, and gestation period. There was also a significant positive relationship between zinc and birthweight. In contrast, copper showed a negative correlation with birthweight and head circumference. Vitamin E and magnesium were not associated with any of the anthropometric measurements, although magnesium showed an increasing trend with birthweight. The data suggest that most of the mothers of the subjects studied may have been marginal with respect to vitamins A and E and zinc. In those with low birthweight babies. a higher intake would have improved their nutritional status and possibly the outcome of their pregnancy. For these low-income mothers, liver and liver products are the cheapest and the best source of vitamins A and E, haem iron, B vitamins and several other essential nutrients; hence the advice of the Department of Health may have been misplaced.

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A R T I C L E

Can art instruct science? William Blake as biological visionary

"As the true method of knowledge is experiment, the true faculty of knowing must be the faculty which experiences."

"Seest thou the little winged fly, smaller than a grain of sand? It has a heart like thee; a brain open to heaven & hell...."

"Energy is the only life, and is from the Body.... Energy is eternal delight."

"Then tell me, what is the material world, and is it dead?" He, laughing. answer'd: "I will write a book on leaves of flowers, if you will feed me on love thoughts & give me now and then A cup of sparkling poetic fancies; so, when I am tipsie, I'll sing to you to this soft lute, and shew you all alive The world, where every particle of dust breathes forth its joy." (1794)

When I started studying William Blake in the 1950s, it seemed that only English majors knew who he was, but today, I think more people might recognize The Tyger as Blakes than would be able to identify poems by Keats, Byron, Shelley, or Wordsworth. After 200 years, his writing seems contemporary, while other poets works have become dated, and are valued mostly as cultural background. But I dont think this means that his work is any easier to understand than it was when he wrote it. It means that other poets tied their writing to frameworks which have receded into the background, while Blakes words were chosen in a way that allowed them to travel across the centuries without loss. Even though such universality is a goal of science as well as of art, most of what passed for science in the 18th century is today of only historical interest.

Everywhere in our culture, authoritarian ignorance has disproportionate influence. Most of the published work in our culture treats the succession of authoritarian academic/scien- tific/political cults as if this were simply the way history and human nature work, and must work. But this mechanical historical process is only superficial, and below this surface, individuals and groups have always lived as though time behaved very differently for them. William Blake was a person who investigated this discrepancy between official cultural progression, and real human possibility, and his ideas might be able to do essentially what he suggested they could do: Provide a way to by-pass the officially established mechanistic view of reality, into a more fully human reality. Since Blake ridiculed established doctrines in medicine, chemistry, mathematics, and Newtonian physics, many people have dismissed him as a religious nut, but the way in which he criticized them indicates that he simply believed that they were bad science; he also criticized conventional art and morality, because he believed that they were destroying art and morality.

A group that was active in the 1950s, called Synectics, developed several mental procedures that they found to be useful in teaching people to solve problems creatively. These included ways to improve thinking by analogy, to get people out of the ruts of conventional thinking. Personification, fantasy, biological imagery, making the familiar strange, they found, seemed to tap into natural biological and mental processes to increase the ability to direct energy toward valid solutions to practical or artistic problems. They found that experts had to overcome their special knowledge before they could usefully solve problems in their field, and they showed that much of the mystery could be removed from the creative process. Simply putting aside dogmatic mental frameworks was crucial.

When you believe that you have adequate, expert knowledge, a passive, logical, deductive form of mental activity seems appropriate. Deduction always goes from a higher level of generality to a lower level of generality. Mental passivity therefore is likely to be associated with the belief that we have the decisive knowledge already stored in memory. If we believe that we create higher degrees of generality, as appropriate solutions to novel problems, then we are committed to an active mental life. Perception, combined with the discovery and invention of new patterns in the world, will be actively oriented toward the future, while the deductive, merely analytical, manner of thought will be tied to the past.

Blakes work, I think, is of continued and increased interest because he discovered something of great importance, namely, how to avoid dogmatisms of all sorts. Many students who are assigned to write about a poem of Blakes are puzzled, and ask what it means. When they find out that they understand the words and the syntax, it turns out that the only problem was that they were taught that they had to interpret poetry. And that they dont think he could have meant what he said. Most twentieth century students are too stodgy to accept Blakes writing easily. In the 1950s, some people couldnt understand Alan Ginsbergs poetry, because they didnt think anyone was allowed to say such things. That is the kind of problem students have with Blake.

But its not just high school and college students who cant believe that Blake meant what he said. I recently reviewed the comments on The Tyger that have been published in the forty years since I wrote my MA thesis on Blake, and it seems that these academic experts are having the same kind of problem. Dostoyevsky wrote about this problem in The Doubleit is the problem of self-assertion, of seeing oneself reflected everywhere in the world. In Dostoyevskys story, Dream of an Odd Fellow, the theme is stated even more clearlythe world is very boring, and everything seems the same as everything else, until you can escape from a certain interpretive framework, to see what is really present to you. In Blakes phrase, if the many become the same as the few when possessed, more, more, is the cry of a mistaken soul; Blake said, over and over, that the many do not become the same as the few, that we are always moving into a new world as we learn more, except when we find ourselves in the mental manacles of interpretation.

Its easy to forget how pervasive philosophical interpretation is in everyday life and in the so-called sciences, and how much the sciences owe to long-standing theological commitments. Within the last generation, many influential people have said that facts dont matter (and I suspect that their favorable reception has owed everything to that attitude.) In the early 1960s, there was a controversy going on between two schools of thought in linguistics and the philosophy of science, the Katz and Fodor controversy. I think Fodor was in the minority at that time, at least among the most prestigious professors in the United States. Fodor said that if we wanted to know about language, we should find out how the language is used, by watching a variety of people using it. His opponents said that, if they were competent to speak the language, they didnt need to do anything except to think, to understand everything about the language. Fodor was an empiricist, his opponents were rationalists. In mathematics, most people are still rationalists. A large school of contemporary thought about computers, called Artificial Intelligence, is operating within a rationalistic framework. Chomskys generative grammar was ultra-rationalistic, and was easy to set up in computers, though it was perfectly useless in itself. Some physicists hold a philosophy of science that is essentially rationalistic. In Platos time, all knowledge could supposedly be derived by introspection and the analysis of innate ideas, and education consisted in drawing out the knowledge that was innate. (Aristotle, who didnt subscribe to Platos rationalism, has nevertheless been blamed for holding opinions that werent sufficiently supported by observation. This was probably because he occasionally relied on the opinions of others, rather than because of any serious defect in his philosophical-scientific method.)

Its important to remember that Rationalism, as used here, isnt simply a love of reason, which is what is often meant when people speak of rationalism. In its historical use among philosophers, rather than being just a devotion to rationality, it is a specific doctrine which denies that experience is the source of knowledge. Historically, Rationalism has been closely allied with mysticism, as an affirmation that knowledge comes from a source beyond the ordinary world of experience and beyond the individual. At the present time, it serves authoritarian science rather than authoritarian theology, though the basic doctrine is the same.

Several contemporary schools of literary theory, sociology, anthropology, even biology, trace their ideas back to Ferdinand de Saussures analysis of language, reading into it a highly rationalistic doctrine for which there is no actual basis. Saussures most important idea was that it is impossible to analyze language into its structural units without simultaneously seeing its use in relation to the world of meanings. Without its meanings, it just isnt language. This is a profoundly anti-rationalist insight, since it shows that symbols take their existence from the experience of communication. But once the symbols exist, they function by the ways they establish distinctions, this being defined by the ways it has been used in distinction to those, that, etc. Every time a word is used, its meaning changes a little, since every use occurs in a new communicative situation. The contemporary rationalistic academic trends prefer to isolate only the principle of meaning through opposition, since it supports the rationalistic illusion of operating strictly on the symbolic level. The symbolic level is only an abstraction, and doesnt exist independently.

A few decades ago, there was a movement called General Semantics that tried to make people more conscious of the way symbols relate to reality. Their ideas were based on a distinction between the concrete use of symbols, and the various levels of abstraction. These distinctions, however, made sense only within a certain theory of how language works, which I think was wrong: It asserted that, if time and space were divided into sufficiently small units, symbols and language could be precise and factual. It ignored the distinction between reality as experienced, and reality as represented in theory. If you keep subdividing a person, John Smith, into smaller moments, you find that there is nothing that represents the known person. The person that you are really referring to is actually a summation of many momentsthe summation is the only concreteness. The person you know is a synthesis, and it is that imaginative synthesis of facts to which the concrete symbol refers. Generality exists in our knowledge of the world, and the distinction between concrete and abstract is likely to create confusion, and reinforces a specific ideological system. Incidentally, the word concrete derives from the roots grown and together, so it is very close in its core meaning to synthesis. A well constructed generalization can be concrete, and a seemingly simple term, such as electron, can be abstract. (Blake said that a line, no matter how finely divided, was still a line; a line exists in our imaginative synthesis of the world, and it is only a denial of that synthesis that can divide its unity into infinitesimals.)

Mathematics has its value in representing certain relationships or patterns, but the rationalistic illusion that the meaning is independently contained and fulfilled by the algorithm, has led many people into dogmatisms and serious errors. Coefficients of reality are often neglected. In practice, you are not very likely to be mistaken if you assume that mathematical descriptions of physical states are always erroneous.

In the 17th and 18th centuries, progress in technology and industry was already making rationalism seem inadequate, but it still served the social purpose of allowing the ruling class to claim that the doctrines it wished to enforce had the support of timeless, innate and universal principles. There was supposed to be a Great Chain of Being, a hierarchy in which the king and the lords were just below the angels, and Reason was a mathematically clear description of the way things were, and should be. As the chain of being finally broke up at the end of the 18th century, the king brought in the Rev. Malthus to explain how war, poverty, and disease served the divine, or kingly, purpose, by controlling population growth, justifying misery and social antagonism in a new way.

There were philosophers, such as John Locke and David Hume, who argued that much of our knowledge is gained through the senses, and there were satirists, such as Henry Fielding, who ridiculed the supposedly divinely sanctioned class system, but Blake took a much simpler, but more radical position, in saying that Reason isnt the same that it will be when we know more, and that reason is only the ratio of things that are presently known, and not the source of new knowledge. Blake kept the idea that experience is the source of knowledge, without reducing experience to the senses. Blake didnt deny the existence of some innate ideas; he didnt think we were born as a blank slate, but there is more to the mind than what we are born with. Imagination and invention and mental striving were able to generate new forms. This commitment to experience as the source of knowledge, rather than just analyzing a stock of innate ideas, made Blakes world one that was oriented toward the future, toward invention and discovery, rather than to memory, established knowledge, and tradition. In its essence, it was antidogmatic.

Rationalism is a system of symbols, in which each symbol is demonstrated to have its own proper place and status. To the extent that reason is held to be innate, the system will be prescriptive and judgmental, rather than simply descriptive, explanatory, and illuminating. When an alternative system is proposed, it may be considered a heresy, if the system from which it dissents is both rationalistic and authoritarian.

Except for the dangers involved in committing a heresy, it is very easy to follow the implications of the system that one finds in ones own mind, since self-assertion contains no principle of corrective contradiction. Essentially, rationalism consists of thinking something is true because you thought of it.

I think of the philosophical Rationalists as being the bureaucrats of the mind, making everything tedious and boring and repetitive. Eliminating Rationalism, then actual individualized full mental life can begin.

Even a heresy, if it is based on rationalism, is past-oriented, and dogmatic. Over the years, scholars have ascribed most of the important heresies, as well as mainstream religious ideas, to Blake. Whatever interpretive system the scholars favor, they are able to find it in Blakes work. Calling Blake a mystic is especially useful when the goal is to claim that the critic is getting at the deepest levels of meaning in Blake, even though there is no clear meaning for the word in contemporary English, and Blake didnt use the term in a way that suggested he would approve of having the word applied to himself.

Blakes notes written in the margins of books make it clear that he wasnt simply adopting anyones doctrinaire opinions, and that he was able to find useful ideas in the thoughts of others even when he disagreed with them on important issues. Blake was not a rationalist, but he agreed with Bishop Berkeleys understanding of the importance of distinguishing thought from language. He recognized that Descartes, Locke, Hume, Newton, had inadequate ideas about the nature of matter, but he didnt accept the simplistic doctrine of extreme rationalism that matter doesnt exist.

When people consider Leonardo de Vinci, they usually make the point that he had mastered every field of knowledge, and so the question of sources and influences doesnt come up. In the 18th century, London was the cultural center of the world; European, Asian, and ancient cultures and ideas were discussed in books, magazines, and conversations. Being an engraver, a painter, a poet, and a political activist, Blakes circle of acquaintances was as wide as anyones could be. England has had, probably since the 17th century or earlier, a counter-culture of opinionated dissenters. I suspect that the people who spent several years studying the classics for a university education were somewhat culturally deprived, relative to the people who participated in the rich unofficial culture, where new ideas in art, science, and philosophy were being discussed. London was also the center of a world-spanning empire, a tyrannical class-system, and an industrial-commercial revolution. The past and the possible futures could be seen from Blakes vantage point.

Among all the published opinions about things that influenced Blake, I have seen only a few discussions of his treatment of scientific ideas, mainly his rejections of Newtons mathematical and physical assumptions, and very few comments on Blakes position on the major philosophical controversies of his time. A biologist, Jacob Bronowsky, wrote a book about Blake, but Bronowskys own biological, historical, and linguistic ideas were relatively conventional. Even though Blakes work is full of images from biology, the critics ignore the fact that Emanuel Swedenborg published very advanced biological research in the middle of the 18th century, and that Erasmus Darwin was known for presenting his ideas on biological evolution in poetry (especially Zoonomia). The title of Blakes book, The Four Zoas, has apparently never led scholars to ask whether it had anything in common with Zoonomia. Even though Blake made many disparaging remarks about Swedenborgs religious books, many people have claimed that Blake was influenced by Swedenborgs religious doctrines, while ignoring the possible influence of the scientific work.

Although the idea that contradiction produces change is associated with Hegels Dialectic, it was an old and well known theme in philosophy. When Blakes idea, that without Contraries there is no progression, is seen in context, I think it is appropriate to think that to a great extent, Blake derived the idea from a consideration of the sexes. Generation, so often discussed in relation to the biblical fall of man, always leads to the issue of the productive interaction of the sexual contraries. The issue of sexual love permeates Blakes work. I suspect that Blake produced even more explicitly sexual work, but since most of his work wasnt really published, when his wife died in 1831, the bulk of his manuscripts and paintings were subject to the whims of their unsophisticated owners. But on the basis of his existing work, it is reasonable to say that sexual and imaginative energy was the motor that Blake saw producing intellectual advancement. This male-female principle of change was more fully explored by Blake than by anyone previously, since he made it concrete and personal, rather than abstract. Working in history, human energy ran into the constrictive, limiting elements, the tyrannies of policy, philosophy, and commerce. For Blake, the interaction of energy with those limits became a philosophy of freedom and revolution.

While Blake discussed the importance of perception in understanding the world, he was remarkable in the care he took to make it clear that he saw the world all alive, in which grains of dust or sand, birds, worms, ants, flies, etc., perceived and experienced in ways that were not different from those of human life. Bishop Berkeley, who said that the material world outside the philosophers mind doesnt exist, added as an afterthought that it exists in the mind of God. If consciousness is the only guarantee of existence, there was no problem in the existence of Blakes world, in which everything was alive and conscious.

Everyone finds it almost obligatory to describe The Lamb as a symbol for Jesus, but then they find the Tygers symbolic meaning more problematic, andfrom Coleridge in the early 19th century down to the newest publications at the end of the 20th centurypeople are boggled by the obscurity of The Fly. But in that poem, Blake makes it clear that there is no obscure symbolism, when he says then am I a happy fly, if I live or if I die, etc. The animal poems are expressions of Blakes evolutionary, vitalistic, cosmology. The tyger, at least, would be too much for a creationist doctrine to handle. If worms and flies and ants are conscious and in the same situation as human beings, the bonds of sympathy and forgiveness are universal.

In a world thats alive and developing, new knowledge is always possible, and imagination has the prophetic function of reporting the trends and processes of development, illuminating the paths toward the future. Reason is subordinate to invention and discovery.

The dualistic conception of matter as distinct from energy and consciousness is a constrictive illusion put in place by the forces of empire, and the living reality would be freed from the inert husks of the wrongly conceived natural world, when in the future the world was freed of tyranny. After Blake, it would be nearly another century before others would see that the crude materialism of Newton and the Natural Philosophers was essentially a life-denying culmination of the worst trends of official religious dogma.

A complete survey of Blakes references to Christianity would be voluminous, and not all of them are immediately clear, and require a careful placing in the context of the ideas that were being discussed in London at that time. But its hard to reconcile the common description of him as a mystic with his reference to Old Nobodaddy aloft, or with his comment that Jehovah gives us a knock on the head, and Jesus soothes it. He always defines god in human terms, so from the conventional viewpoint, he would probably be considered as an atheist or pantheist, but he didnt describe himself or his friends as atheists. When people called Tom Paine an atheist, Blake defended him against the charge. Other friends, Mary Wollstonecraft and William Godwin, were sometimes called atheists, but in their writings, they never expressed very unconventional religious ideas. When we recall that in the early 1990s, George Bush expressed the idea that atheism should be illegal, it is easy to imagine that people in 18th century England wouldnt have felt that it was safe to be called atheists.

In 1803, Blake apparently said something like damn the king, while getting a drunk soldier out of his yard, and was tried for sedition or treason. He was acquitted, because his far more scurrilous written comments hadnt been published, and it didnt occur to the government to look for documentary evidence to support their case. The fact that he printed his own work, and sold only a few copies of his books to affluent friends, probably saved his life, but it accounts for his obscurity during his own lifetime.

Tom Paines writing was published and widely read in prerevolutionary America, but he was considered a criminal in England, and Blake was credited with saving his life by helping him escape to France. Politically and ethically, Blakes writing is similar to that of Paine, Godwin, and Wollstonecraft (often called the first feminist), but his language is usually more vivid. It was probably the clarity of his political opposition that made his work unpublishable during his lifetime. The first complete collection of his work was published in 1927, and until that year, very few people had seen more than a few of his most famous poems.

Blake printed his work by hand, without a press, by writing the text backwards on copper plates, surrounded by his drawings, and then etching away the surrounding copper, so that the image remained elevated, and could be inked and printed as if it were a wood-block. If he hadnt devised this method for printing a few copies of his books, it isnt likely that much of the work would have survived.

Shortly after the French Revolution, William Wordsworth was associated with the Blake-Wollstonecraft-Godwin groups defense of the revolution, but he moved away from the ideals of that group, and adopted more socially acceptable ideas. He finally became Englands poet laureate. Liberty, equality, and brotherhood were replaced by blandly conformist ideas.

The type of individualism that Wordsworth came to advocate was interesting because it was a rejection of exactly that part of Blakes belief that Blake considered to be the essence of Christianity, namely, forgiveness, brotherhood, and bonds of sympathy connecting all beings. In its place, Wordsworth adopted a memory-centered doctrine. During Wordsworths lifetime, his ideology was exceedingly successful, but its rationalistic overtones have kept it tied to the past; it had nothing to offer the future. I think we can get some insight into Wordsworths mind by considering that, on the basis of reading Blakes Songs of Innocence and Experience, he decided that they were written by an insane person. (Blake was aware that slow-witted people, who couldnt follow unconventional thoughts, often considered him to be crazy.}

Everywhere in Blakes work, it is clear that he never underestimated the possibilities of the future, and never imposed false limits onto anything, but he didnt tolerate vagueness or empty abstraction. Sharp definition was essential, and unique particulars were the basis for beauty and knowledge.

For Blake, the dialectical principal was a feature of the world itself, but it also informed his method, his technique, and his rhetoric. One of Blakes powerful insights was that intellectual clarity is achieved by contradiction, opposition, contrast, making distinctions as well as comparisons. The principle of intensification through opposition had special features when it was developed in his painting and writing. Blake gave much of the credit for his style of thinking to the process of spending thousands of hours in the practice of etching. The image you create in the conventional etching technique is made when acid bites into the lines that will be inked; in Blakes new technique, the image is made permanent by the acids corroding away of everything except the sharply defined image. The decisive, dividing, line is essential. Anyone who has spent even a few hours of intense effort working in dry-point or etching understands that, when you stop, the appearance of the world is altered by changes that have taken place in your eyes and brain. Often, his metaphors are literal imaginative insights that have great generality. This kind of knowledge distinguishes the work of a craftsman from that of an academic. The probability is that Blakes art led him to appreciate compatible ideas when he found them, and it doesnt seem likely that he was influenced by them the way an academic is influenced by books, since Blake had his own sources that are generally neglected by intellectuals.

Blake found that contrasts made meanings clear, and made language vivid. Heaven and Hell, Clod and Pebble, Lamb and Tyger, Angel and Devil, Greek and Jew, Innocence and Experience, presented contrasts that encouraged the reader to think about the range of possibilities Blake had in mind. He was always consciously trying to energize the readers mind to get out of dogmatic ruts, to look at things freshly, so he often used the polarities in ways that would surprise the reader, ironically reversing familiar references. A pious commonplace would be contrasted with the disturbing realities that it normally hid. Both in his writing and in conversation, Blake was often playful and teasing, and over-serious people have usually taken him too literally.

Academic commentators are so often attached to their erudite pieties that it seems that they cant read English. In the 18th century, a clod meant just what it means in the 20th century, either a lump of dirt, or a lunkhead. In the Clod and the Pebble, when the Clod speaks the properly sanctimonious phrases, justifying its oppressed misery with a dogma, we have a clue regarding Blakes attitude, but then he makes it perfectly clear by speaking of Heavens despite, literally, Heavens malice (a concept that appears many times in different forms in other parts of his work). Either the commentators assume that the word despite had a different meaning in the 18th century (it didnt), or they assume that Blake made an error of diction, because they choose to alter the meaning to despite Heaven. Just as judges arent allowed to change the wording of the laws that they interpret, literary experts arent allowed to rewrite texts to make them better suit their interpretation.

The same insensitivity to the world of concrete experience that has allowed so many commentators to read their own ideas into Blake, ignoring what he said in plain English, makes satire and irony and sarcasm inaccessible to many people who otherwise seem intelligent; this is especially apparent when scientists comment on literature. Forming an imaginative synthesis of the writer and his meaning requires mental flexibility and energy, rather than just analytical acuity.

Everyone who described Blakes physical appearance remarked on his large head. Blake commented that he didnt like to travel or undergo physical strain, because of its effects on his health. The brain is an energetically expensive organ, which consumes large amounts of glucose. A very large brain puts a special burden on the livers ability to store energy, and is likely to make a person conscious of physiological processes. Blakes descriptions of the process of seeing show that he was integrating his experience into his knowledge, describing brain physiology, incorporating his perceptions and the best scientific knowledge that was available to him, into a philosophical description of the place of conscious life in the world. The pulsation of an artery was the unit of time, a red blood corpuscle was the unit of space, enclosing eternity and infinity, eliminating arbitrary and abstract entities, and placing human life within cosmic life, while revealing cosmic life within the individual.

The idea of a biological cosmos seems strange only when it is considered against an ideology which maintains that life is alone in an immense dead universe. The assumption of a dead, unintelligent, randomly moving physical world is the creation of a series of theological ideas, which Blake perceived as essentially Satanic. Blake used the language of these theologies, but inverted them, showing the ways they were used to obscure reality, and to impose a perverse way of life onto the living world.

Fred Hoyle, the astronomer, said If this were an entirely scientific matter, there is little doubt from the evidence that the case for a fundamentally biological universe would be regarded as substantially proven. (1989)

Over the last few decades, biologists feel that they have established the biochemical unity of life, in which biochemical cycles and genetic codes are widely shared. The idea of ecological interdependence has come to be recognized as an essential part of life, or (as demonstrated by Vernadsky, and suggested by Hoyle) a cosmic principle. Blake often called himself a Christian, and defined Christianity in many novel ways, as art, love, politics, science, but specifically, in his version of Christianity, forgiveness was an essential idea, and nothing lives for itself only. Blakes Christianity as Art was a concrete part of living, and he ridiculed some of the abstract theosophical definitions of god that were common in his time. When his remarks are considered against the background of Spinozistic pantheism, it is the intensification and personalization, the avoidance of abstractions that could permit the attribution of passivity or inertness to any part of reality, that stand out. When he said that the world is alive, he meant that it is a defect of perception that makes Newtons world seem passive, empty, and dead. A few years ago, a movement that called itself deep ecology tried to absolutize the ideas of ecology; Blakes view of the interactive unity of life was as well thought out as any that preceded Vernadskys cosmology.

Rather than elevating any of the ideas of Christianity to an absolute doctrine, Blake used them as parts of an organic whole. The principle of forgiveness was presented as the appropriate response to a world which is always new. The desire for vengeance comes from a delusive commitment to the world of memory. Virginity is constantly renewed in the world of imaginative life. While Blake said that you cant forgive someone until they stop hurting you, the desire to be forgiven indicates that there is an opportunity to resolve the problem.

Although most mathematicians and computer-so-called-scientists are committed to a rationalistic, past-oriented view of their mental operations, and some scientists accept that ideology along with mathematics, the valid, discovery-oriented sciences have to be future-oriented. A first step in avoiding dogmatic assumptions might be phrased as remembering what you are, a living being, and asking how you know things: The interaction with other beings, exchanging energy and information with the environment, experiencing yourself in the world.

Holistic medicine and holistic psychology came into existence as attempts to overcome the dogmatic compartmentalization of reality that is endemic. Whenever rigidity is a problem, looking for ways to create new patterns that by-pass the petrified pattern can lead to a solution. Parkinsons disease and other physical problems have been approached using techniques of intensified or varied stimulation. Increased stimulation--even electromagnetic stimulation-- appears to open alternative patterns. Music, dance, and swimming have been used successfully to improve fluidity in various neurological diseases. Kurt Goldstein (The Organism) worked with brain injuries, and found that the brain has a variety of ways to restore a new balance. Raising the amount of energy thats available can allow natural processes to create a better synthesis. Political and social problems that are culturally determined may follow rules similar to those of organic brain disease.

Optimal assumptions, when assumptions are necessary, are those that dont commit you to undesirable conclusions. For example, in the 1950s, some people made the assumption that nuclear war was inevitable, and made large investments in fallout shelters, which were conceived in terms of world war II bomb shelters, and so resources were diverted from other investments, such as education, which didnt in themselves foreclose future possibilities. Self-fulfilling prophecies and self-limiting assumptions are often built into supposedly practical activities.

The assumption that cancer is genetically determined, and the assumption that regeneration is impossible in the heart or brain, are self-limiting assumptions that have been immensely destructive in biology and medicine. There was no reason to make those assumptions, except for the rationalist culture. Physics, biology, and cosmology are manacled by many unnecessary assumptions. The limits of adaptation, the extent of lifes potential, cant be discovered unless you look for them, but the sciences have built many artificial limitations into their systems.

Avoiding unnecessarily limiting assumptions, looking for patterns rather than randomness, looking for larger patterns rather than minimal forms, avoiding reliance on verbal and symbolic formulations, expecting the future to be differentthese are abstract ways of formulating the idea that the world should be seen with sympathetic involvement, rather than with analytical coldness.

Almost everything which has been denounced as teleological has turned out to be much closer to the truth than the mechanistic views that were promoted as more scientific, and many horrors have been committed by people who have said that nature shouldnt be anthropomorphized, that subjective feelings shouldnt be attributed to the experimental material. The surgeons who operate on babies without anesthesia are operating on the assumption that any being which cant say Im going to sue you is unable to experience pain.

When we analyze the ideas of chemical reaction equilibrium (burning something, for example), or biological adaptation or growth or learning, and see that they are strictly directional in time (which is the basic meaning of teleological), and consistent with Aristotles description of causality, we can see the mysticism that has been imposed on our culture with the idea that teleological explanations are unscientific.

Blake was clearly aware that the reason for making limiting assumptions was to maintain control, and to profit from anothers suffering. Seeing that the sadistic assumptions that were put in place to regulate human life rested on a dichotomizing of soul from body, Blakes correction was to replace them with a unity of consciousness and substance, a living world rather than a dead world.

An imaginative study of his work has the potential to rouse ones abilities and to open an unlimited world of possibilities. I give you the end of a golden string, Only wind it into a ball, It will lead you in at Heavens gate, Built in Jerusalems wall. Blake knew that his work, like anything new in the world, could be understood only by an active mental process.

Every communicative act is original, and understanding it is an invention, a projection, an imaginative synthesis. We can sometimes finish another persons sentence, the way we anticipate the notes in a melody; we predict the intended meaning. If the symbols carried the meaning in a passive rationalistic way, the person receiving the symbols would receive nothing new. Intellect is a process of imaginative synthesis, or it is nothing.

Blake devised a system that would make it possible to think about the world without unconsciously making a commitment to the false limits. He showed, by working within this new philosophical synthesis, that Art, Science, and Politics are structurally and substantially interdependent. The question I asked in the title, can art instruct science? isnt the right question once you see the world from Blakes perspective, since Science is Art, and both must be based on experience and imagination.

Blake used, in a new way, the things that were available in his culture, to reveal the process of creation, on all its levels. He consciously used language in a new way, to free the reader from the stereotypes of conventional language. His methods are relevant, as he knew they would be, for other times and situations.

NOTES AND QUOTATIONS

I happened to read Swedenborg's scientific work just as I was getting interested in concentrating on becoming a biologist, and I realized that it was his scientific knowledge that shows up in Blake's imagery, far more than his theology, which Blake obviously despised. By chance, just after I finished my master's thesis on Blake, I got a job at a Swedenborgian college (Urbana University), where I saw in traditional form the small minded theologism that Blake had seen in Swedenborg. As a result of those experiences, I greatly appreciated the book, The Heaven and Hell of William Blake, by Gholam-Reza Sabri-Tabrizi, which apparently hasn't been very well received academically.

Blakes imagery indicates that he had a great interest in the physical and biological sciences, and he apparently had some direct contacts with the leading scientists in London, some of whom are lampooned in Island in the Moon. Some of Swedenborgs discoveries were probably discussed in these groups.

Although Swedenborgs original works in anatomy and physiology were probably his most impressive contributions, he was also a pioneer in paleontology, cosmology (the nebular hypothesis, in particular), magnetism, crystallography, metallurgy, and endocrinology.

E. P. Thompsons Witness against the Beast is an extremely valuable source for clarifying Blakes vocabulary.

Synectics, W. J. J. Gordon, Harper & Row, 1961. Describes how metaphorical thinking was used for solving practical problems, in the Synectics Research Group in Cambridge, Mass.

In the scientific philosophies of Blakes time, it was common to speak of matter and its primary and secondary qualities. Blake understood that this view of matter was a derivative of awful theologies:

And this is the manner of the Sons of Albion in their strength

They take the Two Contraries which are calld Qualities, with which

Every Substance is clothed, they name them Good & Evil

From them they make an Abstract, which is a Negation

Not only of the Substance from which it is derived

A murderer of its own Body: but also a murderer

Of every Divine Member: it is the Reasoning Power

An Abstract objecting power, that Negatives every thing

This is the Spectre of Man: the Holy Reasoning Power

And in its Holiness is closed the Abomination of Desolation

[Jerusalem, 10]

What is a Church and What Is a Theatre? are they Two & not One? can they Exist Separate?

Are not Religion & Politics the Same Thing? Brotherhood is Religion

O Demonstrations of Reason Dividing Families in Cruelty & Pride! [Jerusalem plate 57]

And he who takes vengeance alone is the criminal of Providence;

If I should dare to lay my finger on a grain of sand

In way of vengeance; I punish the already punishd: O whom

Should I pity if I pity not the sinner who is gone astray! [Jerusalem plate 45]

Imagination has nothing to do with memory. (comment on Wordsworth). Knowledge is not by deduction, but Immediate by Perception or Sense at once. (comment on Berkely).

With Demonstrative Science piercing Apollyon with his own bow! J12.14; E155

Generalizing Art & Science till Art & Science is lost. J38.54; E185

For Art & Science cannot exist but in minutely organized Particulars

Since the difference between a Rationalistic view of the world and a creative view is largely a question of the reality of time, its worth mentioning the work of an astronomer whose cosmological view was based on the reality of time:Possibility of experimental study of properties of time, N. A. Kozyrev, Russian, September 1967, USIA document in English, 49 pages, 1971. J. Narlikar more recently did similar work, including his collaboration with H. Arp, described in Arps Seeing Red: Redshifts, Cosmology, and Academic Science, Apeiron, Montreal, 1998.

© Ray Peat 2006. All Rights Reserved. www.RayPeat.com

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