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Ray Peat, PhD on the Benefits of the Raw Carrot

Also see:
The effect of raw carrot on serum lipids and colon function
Protective Bamboo Shoots
SOS for PMS
Endotoxin-lipoprotein Hypothesis
Endotoxin: Poisoning from the Inside Out
Protection from Endotoxin
Bowel Toxins Accelerate Aging
Protective Cascara Sagrada and Emodin
Fermentable Carbohydrates, Anxiety, Aggression
Intestinal Serotonin and Bone Loss
Autoimmunity and Intestinal Flora
Are Happy Gut Bacteria Key to Weight Loss?

“Endotoxin or other material absorbed from intestinal bacteria contributes to a variety of autoimmune problems, including thyroiditis (Penhale and Young, 1988). Combining an indigestible fiber, such as raw carrot, with mild germicides, such as vinegar and coconut oil, can improve the hormonal environment, while reducing the immunological burden.”

“My basic approach is to lower estrogen and the stress hormones by diet including a daily carrot salad, supported by thyroid supplements as needed.”

“The food industry is promoting the use of various gums and starches, which are convenient thickeners and stabilizers for increasing self-life, with the argument that the butyric acid produced when they are fermented by intestinal bacteria is protective. However, intestinal fermentation increases systemic and brain serotonin, and the short-chain fatty acids can produce a variety of inflammatory and cytotoxic effect. Considering the longevity and stress-resistance of germ-free animals, choosing foods (such as raw carrots or cooked bamboo shoots or cooked mushrooms) which accelerate peristalsis and speed transit through the bowel, which suppressing bacterial growth, seems like a convenient approach to increasing longevity.”

“It takes a few days for the intestine to adjust to raw carrot, but the indigestible fiber is very protective for the intestine. Boiled bamboo shoots, which are also mostly indigestible, have a similar effect. These fibers prevent the reabsorption of estrogen in the intestine, and can shift the balance away from cortisol and estrogen, toward progesterone and thyroid, in just a few days of regular use. Oatmeal and potatoes do provide fiber, but they are good food for bacteria, and bacterial endotoxin is usually the basic problem causing hormone imbalance, by being a chronic burden for the liver, keeping it from storing enough sugar to process thyroid and the other hormones effectively.”

“Coconut oil added to the diet can increase the metabolic rate. Small frequent feedings, each combining some carbohydrate and some protein, such as fruit and cheese, often help to keep the metabolic rate higher. Eating raw carrots can prevent the absorption of estrogen from the intestine, allowing the liver to more effectively regulate metabolism.”

“Things that protect the bowel, such as raw carrots, have far-reaching effects on hormones and immunity.”

“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.”

“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.”

“Polysaccharides and oligosaccharides include many kinds of molecules that no human enzyme can break down, so they necessarily aren’t broken down for absorption until they encounter bacterial or fungal enzymes. In a well maintained digestive system, those organisms will live almost exclusively in the large intestine, leaving the length of the small intestine for the absorption of monosaccharides without fermentation. When digestive secretions are inadequate, and peristalsis is sluggish, bacteria and fungi can invade the small intestine, interfering with digestion and causing inflammation and toxic effects. Lactose malabsorption has been corrected just by correcting a deficiency of thyroid or progesterone…Sometimes having a daily carrot salad (grated, with salt, olive oil, and a few drops of vinegar) will stimulate (and disinfect) the small intestine enough to prevent fermentation.”

“Appetizing foods stimulate the digestive secretions, but it’s important to avoid foods that directly trigger an inflammatory reaction, or that are indigestible and as a result support harmful bacterial growth. Cellulose can accelerate transit through the intestine and lower estrogen systemically(partly by simply preventing the reabsorption of estrogen that has been secreted by the bile), but the lignans found in many seeds and grains tend to promote inflammation. Raw carrots, for example, lower estrogen, while flax meal can increase it. Constipation or diarrhea, or their alternation, usually develops when there is inflammation in the bowel. A laxative can sometimes reduce the inflammation, but it’s important to identify the foods that contribute to the problem. A salad of shredded carrot, with oil and vinegar dressing, has a germicidal action, and is stimulating to the digestive processes. Most salad vegetables, though, are likely to produce intestinal irritation, directly or as a result of bacterial decomposition.”

“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.”

“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.”

“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.”

“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.”

“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.”

“Aging, stress, and heavy consumption of alcohol increase the permeability of the intestine, causing increased absorption of microbial toxins. Laxatives, carrot fiber (not carrotjuice), activated charcoal, and a small amount of sodium thiosulfate decrease the formation and absorption of toxins, increasing the organism’s adaptive capacity.”

“Because some estrogen is secreted In the bile, adequate fiber in the diet (oats, potato. or raw carrots, for example) and regular bowel function help to prevent the build-up of estrogen, which inhibits the thyroid. (Estrogen which has been excreted in the bile can be reabsorbed from the intestIne if there is slow transit time and too little fiber.) A deficiency of B vitamins or protein is also known to prevent the liver from excreting estrogen. One of the ways in which starvatIon inhibits thyroid function is by damaging the liver function. Vegetarians are somelimes dangerously deficient in protein, and in that state the body is very resistant to thyroid hormone. Elevated serum calcium is probably one of the factors in creating a slate of thyroid-resistance during stress.”

“Adequate protein and B vitamins are essential. Vitamin A protects some tissues, such as the breasts, against estrogen’s effects, including cancer, and generally offers protection against estrogen by increasing progesterone. Several studies found that vitamin E protects against estrogen’s harmful effects. A thyroid supplement can reliably lower estrogen, by increasing the liver’s ability to excrete it. Unsaturated oils have a strongly estrogen- promoting action, and should be avoided. Raw carrots can help, by preventing the reabsorption of estrogen which has been secreted into the intestine with the bile. Adequate sunlight helps to maintain a healthy balance of the hormones in certain circumstances, natural progesterone can help to reestablish a balance of hormones”

“While an excess of carotene can inhibit progesterone synthesis, a carrot salad (grated carrots, vinegar, coconut oil, and salt) can often help to normalize progesterone, apparently by protecting against intestinal absorption of bacterial endotoxin, and by helping to reduce the reabsorption of estrogen which has been excreted in the bile.

The beneficial hormonal effects that have been seen during antibiotic therapy (raising progesterone while lowering cortisol and estrogen) can be achieved safely with the carrot salad in most cases, without the possible toxic effects of the antibiotics.”

“Fasting has been found to relieve rheumatoid arthritis, and there is good evidence that a variety of bowel bacteria are involved in arthritis and other “autoimmune diseases.” Bacterial toxins and antigens interact with hormones and the immune systems, and intestinal health should be considered as an integral part of hormone therapy. Raw carrots, by stimulating the intestine, often help to lower estrogen and increase progesterone. One of the thyroid hormone’s important functions is to improve digestion and bowel health.”

“One vegetable has a special place in a diet to balance the hormones, and that is the raw carrot. It is so nearly indigestible that, when it is well chewed or grated, it helps to stimulate the intestine and reduce the reabsorption of estrogen and the absorption of bacterial toxins. In these effects on the bowel, which improve hormonal balance, a carrot salad resembles antibiotic therapy, except that the carrot salad can be used every day for years without harmful side-effects. Many people find that daily use of the raw carrot eliminates their PMS, headaches, or allergies. The use of oil and vinegar as dressing intensifies the bowel-cleansing effect of the salad. Coconut oil is more germicidal and thyroid promoting than olive oil, but a mixture of coconut and olive oil improves the flavor. Lime juice. salt, cheese and meats can be used to vary the flavor.”

“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.”

“My first suggestion for someone with PMS is to avoid thyroid suppression (darkness and endurance exercise should be avoided), and to use my carrot salad recipe: Grated carrots, vinegar, coconut oil and salt are the essentials, garlic and olive oil are optional. Acetic acid and fatty acids released from the coconut oil act at different levels, and the carrot fiber is a timed-release system which also binds toxins and stimulates the bowel; the salt spares magnesium and tends to inhibit excessive prolactin release.”

“The daily use of a few spoonfuls of bran in the breakfast cereal, or of a carrot as a snack (or grated, as a salad), can prevent practically all constipation. A high fiber diet also lowers the risk of bowel cancer, and is being used increasingly for preventing and treating conditions such as colitis and diverticulitis. It turns out that the popular old ” bland diet” without fiber was just about the worst possible thing for colitis. An extra benefit of carrot fiber, besides the bulk and moisture-holding properties, is that it captures and holds fat molecules, removing them from the body and making weight loss easier. The small amount of sugar in carrots is released slowly, so thai it doesn·t disturb blood sugar as much as would the same amount in a different form.”

“Taking “calories” out of context can give bad results – some people avoid carrots as being “high in calories,” but carrots can be very effective for losing weight, partly because their high fiber content binds a large amount of fat and carries it out of the body.”

“Fiber: Carrot fibers are best for intestinal stimulation and binding of fats:”

“I’m not confident of the purity and proper particle size of the charcoal products that are available, so I think bamboo shoot and carrots, along with cascara sagrada as needed, are the safest way to keep endotoxin and estrogen under control.”

“I think hypothyroidism and bowel inflammation are the important thinks in gout. Raw carrot salad and aspirin, and correcting thyroid function, usually take care of it.”

“Since the fiber [CARROT] will delay digestion and reduce absorption of other foods, I think it’s best to eat it between meals, usually in the afternoon.”

“Yes, the plain carrot is good. For people who want more antimicrobial effect, the saturated fats and vinegar are helpful.”

“The intestine is a potential source of reabsorbed estrogen, and a daily raw carrot (grated or shredded, with a little olive oil, vinegar, salt) helps to lower excess estrogen (and endotoxin produced by bacteria). While lowering estrogen, it is likely to lower cortisol and increase progesterone.”

“Bamboo shoots, raw carrot, and flowers of sulfur are other antiseptics that can reduce the white tongue.”

“They aren’t necessary [FIBER], for example milk supports abundant bacterial growth that creates bulk, but when there are digestive and hormonal problems because of bad intestinal flora, the fibers of carrot and bamboo shoots have a disinfecting action. The carrots must be raw for that effect.”

“When a person wants to lose excess fat, limiting the diet to low fat milk, eggs, orange juice, and a daily carrot or two, will provide the essential nutrients without excess calories.”

“Yes, I know people who have lost weight just by eating a raw carrot every day, reducing endotoxin stress.”

“Yes, that’s why a resistant (antiseptic) fiber such as bamboo shoots or raw carrot helps with weight loss, it reduces endotoxin and the stress hormones, and lets the liver metabolize more effectively.”

“A daily raw carrot often helps to balance progesterone, cortisol, and estrogen, by improving intestine-liver functions.”

“It usually takes several days for the digestive system to adjust, with changes in the intestinal rhythm for example, and during that time things like headache and tooth sensitivity can increase. Increased calcium and fiber (raw carrots or boiled bamboo shoots, for example) can help.”

“It takes a few days for the intestine to change its rhythm of peristalsis, and a couple of weeks for the enzymes to adjust to a change of foods. A daily raw carrot helps it to adjust.”

“For several decades I have watched as traditionally safe foods have been altered, and have found that many people have developed allergic problems when their favorite foods were changed by new technologies. Since intestinal bacteria affect the allergenicity of foods that are poorly digested, changing the flora can often relieve the symptoms. Raw carrot contains some antibiotics that can be helpful; oil and vinegar can increase the germicidal effects. It’s important to use oil and vinegar that aren’t allergenic themselves.”

“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.”

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Raw Carrot Salad recommended by FPS. Eat between meals.
C = 8g P = 1g F = 9g
117 calories per serving
Serves 1

Ingredients:
½ to 1 medium carrot
1 t olive oil
1 t refined coconut oil (or additional 1 t olive oil)
½ t favorite vinegar
Pinch of canning and pickling salt

Instructions:
1. Wash carrot thoroughly.
2. Shred carrot vertically and put in bowl.
3. Mix in remaining ingredients. If coconut oil is hard, melt slightly.
4. Pour dressing on carrot salad.

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Ray Peat, PhD on Carbon Dioxide, Longevity, and Regeneration

Also see:
Protective Altitude
Protect the Mitochondria
Lactate Paradox: High Altitude and Exercise
Altitude Improves T3 Levels
Protective Carbon Dioxide, Exercise, and Performance
Synergistic Effect of Creatine and Baking Soda on Performance
Altitude Improves T3 Levels
Altitude Sickness: Therapeutic Effects of Acetazolamide and Carbon Dioxide
Comparison: Carbon Dioxide v. Lactic Acid
Carbon Dioxide Basics
Universal Principle of Cellular Energy
Carbon Dioxide as an Antioxidant
Comparison: Oxidative Metabolism v. Glycolytic Metabolic

“Over the oxygen supply of the body carbon dioxide spreads its protecting wings.”
Friedrich Miescher, Swiss physiologist, 1885

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“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.”

“The end product of respiration is carbon dioxide, and it is an essential component of the life process. The ability to produce and retain enough carbon dioxide is as important for longevity as the ability to conserve enough heat to allow chemical reactions to occur as needed.

Carbon dioxide protects cells in many ways. By bonding to amino groups, it can inhibit the glycation of proteins during oxidative stress, and it can limit the formation of free radicals in the blood; inhibition of xanthine oxidase is one mechanism (Shibata, et al., 1998). It can reduce inflammation caused by endotoxin/LPS, by lowering the formation of tumor necrosis factor, IL-8 and other promoters of inflammation (Shimotakahara, et al., 2008). It protects mitochondria (Lavani, et al., 2007), maintaining (or even increasing) their ability to respire during stress.

The “replicative lifespan” of a cell can be shortened by factors like resveratrol or estrogen that interfere with mitochondrial production of carbon dioxide. Both of those chemicals cause skin cells, keratinocytes, to stop dividing, to take up calcium, and to begin producing the horny material keratin, that allows superficial skin cells to form an effective barrier. This process normally occurs as these cells differentiate from the basal (stem) cells and, by multiplying, move farther outward away from the underlying blood vessels that provide the nutrients that are oxidized to form carbon dioxide, and as they get farther from the blood supply, they get closer to the external air, which contains less than 1% as much CO2 as the blood. This normally causes their eventual hardening into the keratin cells, but when conditions are optimal, numerous layers of moist, translucent cells that give the skin the characteristic appearance of youth, will be retained between the basal cells and the condensed surface layers. (Wilke, et al., 1988)

In other types of tissue, a high level of carbon dioxide has a similar stabilizing effect on cells, preserving stem cells, limiting stress and preventing loss of function. In the lining of the mouth, where the oxygen tension is lower, and carbon dioxide higher, the cells don’t form as much keratin as the skin cells do. In the uterus, the lining cells would behave similarly, except that estrogen stimulates keratinization. A vitamin A deficiency mimics an estrogen excess, and can cause excessive keratinization of membrane cells.”

“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.”

“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).”

“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.”

“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.”

https://www.youtube.com/watch?v=AZkGxrntmTE

“I think of high altitude as analogous to the protected gestational state. (Both progesterone and carbon dioxide are increased in people adapted to high altitude.) Respiratory acidosis, meaning the retention of carbon dioxide, is very protective, and is an outstanding feature of life in the uterus. Even at the time that an embryo is implanting in the uterus, adequate carbon dioxide is crucial. Many of the mysteries of embryology and developmental biology have been explained by the presence of a high level of carbon dioxide during gestation. For example, an injury to the fetus heals without scarring, that is, with complete regeneration instead of the formation of a sort of collagenous plug. Over the last fifty years, several people have discovered that simply enclosing a wound (for example an amputated finger tip) in an air-tight compartment allows remarkably complete regeneration, even in adults, who supposedly have lost the power of regeneration. (Exposure of tissues to air causes them to lose carbon dioxide.)”

“During gestation, after organs have differentiated, nerve cells extend their fibers from the brain to innervate muscles and other tissues. The special conditions of life in the uterus support this process, but something similar can happen during adult life, when damaged nerves regenerate. A major difference between injury to the fetus, and injury to an adult, is that the wound regenerates perfectly without a scar in the fetus, but in the adult, regeneration is often impaired, and a connective tissue scar replaces normally functioning tissue.”

“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).”

“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 hasn’t been carefully studied. Putting an injured arm or leg into a bag of pure carbon dioxide reduces pain and accelerates healing.”

“In the fetus, especially before the fats from the mother’s 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.”

“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.”

“I have been using aging (menopause and the ovaries) and cancer (carbon monoxide as a hormone of “cellular immortality”) to explore the issue of cell renewal and tissue regeneration. Yesterday, Lita Lee sent me an article about K. P. Buteyko, describing his approach to the role of carbon dioxide in physiology and medicine. Buteyko devoted his career to showing that sufficient carbon dioxide is important in preventing an exaggerated and maladaptive stress response. He advocated training in “intentional regulation of respiration” (avoiding habitual hyperventilation) to improve oxygenation of the tissues by retaining carbon dioxide. He showed that a deficiency of carbon dioxide (such as can be produced by hyperventilation, or by the presence of lactic acid in the blood) decreases cellular energy (as ATP and creatine phosphate) and interferes with the synthesis of proteins (including antibodies) and other cellular materials.

When I first heard of Buteyko’s ideas, I saw the systemic importance of carbon dioxide, but I wasn’t much impressed by his idea of intentionally breathing less. If the hyperventilation is produced by anxiety, then a deliberate focussing on respiration can help to quiet the nerves. Knowing that hyperventilation can make a person faint, because loss of carbon dioxide causes blood vessels in the brain to constrict, I saw that additional carbon dioxide would increase circulation to the brain. This seemed like a neat system for directing the blood supply to the part of the brain that was more active, since that would be the part producing the most carbon dioxide.

In a nutrition class, in the late 70s, I described the way metabolically produced carbon dioxide opens blood vessels in the brain, and mentioned that carbonated water, or “soda water,” should improve circulation to the brain when the brain’s production of carbon dioxide wasn’t adequate. A week later, a student said she had gone home that night and (interpreting soda water as bicarbonate of soda in water) given her stroke-paralyzed mother a glass of water with a spoonful of baking soda in it. Her mother had been hemiplegic for 6 months following a stroke, but 15 minutes after drinking the bicarbonate, the paralysis lifted, and she remained normal. Later, a man who had stroke-like symptoms when he drank alcohol late at night, found that drinking a glass of carbonated water caused the symptoms to stop within a few minutes.

Realizing that low thyroid people produce little carbon dioxide, it seemed to me that there might be a point at which the circulatory shut-down of unstimulated parts of the brain would become self-sustaining, with less circulation to an area decreasing the CO2 produced in that area, which would cause further vasoconstriction. Carbon dioxide (breathing in a bag, or drinking carbonated water, or bathing in water with baking soda) followed by thyroid supplementation, would be the appropriate therapy for this type of functional ischemia of the brain.”

“I have been concerned about the probable effects on the fetus of the silly panting respiration that is being taught to so many pregnant women, to use during labor. Panting blows out so much carbon dioxide that it causes vasoconstriction. Possibly the uterus is protected against this, and possibly the fetus produces enough carbon dioxide that it is protected, but this isn’t known. Especially if the mother is hypothyroid, it seems that this could interfere with the delivery of oxygen to the fetus. Besides vasoconstriction, Buteyko points out that the Bohr effect, in which CO2 causes hemoglobin to release oxygen, means that a low level of carbon dioxide decreases the availability of oxygen. If the Bohr effect applies to fetal hemoglobin, then this suggests that the mother’s panting will deprive the fetal tissues of oxygen.

It is normal for the fetus to be exposed to a high concentration of carbon dioxide. Recent experiments with week-old rats show that carbon dioxide, at the very high concentration of 6% powerfully protects against the brain damage caused by oxygen deprivation (tying a carotid artery and administering 8% oxygen). (R. C. Vannucci, et al., 1995.)”

“In general, lactic acid in the blood can be taken as a sign of defective respiration, since the breakdown of glucose to lactic acid increases to make up for deficient oxidative energy production. Normal aging seems to involve a tendency toward excess lactic acid -production, and age-pigment is known to activate the process. Eliminating respiratory toxins (such as unsaturated oils, estrogenic and antithyroid substances, lead, and excess iron) is the most obvious first step to take when there is excess lactic acid formation. Carbon dioxide supplements have been shown experimentally to reduce residual lactate production. Many people experience exhilaration when they go to very high altitudes, and it is known that people generally bum calories faster at high altitude. It has been found that, during intense exercise (which always produces a lactic acid accumulation in the blood), a lower peak accumulation of lactate occurs at high altitude, and this seems to be caused by a reduction in the rate of glycolysis, or glucose consumption. (B.Grassi, et aI.) Since there is less oxygen at high elevation, and since oxygen is used to consume lactic acid, this effect is the opposite of what many people expected. In some sense, respiration becomes more efficient at high altitude. Youth and increased times supported the process by helping to stabilize the high energy metabolism of the brain, and even by stabilizing the “energized” state of water’ that supports brain efficiency. Roman Schmitt has proposed that, 66 million years ago when dinosaurs became extinct and mammals began their rapid evolution, “at that time hydrothermal venting went wild,” releasing huge volumes of carbon dioxide and other substances into the atmosphere.

Antarctic ice cores show there were large increases in atmospheric carbon dioxide in relatively recent times: 10,200, 11,600, and 12,900 years ago, and two broad peaks in carbon dioxide release occurred just 4,200 and 7,700 years ago (Figge and White.) Local or regional increases in carbon dioxide from volcanism could have more continuous effects on brain development.

In times of lower atmospheric carbon dioxide, our Krebs cycle still produces it internally, and the rapid development of the brain during gestation takes advantage of the high concentration of carbon dioxide in the uterus. (These ideas make me doubt the safety of the rapid breathing encouraged by some obstetricians.)”

“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.”

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Inflammation from Radiation

Also see:
Radiation Increases Breast Cancer Incidence
Harm of Prenatal Exposure to Radiation
Caffeine and Skin Protection
Topical Vitamin E and ultraviolet radiation on human skin
Preventing Breast Cancer
We Are Giving Ourselves Cancer
Alice Stewart: The woman who knew too much
Breast Cancer
Radiation and Growth – Ray Peat
Bone Density: First Do No Harm

“MRI (magnetic resonance imaging) and ultrasound imaging are much safer than x-rays and can provide better images of tissues, and can also provide detailed information about tissue functions and metabolism.

Diagnostic x-rays for dentistry, for measuring bone density, for mammography, for examining the brain, lungs, and heart, for “virtual colonoscopies,” for shopping mall whole-body scans, should be abandoned immediately.

The excitation of electrons in the tissues by radiation has catalytic effects tbat produce long-lasting changes in biological functions that are more important than any immediate genetic mutations.” -Ray Peat, PhD

Int J Radiat Oncol Biol Phys. 1990 Dec;19(6):1425-9.
Delayed appearance of lethal and specific gene mutations in irradiated mammalian cells.
Little JB, Gorgojo L, Vetrovs H.
We have examined the occurrence of lethal and 6-thioguanine resistant (hprt locus) mutants among the progeny of irradiated CHO and BALB/3T3 cells. The expression of lethal mutations, as measured by a reduced cloning efficiency in the progeny cell population, was detected up to 30 mean population doublings after x-radiation. Preliminary evidence indicates that the expression of mutations at the hprt locus may also be delayed for at least 6-7 population doublings. These results suggest that radiation can induce genetic instability in cells, resulting in an increased rate of spontaneous mutations which persists for many generations of cell division. These findings are discussed in terms of their possible influence on the response of irradiated tumor cell populations in vivo.

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.
PURPOSE:
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.
MATERIALS AND METHODS:
Blood samples were taken from 453 participants in a long-term epidemiological cohort of A-bomb survivors. Plasma levels of CRP and IL-6 were measured using standard antibody-mediated procedures. Relationships between CRP or IL-6 levels and radiation dose were then investigated by multivariate regression analysis. Blood lymphocytes from each individual were used for immunophenotyping by flow cytometry with murine monoclonal antibodies to CD3, CD4 and CD8.
RESULTS:
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). The elevated CRP and IL-6 levels were associated with decreases in the percentages of CD4(+) helper T-cells in peripheral blood lymphocyte populations.
CONCLUSIONS:
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.

Int J Radiat Biol. 2003 Oct;79(10):777-85.
IL-1beta, TNFalpha and IL-6 induction in the rat brain after partial-body irradiation: role of vagal afferents.
Marquette C, Linard C, Galonnier M, Van Uye A, Mathieu J, Gourmelon P, Clarençon D.
PURPOSE:
To evaluate the central nervous system neuroimmune and inflammatory responses during the prodromal phase of the acute irradiation syndrome in rat brains after partial-body exposure (head-protected) and to investigate the potential neural signalling pathways from the irradiated periphery to the non-irradiated brain.
MATERIAL AND METHODS:
The study included four groups of rats: one irradiated group and one sham irradiated group, each containing non-vagotomized and vagotomized rats. In vagotomized rat groups, the subdiaphragmatic vagal section surgery was carried out 45 days before the irradiation exposure. The rats were partial-body irradiated with the head shielded with (60)Co gamma-rays to a dose of 15 Gy. They were sacrificed 6 h after the end of exposure. The hypothalamus, hippocampus, thalamus and cortex were then collected, and the concentrations of IL-1beta, TNFalpha and IL-6 in each were measured by ELISA assays.
RESULTS:
Six hours after irradiation, IL-1beta levels had increased in the hypothalamus, thalamus and hippocampus, and TNFalpha and IL-6 levels had increased significantly in the hypothalamus. Vagotomy before irradiation prevented these responses.
CONCLUSIONS:
It was concluded that the hypothalamus, hippocampus, thalamus and cortex react rapidly to peripheral irradiation by releasing pro-inflammatory mediators. The results also show that the vagus nerve is one of the major ascending pathways for rapid signalling to the brain with respect to partial body irradiation.

Rinsho Byori. 1994 Apr;42(4):313-9.
[Health effects of atomic bomb radiation].
[Article in Japanese]
Shigematsu I.
The health effects of atomic bomb radiation have been studied by the Atomic Bomb Casualty Commission (ABCC) and its successor, the Radiation Effects Research Foundation (RERF) based on a fixed population of atomic bomb survivors in Hiroshima and Nagasaki which had been established in 1950. The results obtained to the present can be classified into the following three categories: (1) The effects for which a strong association with atomic bomb radiation has been found include malignant neoplasms, cataracts, chromosomal aberrations, small head size and mental retardation among the in utero exposed. (2) A weak association has been found in the several sites of cancers, some non-cancer mortalities and immunological abnormalities. (3) No association has been observed in some types of leukemia, osteosarcoma, accelerated aging, sterility and hereditary effects.

“When a dose of radiation similar to a diagnostic x-ray is given to cells in culture, they are still emitting induced light after an hour or more (Vicker, et al., 1991). The genetic mutations produced by radiation are still occurring hours or days after the exposure; the observations in the Japanese suggest that they might keep occurring years after the exposure.” -Ray Peat, PhD

Radiat Res. 1991 Dec;128(3):251-7.
Ionizing radiation at low doses induces inflammatory reactions in human blood.
Vicker MG, Bultmann H, Glade U, Häfker T.
Irradiation of whole blood with 137Cs gamma rays intensifies the oxidative burst. Oxidant production was used as an indicator of inflammatory cell reactions and was measured by luminol-amplified chemiluminescence after treatment with inflammatory activators including bacteria, the neutrophil taxin formyl-Met-Leu-Phe, the Ca2+ ionophore A23187, the detergent saponin, and the tumor promoter phorbol ester. The irradiation response is dose-dependent up to about 100 microGy, is detectable within minutes, persists at least 1 h, and is transmitted intercellularly by a soluble mediator. The response is completely inhibited by Ca2+ sequestration in the presence of A23187 or by adenosine, indicating its Ca2+ dependency, and by the phospholipase A2 blocker p-bromphenacyl bromide. However, inhibition by the cyclooxygenase blocker aspirin is sporadic or absent. Blood taken after diagnostic examination of lungs with X rays also exhibited intensified chemiluminescence. These reactions implicate a role for specific amplifying mediator pathways, especially metabolites of the arachidonic acid cascade, in the response: “damage and repair” to cells or DNA plays little or no role. Our results provide evidence for a new mechanism of radiation action with possible consequences for the homeostasis of reactions involving inflammation and second messengers in human health and early development.

“People talk about DNA being altered when it is “hit” by radiation, and everyone who has taken a biology course has probably heard that the ”target size” of a gene or a virus determines the likelihood that it will be damaged by a given dose of radiation. That quaint relic of primitive radiation biophysics is useful for nuclear power corporations, and for dentists, and for anyone who wants to sell whole body scans to the public. But that dogma has now been very firmly knocked out by hundreds of direct hits by experimental data, that show that irradiated cells transmit something to other cells that weren’t exposed to the radiation, in a “radiation bystander effect.”” -Ray Peat, PhD

Hum Exp Toxicol. 2004 Feb;23(2):91-4.
Commentary on radiation-induced bystander effects.
Wright EG.
The paradigm of genetic alterations being restricted to direct DNA damage after exposure to ionizing radiation has been challenged by observations in which effects of ionizing radiation arise in cells that in themselves receive no radiation exposure. These effects are demonstrated in cells that are the descendants of irradiated cells (radiation-induced genomic instability) or in cells that are in contact with irradiated cells or receive certain signals from irradiated cells (radiation-induced bystander effects). Bystander signals may be transmitted either by direct intercellular communication through gap junctions, or by diffusible factors, such as cytokines released from irradiated cells. In both phenomena, the untargeted effects of ionizing radiation appear to be associated with free radical-mediated processes. There is evidence that radiation-induced genomic instability may be a consequence of, and in some cell systems may also produce, bystander interactions involving intercellular signalling, production of cytokines and free radical generation. These processes are also features of inflammatory responses that are known to have the potential for both bystander-mediated and persisting damage as well as for conferring a predisposition to malignancy. Thus, radiation-induced genomic instability and untargeted bystander effects may reflect interrelated aspects of inflammatory type responses to radiation-induced stress and injury and contribute to the variety of the pathological consequences of radiation exposures.

“Cortisol is protective against the acute inflammatory effects of radiation (Beetz, et al., 1997), but progesterone has those effects without the handful effects of excess cortisol.” -Ray Peat, PhD
.
Int J Radiat Biol. 1997 Jul;72(1):33-43.
Induction of interleukin 6 by ionizing radiation in a human epithelial cell line: control by corticosteroids.
Beetz A, Messer G, Oppel T, van Beuningen D, Peter RU, Kind P.
The cutaneous radiation syndrome after therapeutic or accidental exposure of human skin to ionizing radiation (IR) is accompanied by inflammatory processes which are controlled partly by proinflammatory cytokines. Besides tumour necrosis factor (TNF)-alpha and interleukin (IL)1, the pluripotent cytokine IL-6 belongs to the key mediators of inflammation. So far, there are no reports about the regulation of IL-6 by IR in epidermal cells. As an in vitro model to study the effects of IR on IL-6 gene expression, we treated the human epithelial HeLa cell line with different single X-ray doses between 1 and 20 Gy. Twenty-four hours after irradiation the IL-6 secretion was dose-dependently enhanced as measured by ELISA. At the transcriptional level, a slight increase of IL-6 transcripts was already detectable 1 h after irradiation, with maximum levels at 2 h, and a decline to baseline levels between 8 and 24 h. Addition of the transcriptional inhibitor actinomycin D inhibited the inducibility of IL-6 mRNA by TPA and IR. As the IL-6 promoter contains multiple binding sites for activated glucocorticoid receptors within the 5′ regulatory region, the potential modulation of IL-6 expression by the corticosteroids hydrocortisone, dexamethasone and mometasone furoate was included in our study to modify the radiation-induced stress response. All corticosteroids applied could efficiently downregulate TPA- or radiation-induced IL-6 expression on both gene expression and protein levels. Mometasone furoate, followed by dexamethasone, was found to be most effective at low concentrations (1 nM), whereas hydrocortisone had to be applied at about 100-fold higher concentrations to achieve comparable inhibition. This experimental model is aimed at understanding the molecular circuits following IR, and thus to provide a basis for the treatment of radiation effects in skin.

Radiat Res. 1994 Jan;137(1):89-95.
Autoantibodies and immunoglobulins among atomic bomb survivors.
Fujiwara S, Carter RL, Akiyama M, Akahoshi M, Kodama K, Shimaoka K, Yamakido M.
The purpose of this study was to determine if exposure to atomic bomb radiation affects immune responsiveness, such as the occurrence of autoantibodies and levels of immunoglobulins. Rheumatoid factor, antinuclear antibody, antithyroglobulin antibody, anti-thyroid-microsomal antibody and immunoglobulin levels (IgG, IgM, IgA and IgE) were measured among 2,061 individuals exposed to atomic bomb radiation in Hiroshima and Nagasaki whose estimated doses ranged from 0 to 5.6 Gy. The prevalence and titers of rheumatoid factor were found to be increased in the individuals exposed to higher radiation doses. The IgA level in females and the IgM level in both sexes increased as radiation dose increased, although the effects of radiation exposure were not large. No effect of radiation was found on the prevalence of antinuclear antibody, antithyroglobulin antibody and anti-thyroid-microsomal antibody or on the levels of IgG and IgE.

JAMA. 2006 Mar 1;295(9):1011-22.
Radiation dose-response relationships for thyroid nodules and autoimmune thyroid diseases in Hiroshima and Nagasaki atomic bomb survivors 55-58 years after radiation exposure.
Imaizumi M, Usa T, Tominaga T, Neriishi K, Akahoshi M, Nakashima E, Ashizawa K, Hida A, Soda M, Fujiwara S, Yamada M, Ejima E, Yokoyama N, Okubo M, Sugino K, Suzuki G, Maeda R, Nagataki S, Eguchi K.
CONTEXT:
Effects of irradiation on thyroid diseases such as thyroid nodules and autoimmune thyroid diseases have not been evaluated among people exposed to radiation more than 50 years in the past.
OBJECTIVE:
To evaluate the prevalence of thyroid diseases and their radiation-dose responses in atomic bomb survivors.
DESIGN, SETTING, AND PARTICIPANTS:
Survey study comprising 4091 cohort members (mean age, 70 [SD, 9] years; 1352 men and 2739 women) who participated in the thyroid study at the Radiation Effects Research Foundation. Thyroid examinations were conducted between March 2000 and February 2003.
MAIN OUTCOME MEASURES:
Prevalence of thyroid diseases, including thyroid nodules (malignant and benign) and autoimmune thyroid diseases, and the dose-response relationship of atomic bomb radiation in each thyroid disease.
RESULTS:
Thyroid diseases were identified in 1833 (44.8%) of the total participants (436 men [32.2% of men] and 1397 women [51.0% of women]) (P<.001). In 3185 participants, excluding persons exposed in utero, not in the city at the time of the atomic bombings, or with unknown radiation dose, the prevalence of all solid nodules, malignant tumors, benign nodules, and cysts was 14.6%, 2.2%, 4.9%, and 7.7%, respectively. The prevalence of positive thyroid antibodies, antithyroid antibody-positive hypothyroidism, and Graves disease was 28.2%, 3.2%, and 1.2%, respectively. A significant linear dose-response relationship was observed for the prevalence of all solid nodules, malignant tumors, benign nodules, and cysts (P<.001). We estimate that about 28% of all solid nodules, 37% of malignant tumors, 31% of benign nodules, and 25% of cysts are associated with radiation exposure at a mean and median thyroid radiation dose of 0.449 Sv and 0.087 Sv, respectively. No significant dose-response relationship was observed for positive antithyroid antibodies (P = .20), antithyroid antibody-positive hypothyroidism (P = .92), or Graves disease (P = .10).
CONCLUSIONS:
A significant linear radiation dose response for thyroid nodules, including malignant tumors and benign nodules, exists in atomic bomb survivors. However, there is no significant dose response for autoimmune thyroid diseases.

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Intestinal Serotonin and Bone Loss

Also see:
Carbohydrates and Bone Health
Ray Peat, PhD on the Benefits of the Raw Carrot
Bowel Toxins Accelerate Aging
Endotoxin: Poisoning from the Inside Out
Protection from Endotoxin
Protective Bamboo Shoots
The effect of raw carrot on serum lipids and colon function
Linoleic Acid and Serotonin’s Role in Migraine
Hypothyroidism and Serotonin
Estrogen Increases Serotonin
Gelatin, Glycine, and Metabolism
Whey, Tryptophan, & Serotonin
Tryptophan, Sleep, and Depression
Anti-Serotonin, Pro-Libido
Serotonin and Melatonin Lower Progesterone

“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.” -Ray Peat, PhD

“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.” -Ray Peat, PhD

“One factor involved in the increased production of TSH in hypothyroidism is that the low metabolic rate allows estrogen to accumulate, leading to increased serotonin production. Serotonin stimulates both TSH and prolactin. Serotonin and prolactin both happen to cause bone loss. They increase nitric oxide, which inhibits mitochondrial respiration. Serotonin increases a cytokine, osteoprotegerin, that inhibits osteoclasts, reducing bone turnover. However, serotonin’s other antimetabolic effects outweigh that effect, and it is a major factor in causing osteoporosis. The antimetabolic factors that slow the rate ofliving also slow the rate of renewal, and on balance lead to tissue atrqphy, fibrosis, inflammation, and degeneration.” -Ray Peat, PhD

J Bone Miner Res. 2011 Sep;26(9):2002-11. doi: 10.1002/jbmr.439.
Efficacy of serotonin inhibition in mouse models of bone loss.
Inose H, Zhou B, Yadav VK, Guo XE, Karsenty G, Ducy P.
In a proof-of-concept study it was shown that decreasing synthesis of gut serotonin through a small molecule inhibitor of Tph1 could prevent and treat ovariectomy-induced osteoporosis in young mice and rats. In this study, we define the minimal efficacy of this Tph1 inhibitor, demonstrate that its activity is improved with the duration of treatment, and show that its anabolic effect persists on interruption. Importantly, given the prevalence of osteoporosis in the aging population, we then show that Tph1 inhibition rescues ovariectomy-induced bone loss in aged mice. It also cures the low bone mass of Lrp5-deficient mice through a sole anabolic effect. Lastly, we provide evidence that inhibition of gut serotonin synthesis can work in concert with an antiresorptive agent to increase bone mass in ovariectomized mice. This study provides a more comprehensive view of the anabolic efficacy of Tph1 inhibitors and further establishes the spectrum of their therapeutic potential in the treatment of bone-loss disorders.

Gastroenterology. 2011 Aug;141(2):439-42. Epub 2011 Jun 17.
The importance of the gastrointestinal tract in the control of bone mass accrual.
Karsenty G, Gershon MD.
One of the least anticipated and less heralded outcomes of mouse genetics has been to rediscover whole organism physiology. Among the many unexpected findings that it has brought to our attention has been the realization that gut-derived serotonin is a hormone-inhibiting bone formation. The importance of this discovery presented in this review is 2-fold. First, it provides a molecular explanation for 2 human genetic diseases-osteoporosis, pseudoglioma, and high bone mass syndrome; second, it suggests a novel and anabolic way to treat osteoporosis. These findings illustrate the importance of the gastrointestinal tract in the regulation of organ physiology at yet another extraluminal site.

Nat Med. 2010 Mar;16(3):308-12. Epub 2010 Feb 7.
Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis.
Yadav VK, Balaji S, Suresh PS, Liu XS, Lu X, Li Z, Guo XE, Mann JJ, Balapure AK, Gershon MD, Medhamurthy R, Vidal M, Karsenty G, Ducy P.
Osteoporosis is a disease of low bone mass most often caused by an increase in bone resorption that is not sufficiently compensated for by a corresponding increase in bone formation. As gut-derived serotonin (GDS) inhibits bone formation, we asked whether hampering its biosynthesis could treat osteoporosis through an anabolic mechanism (that is, by increasing bone formation). We synthesized and used LP533401, a small molecule inhibitor of tryptophan hydroxylase-1 (Tph-1), the initial enzyme in GDS biosynthesis. Oral administration of this small molecule once daily for up to six weeks acts prophylactically or therapeutically, in a dose-dependent manner, to treat osteoporosis in ovariectomized rodents because of an isolated increase in bone formation. These results provide a proof of principle that inhibiting GDS biosynthesis could become a new anabolic treatment for osteoporosis.

Cell. 2008 Nov 28;135(5):825-37.
Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum.
Yadav VK, Ryu JH, Suda N, Tanaka KF, Gingrich JA, Schütz G, Glorieux FH, Chiang CY, Zajac JD, Insogna KL, Mann JJ, Hen R, Ducy P, Karsenty G.
Loss- and gain-of-function mutations in the broadly expressed gene Lrp5 affect bone formation, causing osteoporosis and high bone mass, respectively. Although Lrp5 is viewed as a Wnt coreceptor, osteoblast-specific disruption of beta-Catenin does not affect bone formation. Instead, we show here that Lrp5 inhibits expression of Tph1, the rate-limiting biosynthetic enzyme for serotonin in enterochromaffin cells of the duodenum. Accordingly, decreasing serotonin blood levels normalizes bone formation and bone mass in Lrp5-deficient mice, and gut- but not osteoblast-specific Lrp5 inactivation decreases bone formation in a beta-Catenin-independent manner. Moreover, gut-specific activation of Lrp5, or inactivation of Tph1, increases bone mass and prevents ovariectomy-induced bone loss. Serotonin acts on osteoblasts through the Htr1b receptor and CREB to inhibit their proliferation. By identifying duodenum-derived serotonin as a hormone inhibiting bone formation in an Lrp5-dependent manner, this study broadens our understanding of bone remodeling and suggests potential therapies to increase bone mass.

Annu Rev Med. 2011;62:323-31.
Regulation of bone mass by serotonin: molecular biology and therapeutic implications.
Karsenty G, Yadav VK.
The molecular elucidation of two human skeletal dysplasias revealed that they are caused by an increase or a decrease in the synthesis of serotonin by enterochromaffin cells of the gut. This observation revealed a novel and powerful endocrine means to regulate bone mass. Exploiting these findings in the pharmacological arena led to the demonstration that inhibiting synthesis of gut-derived serotonin could be an effective means to treat low-bone-mass diseases such as osteoporosis.

Clin Calcium. 2010 Dec;20(12):1850-956.
[Control of bone remodeling by nervous system. The role of serotonin in the regulation of bone metabolism].
[Article in Japanese]
Inose H.
There is increasing evidence for a contribution of serotonin to the regulation of bone metabolism. In the periphery, gut derived serotonin (GDS) regulates osteoblast proliferation and bone formation. In the brain, brain derived serotonin regulates bone mass through sympathetic nervous system. In addition, inhibition of GDS biosynthesis can treat osteoporosis in ovariectomized rodents by increasing bone formation. The emerging evidence has suggested that inhibiting GDS biosynthesis could become a new anabolic treatment for osteoporosis in humans.

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Ray Peat, PhD on High Blood Pressure

Also see:
High Blood Pressure and Hypothyroidism
Sodium Deficiency and Stress
Sugar (Sucrose) Restrains the Stress Response
10 Tips for Better Sleep
Light is Right
Aldosterone, Sodium Deficiency, and Insulin Resistance
Low Sodium Diet: High FFA, Insulin Resistance, Atherosclerosis
Aldosterone as an endogenous cardiovascular toxin
Aldosterone and Thrombosis
Sodium Deficiency in Pre-eclampsia
Tryptophan Metabolism: Effects of Progesterone, Estrogen, and PUFA
Estrogen Increases Serotonin
Hypothyroidism and Serotonin
Omega -3 “Deficiency” Decreases Serotonin Producing Enzyme
Enzyme to Know: Tryptophan Hydroxylase
Role of Serotonin in Preeclampsia
Blood Pressure Management with Calcium & Dairy
Hypertension and Calcium Deficiency
Calcium Paradox
Calcium to Phosphorus Ratio, PTH, and Bone Health
Low CO2 in Hypothyroidism
High Estrogen and Heart Disease in Men
Thyroid Status and Cardiovascular Disease
Hypothyroidism and Shift in Death Patterns
A Cure for Heart Disease
Inflammatory TSH
Unsaturated Fats and Heart Damage
“Normal” TSH: Marker for Increased Risk of Fatal Coronary Heart Disease
Thyroid Insufficiency. Is Thyroxine the Only Valuable Drug?

“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.”

“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.”

“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.”

“Pregnant women sometimes develop very high blood pressure. In the 1950s, when new diuretics were being promoted by the drug companies, it became standard practice to give pregnant women diuretics and a low-salt diet to control their blood pressure. It should have been obvious (and it was obvious to people like Tom Brewer who thought physiologically, rather than mechanically) that the increase in pressure was the body’s response to an increased need for circulation. As the fetus grows, the blood volume must expand, to meet the increased circulatory needs of the uterus, placenta, and fetus. Two research projects showed that very large supplements of salt reliably normalized the high blood pressure in women with toxemia- of pregnancy. Other studies showed similar results with a supplement of progesterone. When the blood volume is able to expand as needed, circulation is adequate at normal pressure. When blood pressure is forced down by administering a diuretic to further diminish an already inadequate blood volume, the circulation of oxygen and nutrients to the fetus is seriously impaired, and a huge epidemic of mental retardation and hyperactivity, associated with low birthweight, began in the 1950s, and continued until eventually the fear of malpractice suits stopped the absurd practice.

A few years ago I asked a recently graduated physician what things he would want to consider in a patient with high blood pressure. Some of his suggestions for therapy were very reasonable, but his approach made it clear that he was thinking of circulation in a mechanical way, exactly as a skilled plumber would go about normalizing the circulation of water, without caring very much about what the water was being used for. The circulation of blood is nicely adjusted to meet the demands of the tissues. Blood pressure increases gradually with age, and individuals whose blood pressure stops increasing with age have been found to have a shorter life-expectancy than normal. Apparently, aged tissue is less efficient, and needs a needs a more strongly pumped stream of blood.”

“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 don’t 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.”

“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.”

“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.”

“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.”

“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.”

“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 understandingshock, 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.”

“In the 1950s, when the pharmaceutical industry was beginning topromote some new chemicals as diuretics to replace the traditional mercury compounds, Walter Kempner’s 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.”

“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.”

“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 preeclampsia 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 inanalogous 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).”

“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.”

“In hypothyroidism, thyrotropin-release hormone (TRH) is usually increased, increasing release of TSH. TRH itself can cause tachycardia, “palpitations,” high blood pressure, stasis of the intestine, increase of pressure in the eye, and hyperventilation with alkalosis. It can increase the release of norepinephrine, but in itself it acts very much like adrenalin. TRH stimulates prolactin release, and this can interfere with progesterone synthesis, which in itself affects heart function.”

“This is, to a great extent, the result of deliberate distortion by the drug industry of the issues involved. Beginning in the 1950s, the sale of new patented diuretics (replacing traditional diuretics) began in an atmosphere in which estrogen was being given to pregnant women, to prevent various complications of pregnancy (which in fact were caused by excessive estrogen). Excess estrogen as the cause of toxemia couldn’t be discussed openly, and the diuretics were sold as additional tools for controlling pregnancy-associated water retention, weight gain, high blood pressure, and damage to the fetus. Pregnant women were also told to diet to limit weight gain, and to sharply limit their consumption of salt. Estrogen, diuretics, salt restriction, and dieting were demonstrably all harmful to pregnant women and their babies, but they were imposed by the pharmaceutical medical establishment.”

“After a couple of years, I was satisfied that adequate protein and salt consistently prevented premenstrual edema. I read an article by some people who noticed that their patients who were on low sodium diets “for high blood pressure” very often developed insomnia. They knew that sodium restriction raised adrenalin levels, so they took their patients off the low sodium diet, and cured their insomnia.”

“Since vascular leakiness is involved in the inflammatory syndromes, as well as in shock, I
think it’s reasonable to treat them similarly, keeping in mind the importance of normal blood volume and viscosity. Sodium and sugar help to lower adrenaline, and so they can make a contribution to preventing high blood pressure, while maintaining normal hydration of the blood.”

“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 vohune 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 appean; 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.”

“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.”

“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.”

“In 1973 (in my book, Mind and Tissue) I reviewed old studies of cellular inhibition, which distinguished between the naturally quiet resting state of energized cells, and the state of protective inhibition, which prevents Injury or death from overstimutation and fatigue. In our “establishment physiology,” there has been no coherent theory on cellular inhibition, which means that cellular activity could hardly be understood correctly, either. Most of the facts are known, but they have seldom been put together in meaningful patterns, which would let us see that a few simple principles govern a great range of disturbing phenomena: seizures, shock, hypertension, fibrillation, cramps, restless legs, coma, insomnia, obsessive thinking, migraine, hyperactivity, even cell death and aging.”

“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.”

“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.”

“The use of antiserotonin drugs in alleviating stroke, hypertension, heart failure, diabetes, depression, obesity, rheumatoid arthritis, lupus (SLE), fibrosis, wheezing, and migraine suggests the importance of hyperserotonemia in causing disease.”

“Preeclampsia, or a syndrome of pregnancy induced hypertension, occurs in about 10% of
pregnancies, and it’s the main cause of maternal death and sickness of the newborn.

Thomas Brewer, about 50 years ago, made it clear that a protein deficiency is the main cause of preeclampsia. Protein deficiency causes a general inflammatory condition, with increased serotonin:”

“Aging, shock, hypertension, cancer, heart failure, and many other biological problems involve edema as a central factor, and relieving the edema is probably an essential part of solving those problems.”

“Shock, pneumonia, and hypertension are among the consequences of edema. Understanding edema is essential for understanding stress, for preventing stress induced sickness, and for resuscitation.”

“In the premenstrual syndrome, as in pregnancy, a progesterone deficiency can cause
generalized edema. Tom Brewer, who founded the Society for the Protection of the Unborn
through Nutrion, and S. Shanklin and J. Hodin, in Maternal Nutrition and Child Health, argued that salt restriction, expecially when combined with diuretics and a diet without adequate protein, caused exaggerated edema in pregnancy, producing a great risk of hypertension by reducing the blood volume needed for adequate perfusion of the kidneys, and damaged the development of the fetus, because of inadequate blood perfusion of the uterus and placenta.”

“Recently, a British physician, from Mongolia or northern China, studied the incidence of hypertension in her native region, where people consume at least 30 grams of salt per day. She found no hypertension at all, even among the oldest people. In my experiments, it has taken the body only two or three days to adjust completely to a massive change in salt consumption. Many hormones adjust quickly to retain or release sodium, according to the amount consumed, if the person is otherwise well nourished. Hypothyroid people, however, are unable to maintain a normal sodium concentration in their body fluids even when they increase their salt consumption.”

“Thyroid, progesterone, protein, and salt are powerful defenses against all sorts of stress associated symptoms, including hot flashes, insomnia, cramps, PMS, edema, toxemia of pregnancy, low-birth-weight babies, epilepsy, heart diseases, hypertension, strokes, migraine, inflammatory diseases hypoglycemia, fatigue and depression. The first approach to an appropriate diet would be to use at least a quart of milk and a quart of orange juice daily, well salted chicken broth, and frequent snacks, especially salty foods.”

“The “metabolic syndrome,” that involves diabetes, hypertension, and obesity, is associated
with high PTH (Ahlstrom, et al., 2009; Hjelmesaeth, et al., 2009).”

“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.”

“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.”

“Premenstrual syndrome, preeclampsia or pregnancy hypertension, congestive heart failure, brain swelling and seizures all involve disturbances of salt and water regulation, but the mechanical medical tradition has almost always substituted beliefs for facts.

Because of beliefs about cell physiology, most medical publications have argued for sodium
restriction in those situations, but the evidence is clear that inadequate salt retention is usually their outstanding pathological feature.

Progesterone has been an effective treatment in all of those conditions, and it increases the ability of the kidneys to retain sodium.”

“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 19505 who said that since women with toxemia have hypertension and edema, they should be treated with a diuretic and a low saIt diet, to eliminate water and to reduce blood pressure.”

“The increase of adrenalin, caused by a deficiency of sodium, is one ofthe factors that can
increase blood pressure; if the tissues’s glycogen stores are depleted, the adreoaJin 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.”

“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.”

“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 hannfu1 treatments are introduced. That ideology prevents a comprehensive and rational approach to the prohlems of stress and aging.”

“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.”

“”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.”

“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 E’s 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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“Tom Brewer demonstrated the importance of eating enough salt during pregnancy, to maintain adequate blood volume. When salt is restricted during pregnancy, the inadequate blood volume doesn’t carry enough oxygen and food to the uterus to allow full development of the baby, and the kidneys secrete a hormone to increase the circulation, creating a tendency toward high blood pressure. Following Brewer’s research, I saw that extra sodium should help in other situations involving circulatory inefficiency. Premenstrual edema, insomnia, and even high blood pressure often respond very well to a little extra sodium in the diet. One of the most important effects of sodium is that it tends to spare magnesium. which is likely to be lost during stress and hypothyroidism. If we eat salty foods when we crave them, we are able to retain our magnesium more easily. Sodium also helps to regulate blood sugar, for example by improving its absorption from the intestine. There is even evidence that sodium can spare protein, since, if there isn’t enough sodium to excrete into the urine to balance acids, the kidneys will waste protein to produce ammonium as an ionic substitute for sodium. But I think the most important point to remember is that it is essential for mainting adequate blood volume, and that it is almost always unphysiological and irrational to restrict sodium intake, because reduced blood volume tends to reduce the delivery of oxygen and nutrients to all tissues, leading to many problems. The emotional tension many people feel when they crave salt is, in some cases, the result of increased adrenaIin, reflecting a real biological problem.”

“Part of the reason for the common medical disbelief in the efficacy of vitamin E is that it doesn’t work like a drug – a big dose doesn’t immediately force the blood pressure down. Sometimes, in fact, the first effect is to strengthen a damaged heart, raising the blood pressure for a few days. But it does eventually remove many of the causes of high blood pressure, and I have never seen it fail to lower high blood pressure.”

“Other vitamins that can improve circulation by opening the small blood vessels are folic acid and niacin. Vitamin C can help to eliminate toxins that could contribute to high blood pressure.”

“The fact that estrogen , acting as an antagonist to vitamin E, could promote high blood pressure had distracted my attention from the opposite effect, being produced by an antagonism to thyroxin.”

“According to Barnes, nearly all hypertension can be helped with thyroid.”

“Since thyroxine potentiates adrenalin, which maintains blood pressure, excess’ estrogen. antagonizing thyroid, could tend to lower blood pressure through this system . The thermogenic effect of progesterone might act by way of thyroxin: if so, it might be the best way of counteracting estrogen and promoting thyroxin activity. The opposite reaction to high estrogen-low thyroid is also known to occur: an elevation of brain catecholamines and also an elevation of blood pressure. Thus a thyroid supplement can often correct hypertension, as well as hypotension.”

Posted in General.

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Serotonin and Melatonin Lower Progesterone

Also see:
Melatonin Lowers Body Temperature
Tryptophan, Sleep, and Depression
Carbohydrate Lowers Free Tryptophan
Gelatin > Whey
Serotonin, Fatigue, Training, and Performance
Gelatin, Glycine, and Metabolism
Whey, Tryptophan, & Serotonin
Tryptophan Metabolism: Effects of Progesterone, Estrogen, and PUFA

In 1994 A.V. Sirotkin found that melatonin inhibits progesterone production but stimulates estrogen production, and it’s 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. -Ray Peat, PhD

Although melatonin sometimes antagonizes serotonin in a protective way, in itself it can lower body temperature and alertness, suppressing thyroid and progesterone. (Sirotkin, 1997) -Ray Peat, PhD

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.
The direct influence of indoleamines on ovarian peptide hormones and growth factor secretion, in contrast to steroidogenesis, is yet to be thoroughly investigated. The aim of our in vitro experiments was to investigate the influence of melatonin and serotonin (5-hydroxy-tryptamine) (0.01-10 micrograms/ml) on the release of insulin-like growth factor-I (IGF-I), oxytocin and progesterone by cultured human granulosa cells. It was observed that both melatonin and serotonin stimulate IGF-I release. Melatonin also stimulated oxytocin output. Serotonin increased oxytocin secretion only at the highest dose (10 micrograms/ml). Both melatonin and serotonin were potent inhibitors of progesterone release. The present results suggest a possible involvement of the indoleamines melatonin and serotonin in the direct regulation of growth factor, nonapeptide and steroid hormone secretion by human ovarian cells.

Posted in General.

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Resuscitation: Benefits of ATP, Glucose, and Sodium

Also see:
ATP Regulates Cell Water
Arachidonic Acid’s Role in Stress and Shock
Lactate Paradox: High Altitude and Exercise
Trauma & Resuscitation: Toxicity of Lactated Ringer’s Solution
Sodium Deficiency and Stress

“I have written previously about several dramatically effective treatments for shock that were developed in the last fifty years–for example intravenous ATP, concentrated solutions of sodium chloride or glucose, and the morphine/endorphin-blocker, naloxone. Theoretical reasons have kept some of these techniques from being used as widely as would be appropriate, but gradually the success of the methods is forcing some people to rethink their theories.” -Ray Peat, PhD

“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.” -Ray Peat, PhD

Am J Physiol. 1980 Nov;239(5):H664-73.
Hyperosmotic NaCl and severe hemorrhagic shock.
Velasco IT, Pontieri V, Rocha e Silva M Jr, Lopes OU.
Intravenous infusions of highly concentrated NaCl (2,400 mosmol/l; infused volume 4 ml/kg; equivalent to 10% of shed blood), given to lightly anesthetized dogs in severe hemorrhagic shock, rapidly restore blood pressure and acid base equilibrium toward normality. No appreciable plasma volume expansion occurs for at least 12 h, indicating that fluid shift into the vascular bed plays no essential role in this response. Initial effects wee sustained indefinitely; long term survival was 100%, compared to 0% for a similar group of controls treated with saline. Hemodynamic analysis of the effects of hyperosmotic NaCl showed that these infusions substantially increase mean and pulse arterial pressure, cardiac output and mesenteric flow, whereas heart rate was slightly diminished. These effects immediately follow infusions with no tendency to dissipate with time (6-h observation). We conclude that hyperosmotic NaCl infusions increase the dynamic efficiency of the circulatory system, enabling it to adequately handle oxygen supply and metabolite clearance, despite a critical reduction of blood volume.

Am J Physiol. 1987 Oct;253(4 Pt 2):H751-62.
Hyperosmotic sodium salts reverse severe hemorrhagic shock: other solutes do not.
Rocha e Silva M, Velasco IT, Nogueira da Silva RI, Oliveira MA, Negraes GA, Oliveira MA.
Severe hemorrhage in pentobarbital-anesthetized dogs (25 mg/kg) is reversed by intravenous NaCl (4 ml/kg, 2,400 mosmol/l, 98% long-term survival). This paper compares survival rates and hemodynamic and metabolic effects of hypertonic NaCl with sodium salts (acetate, bicarbonate, and nitrate), chlorides [lithium and tris(hydroxymethyl)aminomethane (Tris)], and nonelectrolytes (glucose, mannitol, and urea) after severe hemorrhage (44.5 +/- 2.3 ml/kg blood loss). Sodium salts had higher survival rates (chloride, 100%; acetate, 72%; bicarbonate, 61%; nitrate, 55%) with normal stable arterial pressure after chloride and nitrate; near normal cardiac output after sodium chloride; normal acid-base equilibrium after all sodium salts; and normal mean circulatory filling pressure after chloride, acetate, and bicarbonate. Chlorides and nonelectrolytes produced low survival rates (glucose and lithium, 5%; mannitol, 11%; Tris, 22%; urea, 33%) with low cardiac output, low mean circulatory filling pressure, and severe metabolic acidosis. Plasma sodium, plasma bicarbonate, mean circulatory filling pressure, cardiac output, and arterial pressure correlated significantly with survival; other parameters, including plasma volume expansion or plasma osmolarity, did not. It is proposed that high plasma sodium is essential for survival.

Am J Physiol. 1981 Dec;241(6):H883-90.
Hyperosmotic NaCl and severe hemorrhagic shock: role of the innervated lung.
Lopes OU, Pontieri V, Rocha e Silva M Jr, Velasco IT
Infusions of hyperosmotic NaCl (2,400 mosmol/l; 4 ml/kg) were given to dogs in severe hemorrhagic hypotension by intravenous injection (72 expts) or intra-aortic injection (25 expts). In 46 experiments intravenous infusions were given during bilateral blockage of the cervical vagal trunks (local anesthesia or cooling). Intravenous infusions (without vagal blockade) restore arterial pressure, cardiac output, and acid-base equilibrium to normal and cause mesenteric flow to overshoot prehemorrhage levels by 50%. These effects are stable, and indefinite survival was observed in every case. Intra-aortic infusions of hyperosmotic NaCl produce only a transient recovery of arterial pressure and cardiac output but no long-term survival. Intravenous infusions with vagal blockage produce only a transient recovery of cardiac output, with non long-term survival. Measurement of pulmonary artery blood osmolarity during and after the infusions shows that a different pattern is observed in each of these three groups and strongly indicates that the first passage of hyperosmotic blood through the pulmonary circulation at a time when vagal conduction is unimpaired is essential for the production of the full hemodynamic-metabolic response, which is needed for indefinite survival.

Crit Care Med. 1992 Feb;20(2):200-10.
Resuscitation of intraoperative hypovolemia: a comparison of normal saline and hyperosmotic/hyperoncotic solutions in swine.
Pascual JM, Watson JC, Runyon AE, Wade CE, Kramer GC.
Abstract
BACKGROUND AND METHODS:
We compared a hypertonic saline-dextran solution (7.5% NaCl/6% dextran-70) with 0.9% NaCl (normal saline) for treatment of intraoperative hypovolemia. Fourteen anesthetized pigs (mean weight 36.3 +/- 2.1 kg) underwent thoracotomy, followed by hemorrhage for 1 hr to reduce mean arterial pressure to 45 mm Hg. A continuous infusion of either solution was then initiated and the flow rate was adjusted to restore and maintain aortic blood flow at baseline levels for 2 hrs.
RESULTS:
Full resuscitation to initial values of aortic blood flow was achieved with both regimens, but the normal saline group required substantially larger volumes and sodium loads to maintain stable hemodynamic values. Normal saline resuscitation produced increases in right ventricular preload (central venous pressure) and afterload (pulmonary arterial pressure and pulmonary vascular resistance), resulting in increased right ventricular work.
CONCLUSIONS:
Hypertonic saline-dextran solution resuscitation of intraoperative hypovolemia is performed effectively with smaller fluid and sodium loads, and is devoid of the deleterious effects associated with fluid accumulation induced by a conventional isotonic solution regimen.

Lancet. 1980 Nov 8;2(8202):1002-4.
Treatment of refractory hypovolaemic shock by 7.5% sodium chloride injections.
de Felippe J Jr, Timoner J, Velasco IT, Lopes OU, Rocha-e-Silva M Jr.
Injections of hyperosmotic (7.5%) sodium chloride (100-400 ml) were given to 12 patients in terminal hypovolaemic shock who had not responded to vigorous volume replacement and corticosteroid and dopamine infusions. Hyperosmotic sodium chloride promptly reversed the shock in 11 of these patients. The immediate effects of the NaCl injections were a moderate rise in arterial pressure, the resumption of urine flow, and recovery of consciousness. These effects tended to persist for a few hours. The hyperosmotic infusion also reduced isosmotic fluid requirement by 90%.

J Trauma. 1994 Mar;36(3):323-30.
A review of the efficacy and safety of 7.5% NaCl/6% dextran 70 in experimental animals and in humans.
Dubick MA, Wade CE.
Recent years have seen a renewed interest in the use of hypertonic-hyperoncotic solutions as plasma volume expanders for the treatment of hemorrhagic hypotension. In particular, a number of studies in experimental animals have addressed the efficacy and safety of small-volume infusions of 7.5% NaCl/6% dextran 70 (HSD). Employing models of fixed volume or fixed pressure hemorrhage, HSD has improved survival and reversed many of the hemodynamic, hormonal, and metabolic abnormalities associated with hemorrhagic shock. In the few human field trials completed to date, HSD has been shown to be potentially beneficial in hypotensive trauma patients who require surgery or have concomitant head injury. Extensive toxicologic evaluations and lack of reports of adverse effects in the human trials indicate that, at the proposed therapeutic dose of 4 mL/kg, HSD should present little risk.

Medicina (B Aires). 1998;58(4):393-402.
Hypertonic saline resuscitation.
Rocha e Silva M.
Treatment of severe hemorrhage offers few theoretical problems, but in practice, severe blood loss usually occurs out of hospital, often in more or less inaccessible scenarios. Controversy rages over ideal fluid, ideal volume, and minimum O2 carrying capacity, but all agree that pre-hospital, isotonic resuscitation is unfeasible. The effects of highly hypertonic 7.5% NaCl (HS) was first described in 1980, when we showed that it induced immediate and long lasting hemodynamic restoration. The addition of 6% dextran-70 to (HSD) significantly enhances the duration and intensity of volume expansion, with no loss of hemodynamic effects. HS/HSD restores cardiac output, arterial pressure, base excess and oxygen availability, induce pre-capillary vasodialtion, moderate hyperosmolarity and hypernatremia, reversal of high glucose and lactate. It interferes with endocrine secretions when administered to animals in hemorrhagic hypotension. HS acts through transient plasma volume expansion, positive inotropic effect on cardiac contractility, precapillary vasodilation through a direct action on vascular smooth muscle. Expansion of circulating volume is part of the mechanism, the extra volume coming from the intracellular compartment fluid, especially from endothelial and red blood cells, which facilitate microcirculatory flow. The new field of interactions of hypertonicity with the immune mechanisms may provide insight into the long lasting effects of hypertonic solutions. Randomized double blind prospective studies on the effects of HS, or HSD, used as first treatment of shock show that both are safe and free from collateral, toxic effects. These studies show an early significant rise in arterial blood pressure and a non-significant trend towards higher levels of survival. HSD administration to patients about to undergo cardiopulmonary bypass for cardiac surgery results in higher cardiac output before, and immediately following cardiopulmonary bypass, as well as zero fluid balance.

Acta Anaesthesiol Scand. 1997 Jan;41(1 Pt 1):62-70.
Hyperosmotic-hyperoncotic solutions during abdominal aortic aneurysm (AAA) resection.
Christ F, Niklas M, Kreimeier U, Lauterjung L, Peter K, Messmer K.
A largely positive perioperative fluid balance during both elective and emergency abdominal aortic aneurysm repair (AAA) may put patients at risk of developing left ventricular failure and may thus contribute to morbidity. In the present paper we report on a prospective study using hyperosmotic-hyperonocotic solutions (HHS) infused during clamping of the aorta, for the prevention of declamping shock, and the associated reduction in perioperative fluid requirements. The major aim of this paper was to determine the efficacy of an HHS infusion when given over 20 minutes and to detect possible adverse effects of HHS. For perioperative fluid replacement 12 patients received crystalloid solutions with HHS [250 ml of 7.2% NaCl combined with either 6% Dextran (n = 3), 6% Hydroxyethylstarch (HES, n = 4) or 10% HES (n = 5)]. In 16 controls, crystalloids with 1000 ml of HES 10% were infused. Patients were invasively monitored and hemodynamic parameters frequently assessed during the operation, which were statistically analyzed in relation to the start of the fluid loading during clamping of the aorta. One patient showed an anaphylactoid reaction to HES, otherwise no side effects of HHS were observed during infusion (no hypotension, no pathological EKG changes). Plasma sodium and chloride concentration as well as osmolality rose resulting in an osmotic gradient and a desired intravascular volume expansion. Prior to declamping pulmonary capillary wedge pressure had increased to the desired value of > 13 mmHg and < 18 mmHg. Oxygen delivery was significantly elevated upon HHS and remained so post declamping, whereas no change was observed in controls. During clamping systemic vascular resistance was significantly decreased, but was unchanged in controls. The perioperative fluid balance of patients receiving HHS was 2471.0 +/- 948.6 ml, which was significantly less than + 3386.7 +/- 1247.9 ml of controls (P < 0.01). We suggest that HHS opens new perspectives in perioperative fluid management of both elective and emergency AAA repair, since hemodynamic parameters are improved and the overall fluid balance is less positive, thus decreasing the likelihood of edema formation. Moreover, the previously described positive microcirculatory effects of HHS may be particular beneficial in some high-risk patients.

Resuscitation. 1989;18 Suppl:S51-61.
Microcirculatory therapy in shock.
Messmer K, Kreimeier U.
The normal microvascular perfusion pattern is characterized by temporal and spatial variations of capillary flow. Local driving pressure, arteriolar vasomotion and endothelial cells are key-factors for local regulation of hydraulic resistance and fluid balance between the blood and tissue compartments. In shock, both the central and particularly the local mechanisms controlling microvascular perfusion are impaired. The microvascular perfusion pattern becomes permanently inhomogeneous due to lack of arteriolar vasomotion, changes of flow properties of blood, endothelial cell swelling and blood cell-endothelium interaction. Hence the objectives of primary shock therapy are to reestablish precapillary pressure, arteriolar vasomotion and to open the occluded microvascular pathways in order to reestablish the surface area needed for exchange of nutrients and drainage of waste product. These effects can not be achieved by vasoactive drugs, unless blood volume has been restored and blood fluidity improved by hemodilution. Whereas the necessary hemodilution can be achieved by conventional volume substitutes (colloids, crystalloids) restoration of vasomotion and reopening of narrowed capillaries can be obtained by small volume resuscitation using hyperosmotic/hyperoncotic salt dextran solution. The potential of this new concept for primary resuscitation and treatment of tissue ischemia is presently explored.

Am J Physiol. 1988 Sep;255(3 Pt 2):H629-37.
Dynamic fluid redistribution in hyperosmotic resuscitation of hypovolemic hemorrhage.
Mazzoni MC, Borgström P, Arfors KE, Intaglietta M.
A mathematical description of blood volume restoration after hemorrhage with resuscitative fluids, particularly hyperosmotic solutions, is presented. It is based on irreversible thermodynamic transport equations and known physiological data. The model shows that after a 20% hemorrhage, the rapid addition of a hypertonic (7.5% NaCl)-hyperoncotic (6% Dextran 70) solution amounting to one-seventh of the shed blood volume reestablishes blood volume within 1 min. Measurements of systemic hematocrit, hemoglobin concentration, and plasma osmolality taken from 13 experiments on anesthetized rabbits verify this prediction. The model shows that immediately after hyperosmotic infusion, water shifts into the plasma first from red blood cells and endothelium and then from the interstitium and tissue cells. The increase in blood volume is transitory; however, it occurs in a fraction of the time compared with isoosmotic fluids at the same infusion rate and is partially sustained by Dextran 70. We theorize that the concurrent hemodilution and endothelial cell shrinkage during hyperosmotic infusion lead to a decreased capillary hydraulic resistance, an effect that is even more significant in capillaries with swollen endothelium. Our results support the significant role of an osmotic mechanism during hyperosmotic resuscitation in quickly restoring blood volume with the added benefit of improved tissue perfusion.

Am J Physiol. 1977 Sep;233(3):R83-8.
Evidence for enhanced uptake of ATP by liver and kidney in hemorrhagic shock.
Chaudry IH, Sayeed MM, Baue AE
It has been shown that infusion of ATP-MgCl2 proved beneficial in the treatment of shock; however, it is not known whether this effect is due to improvement in the microcirculation or direct provision of energy or a combination of the above or other effects. To elucidate the mechanism of the salutary effect of ATP-MgCl2, we have now examined the in vitro uptake of ATP by liver and kidney of animals in shock. Rats were bled to a mean arterial pressure of 40 Torr and so maintained for 2 hrs. After the rats were killed, liver and kidney were removed and slices of tissue (0.3-0.5 mm thick) were incubated for 1 h in 1.0 ml of Krebs-HCO3 buffer containing 10 mM glucose, 5 mM MgCl2, and 5 mM [8-14C]ATP or 5 mM [8-14C]ADP, or 5 mM [8-14C]AMP, or 5 mM [8-14C]adenosine in 95% O2-5% CO2 and then homogenized. Tissue and medium samples were subjected to electrophoresis to separate and measure the various nucleotides. The uptake of [14C]ATP but not that of [14C]ADP or [14C]adenosine by liver and kidney slices from animals in shock was 2.5 times greater than the corresponding uptake by control slices. Thus, the beneficial effect of ATP-MgCl2 in shock could be due to provision of energy directly to tissue in which ATP levels were lowered.

Prog Clin Biol Res. 1989;299:19-31.
ATP-MgCl2 and liver blood flow following shock and ischemia.
Chaudry IH.
The information available indicates that following hepatic ischemia and reflow, there is decreased tissue ATP levels, decreased tissue and mitochondrial magnesium levels, and decreased mitochondrial capability. Associated with these changes are altered cellular functions. Administration of ATP-MgCl2 following ischemia significantly improves total and microcirculatory blood flow, tissue and mitochondrial magnesium levels, tissue ATP stores, cellular functions, and the survival of animals. In contrast to ATP-MgCl2, administration of ATP or MgCl2 alone after ischemia was ineffective in improving cellular functions and tissue and mitochondrial magnesium levels. ATP-MgCl2 therefore appears to be a promising adjunct to the treatment of shock and ischemia.

Magnesium. 1986;5(3-4):211-20.
The role of ATP-magnesium in ischemia and shock.
Chaudry IH, Clemens MG, Baue AE.
Although much is known about the role of Mg in cardiomyopathies of different etiology, very little is known about the changes in hepatic Mg levels following hemorrhagic shock or ischemia to the liver. Information available indicates that tissue and mitochondrial Mg levels may be altered following shock and ischemia and that such alterations may be responsible for the depressed cellular function during those conditions. MgCl2 administration following shock or ischemia was ineffective in improving tissue and mitochondrial Mg levels and cellular functions. Administration of ATP complexed with MgCl2, however, increased tissue and mitochondrial Mg levels, tissue ATP stores and cellular functions and proved beneficial for the survival of animals. ATP-MgCl2 administration also increased cardiac output while decreasing myocardial as well as total body O2 consumption. The potential mechanisms of the beneficial effects of ATP-MgCl2 are discussed. ATP-MgCl2 can be given safely to humans and it decreases myocardial O2 consumption and increases cardiac output without producing hypotension. A clinical trial of ATP-MgCl2 in patients with various adverse circulatory conditions is underway at our institution.

Surgery. 1975 Jun;77(6):833-40.
Evidence for enhanced uptake of adenosine triphosphate by muscle of animals in shock.
Chaudry IH, Sayeed MM, Baue AE.
Although it has been shown that infusion of adenosine triphosphate (ATP)-magnesium chloride (MgCl2) proved beneficial in the treatment of shock, it is not known whether this effect is due to improvement in the microcirculation or to direct provision of energy. In searching for the mechanism of this, we have now examined the in vitro uptake of ATP by soleus muscle of animals in shock. Rats were bled to a mean arterial pressure of 40 mm. Hg and so maintained for 2 hours. Following death the two soleus muscles from each animal were removed and incubated in Krebs-HCO3 buffer containing 10 mM. of glucose, 5 mM. (8–14C) of ATP, 5 mM. (8–14C) of ADP, or 0.5 mM. (8–14C) of adenosine, and 5 mM. of MgCl2 for 1 hour under an atmosphere of 95 percent O2 to 5 percent CO2. Following homogenization and centrifugation, samples of the muscle extract and the medium were subjected to electrophoresis to separate the various nucleotides. The concentrations of the several nucleotides in medium and muscle were calculated from the radioactivity observed in each fraction. The uptake of 14-C-ATP by muscles from animals in shock was three times greater than was the uptake by control muscles. This leads us to conclude that the beneficial effect of ATP-MgCl2 to animals in shock could be due to provision of energy directly to tissues in which ATP levels were lowered

Surgery. 1966 Jan;59(1):66-75.
Protective effect of ATP in experimental hemorrhagic shock.
Sharma GP, Eiseman B.

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Sodium Improves Premature Infant Development

Also see:
Sodium Deficiency in Pre-eclampsia
Nutrition and Brain Growth in Chick Embryos
PUFA, Development, and Allergy Incidence

“Sodium is required for cells to cells to absorb glucose and amino acids.

In the fetus and newborn baby, sodium promotes growth. Progesterone, sodium, and glucose are limiting factors in the growth of the baby’s brain; whey they are deficient, cells die instead of growing.

The fact is the sodium energizes. It helps to remove calcium from the cell, to produce ATP, and to promote absorption of glucose and amino acids.” -Ray Peat, PhD

Pediatr Nephrol. 1993 Dec;7(6):871-5.
The influence of sodium on growth in infancy.
Haycock GB.
Sodium (Na) is an important growth factor, stimulating cell proliferation and protein synthesis and increasing cell mass. Sodium chloride (NaCl) deprivation inhibits growth, as reflected by reduced body and brain weight, length, muscle and brain protein and RNA content and brain lipid content compared with controls. This is not due to deficiency of other nutrients since control and experimental diets were identical except for NaCl content. Subsequent NaCl supplementation restores growth velocity to control values but does not induce “catch-up” growth. In humans, salt loss causes growth failure and subsequent salt repletion improves growth. Preterm infants < 32 weeks’ gestation at birth are renal salt losers in the first 2 weeks of post-natal life and are vulnerable to hyponatraemia. This can be prevented by increasing Na intake, which also produces accelerated weight gain that persists beyond the period of supplementation. Early nutrition in preterm infants can affect subsequent growth and also cognitive function: this is probably multifactorial, but NaCl intake differed substantially between study groups and is likely to be an important factor. The mechanism whereby Na promotes cell growth is not understood, but stimulation of the membrane Na+,H(+)-antiporter with alkalinization of the cell interior is a likely possibility.

Arch Dis Child Fetal Neonatal Ed. 2002 March; 86(2): F120–F123.
Effect of salt supplementation of newborn premature infants on neurodevelopmental outcome at 10–13 years of age
J Al-Dahhan, L Jannoun, and G Haycock
Background: The nutritional requirements of prematurely born infants are different from those of babies born at term. Inadequate or inappropriate dietary intake in the neonatal period may have long term adverse consequences on neurodevelopmental function. The late effect of neonatal sodium deficiency or repletion in the premature human infant on neurological development and function has not been examined, despite evidence in animals of a serious adverse effect of salt deprivation on growth of the central nervous system.
Methods: Thirty seven of 46 children who had been born prematurely (gestational age of 33 weeks or less) and allocated to diets containing 1–1.5 mmol sodium/day (unsupplemented) or 4–5 mmol sodium/day (supplemented) from the 4th to the 14th postnatal day were recalled at the age of 10–13 years. Detailed studies of neurodevelopmental performance were made, including motor function and assessment of intelligence (IQ), memory and learning, language and executive skills, and behaviour. Sixteen of the children were found to have been in the supplemented group and 21 in the unsupplemented group.
Results: Children who had been in the supplemented group performed better in all modalities tested than those from the unsupplemented group. The differences were statistically significant (analysis of variance) for motor function, performance IQ, the general memory index, and behaviour as assessed by the children’s parents. The supplemented children outperformed the unsupplemented controls by 10% in all three components of the memory and learning tests (difference not significant but p < 0.1 for each) and in language function (p < 0.05 for object naming) and educational attainment (p < 0.05 for arithmetic age).
Conclusions: Infants born at or before 33 weeks gestation require a higher sodium intake in the first two weeks of postnatal life than those born at or near term, and failure to provide such an intake (4–5 mmol/day) may predispose to poor neurodevelopmental outcome in the second decade of life.

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Deep Barbell Squat, Strength, and Performance

J Strength Cond Res. 2012 Jul 12. [Epub ahead of print]
Effect of Squat Depth and Barbell Load on Relative Muscular Effort in Squatting.
Bryanton MA, Kennedy MD, Carey JP, Chiu LZ.
ABSTRACT: Resistance training is used to develop muscular strength and hypertrophy. Large muscle forces, in relation to the muscle’s maximum force generating ability, are required to elicit these adaptations. Previous biomechanical analyses of multi-joint resistance exercises provide estimates of muscle force but not relative muscular effort (RME). The purpose of this investigation was to determine the relative muscular effort (RME) during squat exercise. Specifically the effects of barbell load and squat depth on hip extensor, knee extensor and ankle plantar-flexor RME were examined. Ten strength-trained women performed squats (50-90% 1 RM) in a motion analysis laboratory to determine hip extensor, knee extensor and ankle plantar-flexor net joint moment (NJM). Maximum isometric strength in relation to joint angle for these muscle groups was also determined. RME was determined as the ratio of NJM to maximum voluntary torque matched for joint angle. Barbell load and squat depth had significant interaction effects on hip extensor, knee extensor and ankle plantar-flexor RME (p<0.05). Knee extensor RME increased with greater squat depth but not barbell load, whereas the opposite was found for the ankle plantar-flexors. Both greater squat depth and barbell load increased hip extensor RME. These data suggest training for the knee extensors can be performed with low relative intensities but require a deep squat depth. Heavier barbell loads are required to train the hip extensors and ankle plantar-flexors. In designing resistance training programs with multi-joint exercises, how external factors influence RME of different muscle groups should be considered to meet training objectives.

fps squat

J Strength Cond Res. 2012 Mar;26(3):772-6.
Are changes in maximal squat strength during preseason training reflected in changes in sprint performance in rugby league players?
Comfort P, Haigh A, Matthews MJ.
Because previous research has shown a relationship between maximal squat strength and sprint performance, this study aimed to determine if changes in maximal squat strength were reflected in sprint performance. Nineteen professional rugby league players (height = 1.84 ± 0.06 m, body mass [BM] = 96.2 ± 11.11 kg, 1 repetition maximum [1RM] = 170.6 ± 21.4 kg, 1RM/BM = 1.78 ± 0.27) conducted 1RM squat and sprint tests (5, 10, and 20 m) before and immediately after 8 weeks of preseason strength (4-week Mesocycle) and power (4-week Mesocycle) training. Both absolute and relative squat strength values showed significant increases after the training period (pre: 170.6 ± 21.4 kg, post: 200.8 ± 19.0 kg, p < 0.001; 1RM/BM pre: 1.78 ± 0.27 kg·kg(-1), post: 2.05 ± 0.21 kg·kg(-1), p < 0.001; respectively), which was reflected in the significantly faster sprint performances over 5 m (pre: 1.05 ± 0.06 seconds, post: 0.97 ± 0.05 seconds, p < 0.001), 10 m (pre: 1.78 ± 0.07 seconds, post: 1.65 ± 0.08 seconds, p < 0.001), and 20 m (pre: 3.03 ± 0.09 seconds, post: 2.85 ± 0.11 seconds, p < 0.001) posttraining. Whether the improvements in sprint performance came as a direct consequence of increased strength or whether both are a function of the strength and power mesocycles incorporated into the players’ preseason training is unclear. It is likely that the increased force production, noted via the increased squat performance, contributed to the improved sprint performances. To increase short sprint performance, athletes should, therefore, consider increasing maximal strength via the back squat.

J Strength Cond Res. 2012 Feb 15. [Epub ahead of print]
Influence of squatting depth on jumping performance.
Hartmann H, Wirth K, Klusemann M, Dalic J, Matuschek C, Schmidtbleicher D.
It is unclear if increases in one repetition maximum (1-RM) in quarter squats result in higher gains compared to full depth squats in isometric force production and vertical jump performance. The aim of the research projects was to compare the effects of different squat variants on the development of 1-RM and their transfer effects to Countermovement (CMJ) and Squat Jump (SJ) height, maximal voluntary contraction (MVC) and maximal rate of force development (MRFD). Twenty-three women and 36 men (mean age: 24.11±2.88) were parallelized into three groups based on their CMJ height: deep front squats (FSQ, n=20), deep back squats (BSQ, n=20) and quarter back squats (BSQ¼, n=19). In addition a control group (C, n=16) existed (mean age: 24.38±0.50). Experimental groups trained 2 d·wk for 10 weeks following a strength-power periodization, which produced significant (p≤0.05) gains of the specific squat 1-RM. FSQ and BSQ attained significant (p≤0.05) elevations in SJ and CMJ without any interaction effects between both groups (p≥0.05). BSQ¼ and C did not reveal any significant changes of SJ and CMJ. FSQ and BSQ had significantly higher SJ scores over C (p≤0.05). BSQ did not feature any significant group difference to BSQ¼ (p=0.116) in SJ, whereas FSQ showed a trend towards higher SJ heights over BSQ¼ (p=0.052). FSQ and BSQ presented significantly (p≤0.05) higher CMJ heights over BSQ¼ and C. Post-test in MVC and MRFD demonstrated no significant changes for BSQ. Significant declines in MRFD for FSQ in the right leg (p≤0.05) without any interaction effects for MVC and MRFD between both FSQ and BSQ were found. Training of BSQ¼ resulted in significantly (p≤0.05) lower RFD and MVC values in contrast to FSQ and BSQ. Quarter squat training elicited significant (p≤0.05) transfer losses into the isometric maximal and explosive strength behavior. Our findings therefore contest the concept of superior angle specific transfer effects. Deep front and back squats guarantee performance-enhancing transfer effects of dynamic maximal strength to dynamic speed-strength capacity of hip and knee extensors compared to quarter squats.

A Comparison Of Muscular Activation During The Back Squat And Deadlift to the Countermovement Jump” (2011). Theses and Dissertations. Paper 1.
Robbins, David CSCS, NASM-CPT
The purpose of this study was to determine whether the back squat (BS) or deadlift (DL) is most similar to the countermovement jump (CMJ) in terms of peak muscular activation. The muscles assessed in this study were the erector spinae (ES), gluteus maximus (GM), biceps femoris (BF), vastus medialis (VM), and gastrocnemius (GN). These five muscles were chosen do to their involvement in all of these exercises. Ten college-aged males (24±1.18yrs) with a minimum of 1 year strength training experience volunteered for this study. Participants must have been strength trained and could BS and DL 1.5 x bodyweight. Results showed that only the peak muscular activation of the GN was significantly different (p<0.05) among all muscles between the BS (3.97mV) and CMJ (8.36mV). There were no significant differences between the DL (6.20mV) and CMJ in muscular activation. However when a Pearson Product Correlation was performed, the CMJ and DL showed a weak correlation among all muscles (ES=0.27, GM=0.42, BF=0.46, VM=0.45, GN=0.24). The CMJ and BS only showed a weak correlation among the ES, BF and GN (0.44, 0.22, and 0.32 respectively) and strong correlation for the GM and VM (r = 0.73, 0.77, respectively). This study suggests that in terms of peak muscular activation, the DL is more similar to the CMJ than the BS since no significant differences were found in muscular activation. However, muscle activation of the VM and GM during the BS was strongly correlated to the CMJ.

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Protective Altitude

Also see:
Lactate Paradox: High Altitude and Exercise
Carbon Dioxide as an Antioxidant
Altitude Improves T3 Levels
Protective Carbon Dioxide, Exercise, and Performance
Synergistic Effect of Creatine and Baking Soda on Performance
Ray Peat, PhD on Carbon Dioxide, Longevity, and Regeneration
Altitude Sickness: Therapeutic Effects of Acetazolamide and Carbon Dioxide

Quotes by Ray Peat, PhD:
“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.”

“K. P. Buteiko believed that increased carbon dioxide in the body fluids sometimes caused cancers to disappear. In many studies over the last 40 years (and the trend can also be seen in insurance statistics published in 1912), it is clear that cancer mortality is much lower at high altitude. Under all conditions studied, the characteristic lactic acid metabolism of stress and cancer is suppressed at high altitude, as respiration is made more efficient. The Haldane effect shows that carbon dioxide retention is increased at high altitude.

Studying athletes at sea level and at high altitude, it was seen that less lactic acid is produced by maximal exercise at high altitude than at sea level. Since oxygen deficiency in itself tends to cause the formation of lactic acid, this has been called the “lactate paradox”; the expectation was that more lactic acid would be formed, yet less was produced. Something was turning off the production of lactic acid. Normally, it is oxidative respiration that turns off glycolysis and lactic acid production, so that in exercise beyond the ability of the body to deliver oxygen, and in cancer with its respiratory defect, glycolysis produces lactic acid. So, something is happening at high altitude which turns off glycolysis.

The Haldane effect is a term for the fact that hemoglobin gives up oxygen in the presence of carbon dioxide, and releases carbon dioxide in the presence of oxygen. It is the increased retention of carbon dioxide that accounts for the “lactate paradox.” Carbon dioxide activates the Krebs cycle, but it also combines with ammonium, and in doing so, deactivates glycolysis because ammonium activates a regulatory enzyme. At high elevation, carbon dioxide is retained, and lactic acid formation is suppressed. (This is called the Pasteur effect, but altitude physiologists haven’t begun thinking in these directions.) Comparing very low altitude (Jordan valley, over 1000 feet below sea level) with moderate altitude (620 meters above sea level), ACTH was increased in runners after a race only at the low altitude, indicating that the stress reaction was prevented by a moderate increase of altitude. (el-Migdadi, et aI., 1996.)

The perspective we get on cancer, from the high altitude studies, allows us to go beyond the specific issue of cancer, to the more general issue of stress and regeneration. In outline, stress alters the physical nature of the cellular substance in a way that activates the cell, in which case it will either die from exhaustion, or grow into new cells. The replacement of injured cells means that mutations need not accumulate, and this renewal with elimination of mutant cells has been observed in sun-damaged skin. Among the many layers of form-generating and form-sustaining systems, the balance of electrical fields has a basic place.”

‎”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.”

Radiat Res. 1987 Nov;112(2):381-90.
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.

N Engl J Med. 1977 Mar 17;296(11):581-5.
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.

Circulation. 2009 Aug 11;120(6):495-501. Epub 2009 Jul 27.
Lower mortality from coronary heart disease and stroke at higher altitudes in Switzerland.
Faeh D, Gutzwiller F, Bopp M; Swiss National Cohort Study Group.
BACKGROUND:
Studies assessing the effect of altitude on cardiovascular disease have provided conflicting results. Most studies were limited because of the heterogeneity of the population, their ecological design, or both. In addition, effects of place of birth were rarely considered. Here, we examine mortality from coronary heart disease and stroke in relation to the altitude of the place of residence in 1990 and at birth.
METHODS AND RESULTS:
Mortality data from 1990 to 2000, sociodemographic information, and places of birth and residence in 1990 (men and women between 40 and 84 years of age living at altitudes of 259 to 1960 m) were obtained from the Swiss National Cohort, a longitudinal, census-based record linkage study. The 1.64 million German Swiss residents born in Switzerland provided 14.5 million person-years. Relative risks were calculated with multivariable Poisson regression. Mortality from coronary heart disease (-22% per 1000 m) and stroke (-12% per 1000 m) significantly decreased with increasing altitude. Being born at altitudes higher or lower than the place of residence was associated with lower or higher risk.
CONCLUSIONS:
The protective effect of living at higher altitude on coronary heart disease and stroke mortality was consistent and became stronger after adjustment for potential confounders. Being born at high altitude had an additional and independent beneficial effect on coronary heart disease mortality. The effect is unlikely to be due to classic cardiovascular disease risk factors and rather could be explained by factors related to climate.

Nephrol Dial Transplant. 2012 Jun;27(6):2411-7. Epub 2012 Jan 17.
Altitude and the risk of cardiovascular events in incident US dialysis patients.
Winkelmayer WC, Hurley MP, Liu J, Brookhart MA.
BACKGROUND:
Altitude is associated with all-cause mortality in US dialysis patients, but its association with cardiovascular outcomes has not been assessed. We hypothesized that higher altitude would be associated with lower rates of cardiovascular events due to an altered physiological response of dialysis patients to altitude induced hypoxia.
METHODS:
We studied 984,265 patients who initiated dialysis from 1995 to 2006. Patients were stratified by the mean elevation of their residential zip codes and were followed from the start of dialysis to the occurrence of several validated cardiovascular endpoints: myocardial infarction, stroke, cardiovascular death and a composite of these end points. Incidence rate ratios across altitude strata were estimated using proportional hazards regression.
RESULTS:
All outcomes occurred less frequently among patients living at higher altitude compared with patients living at or near sea level, and the association appeared monotonic for all outcomes except for stroke, which was most incident in the 250-1999 ft group. Compared with otherwise similar patients residing at or near sea level, patients living at ≥ 6000 ft had 31% [95% confidence interval (CI): 21-41%] lower rates of myocardial infarction, 27% (95% CI: 15-37%) lower rates of stroke and 19% (95% CI: 14-24%) lower rates of cardiovascular death. Additional adjustment for biometric information did not materially change these findings. Effect modification between race and altitude was only consistently significant for Native Americans. Altitude did not significantly alter the rates of non-cardiovascular death.
CONCLUSION:
We conclude that dialysis patients at higher altitude experience lower rates of cardiovascular events compared to otherwise similar patients at lower altitude.

Biull Eksp Biol Med. 1980 Apr;89(4):498-501.
[Morphologic characteristics of the hearts of argali continuously dwelling at high mountain altitudes].
[Article in Russian]
Zhaparov B, Kamitov SKh, Mirrakhimov MM.
The hearts of argali 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.

Biull Eksp Biol Med. 1976 Jun;81(6):729-32.
[Myocardial cell ultrastructure of yaks dwelling at high altitudes].
[Article in Russian]
Zhaparov B, Mirrakhimov MM.
The ultrastructure of myocardial cells of the left, right ventricle, and the ventricular septum was studied in the Altai and Pamir Yaks permanently living at the altitude of 3000-3600 m. Electron microscopic studies of myocardial cells revealed, along with the normal mitochondria, the ones with a peculiar structure of the cristae; these had the appearance of polyhedral wavy membranes in some groups of the mitochondria, and of polyhedral netted structures – in the others. Considerable accumulations of glycogen granules were found beneath the sarcolemma, in the perinuclear cytoplasmic zone and between the myofibrils. The results suggest that by undulating and creating a certain structural regularity the mitochondrial cristae increased their active area ensuring the efficacy of the mitochondrial function. Considerable accumulation of glycogen granules in the majority of myocardial cells seems to maintain the energy potential of the myocardium preventing the development of hypoxia.

Biull Eksp Biol Med. 1977 Jul;84(7):109-12.
[Change in the ultrastructure of rat myocardium under the influence of 12-months’ adaptation to high altitude].
[Article in Russian]
Zhaparov B, Mirrakhimov MM.
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.

Arkh Patol. 1981;43(2):66-71.
[Ultrastructural bases of myocardial metabolic disorders under physical loads in alpine adaptation].
[Article in Russian]
Kononova VA.
Ultrastructural and metabolic manifestations of adaptation mechanisms of myocardium of white rats were studied in highlands (Tuya-Ashu pass, 3200 meter above sea level) upon treatment with dosed physical loading. The development of processes of myocardial adaptation to highland hypoxia was found to be step-wise and manifested by the development of destructive and compensatory-adaptative processes. Physical loads in the early period of adaptation resulted in destruction and loss of mitochondria and other intracellular organelles. Prolonged effect of physical loads and hypoxia was accompanied by mobilization of protein synthesis, activation of metabolic enzymes and new formation of mitochondria and myofibrills.

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