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Potential Adverse Cardiovascular Effects from Excessive Endurance Exercise

Also see:
The Exercise Equivalent of a Cheeseburger? New Research Says Endurance Running May Damage Health
Can Endurance Sports Really Cause Harm? The Lipopolysaccharides of Endotoxemia and Their Effect on the Heart
Exercise Induced Stress
Exercise and Effect on Thyroid Hormone
Exercise Induced Menstrual Disorders
Ray Peat, PhD: Quotes Relating to Exercise
Ray Peat, PhD and Concentric Exercise
Running on Empty


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

Dr. James O’Keefe, Clinical Cardiologist from Saint Luke’s Mid America Heart Institute in Kansas City, Missouri, describes the risks and benefits of extreme endurance exercise, emphasizing the importance of moderation.

One Running Shoe in the Grave: New Studies on Older Endurance Athletes Suggest the Fittest Reap Few Health Benefits from The Wall Street Journal
Excessive Endurance Training Can Be Too Much of a Good Thing, Research Suggests from Science Daily

Mayo Clin Proc. 2012 Jun;87(6):587-95. doi: 10.1016/j.mayocp.2012.04.005.
Potential adverse cardiovascular effects from excessive endurance exercise.
O’Keefe JH, Patil HR, Lavie CJ, Magalski A, Vogel RA, McCullough PA.
A routine of regular exercise is highly effective for prevention and treatment of many common chronic diseases and improves cardiovascular (CV) health and longevity. However, long-term excessive endurance exercise may induce pathologic structural remodeling of the heart and large arteries. Emerging data suggest that chronic training for and competing in extreme endurance events such as marathons, ultramarathons, ironman distance triathlons, and very long distance bicycle races, can cause transient acute volume overload of the atria and right ventricle, with transient reductions in right ventricular ejection fraction and elevations of cardiac biomarkers, all of which return to normal within 1 week. Over months to years of repetitive injury, this process, in some individuals, may lead to patchy myocardial fibrosis, particularly in the atria, interventricular septum, and right ventricle, creating a substrate for atrial and ventricular arrhythmias. Additionally, long-term excessive sustained exercise may be associated with coronary artery calcification, diastolic dysfunction, and large-artery wall stiffening. However, this concept is still hypothetical and there is some inconsistency in the reported findings. Furthermore, lifelong vigorous exercisers generally have low mortality rates and excellent functional capacity. Notwithstanding, the hypothesis that long-term excessive endurance exercise may induce adverse CV remodeling warrants further investigation to identify at-risk individuals and formulate physical fitness regimens for conferring optimal CV health and longevity.

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By Team FPS – June 4, 2012

Ray Peat and Bud Weiss: The Biology of Carbon Dioxide (October 9, 2010)

Also see:
Master List – Ray Peat, PhD Interviews

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

In this video, Dr. Ray Peat discusses his alternative views on carbon dioxide as it relates to Biology. In his view, the health of the organism is governed by the stability and coherent functioning of its cells and tissues. Carbon dioxide, through a variety of biochemical reactions, is one of the chief agents of this stability. Rather than being a toxic metabolic afterthought, it is integral to health, emotional wellbeing and longevity.
Dr. Peat started his scientific career in the 70’s with Dr. Soderwall at the University of Oregon. He is a doctor of Biology who specializes in the physiology of organisms, with an emphasis on the energy and structure of living systems.

His notable influences cited in the video include: Dr. Gilbert Ling, William Koch, Albert Szent-Gyorgyi, Otto Warburg and Hans Selye. Other people mentioned include Swedenborg, J.C. Bose, William Blake, S.W. Stromp and Mae-Won Ho.

Ray Peat’s work may be found at his website, www.raypeat.com

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By Team FPS – June 4, 2012

Plant Toxins in Response to Stress

Also see:
Toxic Plant Estrogens
Carrageenan: A pseudo-latex allergy

Some plants have specific “pests,” such as insects, that have adapted to be resistant to that plant’s toxins, but if the plant and its predator are to survive, there has to be a balance between the plant tissue’s digestibility and its toxicity. Injury of a plant stimulates it to make increased amounts of its defensive chemicals. -Ray Peat, PhD

Science. 1972 May 5;176(4034):512-4.
Toxic substances in plants and the food habits of early man.
Leopold AC, Ardrey R.
The widespread occurrence of toxic substances in plants must have greatly restricted their usefulness as food for primitive man. The development of cooking of plant products is suggested to have been a major evolutionary advance, making a major increase in the vegetable materials palatable to man; this technical advantage apparently occurred only in the most recent 2 percent of the anthropological record.

I think far too little attention is being given to the effects of abnormal and stressful growth conditions on the plants’ natural defense systems. Plants normally synthesize some toxins and inhibitors of digestive enzymes to discourage attacks by bacteria, fungi, insects, and other predators. When a plant is injured or otherwise stressed, it produces more of the defensive substances, and very often they communicate their stress to other plants, and the resulting physiological changes can cause changes in seeds that affect the resistance of the progeny. (Agrawal, 2001). -Ray Peat, PhD in “Milk in context: allergies, ecology, and some myths”

Am Nat. 2001 May;157(5):555-69.
Transgenerational consequences of plant responses to herbivory: an adaptive maternal effect?
Agrawal AA.
Herbivory has many effects on plants, ranging from shifts in primary processes such as photosynthesis, growth, and phenology to effects on defense against subsequent herbivores and other species interactions. In this study, I investigated the effects of herbivory on seed and seedling characteristics of several families of wild radish (Raphanus raphanistrum) to test the hypothesis that herbivory may affect the quality of offspring and the resistance of offspring to plant parasites. Transgenerational effects of herbivory may represent adaptive maternal effects or factors that constrain or amplify natural selection on progeny. Caterpillar (Pieris rapae) herbivory to greenhouse-grown plants caused plants in some families to produce smaller seeds and those in other families to produce larger seeds compared with undamaged controls. Seed mass was positively associated with probability of emergence in the field. The number of setose trichomes, a putative plant defense, was higher in the progeny of damaged plants in some families and lower in the progeny of damaged plants in other families. In a field experiment, plant families varied in their resistance to several herbivores and pathogens as well as in growth rate and time to flowering. Seeds from damaged parent plants were more likely to become infested with a plant virus. Although herbivory on maternal plants did not directly affect interactions of offspring with other plant parasites, seed mass influenced plant resistance to several attackers. Thus, herbivory affected seed characters, which mediated interactions between plants and their parasites. Finally, irrespective of seed mass, herbivory on maternal plants influenced components of progeny fitness, which was dependent on plant family. Natural selection may act on plant responses to herbivory that affect seedling-parasite interactions and, ultimately, fitness.

“One of many substances produced by plants in response to injury is chitinase, an enzyme that breaks down chitin, a polysaccharide that is a structural component of fungi and insects. Chitinase, which is produced by bacteria and humans, as well as by plants and other organisms, is involved in developmental processes as well as in the innate immune system. In plants, the enzyme is induced by ethylene and salicylate, in animals by estrogen, light damage, and infections, and can be demonstrated in polyps and cancers.

 

The two main classes of plant allergens are the stress-induced chitinases, and seed storage proteins, such as gluten. The chitinase allergens are responsible for reactions to latex (which is secreted by rubber trees in reaction to a wound), bananas, avocados, many other fruits and vegetables, and some types of wood and other plant materials. Intensive agricultural methods are increasing the formation of the defensive chemicals, and the industrialized crops are responsible for the great majority of the new allergies that have appeared in the last 30 years.” -Ray Peat, PhD in “Milk in context: allergies, ecology, and some myths”

Kokuritsu Iyakuhin Shokuhin Eisei Kenkyusho Hokoku. 1998;(116):46-62.
[Plant defense-related proteins as latex allergens].
[Article in Japanese]
Yagami T.
Immediate-type allergic reactions to latex products made from natural rubber are called latex allergy. One of the notable features of latex-allergic people is their cross-reactivity to various vegetable foods and pollen. The structurally similar proteins which most kinds of plants potentially induce must be responsible for these cross-reactions. However, the taxonomical dissimilarity among the causative plants has kept us from concrete explanations of such cross-reactive allergens. We have speculated that plant defense-related proteins are a possible cause of the latex allergy. The well-known serologic relationships and sequence similarities of these ubiquitous plant proteins can explain the cross-reactivity without difficulty. Rubber trees cultured in plantation farms are repeatedly tapped and treated with phytohormones. These stresses would result in the significant induction of defense-related proteins. Indeed, we were able to detect defense-related enzymes in latex extracts. Moreover, three hydrolytic enzymes (beta-1,3-glucanase, chitinase/lysozyme, and carboxylesterase) that are very likely to take a defensive role were specifically recognized by the IgE antibodies of latex-allergic people and atopic patients. These experimental results strongly support our hypothesis. Because of their conserved structures, defense-related proteins should form a family of plant pan-allergens.

Clin Exp Allergy. 1999 May;29(5):673-80.
Isolation and characterization of major banana allergens: identification as fruit class I chitinases.
Sanchez-Monge R, Blanco C, Díaz-Perales A, Collada C, Carrillo T, Aragoncillo C, Salcedo G.
BACKGROUND:
Banana allergy has been associated with the latex-fruit syndrome. Several IgE-binding components, the relevant ones being proteins of 30-37-kDa, have been detected in banana fruit, but none of them have been isolated and characterized yet. Objective To purify and characterize the 30-37 kDa banana allergens.
METHODS:
Fifteen patients allergic to banana were selected on the grounds of a latex-allergic population. Prick by prick tests to this fruit were performed. Total and specific IgE to banana were determined. Banana allergens were isolated by affinity chromatography, followed by cation-exchange chromatography. Their characterization includes N-terminal sequencing, enzymatic activity assays, immunodetection with sera from allergic patients and with antichitinase antibodies, and CAP and immunoblot inhibition tests. Skin prick tests with banana extracts and with the purified allergens were also carried out.
RESULTS:
Two major IgE-binding proteins of 34 and 32 kDa, also recognized by polyclonal antibodies against chestnut chitinases, were immunodetected in crude banana extracts. Purification and characterization of both proteins have allowed their identification as class I chitinases with an hevein-like domain. Each isolated allergen reached inhibition values higher than 90% in CAP inhibition assays, and fully inhibited the IgE-binding by the crude banana extract when tested by an immunoblot inhibition method. The two purified allergens provoked positive skin prick test responses in more than 50% of the banana-allergic patients.
CONCLUSIONS:
Class I chitinases with an hevein-like domain are major allergens in banana fruit. Their presence in other fruits and nuts, such as avocado and chestnut, could explain the cross-sensitization among these foods.

J Allergy Clin Immunol. 1998 Mar;101(3):379-85.
Plant defense-related enzymes as latex antigens.
Yagami T, Sato M, Nakamura A, Komiyama T, Kitagawa K, Akasawa A, Ikezawa Z.
BACKGROUND:
Latex allergy is an increasing hazard to people who frequently come into contact with latex products. Of interest concerning this immediate-type allergy is the cross-reactivity to various vegetable foods and pollen. Despite its high prevalence, no adequate explanation has been provided for the cross-reactive antigens.
OBJECTIVE:
We have hypothesized that a series of plant defense-related proteins act as latex allergens, as well as vegetable food allergens. To evaluate this hypothesis, hydrolytic enzymes that are very likely to take on defensive roles in rubber trees were examined for their antigenicity.
METHODS:
By applying chromatographic procedures, defense-related enzymes were separated from nonammoniated latex (NAL). Their antigenicity was examined by immunoblotting and ELISA with sera containing IgE antibodies to crude latex proteins.
RESULTS:
Three kinds of hydrolytic enzymes (basic beta-1,3-glucanases [35, 36.5, and 38 kd], a basic chitinase/lysozyme [29.5 kd], and an acidic esterase [44 kd]) were separated from NAL. They were recognized by IgE antibodies from a significant number of patients allergic to latex. The basic beta-1,3-glucanases and the acidic esterase were also strongly recognized by IgE antibodies from several atopic subjects who were allergic to various vegetable foods rather than latex products.
CONCLUSION:
It was ascertained that the three defense-related enzymes separated from NAL constituted part of the latex antigens. Taking together the well-known serologic or immunologic relationships and amino acid sequence similarities of defense-related proteins coming from phylogenetically distant plant species, we can suspect their universal antigenicity and cross-reactivity.

Clin Exp Allergy. 2002 Mar;32(3):455-62.
Cloning and molecular characterization of the Hevea brasiliensis allergen Hev b 11, a class I chitinase.
O’Riordain G, Radauer C, Hoffmann-Sommergruber K, Adhami F, Peterbauer CK, Blanco C, Godnic-Cvar J, Scheiner O, Ebner C, Breiteneder H.
BACKGROUND:
In the last 10 years type-I allergy against proteins from Hevea brasiliensis latex has become an acknowledged medical issue. Fruit-allergic patients represent one risk group for developing latex allergy. Class I chitinases have been identified from chestnut, avocado and banana as relevant allergens. The chitin binding (hevein) domain from these class I chitinases has been postulated to bear the important IgE binding epitopes.
OBJECTIVE:
To clone the cDNA of an allergenic latex class I chitinase, to express the recombinant protein and to determine its IgE cross-reactivity with hevein (Hev b 6.02).
METHODS:
A full-length cDNA coding for a class I chitinase has been isolated from Hevea latex RNA by reverse transcription followed by PCR. The chitinase encoding sequence has been subcloned into the pMAL expression vector and expressed in E. coli as a fusion protein to maltose binding protein. The highly enriched recombinant protein fraction has been tested for its IgE binding capacity in immunoblots and ELISA. Furthermore, the pathogenesis-related function of the recombinant protein was tested in a fungal growth inhibition assay.
RESULTS:
The Hevea brasiliensis latex chitinase, designated Hev b 11, displays 70% identity to the endochitinase from avocado and its hevein-domain 58% to hevein (Hev b 6.02). The recombinant Hev b 11-maltose binding protein is recognized by latex- and fruit-allergic patients with IgE binding in both, ELISA and immunoblots. Pre-incubation of sera with rHev b 11-maltose binding protein showed an overall 16% inhibition of subsequent binding to rHev b 6.02-maltose binding protein on solid phase. The growth of F. oxysporum was inhibited in a dose dependent manner by addition of rHev b 11-maltose binding protein to the culture.
CONCLUSIONS:
Hev b 11, a class I chitinase, is another allergen from Hevea latex with a chitin binding domain and displays a different IgE binding capacity compared with hevein.

Biochem Soc Trans. 2002 Nov;30(Pt 6):935-40.
The latex-fruit syndrome.
Wagner S, Breiteneder H.
Approximately 30-50% of individuals who are allergic to natural rubber latex (NRL) show an associated hypersensitivity to some plant-derived foods, especially freshly consumed fruits. This association of latex allergy and allergy to plant-derived foods is called latex-fruit syndrome. An increasing number of plant sources, such as avocado, banana, chestnut, kiwi, peach, tomato, potato and bell pepper, have been associated with this syndrome. The prevailing hypothesis is that allergen cross-reactivity is due to IgE antibodies that recognize structurally similar epitopes on different proteins that are phylogenetically closely related or represent evolutionarily conserved structures. Several types of proteins have been identified to be involved in the latex-fruit syndrome. Two of these are plant defence proteins. Class I chitinases containing an N-terminal hevein-like domain cross-react with hevein (Hev b 6.02), a major IgE-binding allergen for patients allergic to NRL. A beta-1,3-glucanase was identified as an important latex allergen which shows cross-reactivity with proteins of bell pepper. Another important NRL allergen, Hev b 7, is a patatin-like protein that shows cross-reactivity with its analogous protein in potato. Furthermore, patients with allergy to plant-derived foods and associated pollinosis show a high frequency of IgE reactivity to the pan-allergen profilin, which may cause positive serum IgE determinations to NRL. Although there is much information about the plant-derived foods and some data about the allergens involved in the latex-fruit syndrome, it is not always clear whether latex sensitization precedes or follows the onset of food allergy.

Clin Exp Allergy. 2004 Nov;34(11):1739-46.
Characterization of cross-reactive bell pepper allergens involved in the latex-fruit syndrome.
Wagner S, Radauer C, Hafner C, Fuchs H, Jensen-Jarolim E, Wüthrich B, Scheiner O, Breiteneder H.
BACKGROUND:
Between 30% and 50% of individuals who are allergic to latex products are also allergic to specific plant foods, a fact that is well documented as the latex-fruit syndrome. Simultaneous sensitization to latex and bell pepper has been previously reported. Although bell pepper fruits are frequently consumed raw, cooked or as a spice, little is known about the cross-reactive allergens.
OBJECTIVE:
In this study we wished to identify bell pepper allergens involved in the latex-fruit syndrome.
METHODS:
Sera of four patients who displayed clinical symptoms to latex and bell pepper were used in immunoblot studies on protein extracts of three different cultivars of fresh bell pepper and fresh Hevea latex. Cross-reactive allergens were identified by inhibition experiments using recombinant Hev b 8 (latex profilin), and natural Hev b 2 (latex beta-1,3-glucanase) in addition to the protein extracts. A novel cross-reactive IgE-reactive 30 kDa protein was subjected to sequence analysis.
RESULTS:
Three patients displayed IgE to profilins from bell pepper fruits and latex. Two patients possessed IgE to Hev b 2, a latex beta-1,3-glucanase, and a homologous protein in bell pepper. One patient possessed IgE reactive with a protein of 30 kDa identified by N-terminal sequencing as an l-ascorbate peroxidase and another patient to a protein of 38 kDa. Additionally, IgE binding proteins in two higher molecular weight ranges showed cross-reactive capacities.
CONCLUSION:
Our findings show on the molecular level that bell pepper is part of the latex-fruit syndrome. For the first time we have identified the major latex allergen Hev b 2, a beta-1,3-glucanase, and the bell pepper l-ascorbate peroxidase as cross-reactive allergens. We were also able to show that profilins are responsible for some of the IgE cross-reactivity.

J Allergy Clin Immunol. 1999 Mar;103(3 Pt 1):507-13.
Class I chitinases as potential panallergens involved in the latex-fruit syndrome.
Blanco C, Diaz-Perales A, Collada C, Sánchez-Monge R, Aragoncillo C, Castillo R, Ortega N, Alvarez M, Carrillo T, Salcedo G.
BACKGROUND:
Latex-fruit cross-sensitization has been fully demonstrated. However, the antigens responsible for this “latex-fruit syndrome” have not been identified. We have recently shown that class I chitinases are relevant chestnut and avocado allergens.
OBJECTIVE:
We sought to evaluate the in vivo and in vitro reactions of purified chestnut and avocado chitinases in relation to the latex-fruit syndrome.
METHODS:
From a latex-allergic population, eighteen patients allergic to chestnut, avocado, or both were selected. Skin prick tests (SPTs) were performed with crude chestnut and avocado extracts, chitinase-enriched preparations, and purified class I and II chitinases from both fruits. CAP-inhibition assays with the crude extracts and purified proteins were carried out. Immunodetection with sera from patients with latex-fruit allergy and immunoblot inhibition tests with a latex extract were also performed. Eighteen subjects paired with our patients and 15 patients allergic to latex but not food were used as control groups.
RESULTS:
The chestnut class I chitinase elicited positive SPT responses in 13 of 18 patients with latex-fruit allergy (72%), and the avocado class I chitinase elicited positive responses in 12 of 18 (67%) similarly allergic patients. By contrast, class II enzymes without a hevein-like domain did not show SPT responses in the same patient group. Each isolated class I chitinase reached inhibition values higher than 85% in CAP inhibition assays against the corresponding food extract in solid phase. Immunodetection of the crude extracts and the purified class I chitinases revealed a single 32-kd band for both chestnut and avocado. Preincubation with a natural latex extract fully inhibited the IgE binding to the crude extracts, as well as to the purified chestnut and avocado class I chitinases.
CONCLUSION:
Chestnut and avocado class I chitinases with an N-terminal hevein-like domain are major allergens that cross-react with latex. Therefore they are probably the panallergens responsible for the latex-fruit syndrome.

Curr Opin Allergy Clin Immunol. 2001 Apr;1(2):177-83.
The role of plant panallergens in sensitization to natural rubber latex.
Salcedo G, Diaz-Perales A, Sanchez-Monge R.
Latex allergy represents an increasing occupational problem, mainly among healthcare workers. An association between latex allergy and hypersensitivity to some plant foods, particularly fruits (the latex-fruit syndrome), has been established. Class I chitinases with an N-terminal hevein-like domain from avocado, chestnut, banana and other foods, and latex hevein seem to be the allergens responsible for the cross-reactions involved in the latex-fruit syndrome. The potential role of other latex allergens, such as profilin, Hev b 5, Hev b 7 and beta-1,3-glucanases, in the co-sensitization to latex and plant foods is also discussed.

Curr Allergy Asthma Rep. 2003 Jan;3(1):47-53.
Latex-fruit syndrome.
Blanco C.
Natural rubber latex immunoglobulin E-mediated hypersensitivity is probably one of the most relevant challenges that has been faced in the treatment of allergies during recent years. Additionally, allergen cross-reactivity has arisen as another very important problem, in the difficulty in diagnosing it and in its clinical implications. It is clear that some latex allergens cross-react with plant-derived food allergens, the so-called latex-fruit syndrome, with evident clinical consequences. Although the foods most frequently involved are banana, avocado, kiwi, and chestnut, several others are also implicated. Investigations point to a group of defense-related plant proteins, class I chitinases, which cross-react with a major latex allergen, hevein, as the panallergens responsible for the syndrome. This review focuses on our current understanding of the latex-fruit syndrome.

J Am Diet Assoc. 2000 Nov;100(11):1381-4.
The latex and food allergy connection.
Perkin JE.
Natural rubber latex is used in the manufacture of many products in the United States. As natural rubber latex allergy becomes of increasing concern, dietitians need to have an understanding of this allergy and how it relates to workplace safety, employee health, and patient feeding and counseling. Natural rubber latex contains more than 35 proteins that may be related to Type I, Ig-E-mediated allergy in numerous segments of the population, including health care workers and patients. Many foods, especially chestnut, banana, and avocado, have the potential to cross-react with natural rubber latex. Chitinase enzymes, related to plant defense, are believed to be involved in this cross-reaction. A strong connection between food allergy and natural rubber latex allergy is recognized and described in this review.

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By Team FPS – June 3, 2012

Blood Pressure Management with Calcium & Dairy

Also see:
Hypertension and Calcium Deficiency
Calcium Paradox
Calcium to Phosphorus Ratio, PTH, and Bone Health
Low CO2 in Hypothyroidism

Nutr Rev. 2013 Mar;71(3):149-57. doi: 10.1111/nure.12017.
Dairy and blood pressure: a fresh look at the evidence.
Park KM, Cifelli CJ.

J Am Coll Nutr. 2009 Feb;28 Suppl 1:103S-19S.
Milk products, dietary patterns and blood pressure management.
Kris-Etherton PM, Grieger JA, Hilpert KF, West SG.

J Am Coll Nutr. 2009 Apr;28(2):142-9.
Effects of dairy products on intracellular calcium and blood pressure in adults with essential hypertension.
Hilpert KF, West SG, Bagshaw DM, Fishell V, Barnhart L, Lefevre M, Most MM, Zemel MB, Chow M, Hinderliter AL, Kris-Etherton PM.

Br J Nutr. 2009 Jan;101(1):59-67. Epub 2008 May 20.
Low-fat dairy products and blood pressure: follow-up of 2290 older persons at high cardiovascular risk participating in the PREDIMED study.
Toledo E, Delgado-Rodríguez M, Estruch R, Salas-Salvadó J, Corella D, Gomez-Gracia E, Fiol M, Lamuela-Raventós RM, Schröder H, Arós F, Ros E, Ruíz-Gutiérrez V, Lapetra J, Conde-Herrera M, Sáez G, Vinyoles E, Martínez-González MA.

Hypertension. 1994 Apr;23(4):513-30.
Dietary calcium and blood pressure in experimental models of hypertension. A review.
Hatton DC, McCarron DA.

Semin Nephrol. 1995 Nov;15(6):593-602.
Mechanisms of calcium’s effects on blood pressure.
Hatton DC, Yue Q, McCarron DA.

Br J Pharmacol. 1993 Apr;108(4):948-58.
Effects of high calcium diet on arterial smooth muscle function and electrolyte balance in mineralocorticoid-salt hypertensive rats.
Arvola P, Ruskoaho H, Pörsti I.

Br J Pharmacol. 1995 Aug;115(8):1455-62.
Dietary calcium and magnesium supplements in spontaneously hypertensive rats and isolated arterial reactivity.
Mäkynen H, Kähönen M, Arvola P, Wuorela H, Vapaatalo H, Pörsti I.

Am J Clin Nutr. 2009 Jun;89(6):1877-83. Epub 2009 Apr 15.
Inverse association between dairy intake and hypertension: the Rotterdam Study.
Engberink MF, Hendriksen MA, Schouten EG, van Rooij FJ, Hofman A, Witteman JC, Geleijnse JM.

Hypertension. 2008 Apr;51(4):1073-9. Epub 2008 Feb 7.
Dietary intake of dairy products, calcium, and vitamin D and the risk of hypertension in middle-aged and older women.
Wang L, Manson JE, Buring JE, Lee IM, Sesso HD.

J Hypertens. 2006 Apr;24(4):671-81.
Independent contribution of dairy products and calcium intake to blood pressure variations at a population level.
Ruidavets JB, Bongard V, Simon C, Dallongeville J, Ducimetière P, Arveiler D, Amouyel P, Bingham A, Ferrières J.

J Hum Hypertens. 2002 Feb;16(2):105-10.
A cross-sectional study on association of calcium intake with blood pressure in Japanese population.
Morikawa Y, Nakagawa H, Okayama A, Mikawa K, Sakata K, Miura K, Ishizaki M, Yoshita K, Naruse Y, Kagamimori S, Hashimoto T, Ueshima H.

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By Team FPS – June 3, 2012

Hypothyroidism, Intestinal Bacterial Overgrowth, & Lactose Intolerance

Also see:
Autoimmunity and Intestinal Flora
Lactose Intolerance, Starch, Fructose, Sucrose, & Thyroid Status
Ray Peat, PhD on the Benefits of the Raw Carrot
The effect of raw carrot on serum lipids and colon function
Protective Bamboo Shoots
Fermentable Carbohydrates, Anxiety, Aggression

Courtesy of Danny Roddy’s Work:
“The gastrointestinal tract is particularly sensitive to general stress. Loss of appetite is one of the first symptoms in the great “syndrome of just being sick,” and this may he accompanied by vomiting, diarrhea, or constipation.” – Hans Selye (The Stress of Life)

“In hypothyroidism, digestion in the stomach and intestines is delayed. The concentration of acid and enzymes involved in digestion may be diminished. Motility of the gut is reduced and food is propelled more slowly along the tract. Absorption through the intestinal wall is slower.” -Broda Barnes, MD, PhD

“The somewhat erratic digestion and absorption of food in the hypothyroid patient is one factor. Another is sluggishness of the liver, which may occur when thyroid function is low, with the result that stored glucose in the liver is not released properly as blood sugar begins to fall. There is usually an adequate store of glucose in the liver to last until the next regular meal but. if it is not released, hypoglycemia, or low blood sugar, may develop and call for extra food. Thyroid therapy improves digestion and absorption so that there is a more constant supply of nourishment in the blood; it also sensitizes the liver to the need for glucose release after digestion is complete.” -Broda Barnes, MD, PhD

Quote by Ray Peat, PhD:
“Bacterial overgrowth in the small intestine can be caused by hypothyroidism (Lauritano, et al., 2007), and the substances produced by these bacteria can damage the lining of the small intestine, causing the loss of lactase enzymes (Walshe, et al., 1990).”

“Once we accept Warburg’s thesis, that damaged respiration is the prime cause of cancer, the therapeutic use of thyroid in cancer seems obvious. Aging and estrogen-dominance are other states in which cells seem to be relatively insensitive to thyroid hormones. (Unsaturated fats are involved in resistance to thyroid, and promote the incidence of cancer in a variety of ways.) If the liver is a main site of T4′s conversion to T3, cancer patients may require very large doses of thyroid hormone, or else direct use of T3 (possibly in large doses), since the liver is so likely to be inefficient. Incidentally, thyroid’s ability to improve digestion and peristalsis is important for liver function; endotoxin absorbed from the intestine can be a serious burden to the liver, and it is known to cause a large increase in the blood estrogen level.”

“In hypothyroidism there is little stomach acid, and other digestive juices (and even intestinal movement) are in-adequate, so gas and constipation are common. Foods aren’t assimilated well, so even on a seemingly adequate diet there is ‘internal malnutrition.'”

“The absorption and retention of magnesium, sodium, and copper, and the synthesis of proteins, are usually poor in hypothyroidism. Salt craving is common in hypothyroidism, and eating additional sodium tends to raise the body temperature, and by decreasing the production of aldosterone, it helps to minimize the loss of magnesium, which in turn allows cells to respond better to the thyroid hormone. This is probably why a low sodium diet increases adrenalin production, and why eating enough sodium lowers adrenalin and improves sleep. The lowered adrenalin is also likely to improve intestinal motility.”

“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.”

“The upper part of the small intestine is sterile in healthy people. In the last 40 years, there has been increasing interest in the “contaminated small-bowel syndrome,” or the “small intestine bacterial overgrowth syndrome.” When peristalsis is reduced, for example by hypothyroidism, along with reduced secretion of digestive fluids, bacteria are able to thrive in the upper part of the intestine. Sugars are very quickly absorbed in the upper intestine, so starches and fibers normally provide most of the nourishment for bowel bacteria…Thyroid hormone increases digestive activity, including stomach acid and peristalsis, and both thyroid and progesterone increase the ability of the intestine to absorb sugars quickly; their deficiency can permit bacteria to live on sugars as well as starches.”

“Any starch can support the growth of toxic bacteria in the small intestine, where there should be no bacteria. Cocoa and the flour both contain starch and fiber that can stimulate bacteria and inflammation, but they are both very common allergens. The effects of a particular food can last for days or weeks”

J Clin Endocrinol Metab. 2007 Nov;92(11):4180-4. Epub 2007 Aug 14. Association between hypothyroidism and small intestinal bacterial overgrowth. Lauritano EC, Bilotta AL, Gabrielli M, Scarpellini E, Lupascu A, Laginestra A, Novi M, Sottili S, Serricchio M, Cammarota G, Gasbarrini G, Pontecorvi A, Gasbarrini A.
OBJECTIVES:
Small intestinal bacterial overgrowth is defined as an abnormally high bacterial population level in the small intestine. Intestinal motor dysfunction associated with hypothyroidism could predispose to bacterial overgrowth. Luminal bacteria could modulate gastrointestinal symptoms and interfere with levothyroxine absorption. The aims of the present study were to assess the prevalence and clinical pattern of bacterial overgrowth in patients with a history of overt hypothyroidism and the effects of bacterial overgrowth decontamination on thyroid hormone levels.
METHODS:
A total of 50 consecutive patients with a history of overt hypothyroidism due to autoimmune thyroiditis was enrolled. Diagnosis of bacterial overgrowth was based on positivity to a hydrogen glucose breath test. Bacterial overgrowth positive patients were treated with 1,200 mg rifaximin each day for a week. A glucose breath test, gastrointestinal symptoms, and thyroid hormone plasma levels were reassessed 1 month after treatment.
RESULTS:
A total of 27 patients with a history of hypothyroidism demonstrated a positive result to the breath test (27 of 50, 54%), compared with two in the control group (two of 40, 5%). The difference was statistically significant (P < 0.001). Abdominal discomfort, flatulence, and bloating were significantly more prevalent in the bacterial overgrowth positive group. These symptoms significantly improved after antibiotic decontamination. Thyroid hormone plasma levels were not significantly affected by successful bacterial overgrowth decontamination.
CONCLUSIONS:
The history of overt hypothyroidism is associated with bacterial overgrowth development. Excess bacteria could influence clinical gastrointestinal manifestations. Bacterial overgrowth decontamination is associated with improved gastrointestinal symptoms. However, fermenting carbohydrate luminal bacteria do not interfere with thyroid hormone levels.

Gut. 1990 Jul;31(7):770-6. Effects of an enteric anaerobic bacterial culture supernatant and deoxycholate on intestinal calcium absorption and disaccharidase activity. Walshe K, Healy MJ, Speekenbrink AB, Keane CT, Weir DG, O’Moore RR.
Fifty two strains of anaerobic bacteria isolated from the upper gut of patients with small intestinal bacterial overgrowth were screened for phospholipase activity. Bacteroides melaninogenicus spp intermedius had the greatest activity. The effects of culture supernatants of this organism and deoxycholate on intestinal calcium absorption and disaccharidase activity were studied using a rat closed loop model. The supernatant decreased the in vitro uptake of calcium by 15% (p less than 0.001). Deoxycholate reduced calcium uptake by 16% (p less than 0.001). Combined culture supernatant and deoxycholate reduced calcium uptake by 39% (p less than 0.001) suggesting a potentiation of supernatant activity by deoxycholate. Culture supernatant and deoxycholate, both alone and combined, significantly reduced lactase, sucrase, and maltase activity. Electron microscopic evidence showed degeneration of microvilli, disruption of mitochondrial structure, and swelling of the endoplasmic reticulum after exposure of the intestinal loops to the supernatant or deoxycholate.

Indian J Endocrinol Metab. 2014 May-Jun; 18(3): 307–309. Link between hypothyroidism and small intestinal bacterial overgrowth Anant D. Patil

Altered gastrointestinal (GI) motility is seen in many pathological conditions. Reduced motility is one of the risk factors for development of a small intestinal bacterial overgrowth (SIBO). Hypothyroidism is associated with altered GI motility. The aim of this article was to study the link between hypothyroidism, altered GI motility and development of SIBO. Published literature was reviewed to study the association of altered GI motility, SIBO and hypothyroidism. Altered GI motility leads to SIBO. SIBO is common in patients with hypothyroidism. Patients with chronic GI symptoms in hypothyroidism should be evaluated for the possibility of SIBO. Both antibiotics and probiotics have been studied and found to be effective in management of SIBO.

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By Team FPS – June 3, 2012

High Milk Protein Lowers Stress

“One of the reasons a lot of people give, if they have overcome the idea that milk forms mucous, or is a risk for diseases and so on; one of their arguments is that it makes them fat. But, all the research on animals, and as far as it goes, human research, shows that milk is probably the best reducing foods there is. The mechanisms for that are now known. Not only the anti-stress effects of casein, and a good balance of saturated fats and so on, but the calcium alone is very important metabolic regulator, that it happens to inhibit the fat-forming enzymes fatty acid synthase, and incidentally that’s a characteristic enzyme that goes wild in cancer. But calcium and milk inhibit that fatty acid synthase, reducing the formation of fats and at the same time it activates the uncoupling proteins in the mitochondria, which are associated with increased longevity. Because they, by increasing the metabolic rate, the uncoupling proteins burn calories faster but they protect against free-radical oxidation. That they pull the fuel through the oxidation process so fast in effect, that none of it goes astray in random oxidation, where if you inhibit your energy producing enzymes you tend to get random, stray oxidation that damage the mitochondria. So the uncoupling proteins burn calories faster, at the same time that your reducing fat synthesis and milk is, as far as I know, they only food does both of those things simultaneously.” -Ray Peat, PhD

Indian J Exp Biol. 2003 Apr;41(4):367-9.
Protection of adrenocortical activity by dietary casein in ether anaesthetized rats.
Biswas NM, Chattopadhyay A, Sarkar M.
Adrenal delta5-3beta-hydroxysteroid dehydrogenase (delta5-3beta-HSD) activity and serum corticosterone level were significantly higher in rats fed with 5% casein or 4% albumin diets after 1 hr of ether anaesthetic stress as compared to the controls, 5% casein and 20% casein (equivalent to 4% albumin) respectively. Ether anaesthesia to 20% casein fed rats caused no change in adrenal delta5-3beta-HSD activity and serum corticosterone level when compared with controls fed 20% casein diet. The results suggest that high milk protein diet may prevent acute stress effects by protecting adrenocortical activity. The present investigation opens up a new area of management of stress.

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By Team FPS – June 3, 2012

Autoimmunity, Thyroiditis, and Intestinal Flora

Also see:
Ray Peat, PhD on the Benefits of the Raw Carrot
How does estrogen enhance endotoxin toxicity? Let me count the ways.
Autoimmune Disease and Estrogen Connection
The effect of raw carrot on serum lipids and colon function
Protective Bamboo Shoots
Endotoxin: Poisoning from the Inside Out
Hypothyroidism, Intestinal Bacterial Overgrowth, & Lactose Intolerance

“Endotoxin or other materials absorbed from intestinal bacteria contributes to a variety of autoimmune problems, including thyroiditis (Penhale and Young, 1988). Combining 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.” -Ray Peat, PhD from “Thyroiditis. Some confusions and causes of “autoimmune disease””

Clin Exp Immunol. 1988 May;72(2):288-92.
The influence of the normal microbial flora on the susceptibility of rats to experimental autoimmune thyroiditis.
Penhale WJ, Young PR.
Female PVG/c strain rats maintained under specific pathogen-free conditions until weaning were found to be significantly less susceptible to the induction of autoimmune thyroiditis by thymectomy and irradiation than conventionally reared rats of the same strain. Other SPF-derived strains had a similarly low susceptibility, thus pointing to an important external factor influencing the induction of autoimmunity by this procedure. It was found that the oral administration of antibiotics followed by fresh, homogenized, intestinal contents obtained from conventionally reared rats to newly weaned SPF PVG/c rats significantly augmented their autoimmune susceptibility. The offspring of female SPF rats which had been treated in late pregnancy with oral antibiotics and conventional intestinal contents were similarly more susceptible than the offspring of non-treated counterparts. It is proposed that the composition of the normal gastrointestinal flora of conventionally reared rats profoundly influences susceptibility to the induction of autoimmune thyroiditis in this particular experimental model, possibly by antigenic cross-reactivity with thyroid tissue.

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By Team FPS – June 2, 2012

Ovarian Cysts

Also see:
Estrogen, Uterine Fibroids, and Thyroid Nodules
Quotes: Thyroid, Estrogen, Menstrual Symptoms, PMS, and Infertility
Autoimmune Disease and Estrogen Connection
Hormonal profiles in women with breast cancer
PUFA Increases Estrogen
PUFA Inhibit Glucuronidation
PUFA Promote Cancer
Maternal PUFA Intake Increases Breast Cancer Risk in Female Offspring
Vitamin A: Anti-Cancer and Anti-Estrogen
Toxic Plant Estrogens
The Dire Effects of Estrogen Pollution
Progesterone: Essential to Your Well-Being
Alcohol Consumption – Estrogen and Progesterone In Women
Estrogen, Endotoxin, and Alcohol-Induced Liver Injury
Estrogen Levels Increase with Age
Fat Tissue and Aging – Increased Estrogen
Estrogen Related to Loss of Fat Free Mass with Aging
Bisphenol A (BPA), Estrogen, and Diabetes
Shock Increases Estrogen

“Animal experiments show that lack of thyroid hormone can cause cystic ovaries.” -Ray Peat, PhD in “Nutrition for Women”

“Animals which are artificially made hypothyroid develop cystic ovaries, so it is reasonable to consider hypothyroidism as an important factor when women have cystic ovaries.” -Ray Peat, PhD

“In my own experience, no patient has required a hysterectomy for pathological bleeding unless uterine fibroids were present. If organic problems could be ruled out, as they could in the great majority of cases, thyroid deficiency usually could be detected and treatment with thyroid solved the problem. The need for other surgery may be minimized by adequate thyroid therapy in women with low thyroid function. Cysts on the ovary are common in such women and correction of the thyroid deficiency often eliminates the cysts. Fibroid tumors have been rare in hypothyroid women who have been maintained on adequate thyroid therapy. It is possible to produce fibroids in experimental animals by injection of estrogen, and there is evidence of excess of estrogen in hypothyroid women.” -Dr. Broda Barnes

Animal Reproduction Science Volume 39, Issue 2 , Pages 159-168, July 1995
The importance of thyroid hormone in experimental ovarian cyst formation in gilts
Remigiusz Fitko, Jan Kucharski, Beata Szlezyngier

The Anatomical Record Volume 90, Issue 2, pages 93–99, October 1944
Occurrence of follicular cysts in thyroidectomized rats treated with diethylstilbestrol
Ralph G. Janes

The Anatomical Record Volume 131, Issue 3, pages 487–499, July 1958
Hormonal influences on the gonadotrophin sensitive hypothyroid rat ovary
James H. Leathem

Proc Soc Exp Biol Med. 1991 Nov;198(2):737-41.
Circulating hormone concentrations in hypothyroid rats with induced polycystic ovaries.
Lee MT, Adams WC, Bruot BC.

Biol Reprod. 1986 Oct;35(3):542-8.
Hormonal changes during the early development of ovarian cysts in the rat.
Lee MT, Bruot BC, Adams WC.

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By Team FPS – May 31, 2012

Preventing Breast Cancer

Preventing Breast Cancer by John Gofman, MD

Alice Stewart: The woman who knew too much
Alice Mary Stewart
Alice Stewart, 95; Linked X-Rays to Diseases
Dr. Alice Stewart, Low-Level Radiation, and the Fetus
Book: The Woman Who Knew Too Much: Alice Stewart and the Secrets of Radiation
Inflammation from Radiation
Harm of Prenatal Exposure to Radiation
Caffeine and Skin Protection
Topical Vitamin E and ultraviolet radiation on human skin
Radiation and Growth – Ray Peat
Bone Density: First Do No Harm
Executive Summary, Radiation from Medical Procedures in the Pathogenesis of Cancer and Ischemic Heart Disease: Dose-Response Studies with Physicians per 100,000 Population
Quotes and more from Dr. John Gofman
John W. Gofman, 88, Scientist and Advocate for Nuclear Safety, Dies
Breast Cancer

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By Team FPS – May 29, 2012

Ben Goldacre: Battling bad science

Also see:
What Doctors Don’t Know About the Drugs They Prescribe

So I’m a doctor, but I kind of slipped sideways into research, and now I’m an epidemiologist. And nobody really knows what epidemiology is. Epidemiology is the science of how we know in the real world if something is good for you or bad for you. And it’s best understood through example as the science of those crazy, wacky newspaper headlines. And these are just some of the examples.

These are from the Daily Mail. Every country in the world has a newspaper like this. It has this bizarre, ongoing philosophical project of dividing all the inanimate objects in the world into the ones that either cause or prevent cancer. So here are some of the things they said cause cancer recently: divorce, Wi-Fi, toiletries and coffee. Here are some of the things they say prevents cancer: crusts, red pepper, licorice and coffee. So already you can see there are contradictions. Coffee both causes and prevents cancer. And as you start to read on, you can see that maybe there’s some kind of political valence behind some of this. So for women, housework prevents breast cancer, but for men, shopping could make you impotent. So we know that we need to start unpicking the science behind this.

And what I hope to show is that unpicking dodgy claims, unpicking the evidence behind dodgy claims, isn’t a kind of nasty carping activity; it’s socially useful, but it’s also an extremely valuable explanatory tool. Because real science is all about critically appraising the evidence for somebody else’s position. That’s what happens in academic journals. That’s what happens at academic conferences. The Q&A session after a post-op presents data is often a blood bath. And nobody minds that. We actively welcome it. It’s like a consenting intellectual S&M activity. So what I’m going to show you is all of the main things, all of the main features of my discipline — evidence-based medicine. And I will talk you through all of these and demonstrate how they work, exclusively using examples of people getting stuff wrong.

So we’ll start with the absolute weakest form of evidence known to man, and that is authority. In science, we don’t care how many letters you have after your name. In science, we want to know what your reasons are for believing something. How do you know that something is good for us or bad for us? But we’re also unimpressed by authority, because it’s so easy to contrive. This is somebody called Dr. Gillian McKeith Ph.D, or, to give her full medical title, Gillian McKeith. (Laughter) Again, every country has somebody like this. She is our TV diet guru. She has massive five series of prime-time television, giving out very lavish and exotic health advice. She, it turns out, has a non-accredited correspondence course Ph.D. from somewhere in America. She also boasts that she’s a certified professional member of the American Association of Nutritional Consultants, which sounds very glamorous and exciting. You get a certificate and everything. This one belongs to my dead cat Hetti. She was a horrible cat. You just go to the website, fill out the form, give them $60, and it arrives in the post. Now that’s not the only reason that we think this person is an idiot. She also goes and says things like, you should eat lots of dark green leaves, because they contain lots of chlorophyll, and that will really oxygenate your blood. And anybody who’s done school biology remembers that chlorophyll and chloroplasts only make oxygen in sunlight, and it’s quite dark in your bowels after you’ve eaten spinach.

Next, we need proper science, proper evidence. So, “Red wine can help prevent breast cancer.” This is a headline from the Daily Telegraph in the U.K. “A glass of red wine a day could help prevent breast cancer.” So you go and find this paper, and what you find is it is a real piece of science. It is a description of the changes in one enzyme when you drip a chemical extracted from some red grape skin onto some cancer cells in a dish on a bench in a laboratory somewhere. And that’s a really useful thing to describe in a scientific paper, but on the question of your own personal risk of getting breast cancer if you drink red wine, it tells you absolutely bugger all. Actually, it turns out that your risk of breast cancer actually increases slightly with every amount of alcohol that you drink. So what we want is studies in real human people.

And here’s another example. This is from Britain’s leading diet and nutritionist in the Daily Mirror, which is our second biggest selling newspaper. “An Australian study in 2001 found that olive oil in combination with fruits, vegetables and pulses offers measurable protection against skin wrinklings.” And then they give you advice: “If you eat olive oil and vegetables, you’ll have fewer skin wrinkles.” And they very helpfully tell you how to go and find the paper. So you go and find the paper, and what you find is an observational study. Obviously nobody has been able to go back to 1930, get all the people born in one maternity unit, and half of them eat lots of fruit and veg and olive oil, and then half of them eat McDonald’s, and then we see how many wrinkles you’ve got later.

You have to take a snapshot of how people are now. And what you find is, of course, people who eat veg and olive oil have fewer skin wrinkles. But that’s because people who eat fruit and veg and olive oil, they’re freaks, they’re not normal, they’re like you; they come to events like this. They are posh, they’re wealthy, they’re less likely to have outdoor jobs, they’re less likely to do manual labor, they have better social support, they’re less likely to smoke — so for a whole host of fascinating, interlocking social, political and cultural reasons, they are less likely to have skin wrinkles. That doesn’t mean that it’s the vegetables or the olive oil.

(Laughter)

So ideally what you want to do is a trial. And everybody thinks they’re very familiar with the idea of a trial. Trials are very old. The first trial was in the Bible — Daniel 1:12. It’s very straightforward — you take a bunch of people, you split them in half, you treat one group one way, you treat the other group the other way, and a little while later, you follow them up and see what happened to each of them. So I’m going to tell you about one trial, which is probably the most well-reported trial in the U.K. news media over the past decade. And this is the trial of fish oil pills. And the claim was fish oil pills improve school performance and behavior in mainstream children. And they said, “We’ve done a trial. All the previous trials were positive, and we know this one’s gonna be too.” That should always ring alarm bells. Because if you already know the answer to your trial, you shouldn’t be doing one. Either you’ve rigged it by design, or you’ve got enough data so there’s no need to randomize people anymore.

So this is what they were going to do in their trial. They were taking 3,000 children, they were going to give them all these huge fish oil pills, six of them a day, and then a year later, they were going to measure their school exam performance and compare their school exam performance against what they predicted their exam performance would have been if they hadn’t had the pills. Now can anybody spot a flaw in this design? And no professors of clinical trial methodology are allowed to answer this question. So there’s no control; there’s no control group. But that sounds really techie. That’s a technical term. The kids got the pills, and then their performance improved.

What else could it possibly be if it wasn’t the pills? They got older. We all develop over time. And of course, also there’s the placebo effect. The placebo effect is one of the most fascinating things in the whole of medicine. It’s not just about taking a pill, and your performance and your pain getting better. It’s about our beliefs and expectations. It’s about the cultural meaning of a treatment. And this has been demonstrated in a whole raft of fascinating studies comparing one kind of placebo against another. So we know, for example, that two sugar pills a day are a more effective treatment for getting rid of gastric ulcers than one sugar pill. Two sugar pills a day beats one sugar pill a day. And that’s an outrageous and ridiculous finding, but it’s true. We know from three different studies on three different types of pain that a saltwater injection is a more effective treatment for pain than taking a sugar pill, taking a dummy pill that has no medicine in it — not because the injection or the pills do anything physically to the body, but because an injection feels like a much more dramatic intervention. So we know that our beliefs and expectations can be manipulated, which is why we do trials where we control against a placebo — where one half of the people get the real treatment and the other half get placebo.

But that’s not enough. What I’ve just shown you are examples of the very simple and straightforward ways that journalists and food supplement pill peddlers and naturopaths can distort evidence for their own purposes. What I find really fascinating is that the pharmaceutical industry uses exactly the same kinds of tricks and devices, but slightly more sophisticated versions of them, in order to distort the evidence that they give to doctors and patients, and which we use to make vitally important decisions.

So firstly, trials against placebo: everybody thinks they know that a trial should be a comparison of your new drug against placebo. But actually in a lot of situations that’s wrong. Because often we already have a very good treatment that is currently available, so we don’t want to know that your alternative new treatment is better than nothing. We want to know that it’s better than the best currently available treatment that we have. And yet, repeatedly, you consistently see people doing trials still against placebo. And you can get license to bring your drug to market with only data showing that it’s better than nothing, which is useless for a doctor like me trying to make a decision.

But that’s not the only way you can rig your data. You can also rig your data by making the thing you compare your new drug against really rubbish. You can give the competing drug in too low a dose, so that people aren’t properly treated. You can give the competing drug in too high a dose, so that people get side effects. And this is exactly what happened which antipsychotic medication for schizophrenia. 20 years ago, a new generation of antipsychotic drugs were brought in and the promise was that they would have fewer side effects. So people set about doing trials of these new drugs against the old drugs, but they gave the old drugs in ridiculously high doses — 20 milligrams a day of haloperidol. And it’s a foregone conclusion, if you give a drug at that high a dose, that it will have more side effects and that your new drug will look better.

10 years ago, history repeated itself, interestingly, when risperidone, which was the first of the new-generation antipscyhotic drugs, came off copyright, so anybody could make copies. Everybody wanted to show that their drug was better than risperidone, so you see a bunch of trials comparing new antipsychotic drugs against risperidone at eight milligrams a day. Again, not an insane dose, not an illegal dose, but very much at the high end of normal. And so you’re bound to make your new drug look better. And so it’s no surprise that overall, industry-funded trials are four times more likely to give a positive result than independently sponsored trials.

But — and it’s a big but — (Laughter) it turns out, when you look at the methods used by industry-funded trials, that they’re actually better than independently sponsored trials. And yet, they always manage to to get the result that they want. So how does this work? How can we explain this strange phenomenon? Well it turns out that what happens is the negative data goes missing in action; it’s withheld from doctors and patients. And this is the most important aspect of the whole story. It’s at the top of the pyramid of evidence. We need to have all of the data on a particular treatment to know whether or not it really is effective. And there are two different ways that you can spot whether some data has gone missing in action. You can use statistics, or you can use stories. I personally prefer statistics, so that’s what I’m going to do first.

This is something called funnel plot. And a funnel plot is a very clever way of spotting if small negative trials have disappeared, have gone missing in action. So this is a graph of all of the trials that have been done on a particular treatment. And as you go up towards the top of the graph, what you see is each dot is a trial. And as you go up, those are the bigger trials, so they’ve got less error in them. So they’re less likely to be randomly false positives, randomly false negatives. So they all cluster together. The big trials are closer to the true answer. Then as you go further down at the bottom, what you can see is, over on this side, the spurious false negatives, and over on this side, the spurious false positives. If there is publication bias, if small negative trials have gone missing in action, you can see it on one of these graphs. So you can see here that the small negative trials that should be on the bottom left have disappeared. This is a graph demonstrating the presence of publication bias in studies of publication bias. And I think that’s the funniest epidemiology joke that you will ever hear.

That’s how you can prove it statistically, but what about stories? Well they’re heinous, they really are. This is a drug called reboxetine. This is a drug that I myself have prescribed to patients. And I’m a very nerdy doctor. I hope I try to go out of my way to try and read and understand all the literature. I read the trials on this. They were all positive. They were all well-conducted. I found no flaw. Unfortunately, it turned out, that many of these trials were withheld. In fact, 76 percent of all of the trials that were done on this drug were withheld from doctors and patients. Now if you think about it, if I tossed a coin a hundred times, and I’m allowed to withhold from you the answers half the times, then I can convince you that I have a coin with two heads. If we remove half of the data, we can never know what the true effect size of these medicines is.

And this is not an isolated story. Around half of all of the trial data on antidepressants has been withheld, but it goes way beyond that. The Nordic Cochrane Group were trying to get a hold of the data on that to bring it all together. The Cochrane Groups are an international nonprofit collaboration that produce systematic reviews of all of the data that has ever been shown. And they need to have access to all of the trial data. But the companies withheld that data from them, and so did the European Medicines Agency for three years.

This is a problem that is currently lacking a solution. And to show how big it goes, this is a drug called Tamiflu, which governments around the world have spent billions and billions of dollars on. And they spend that money on the promise that this is a drug which will reduce the rate of complications with flu. We already have the data showing that it reduces the duration of your flu by a few hours. But I don’t really care about that. Governments don’t care about that. I’m very sorry if you have the flu, I know it’s horrible, but we’re not going to spend billions of dollars trying to reduce the duration of your flu symptoms by half a day. We prescribe these drugs, we stockpile them for emergencies on the understanding that they will reduce the number of complications, which means pneumonia and which means death. The infectious diseases Cochrane Group, which are based in Italy, has been trying to get the full data in a usable form out of the drug companies so that they can make a full decision about whether this drug is effective or not, and they’ve not been able to get that information. This is undoubtedly the single biggest ethical problem facing medicine today. We cannot make decisions in the absence of all of the information.

So it’s a little bit difficult from there to spin in some kind of positive conclusion. But I would say this: I think that sunlight is the best disinfectant. All of these things are happening in plain sight, and they’re all protected by a force field of tediousness. And I think, with all of the problems in science, one of the best things that we can do is to lift up the lid, finger around in the mechanics and peer in.

Thank you very much.

(Applause)

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By Team FPS – May 6, 2012