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Adaptive Innovations in Medicine: Vitamin D, Iodine, and Selenium

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1 Adaptive Innovations in Medicine: Vitamin D, Iodine, and Selenium
Donald W. Miller, Jr., M.D. Professor of Surgery, Division of Cardiothoracic Surgery University of Washington School of Medicine 65th Annual Meeting Association of American Physicians and Surgeons Phoenix, Arizona September 12, 2008

2 Christensen CM, Bohmer R, Kenagy J
Christensen CM, Bohmer R, Kenagy J. Will Disruptive Innovations Cure Health Care? Harvard Business Review 2000;78(Sept-Oct):



5 Christensen CM, Bohmer R, Kenagy J
Christensen CM, Bohmer R, Kenagy J. Will Disruptive Innovations Cure Health Care? Harvard Business Review 2000;78(Sept-Oct):

6 Recommended Dietary Allowance (RDA) for Vitamin D:
Knightsbridge, Westminster London In 1890, Palm concluded that rickets was caused by lack of exposure to sunlight, because even though children in Britain had better diets and better sanitary conditions, they were more susceptible to rickets. He concluded it was because children in the tropics got plenty of sunshine. In the 1800s and early 1900s, children in smog-filled, crowded urban areas suffered from the ‘rickets’. >90% of children in larger European cities and ~80% of children in Boston suffered from the disease. Recommended Dietary Allowance (RDA) for Vitamin D: 400 IU/day To prevent rickets in children and osteomalacia in adults

7 Vitamin D Deficiency Rickets, Osteomalacia Influenza, Tuberculosis
MS, RA, SLE, Type I diabetes Hypertension, CAD, PVD, CHF Syndrome X, Type 2 Diabetes Chronic Fatigue, SAD, Depression Cataracts, Infertility Osteoporosis Cancer Other autoimmune diseases: Crohn’s disease, Hashimoto’s disease

8 + cells throughout the body
Vitamin D 25(OH)D 1,25(OH)D 26 + cells throughout the body Vertebrate steroids Steroid hormones Sex steroids are a subset of sex hormones that produce sex differences or support reproduction. They include androgens, estrogens, and progestagens. Corticosteroids include glucocorticoids and mineralocorticoids. Glucocorticoids regulate many aspects of metabolism and immune function, whereas mineralocorticoids help maintain blood volume and control renal excretion of electrolytes. Anabolic steroids are a class of steroids that interact with androgen receptors to increase muscle and bone synthesis. There are natural and synthetic anabolic steroids. In popular language the word "steroids" usually refers to anabolic steroids. Cholesterol which modulates the fluidity of cell membranes and is the principle constituent of the plaques implicated in atherosclerosis. Characterized by a carbon skeleton with four fused rings, generally arranged in a fashion UVB photons 7-dehydrocholesterol

9 Nuclear Receptors

10 System and Tissue Distribution of Nuclear Vitamin D Receptors (VDR)
System Tissue Immune Thymus, bone marrow, macrophages, B cells, T cells Gastrointestinal Esophagus, stomach, small intestine, colon, rectum Cardiovascular Endothelial cells, smooth muscle cells, myocytes Respiratory Lung alveolar cells Hepatic Liver parenchyma cells Renal Proximal and distal tubules, collecting duct Endocrine Parathyroid, thyroid, pancreatic beta cells Exocrine Parotid gland, sebaceous gland CNS Brain neurons, astrocytes, microglia Epidermis/appendage Skin, breast, hair follicles Musculoskeletal Osteoblasts, osteocytes, chondrocytes, striated muscle Connective Tissue Fibroblasts, stroma Reproductive Testis, ovary, placenta, uterus, endometrium, yolk sac

11 Nutrigenomics Vitamin D
Wood and colleagues analyzed vitamin D-induced gene expression in a human colon cancer cell line. They identified 12 genes that exhibited statistically significant increase in expression, two of which are known to have anti-proliferative effects. Physiological Genomics 17: (2004) /04 $5.00 © 2004 American Physiological Society DNA microarray analysis of vitamin D-induced gene expression in a human colon carcinoma cell line Richard J. Wood1, Laurie Tchack1, Giana Angelo1, Richard E. Pratt2 and Larry A. Sonna3,4 Note fallout prep if have no KI Confirmatory PCR for 1,25-dihydroxyvitamin D-regulated genes found by Affymetrix GeneChip transcriptional profiling Wood RJ, Tchack L, Angelo G, etal. DNA Microarray Analysis of Vitamin D-induced Gene Expression in a Human Colon Carcinoma Cell Line. Physiological Genomics 2004;17:

12 Human Migration Out of Africa
Mutation in one rung in the 3 billion rungs on the DNA double-helix ladder – only a change in one base pair 35° S Lamson Rl, etal. SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Science 2005;310:


14 Indigenous Human Skin Color by Latitude
Jablonski NG, Chaplin G. The evolution of human skin coloration. J Hum Evol 2000;39:57-106

15 Seasonal Variation in 25-hydroxyvitamin D Levels in People at Latitude 48° N
Seasonal variation of 25(OH)D levels in a population-based sample of inhabitants of a small southern German town, aged 50–80 years. (Reproduced/amended with kind permission of Springer Science and Business Media, Scharla, S.H., 1998.) Cannell JJ, etal. Epidemic influenza and vitamin D. Epidemiol Infect 2006;134:

16 Influenza story, two prinicple actions of macrocytes
Cannell JJ, etal. Epidemic influenza and vitamin D. Epidemiol Infect 2006;134:

17 Noncalcemic Functions of 1,25-dihydroxyvitamin D
Cytokines Noncalcemic functions of 1,25(OH)2 D. Vitamin D coming from the photoproduction of previtamin D or coming from the diet is converted in the liver to 25(OH)D by the vitamin 25-OHase. 25(OH)D is converted in the kidneys by 1-OHase. 1,25(OH)2D not only regulates calcium and phosphorus metabolism but can stimulate the pancreas to produce insulin and to downregulate the renal production of renin. 1,25(OH)2D also interacts with its nuclear receptor (VDR) in a wide variety of tissues and cells and helps maintain normal cell proliferation and differentiation. 25(OH)D can also be converted to 1,25(OH)2D in a wide variety of cells, including colon, prostate, and breast, for the autocrine production of 1,25(OH)2D. It is believed that the autocrine production of 1,25(OH)2D is important for regulating cell growth and maturation, which decreases risk of the cell becoming malignant. 25(OH)D also is metabolized in macrophages by the 1-OHase to produce 1,25(OH)2D. The expression of the VDR and 1-OHase is upregulated when TLR2/1 is stimulated by LPS. This results in an increase in the expression of the VDR and the 1-OHase. The increase production of 1,25(OH)2D increases the nuclear expression of cathelicidin (CD) in the macrophage, which is a cationic peptide that causes the destruction of infective agents including M. tuberculosis. Inappropriate activation of the renin-angiotensin system, which plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis, may represent a major risk factor for hypertension, heart attack, and stroke. Mounting evidence from clinical studies has demonstrated an inverse relationship between circulating vitamin D levels and the blood pressure and/or plasma renin activity, but the mechanism is not understood. We show here that renin expression and plasma angiotensin II production were increased severalfold in vitamin D receptor–null (VDR-null) mice, leading to hypertension, cardiac hypertrophy, and increased water intake. However, the salt- and volume-sensing mechanisms that control renin synthesis are still intact in the mutant mice. In wild-type mice, inhibition of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] synthesis also led to an increase in renin expression, whereas 1,25(OH)2D3 injection led to renin suppression. We found that vitamin D regulation of renin expression was independent of calcium metabolism and that 1,25(OH)2D3 markedly suppressed renin transcription by a VDR-mediated mechanism in cell cultures. Hence, 1,25(OH)2D3 is a novel negative endocrine regulator of the renin-angiotensin system. Its apparent critical role in electrolytes, volume, and blood pressure homeostasis suggests that vitamin D analogues could help prevent or ameliorate hypertension. Adaptive Innate Immune modulation

18 Tuberculosis Treated with Sunshine
Tuberculosis patients lie in beds on the porch of a building at the Jewish consumptives Relief Sanatorium, 1600 Pierce Street, Lakewood, CO.  This facility later became the American Medical Center and then the AMC Cancer Research Center. Vitamin D acts as a potent immune modulator. It induces a Toll-Like Receptor (TLR) gene which in turn promotes production of human cathelicidin antimicrobial peptide (CAMP) by white blood cells. [ii] This CAMP stuff is part of the innate immune system and provides a rapid response used to repel assaults from numerous infectious organisms including bacteria, viruses, fungi, and parasites and tuberculosis. [iii] [iv] It is our first line of defense against infection.

19 Immunomodulatory Effects of 1,25-dihydroxyvitamin D
Fig. 1: The immunomodulatory effects of 1,25(OH)2D3. At the level of the antigen-presenting cell (such as the dendritic cell [DC]), 1,25(OH)2D3 inhibits the surface expression of MHC II-complexed antigen and of co-stimulatory molecules as well as the production of the cytokine IL-12, thereby indirectly shifting the polarization of T-lymphocytes from a Th1 towards a Th2 phenotype. 1,25(OH)2D3 exerts its immunomodulatory effects also directly at the level of the T-lymphocytes by inhibiting the production of Th1 cytokines IL-2 and IFN-g and stimulating the production of Th2 cytokines. Moreover, 1,25(OH)2D3 favours the induction of regulatory T-lymphocytes. Both Th2 and T regulatory cells (Treg) are able to inhibit Th1 lymphocytes through the production of counteracting or inhibitory cytokines. Together these immunomodulatory effects of 1,25(OH)2D3 can lead to the protection of target tissue in autoimmune diseases and transplantation. Ag, Antigen; TCR, T-cell receptor; TGF-b, transforming growth factor-b; Mf, macrophages; Tc, cytotoxic T-lymphocyte; TNF-a, tumour necrosis factor-a.

20 Multiple Sclerosis in World War II Veterans by Latitude and State of Residence
Multiple Sclerosis Prevalence of U.S. WW II Veterans at Time of Entry into the Armed Forces vs. Latitude according to latitude and state of residence in the U.S. at entry into active duty (EAD): Wallin MT, etal. Multiple sclerosis in US veterans… Ann Neurol 2004;55:65-71

21 Breast Cancer Mortality Rates and Contours of Annual Mean Daily Solar Irradiance
FIGURE 2— Age-adjusted breast cancer mortality rates, by county area, and contours of annual mean daily solar irradiance in Langleys (calories/cm2), United States, 1970–1994. Source. Developed through use of National Cancer Institute and National Oceanic and Atmospheric Administration data (available at and Lappe JM, etal. Vitamin D and calcium supplementation reduces cancer risk: Results of a randomized trial. Am J Clin Nutr 2007;85:

22 25-hydroxyvitamin D3 Blood Levels
Calcium Absorption Severely deficient < 8 ng/ml Deficient ng/ml Insufficient ng/ml Sufficient ng/ml Optimal ng/ml Excessive ng/ml Toxic >150 ng/ml 32 ng/ml PTH Levels Insufficient: too low for good health (1 ng/ml = 2.5 nmol/L, 1 nmol/L = O.4 ng/ml)

23 Preop Vitamin D3 levels in 73 Veterans Undergoing Heart Surgery at the Seattle VA Hospital
No. of Patients History of Cancer 25-hydroxyvitamin D3 Level (ng/ml) 7 (9.6 %) 1 (colon) < 8 (severely deficient) 41 (56.2%) 6* (deficient) 9 (12.3%) (insufficient) 13 (17.8%) (sufficient) 3 (4.1%) (optimal) From Dec 2006 to July 2007 Our low rate of wound infections and post-pericardiotomy syndrome * Prostrate cancer – 3; Colon cancer – 1; Tonsillar cancer – 1; Melanoma -- 1 Surgery performed December 2006 – July 2007

24 Sources of Vitamin D Cholecalciferol (D3) and Ergocalciferol (D2)
Dietary Natural Salmon (wild, 3.5 oz) IU D3 Salmon (farmed, 3.5 oz) IU D2 or D3 Cod liver oil (1 tsp) IU D3 Tuna (canned, 3.6 oz) IU D3 Egg yolk IU D 2 or D3 Fortified Foods Milk (8 oz) IU D3 Orange juice (8 oz) IU D3 Infant formula (8 oz) IU D3 Butter (3.5 oz) IU D3 Breakfast cereals/serving IU D3 Supplements Prescription Ergocalciferol (D2) ,000 IU/capsule Over the Counter Multivitamins IU D2 or D 3 Cholecalciferol (D3) , 800, 1000, 2000, 5000 and ,000 IU/tablet Skin synthesizes 20,000 IU D3 in 20 minutes when exposed to sunlight 5,000 IU D ,000 IU D3 OTC at,

25 Serum 25-hydroxyvitamin D3 Levels on 0, 1000, 5000, and 10,000 IU of Vitamin D3 a Day
(80 ng/ml) 80 ng/ml 10,000 IU qd 60 ng/ml (60 ng/ml) 5000 IU qd 30 ng/ml (30 ng/ml) 1000 IU qd How much vitamin D do we need? Winter in Nebraska, 16 men/group Heany RP, etal. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003;77:

26 Benefits of Vitamin D Skeletal-muscular Infections Cancer
Strong muscles and bones Infections Prevent influenza, treat tuberculosis Cancer Prevent breast, colon, and prostate cancer ? Suppress metastasizes Autoimmune Diseases Prevent multiple sclerosis and type 1 diabetes Cardiovascular Disease Slow progression of atherosclerosis Treat hypertension and congestive heart failure Neuropsychiatric Disorders Prevent schizophrenia and relieve depression

27 Iodine Why does iodine kill bacteria and fungi, and yet we and other plants and animals can’t live without it? And why does seaweed contain such high concentrations of this scarce element? It turns out that iodine has played a pivotal role in evolution. 27

28 Iodine in Surgery 28

29 Thyroid-related Iodine Deficiency Pyramid
1-10% Cretinism Mental Retardation 5-30 % Worsening Iodine Deficiency Loss of Energy due to Hypothyroidism 30-70 % 29

30 Iodine in Thyroid Hormones
The conventional medical view is that the only known function of iodine in the human body is as an essential component of the thyroid hormones thyroxine (T^sub 4^) and triiodothyronine (T^sub 3^). T^sub 4^ contains four atoms (59% by weight) and T^sub 3^ contains three atoms (65% by weight) of iodine per molecul Iodine atoms 30

31 The Mainstream Medical View of Iodine
The thyroid gland is the only organ that needs iodine, in microgram amounts, for biosynthesis of thyroid hormones. RDA for Iodine: μg/day 2) A daily intake of more than 1-2 mg/day of iodine is excessive and potentially harmful. As per the AMA, NIH National Research Council, Institute of Medicine, Joint UN FAO/WHO Expert Committee on Food Additives, and the EU IPCS IPCUS—International Programme on Chemical Safety, a collaborative venture of WHO, UN Environment Programme, International labour Organization. FAO—Food and Agricultural Organization of the United Nations These authorities include the American Medical Association, the NIH National Research Council, the joint Food and Agricultural Organization of the United Nations and World Health Organization Expert Committee, and the European Union International Programme on Chemical Safety, which is a collaborative venture of WHO, UN Environment Programme, and the International labour Organization. 31

32 Extrathyroidal Benefits of Iodine
Formation of the Earth’s Atmosphere Role in photosynthesis Antioxidant Prevent lipid peroxidation Fibrocystic disease of the breast Cancer Trigger apoptosis Immune system Suppress autoimmunity Coat external proteins rendering them non-allergic Mucosal Defense Provide antisepsis in mouth, stomach, and vagina Civil Defense Against radioactive fallout

33 The Earth’s 3rd Atmosphere, from 2.2 Ga
Oxygen Level in Atmosphere (Percent) Billion Years Ago Life arose on the planet around 3.8 BYA in the form of single-cell bacteria. About 500 M years later a new kind of bacteria evolved called cyanobacteria, also known as Blue-Green Algae. This bacteria produces a protein, chlorophyll, that can absorb the energy in sunlight and use it to power a chemical reaction that turns water and carbon dioxide into food. Cyanobacteria take 6 molecules of CO2 and 6 molecules of water and produce one molecule of sugar and six molecules of oxygen. It uses the sugar, dextrose, to make ATP (adenosine triphosphate), the chemical “fuel” that sustains all living things. Oxygen is a waste product that it discharges into the atmosphere. Over the last several billion years, cyanobacteria have been expelling oxygen into the atmosphere, where it has maintained a level of 21 percent for the last billion years. In addition to making oxygen, cyanobacteria were the first life forms to develop an affinity for iodine. Why? It turns out this organism needs iodine to protect itself from the toxic effects of oxygen that it produces. 1st atmosphere H and He from solar nebula Lost to solar wind 2nd atmosphere H20, CO2 and SO2 from volcanic degassing Transformed by photosynthesis Current atmosphere N2, O2, from photosynthesis and constant N2 production Photosynthesis by cyanobacteria began > Ga CO2 + H2O ---> CH2O + O2 No evidence for free O2 before ~2.4 Ga Reduced gases in atmosphere & reduced crust consume O2 produced during Ga Hydrogen escape irreversibly oxidizes atmosphere Mantle dynamics & redox evolution reduce O2 sink over time Geologic & geochemical evidence for O2 : Oxidized Fe & Mn mineral deposits Detrital uraninite & pyrite Paleosols Redbeds Sulfur isotopes Eukaryotes Conclusion: Rapid rise of free O Ga 4.6 bya Formation of the Earth 3.5 bya Abiotic synthesis, 3.2 bya Denitrification 2.3 bya Oxygen-producing photosynthesis by cyanobacteria Start of ozone formation 1.8 bya Nitrification (aerobic) 1.5 bya Nitrogen fixation (aerobic) 1.4 bya Earliest eukaryotes 0.57 bya First shelled invertebrates bya Primitive fish bya First land plants -- oxygen and ozone increase Photosynthesis first done by Cyanobacteria: 6CO2 + 6H2O → C 6H12 O6 + 6O2 Cyanobacteria are also the first life forms to tolerate and use………………… Iodine 33

34 Kingdoms of Life Algae Eukaryotic cells Plants Animals Fungi
Protista Prokaryotic cells 5. Monera Cyanobacteria Other Bacteria Archaea Algae Seaweed: Kelp, etc. Blue Green Algae

35 Iodine as an Antioxidant
Reactive Oxygen Species I- + H2O HIO + OH- HIO + I- + H I2 + H2O Inside the cells of living things, oxygen breeds reactive oxygen species, superoxide anion, hydrogen peroxide, and the hydroxyl radical. The hydroxyl radical wreaks havoc and damages the cell by reacting with lipids in the cellular membranes, nucleotides in DNA, and the tyrosine and sulphydryl groups in proteins. In algae, in a species of kelp, Kupper et al. have shown that iodine functions as an antioxidant. It neutralizes hydrogen peroxide by converting it first to hypiodious acid and then water, thereby blocking the conversion of hydrogen peroxide into the highly destructive hydroxyl radical. This ability of inorganic iodine to neutralize free radicals and other reactive oxygen species made photosynthesis possible. Free radicals are a byproduct of biological oxidation HIO = hypiodious acid Iodine spontaneously reacts with hydrogen peroxide to form HIO ROS cause damage by reacting with lipids in cellular membranes, nucleotides in DNA, sulphydryl groups in proteins, and cross-linking/fragmentation of ribonucleoproteins Fenton reaction (catalyzed by copper or iron): H2O2 in OH ROS cause cancer. Involved in both the initiation and progression of cancer. Other ROS: singlet oxygen and hypochlorite ROS also have a regulatory role in cellular metabolism Kupper FC, et al. Iodine uptake in Laminariales involves extracellular, haloperoxidase-mediated oxidation of iodide. Planta 1998;207: 35

36 Reactive Oxygen Species
Ionizing Radiation Photosynthesis: Chlorophyll Sunlight CO2 Lane, N. Oxygen: The Molecule that Changed the World London: Oxford University Press, 2004. 36

37 Iodine as an Antioxidant
Prevent Lipid Peroxidation Omega 6 Arachidonic Acid (AA) Iodolactone I- Omega 3 Docosahexaenoic Acid (DHA) 37

38 Fibrocystic Breast Disease
Fibrous tissue Epithelial and apocrine hyperplasia Elemental Iodine, I2, more effective than Iodide, I- In milligram amounts Many women are troubled with painful, lumpy breasts. The incidence of fibrocystic breast disease in American women was found to be very low, 3 percent, when studied in the 1920s. Today 90 percent of women have fibrocystic breast disease. In this disorder, epithelial hyperplasia occurs, along with apocrine gland metaplasia, and fluid-filled cysts form, accompanied by fibrosis. Six million women with fibrocystic disease have moderate to severe breast pain and tenderness that lasts more than 6 days during the menstrual cycle. In animal studies, female rats fed an iodine-free diet develop fibrocystic changes in their breasts. Iodine in its diatomic, elemental form, as I2, cures it. Several studies, most notably this one by Ghent and colleagues, show that iodine effectively relieves signs and symptoms of fibrocystic breast disease in 70 percent of patients. This paper is a composite of three clinical studies, two in Canada and one in Seattle. The study done in Seattle, by two surgeons at the Virginia Mason Clinic, Drs. Donald Low and Lucius Hill, is the most impressive. It is a randomized, double-blind, placebo-controlled trial designed to compare elemental iodine, I-2, in a dose of 3 to 5 mg, to a placebo, in this case an aqueous mixture of a brown vegetable dye with quinine. They were followed for six months and subjective and objective changes in their fibrocystic breast disease tracked. Ghent WR, Eskin BA, Low DA, Hill LP. Iodine replacement in fibrocystic disease of the breast. Can J Surg 1993;36: 38

39 Diatomic Iodine (I2)Treatment for Fibrocystic Disease Special Report of Efficacy and Safety Results (Submitted to FDA 21 March 1995) In the Canadian Journal of Surgery report 56 women were enrolled in this study, and the results were not subjected to statistical analysis; but two years later a company sponsor subjected the data, enlarged to include 92 women followed for 7 months, to a rigorous statistical analysis. Seeking FDA approval for a clinical trial of iodine in mg doses to treat this disease this company, Minitex, Inc., submitted a Special Report on iodine’s efficacy and safety to the FDA. This report showed that iodine had a highly statistically significant effect on fibrocystic disease, with a p value of less than In two-thirds of the women, it reduced breast tenderness, nodularity, fibrosis, hyperactivity and number of macroscysts, the five parameters measured in the total breast examination score done by an investigator blinded to which treatment the woman had, iodine or placebo The FDA declined to approve a larger trial, saying, according to Dr. Low, the lead investigator, that it could not endorse the trial because iodine is a natural substance and not a drug. Very few doctors who treat breast disease know about the Canadian Journal of Surgery study, or a Russian one that predated it and showed a 70 percent success rate with iodine for fibrocystic disease, and none know about the Minitex FDA report, which until now has been kept confidental. They adhere to the thyroid-only dogma of iodine. Hyperactivity: breast tension characterized by a cone-shpaed density behind the areola. The Virginia Mason Randomized Controlled Trial 39

40 Iodine-Induced Apoptosis in Lung Cancer
Fig. 3. KI induces apoptosis in >95% H1299NIS/TPOcells after a 48-h incubation. A, H1299NIS/TPOcells in KI; B, H1299CV cells in KI; C, H1299NIS cells in KI; D, H1299NIS/TPO cells in KCl. Apoptotic cells were stained red, whereas viable cells remain unstained or pale pink. Iodine Sensitive Lung Cancer Cells Parent (unmodified) Lung Cancer Cells Zhang L. et al. Nonradioactive iodide effectively induces apoptosis in genetically modified lung cancer cells. Cancer Res 2003;63: 40

41 Effect of Iodine on Tumor Growth in Mice
Genetically Modified Tumor Xenograft Controls Genetically Modified Tumor Xenograft with Iodine Fig. 5. Nonradioactive iodide effectively limits the growth of NIS/TPO-modified tumor xenografts in SCID mice. A, KI markedly reduces tumor volume in NIS/TPO-modified tumor xenografts. *, P < 0.05; **, P < 0.01; ***, P < compared with nontreated H1299NIS/TPOtumors. B, photographs of tumors from each group of mice. H1299CV, n = 9; H1299CV+KI, n = 9; H1299NIS/TPO, n = 9; H1299NIS/TPO+KI, n = 12; bars, ±SD. Zhang L. et al. Nonradioactive Iodide Effectively Induces Apoptosis in Genetically Modified Lung Cancer Cells. Cancer Res 2003;63: 41

42 Nutrigenomics Iodine Down-regulated genes Up-regulated genes
In this recently published study, Stoddard and coworkers analyzed the effect of Lugol’s iodine solution on gene expression in the estrogen responsive MCF-7 breast cancer cell line. Microarray analysis identified 20 genes that were up-regulated and 14 genes that were down-regulated in response to iodine treatment Down-regulated genes Up-regulated genes Stoddard FR, Brooks AD, Eskin BA, Johannes GJ. Iodine Alters Gene Expression in the MCF7 Breast Cancer Cell Line: Evidence for an Anti-Estrogen Effect of Iodine. International Journal of Medical Sciences 2008;5:

43 Evidence that Iodine Prevents Breast Cancer
Animal Studies Reduced incidence in rats given carcinogens Human Studies Kills cancer cells grown in vitro Absorbed by cancer-prone ductal epithelium Epidemiological Studies Increased incidence with goiter Lower incidence in people who eat seaweed and fish There is a growing amount evidence showing that iodine prevents breast cancer. Animal studies show that iodine protects rats given a carcinogen from developed breast cancer. Iodine kills human breast cancer cells grown in a test tube. Cells in the breast that develop cancer are the same one that absorb iodine. People with iodine deficiency disorders manifested by a goiter have a 3 times greater incidence of breast cancer, and people who consume a lot of iodine have a low incidence of breast cancer. Miller DW. Extrathyroidal Benefits of Iodine. J Am Phys Surg 2006;11(4-Winter): 43

44 Organs with Iodine Concentrating Ability Via the Sodium/Iodine Symporter Pump
125I total-body scintiscans Stomach Mucosa Mammary Glands Salivary Glands Other: Cervix and Ovaries Thymus Epidermis Choroid Plexus Articular, Arterial, and Skeletal Systems Choroid plexus--A vascular proliferation of the cerebral ventricles that serves to regulate intraventricular pressure by secretion or absorption of cerebrospinal fluid. vascular complex in 3rd and 4th ventricle that forms cerebrospinal fluid (CSF). 30 min hr hr Venturi S, et al. Role of Iodine in Evolution and Carcinogenesis of Thyroid, Breast and Stomach. Adv Clin Path 2000;4:11-17. 44

45 Albert Szent-Györygi (1893-1986)
In 1937, when awarded the Noble Prize for discovering vitamin C In 1983, at the Marine Biological Laboratory, Woods Hole, MA 45

46 Iodine in Dermatology Sporotrichosis Nodular Pyoderma Vasculitis
Sterling JB, Heymann WR. Potassium iodide In dermatology: A 19th century drug for the 21st century—uses, pharmacology, adverse effects, and contraindications. J Am Acad Dermatol 2000;43: Nodular Vasculitis Pyoderma Gangrenosum 46

47 Iodine Poisoning Ingested 15 gm of Iodine – 100,000 x the RDA of gm (150 μg) Serum Iodide level was 2,950 ug/dL (normal is 3.5 μg/dL with daily intake of 150 ug Iodine) Salivary Iodide Level 60,000 ug/dL (normal 105 μg/dL) Treatment for COPD, up to 36 gm/day Peace Corps workers 50 mg a day, 44% got a goiter “Underlying thyroid disease.” Iodism: Rare; tends to be dose related Unpleasant taste, frontal headache, acne Resolves after stopping iodine actually caused by bromine release Iodine-induced hyperthyroidism “Long standing iodine deficiency can cause hyperactive nodules. When start taking iodine, symptoms can occur as nodules absorb iodine.” Hyperthyroidism, then, starts as an iodine-deficiency disorder decrease dose and proceed slowly. Delange, FM. Iodine Deficiency. The Thyroid. Lippencott Williams, Wilkens, p 47

48 Worldwide Iodine Nutrition
Based on Measurements of Median Urinary Iodine Excretion Median Urinary Iodine Concentration (mcg/L)Corresponding Approximate Iodine Intake (mcg/day) Iodine Nutrition<20 <30 Severe deficiency Moderate deficiency Mild deficiency Optimal More than adequate >299 >449 Possible excess Median Urinary Iodine Concentration (mcg/L) Corresponding Approximate Iodine Intake (mcg/day) Median urinary iodine concentration of ug/L with corresponding approximate iodine intake ug/day International Council for the Control of Iodine Deficiency Disorders. Current IDD Status Database, 2003. 48

49 Iodine Intake in Japan Iodine Intake 1950-1963:
13.8 mg/per capita/day (average 4.5 gm seaweed a day. Measured Iodine content 0.3mg/gm) Seaweed consumption in 2001: gm (dry weight) Iodine Intake 2001: mg If Iodine content the same (was not measured) In 1964 the Nutrition Section in the Bureau of Public Health in Japan published a study on Japanese food intake by food group. Their intake of seaweed averaged 4.5 grams a day. The measured the iodine content of the seaweed consumed and found sufficient to provide an average iodine intake of 13.8 mg/day. 95 percent of the iodine they consume comes from seaweed. Without measuring its iodine content, public health officials say that Japanese seaweed consumption in 2001 had risen to 14.6 grams a day. Assuming the same concentration of iodine in the seaweed, this would provide a current day iodine intake of 43.8 mg/day. Nutrition in Japan, Nutrition Section, Bureau of Public Health, Ministry of Health and Welfare, Tokyo, Japan, March 1965. 49

50 Iodine Intake in the United States
Urinary iodine levels (µg/L) in the United States, age 6-74 NHANES I, NHANES III, NHANES 2000 Median 32.00 14.5 16.1 SE 0.6   0.3 0.7 1Hollowell, JE et al. Iodine nutrition in the United States. Trends and public health implications: Iodine excretion data from National Health and Nutrition Examination Surveys I and III ( and ). J Clin Endocrinol Metab 83: Current Average Daily Intake of Iodine: 240 µg (0.24 mg) Iodine Intake in 1970s: µg (0.48 mg) 320 145 161 Medical authorities in the United States have established a RDA for iodine of 150 ug/day, which is “adequate to maintain normal thyroid function, growth, and development.” This allowance is designed to prevent goiter formation. The main source of iodine consumption by Americans is table salt. Iodide is added to table salt, in a concentration of 70 ug of iodine per gram of salt. The average daily intake of iodine in the U.S. is 249 ug, or 0.24 mg, approximately 1/100th of Japanese consumption. This is half the amount consumed by Americans 30 years ago, when iodine, rather than bromine, was used as a dough conditioner for making bread. Less than 50 ug/L in 11.7%, a 4-5 fold increase 50

51 Health Comparisons: United States and Japan
United States Japan Incidence of Breast Highest in World Lowest Cancer Life Expectancy years years (48th/226 countries) (No. 6) Infant Mortality Rate (deaths under age 1 per (Lowest in World) 1,000 live births) The incidence of breast cancer in this country is the highest in the world. One in 7 American women will get breast cancer. Japan has the lowest incidence of breast cancer. The life expectancy in the U.S years, 48th in the 226 countries surveyed. In Japan it is years. It is number 6, after Andorra, Macau, San Marino, Singapore, and Hong Kong. And the infant mortality rate in Japan is the lowest in the world, half that in the United States. Could this disparity in health be due to these countries respective difference in iodine consumption 51

52 On Truth Leo Tolstoy: I know that most men, including those at ease with problems of the greatest complexity,… George Orwell: At any given moment there is an orthodoxy,… Albert Guérard: When you seek a new path to truth, you must expect to find it blocked by expert opinion. Tolstory: I know that most men, including those at ease with problems of the greatest complexity, can seldom accept even the simplest and most obvious truth if it be such as would oblige them to admit the falsity of conclusions which they have delighted in explaining to colleagues, which they have proudly taught to others, and which they have woven, thread by thread, into the fabric of their lives. Orwell: At any given moment there is an orthodoxy, a body of ideas which it is assumed that all right-thinking people will accept without question. Anyone who challenges the prevailing orthodoxy finds himself silenced with surprising effectiveness. A genuinely unfashionable opinion is almost never given a fair hearing, either in the popular press or in the highbrow periodicals 52

53 “Medical Science” on Iodine: Then and Now
A thyroid-centered consensus recommending 150 g/day iodine allowance and not to exceed 300 g/day Without evidence, endocrinologists decree that >1 mg is potentially harmful Allopathic physicians ignore studies that show iodine in milligram doses cures fibrocystic disease of the breast Then 1779: The Coventry Remedy used to treat goiter revealed to be burnt sea sponge 1811: Iodine discovered (Bernard Courtois) 1816: Sea sponge found to contain high quantities of iodine (Andrew Fyfe) 1819: Tincture of Iodine alone shown to shrink goiter (Jean Coindet) A chain of evidence Iodine needs to be taken out of the hands of endocrinologists achieved with mg/day (RDA mg/day) Decree, without evidence, that iodine > 1 mg/day is excessive Absence of goiter, mental retardation, and cretinism deemed iodine sufficiency Consider urine iodide levels a reliable index of iodine intake Total body content of iodine 25 mg, with % in the thyroid gland 53

54 Dose-Related Benefits
The Truth on Iodine Dose-Related Benefits In microgram (μg) amounts: In milligram (mg) amounts: In gram (g) amounts: For thyroid hormones Prevent (and treat) fibrocystic disease of the breast Prevent cancer Balance immune system Achieve optimal health Treat various dermatologic, pulmonary, cardiovascular, and fungal diseases Gram amounts: Wright JV. ONE MINERAL CAN HELP A MYRIAD OF CONDITIONS FROM ATHEROSCLEROSIS TO "COPD"TO ZITS. Availabable at: Accessed June 21, 2006. 54

55 Different Kinds of Iodine
Inorganic, Nonradioactive (127I) KI, SSKI, Lugol’s Solution, Iodoral, Tincture of Iodine, Povidone-Iodine Organic Endogenous Thyroid hormones Synthetic Amiodarone Radiocontrast media Iopanoic acid, Meglumine Iotroxate, Propyliodone, etc. (Inorganic) Radioactive Isotopes Iodine essential for normal growth and development is organically bound in thyroid hormones. Inorganic, nonradioactive iodine Iopanoic acid, Meglumine Iotroxate, Propyliodone, etc. Iopanoic acid an oral tracer, used for cholangiography; propyliodone is insufflated into the lungs for bronchography Thee isotopes used: I-123, I-125, I-131 55

56 (Inorganic) Oral Iodine Supplements
KI (Potassium Iodide) A 130 mg tablet contains 100 mg of iodide SSKI (Saturated Solution of Potassium Iodide) 38 mg/drop iodide (760 mg/ml) 19 mg/drop in Tahoma Clinic’s SSKI Tri-Quench Lugol’s Solution -- 5% iodine (I2) and 10% KI 6.5 mg/drop blend of iodine and iodide (130 mg/ml) Iodoral -- 5% iodine and 10% KI One tablet = 12.5 mg blend of iodine and iodide Inorganic, nonradioactive 56

57 Organic Iodine: Amiodarone

58 The Iodine Project Hypothesis: Whole body sufficiency of iodine requires mg (12.5 mg), not μg (150 μg ) daily amounts Principle Investigators Guy Abraham MD, 1997: Optimox Corp., Torrance, CA Jorge Flechas MD, 2000 (1,000 pts.): Flechas Family Practice, Hendersonville, NC David Brownstein MD, 2003 (3,000 pts.): Center for Holistic Medicine, West Bloomfield, MI Iodine Loading Test Take 50 mg iodine, urine collected for 24 hours Less than 90 % excretion indicates iodine insufficiency Total body iodine sufficiency 1,500 mg. Stantdard view is that the body contains mg of iodine, of which 30 mg is in the thyroid galnd Must be a complete nutritional programs, with selenium, magnesium, and Omega 3 fatty acids in particular. Iodoral: 27 cents a dose (90 for 43.93); Lugol’s 4 cents a dose (300 doses—2 drops—for 10.99) 58

59 Benefits Patients Report Taking Iodine in Milligram Doses (100+ times the RDA)
Feel Healthier Sense of Well-Being Lifting of Brain Fog Increased Energy – Achieve More in Less Time Feel Warmer in Cold Environments Need Less Sleep Regular Bowel Movements Improved Skin Complexion Overall sense of well-being Consuming iodine in mg doses should be coupled with a complete nutritional program that includes adequate amounts of selenium, magnesium, and Omega 3 fatty acids, in particular. An iodine intake that is 100x the RDA, as one observer puts it, is “the simplest, safest, most effective and least expensive way to help solve the health care crisis crippling our nation.” Americans would do well to emulate the Japanese and increase their iodine intake, if not by eating seaweed, then with two drops of Lugol’s solution a day. Less than 1 percent, and those patients, if followed by a physician schooled in the extrathyroidal benefits, cut back on the amount of iodine consumed and have no long-term consequences. 59

60 Selenium VIA Atomic Weight Selenium Molybdenum Iodine

61 Selenium in Soil: U.S. and Europe
Led by Brazil nuts, which have high concentrations of selenium, plants extract selenium from the soil. "Selenium deficiency is a major problem for livestock or wildlife in at least 37 states and costs beef, dairy, and sheep producers an estimated $545 million in losses every year. " soil scientist Gary S. Bañuelos Concentrations of selenium in the soil depends on the rocks from which the soil was derived. The Northwest, Southeast, and Great Lakes states have low (<.05 ppm) soil selenium concentrations because the soils in those areas were derived from volcanic deposits or well-washed coastal deposits. Soils originating from cretaceous shale, such as found in South Dakota, Montana, Wyoming, Nebraska, Kansas, Utah, Colorado, and New Mexico, tend to have high (2 to 10 ppm) soil selenium concentrations.

62 Selenium-containing Proteins
Glutathione peroxidase Iodothyronine deiodinase Thioredoxin reductase Selenoprotein P Selenoprotein W Prostrate epithelial selenoprotein

63 Selenium and Cardiac Function post Ischemia-Reperfusion
Fig. 4. Effect of selenium supplementation on contractile function following 22.5 min of ischemia and 45 minutes reperfusion in isolated perfused rat hearts. Contractile function was measured as (A) end diastolic pressure after 45 min reperfusion and (B) % recovery of rate pressure product after 45 min reperfusion. Values are presented as mean+ SEM. (#p<0.01 vs. controls, *p<().05 Vs. controls). Effects of dietary selenium on glutathione peroxidase and thioredoxin reductase activity and recovery from cardiac ischemia-reperfusionKylie Venardos,  Glenn Harrison,  John Headrick,  Anthony Perkins. Journal of Trace Elements in Medicine and Biology. Stuttgart: 2004. Vol.18, Iss. 1;  pg. 81, 8 pgs »Jump to full text    »Translate document from:   »More Like This - Find similar documentsAuthor(s):Kylie Venardos,  Glenn Harrison,  John Headrick,  Anthony PerkinsDocument types:General InformationSection:SELENIUM SPECIALPublication title:Journal of Trace Elements in Medicine and Biology. Stuttgart: 2004. Vol. 18, Iss. 1;  pg. 81, 8 pgs Vernardos K, etal. Effects of dietary selenium on glutathione peroxidase and thioredoxin reductase activity and recovery from cardiac ischemia-reperfusion. J Trace Elements Med Biol 2004;18(1):81-89.

64 Selenium and Sepsis Figure 2. Admission plasma selenium concentration related to severity of sepsis. p <or=to .05 for sepsis vs. severe sepsis; p <or=to .05 for sepsis vs. septic shock (analysis of variance). Dashed line, mean +/- SD normal plasma selenium concentration (1.00 +/ [micro sign]mol/L); n, number of patients, including, in parentheses, number of nonsurviving patients, for each sepsis severity grade. Values are expressed as median (middle line in the box) with the top and bottom of the box encompassing the 25th to the 75th percentiles; capped lines indicate the tenth to 90th percentiles of the data; circles, values above the 90th and below the tenth percentiles. © Williams & Wilkins All Rights Reserved. Volume 26(9), September 1998, pp Selenium, systemic immune response syndrome, sepsis, and outcome in critically ill patients [Clinical Investigations] Forceville, Xavier MD; Vitoux, Dominique PhD; Gauzit, Remy MD; Combes, Alain MD; Lahilaire, Pierre MD; Chappuis, Philippe PhD Forceville X, etal. Selenium, systemic immune response syndrome, sepsis, and outcome in critically ill patients. Crit Care Med 1998;26(9):

65 Harborview Antioxidant Supplementation Protocol
Vitamin C 1000 mg IV tid x 2 days, then 1000 mg po/ng/ft x 5 days Vitamin E 1500 IU po/ng/ft bid x 7 days Selenium 400 g IV qd x 2 days, then 400 g po/ng/ft x 5 days Nathans AB, Neff MJ, Jurkovich GJ, Klotz P, Farver K, Ruzinski JT, Radella F, Garcia I, Maier RV. Randomized, Prospective Trial of Antioxidant Supplementation in Critically Ill Surgical Patients. Ann Surg 2002;236(6):

66 Selenium and Cancer A number of studies show that a low selenium status is associated with an increased risk of cancer. The landmark Nutritional Prevention of Cancer trial, reported in 1996, recruited 1300 patients with nonmelanoma skin cancer who were randomized to receive 200 mcg of selenium a day or a placebo for a mean 4 ½ years. Selenium decreased the overall incidence of cancer by 35% and cancer mortality by 50%. Prostrate cancer decreased by 63%; colorectal cancer, by 58%; and the incidence of lung cancer decreased by 46%. The Relevance of Selenium to Immunity, Cancer, and Infectious/Inflammatory DiseasesMilly Ryan-Harshman,  Walid Aldoori. Canadian Journal of Dietetic Practice and Research. Markham: Summer Vol.66, Iss. 2;  pg. 98, 5 pgs Effect on various cancers: Following Clark et al.'s (16) publication of results from their randomized, controlled trial with skin cancer patients, other researchers revisited data from several prospective studies to ascertain the relationship between selenium and cancer. Clark et al. (16) found no effect on skin cancer incidence in 1,312 patients receiving 200 µg of selenium or placebo daily for four or more years (selenium group, n = 653; placebo group, n=659). However, they did find reductions in total cancer mortality and total cancer incidence, particularly for prostate, colorectal, and lung cancers (Table 2). Enlarge 200%Enlarge 400%Table 2Selenium supplementation1 and cancer: trial results (16) 16. Clark LC, Combs GF, Turnbull BW, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin: a randomized controlled trial. JAMA 1996;276: Clark LC, etal. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin: a randomized controlled trial. JAMA 1996;276:

67 Selenium and Cancer Antioxidant protection and enhanced immune surveillance are two possible mechanisms for the anticancer actions of selenium. Others include enhancement of apoptosis, regulation of cell proliferation, suppression of angiogenesis, and inhibition of tumor cell invasion. Two metabolites of selenium, shown here, may play a major role. Investigators have shown that they produce the anticancer effects listed in animals given Se in supranutritional but non-toxic doses. For we humans this would be mcg of selenium. Fig. 2. Proposed cellular effects of hydrogen selenide and methylselenol. Selenium as an anticancer nutrient: roles in cell proliferation and tumor cell invasion Huawei Zeng , a, and Gerald F. Combs Jra 2007; [Epub ahead of print June 27] Zeng H, Combs GF Jr. Selenium as an anticancer nutrient: roles in cell proliferation and tumor cell invasion. J Nutr Biochem 2007; [Epub ahead of print June 27}

68 Change in the US Death Rates* by Cause, 1950 & 2002
Rate Per 100,000 1950 2002 Compared to the rate in 1950, the cancer death rate was about the same in 2002, while rates for other major chronic diseases decreased during this period. Heart Diseases Cerebrovascular Diseases Pneumonia/ Influenza Cancer * Age-adjusted to 2000 US standard population. Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised. 2002 Mortality Data: US Mortality Public Use Data Tape, 2002, NCHS, Centers for Disease Control and Prevention, 2004

69 A Disruptive Innovation in Health Care
Take: Vitamin D IU/day — 10x its RDA (400 IU) Iodine mg/day — 100x its RDA (150 μg) Selenium 200 μg/day — 4x its RDA (55 μg)

70 “The Moon Goddess’ Role in Human Health”
“Extrathyroidal Benefits of Iodine” “Iodine for Health” “Vitamin D in a New Light” Moon Goddess Draped in her glimmering veil of stars, the Goddess Selene tenderly guides the moon on its celestial journey, keeping watch over the night-bathed earth. Her face is lit by the gentle glow of moonbeams from the heavens and by the profound power of her own inner peace and love for mankind. Definition: Selene was the Greek moon goddess, daughter of the Titans Hyperion and Theia (according to Hesiod), and the sister of Helios and Eos. Later, she was identified with Artemis and called Phoebe. As Phoebe she was a huntress and archer. Selene was worshiped on the days of full and new moons. She is described in the Homeric Hymn to Semele as mating with Zeus, through which union she produced Pandeia. She was in love with Endymion, according to Sappho and later sources. With him she had fifty daughters representing the months between the Olympic games. Every night, Selene visited and embraced Endymion, who slept as a result of the gift to him of eternal life and youth through eternal sleep. Also Known As: Phoebe

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