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Hi Dave,

In my previous e-mail, i did mean the "correspondence", not the article itself, plus your comments. It was kind of late, and so i did find myself skipping prior e-mails on the subject, and quickly reading yours. As always, thanks for your great and tireless efforts with our group. My Best Wishes to you and your family for the NEW YEAR.

Subject: Re: Article on Vitamin DTo: Date: Tuesday, December 30, 2008, 2:10 AM

Hi athan;Thanks for posting this article. Before adding my own personal comments [it's a very controversial issue!!], I thought it would be good to share some of the correspondence that this article generated in "BioEssays" earlier this year. There were 2 letters followed by a reply by Marshall:____________ _________ _________ ______BioEssays 30:506-507, 2008 Wiley Periodicals, Inc. B. GrantSunlight, Nutrition, and Health Research Center (SUNARC)P.O. Box 641603, San Francisco, CA 94164-1603.E-mail: wbgrant (AT) infionline (DOT) netCedric F. GarlandDepartment of Family and Preventive Medicine 0631CUniversity of California San Diego, La Jolla, CA.For readers wishing additional supporting references please contact Dr GrantThe health benefits of vitamin D greatly outweigh the health

risksSir,In his recent essay, Trevor G. Marshall explores how vitamin D supplementation may be contributing to the current epidemics of obesity and chronic disease.(1) Unfortunately, he has overlooked many important papers that disagree with his hypothesis. This letter points out some of the omissions.The health benefits of vitamin D3 have been reviewed recently.(2) The benefits for bone health have been known for nearly a century. Benefits for cancer, infectious diseases, autoimmune diseases and metabolic diseases have been identified in the past three decades.Starting in the 1980s, largely observational evidence mounted that solar ultraviolet- B (UVB) irradiance and vitamin D reduce the risk of many types of cancer.(3) Based on observational studies, it is estimated that 2500 and 3600 International Units (IU) of vitamin D3 are required daily for a 30-50% reduction in risk of

colorectal and breast cancer, respectively. (4,5) A recent randomized, double-blind, placebo controlled clinical trial that studied post-menopausal women in Nebraska found a 77% reduction in all-cancer incidence between the ends of the first and fourth years,(5) adding strong support to the observational studies.Vitamin D enhances innate immunity through induction of human cathelicidin, LL-37.(1) LL-37 helps control both bacterial and viral infections. A recent post-hoc analysis of vitamin D3 supplementation for post-menopausal women living in New York State found substantial benefits in reducing the common cold and influenza for 800 IU/day, and very strong benefits for 2000 IU/day.(6) Benefits also appear to be strong for septicaemia (Grant, submitted).Many autoimmune diseases appear to arise from an improper immune response to viral infections. Since LL-37 reduces the risk of viral

infections, it may also influence the risk of autoimmune diseases such as multiple sclerosis. The well-known increase in prevalence of multiple sclerosis with increasing latitude is consistent with this hypothesis.There is also a growing body of literature that low vitamin D status is a risk factor for many metabolic diseases, including hypertension, type 2 diabetes, and cardiovascular disease.(2) A recent observational study found that vitamin D deficiency is associated with incident cardiovascular disease.(7)There are some diseases where vitamin D supplementation may be contraindicated. These include granulomatous diseases such as sarcoidosis where local production of 1,25-dihydroxyvitam in D (calcitriol) in response to the disease can leak into the serum and dysregulate calcium metabolism.( 8)The current vitamin D3 fortification of food in the United States contributes an

average of 250-300 IU/day to the American diet. This amount is too low to have a substantial beneficial effect on risk of cancer. Intake or production of vitamin D3 of 1000-2000 IU/day seems now to be required for optimal health, and typically will raise serum 25-hydroxyvitamin D (calcidiol) levels to 40-60 ng/mL.(4,6,9)It is possible that the reason that there have not been more clinical trials of vitamin D supplementation clinical trials is that there is little income in selling vitamin D3 (a year's supply of 1500 IU/day costs less than $20 U.S.), and such trials are expensive.The rising prevalence of obesity in the United States has been attributed to over consumption of popular energy-dense foods compared to energy output.(10) Until obesity is eliminated, increased vitamin D3 supplementation and fortification of foods could provide substantial health benefits, including reduced incidence of

several serious diseases.DisclosureWBGreceives funding from the UV Foundation (McLean, VA), the Vitamin D Society (Canada), and the European Sunlight Association.References1. Marshall TG. 2008. Vitamin D discovery outpaces FDA decision making. Bioessays 30:173-182.2. Holick MF. 2007. Vitamin D deficiency. N Engl J Med 357:266-281.3. Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H et al. 2006. The role of vitamin D in cancer prevention. Am J Public Health 96:252-261.4. Garland CF, Grant WB, Mohr SB, Gorham ED, Garland FC. 2007. What is the dose-response relationship between vitamin D and cancer risk? Nutr Rev 65:S91-95.5. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. 2007. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 85:1586-1591.6. Aloia JF, Li-Ng M. 2007. Re: epidemic influenza and

vitamin D. Epidemiol Infect 135:1095-1096; author reply 1097-1098.7. Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, et al. 2008. Vitamin D Deficiency and Risk of Cardiovascular Disease. Circulation [Epub ahead of print].8. Hewison M, Burke F, KN, Lammas DA, Sansom DM, et al. 2007. Extra-renal 25-hydroxyvitamin D3-1alpha-hydroxyla se in human health and disease. J Steroid Biochem Mol Biol 103:316-321.9. Cannell J, Hollis B, Zasloff M, Heaney R. 2008. Diagnosis and treatment of vitamin D deficiency. Expert Opin Pharmacother 9:107-118.10. Pollan M. 2006. The Omnivore's Dilemma; Natural History of Four Meals. New York: Penguin Press. 430____________ _________ _________ ______BioEssays 30:508-509, 2008 Wiley Periodicals,Barbara J. BoucherCentre for Diabetes & Metabolic MedicineBarts & the London Medical & Dental School, London, UKE-mail: bboucher (AT) doctors (DOT) org.ukDOI 10.1002/bies. 20751Published online in Wiley InterScience (www.interscience. wiley.com) .Comment on "Vitamin D discovery outpaces FDA decision making""Before you let the sun in, make sure it wipes its shoes"Dylan , Under Milk Wood. 1954Sir,It is always wise to consider evidence from points of view other than those that are current `received wisdom' so that we can see clearly what we are really looking at. Thus, the above review is of considerable interest.(1) The author postulates that circulating hormonal [activated] vitamin D (calcitriol) concentration is more important than circulating 25-hydroxyvitamin D [25-(OH)D] in the determination of tissue functions that are modulated by vitamin D. He also appears to suggest that changes in circulating 25-hydroxy vitamin D reflect

changes in calcitriol formation and uptake rather than availability of vitamin D and that circulating calcitriol concentration tells us about vitamin D effectiveness. This would indeed be the case if all tissues depended on uptake of calcitriol from the circulation for their supplies of hormonal vitamin D. However, many tissues express the hydroxylase activating vitamin D and several have been confirmed as producers of calcitriol in situ.(2-4) Such tissues must use circulating 25-(OH)D, the substrate for activation by 25-hydroxyvitamin D 1-alphahydroxylase. Thus, for example, in the placenta, calcitriol is produced in large amounts from early in pregnancy with increases in circulating maternal calcitriol and reductions in maternal circulating 25-(OH)D.(4) However, to suggest that all variation on serum 25-(OH)D concentrations in different disease processes reflects changes in local tissue vitamin D

activation to the exclusion of variations due to the amount of vitamin D in the body would be to ignore the massive changes in serum 25-(OH)D seen within hours of exposure to UVB, without any changes in circulating calcitriol(5) and would not explain the remarkable seasonal variations in serum 25-(OH)D seen with variation in available effective UVB from sunlight, with variations in dietary intake of vitamin D and with supplement use. In Sweden for example, in a group of 116 women in the winter, an average serum 25(OH)D of 69 nmol/l was accounted for by the following: (1) daily intake of normally fortified Swedish foods, 6.2 nmol/l, (2) three fish meals/week, 25.5 nmol/l, (3) regular vitamin supplement use, 11.0 nmol/l and (4) a vacation in the sun within the last 6 months, 14.5 nmol/l, which leaves 11.8 nmol/l of 25-(OH)D to be accounted for the balance between incoming vitamin D and the amount of

25-(OH)D being consumed by local vitamin D activating tissues.(6,7) In addition, however much ultraviolet B effective for induction of vitamin D synthesis [effUVb] one is exposed to, vitamin D toxicity does not develop because of feed-back mechanisms in the skin itself.(8) Similarly, feedback mechanisms ensure that circulating calcitriol is virtually unchanged in the face of reductions in serum 25-(OH)D in the circulation until there is clinically obvious vitamin D deficiency with bone disease such as rickets or osteomalacia when calcitriol does eventually fall, though even then, in some case, serum calcitriol is found to be increased.(9) These findings challenge the argument that vitamin D modulation of tissue function depends predominantly on circulating calcitriol and explain why vitamin D repletion continues to be judged at present by circulating concentrations of the storage adduct, 25-(OH)D,

acting as it does as the substrate for local tissue activation throughout the body and not just in the kidney. In support of this position, it is well known that measurement of circulating calcitriol [hormonally active 1,25dihydroxyvitami n D] is unhelpful in the assessment of vitamin D repletion since its concentrations are normally so tightly regulated across a wide range of concentrations of 25-(OH)D.(10) Finally, the fact that vitamin D activation has been demonstrated in several of the extrarenal human tissues known to express specific vitamin D activating 1-alpha hydroxylase supports the view that assessment of substrate availability of vitamin D, as reflected by serum 25-(OH)D, is likely to be of importance in the assessment of vitamin D repletion in humans.References1. Marshall TG. 2008. Vitamin D discovery outpaces FDA decision making. BioEssays 30:173-182.2. Hewison M,

Burke F, KN, Lammas DA, Sansom DM, et al. 2007. Extra-renal 25-hydroxyvitamin Da-1alpha-hydroxyla se in human health and disease. J Steroid Biochem Mol Biol 103:316-321.3. Merke J, Milde P, Lewicka S, Hugel U, Mangelsdorf DJ, et al. 1989. J Clin Invest. 83:1903-1915.4. KN, Bulmer JN, Kilby MD, Hewison M. 2004. Vitamin D and placental-decidual function. J Soc Gynecol Investig 11:263-271.5. Landin-Wilhelmsen K, Wilhelmsen L, Wilske J, Lappas G, Rosen T, et al. 1995. Sunlight increases serum 25(OH) vitamin D concentration whereas 1,25(OH)2D3 is unaffected. Results from a general population study in Goteborg, Sweden (The WHO MONICA Project). Eur J Clin Nutr 49: 44-407.6. Engelsen O, Brustad M, Aksnes L, Lund E. 2005. Daily duration of vitamin D synthesis in human skin with relation to latitude, total ozone, altitude, ground cover, aerosols and cloud thickness. Photochem Photobiol

81:1287-1290.7. Burgaa A, Akesson A, Oster A, sson K, Wolk A. 2007. Associations of diet, supplement use and ultraviolet B radiation exposure with vitamin D status in Swedish women during winter. Am J Clin Nutr 86: 404.8. Bickle DD. 1997. Vitamin D and Skin. Chapter 25 in Vitamin D. Ed. Feldman D, Glorieux FH, Wesley Pike J. 379-394.9. Pettifor JM, s ED. 1997. Vitamin D deficiency and nutritional rickets in children. Chapter 42 in Vitamin D. Ed. Feldman D, Glorieux FH, Wesley Pike J. 663-678.10. Hollis B. 1997. Detection of vitamin D and its major metabolites. Chapter 38 in Vitamin D. Ed. Feldman D, Glorieux FH, Wesley Pike J. 587-606.____________ _________ _________ ______BioEssays 30:510-511, 2008 Wiley Periodicals, Inc.Trevor G. MarshallSchool of Biological Sciencesand Biotechnologyc/o 3423 Hill Canyon AvenueMurdoch UniversityWestern

AustraliaE-mail: trevor.m@autoimmuni tyresearch. orgAuthor's reply to correspondence from Drs Grant, Garland, and BoucherSir,The primary function of calcitriol, 1,25-dihydroxyvitam in-D (1,25-D), is to activate the Vitamin D Nuclear Receptor (VDR), enabling transcription and transrepression of genes. Even pathways previously thought to be 'non-genomic' have been shown to rely upon gene transcription. (1) Thus, the measured level of 25-hydroxyvitamin- D (25-D) is not sufficient to determine "Vitamin D deficiency" or "Vitamin D status". Only the 1,25-D form of Vitamin D has the ability to activate the VDR to transcribe genes, and therefore only measurements including this metabolite can accurately describe the overall homeostasis of the Vitamin D metabolism in man [see Ref. 2, Fig. 1].Dr Boucher has

highlighted many of the difficulties confronting clinical medicine as it expands its knowledge base from the level of tissues, as seen under the microscope, to that of individual genes and proteins, interacting at the submicroscopic scale of the molecule. Even though there are decades of clinical studies attempting to delineate the association between health, disease and the Vitamin D metabolites, any study conducted without reference to genes, or transcription, must necessarily lead to an incomplete characterization.Drs. Grant and Garland correctly note that low levels of 25-D are associated with many diseases. Yet they extrapolate that observation to imply that a causal relationship should be expected between this (largely inactive) metabolite, and those disease states. This is a non sequitur, as our article shows there is not a first-order mass-action relationship between the dosage of

exogenous Vitamin D and the measured level of the 25-D metabolite (see Ref. 2, Fig. 1). Not only are there multiple metabolic feedback control mechanisms, there are control inputs via Protein Kinase A (PKA), in addition to the steroid and xenobiotic ligands of PXR. Our article explains why the observed lower level of 25-D metabolite is a symptom of Vitamin D dysregulation resulting from the disease state, an attempt by the body to bring the level of the active metabolite back into its control range.Exploring the cause of the obesity epidemic, we took the rhetorical question from Bajzer and Seeley,(3) "are gut bacteria a factor in the obesity epidemic", and built a detailed putative pathogenesis, based on our molecular, and clinical, knowledge. Specifically cited were two carefully controlled studies,(4,5) which had failed to show a causal relationship between lifestyle, nutritional choices and

obesity. It would have been helpful if Grant and Garland could have addressed any specific failings they might have seen in those controlled studies, rather than give the citation they chose(6) as the basis for their argument.They suggest that deficiencies in the available clinical trials can be blamed on the low profit potential from sales of the secosteroid itself. Although the direct cost of Vitamin D supplements may not be great, there is money to be made from market positioning, enough to attract the interest of a large multinational. Our article explains how the Coca-Cola Company has petitioned the FDA to be allowed to add a high level of Vitamin D to their brands of orange juice, so that they can claim that it reduces the risk of osteoporosis. (7) There is clearly money available for higher quality studies. However, because this secosteroid is still classified as a vitamin, rather than

as a drug, the FDA has not yet begun insisting that a more rigorous understanding of the underlying biology be brought to bear upon Vitamin D trial design.Grant and Garland accept that sarcoidosis is a chronic inflammatory diagnosis in which Vitamin D supplementation might do harm, but we feel they need to address why other autoimmune diagnoses might not be similarly exacerbated by supplementation. Our 2004 paper "Sarcoidosis succumbs to antibiotics - implications for autoimmune disease"(8) canvassed a homogeneity of inflammatory pathogeneses, a hypothesis that has subsequently been supported by the emerging clinical evidence.(9- 11)We do not disagree with the primary premise of Grant and Garland, that Vitamin D supplementation of the food supply is one of the most important public health issues of our time. Our article is arguing that more sophisticated study designs will be needed if

one is to definitively evaluate the metabolism responsible for expression of at least 913 genes. Only then can we determine if, and to what degree, addition of Vitamin D to the food chain might be beneficial to the public's health.References1. Bravo S, Paredes R, Izaurieta P, Lian JB, Stein JL, et al. 2006. The classic receptor for 1alpha,25-dihydroxy vitamin D3 is required for non-genomic actions of 1alpha,25-dihydroxy vitamin D3 in osteosarcoma cells. J Cell Biochem 99:995-1000.2. Marshall TG. 2008. Vitamin D discovery outpaces FDA decision making. BioEssays 30:173-182.3. Bajzer M, Seeley RJ. 2006. Physiology: obesity and gut flora. Nature 444: 1009-1010.4. Caballero B, Clay T, SM, Ethelbah B, Rock BH, et al. 2003. Pathways Study Research Group. Pathways: a school-based, randomized controlled trial for the prevention of obesity in American Indian schoolchildren. Am J

Clin Nutr 78:904-905.5. Reilly JJ, L, Montgomery C, on A, Fisher A, et al. 2006. Physical activity to prevent obesity in young children: cluster randomised controlled trial. BMJ 333:1041.6. Pollan M. 2006. The Omnivore's Dilemma; Natural History of Four Meals. Penguin Press, New York. 430 pp.7. DHHS Food and Drug Administration. 2007. Food Labeling; Health Claims; Calcium and Osteoporosis, and Calcium, Vitamin D, and Osteoporosis. 21 CFR Part 101 [Docket No. 2004P-0464] Federal Register/Vol. 72, No. 3/Friday, January 5, 2007.8. Marshall TG, Marshall FE. 2004. Sarcoidosis succumbs to antibiotics - implications for autoimmune disease. Autoimmunity Reviews 3:295-3001.9. Waterhouse JC, Marshall TG, Fenter B, Mangin M, Blaney G. 2006. High levels of active 1,25-dihydroxyvitam in D despite low levels of the 25-hydroxyvitamin D precursor - Implications of dysregulated vitamin D for

diagnosis and treatment of Chronic Disease. In: Stoltz VD, editor. Vitamin D: New Research, Vol. 1. New York: Nova Science Publishers.10. Arnson Y, Amital H, Shoenfeld Y. 2007. Vitamin D and autoimmunity: New aetiological and therapeutic considerations. Ann Rheum Dis 66(9):1137-1142.11. Marshall TG. 2006. VDR Nuclear Receptor Competence is the Key to Recovery from Chronic Inflammatory and Autoimmune Disease. Abstractpresentation, Days of Molecular Medicine 2006. Copy available from URL http://autoimmunity research. org/karolinska- handout.pdf.____________ _________ _________ ______Best regards,Dave (father of (23); PSC 07/03; UC 08/03)

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