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Vitamin D - Health panacea or false prophet (Klotho gene) – Jan 2013

Vitamin D: Health panacea or false prophet?

Nutrition 29 (2013) 37-41, Article history: Received 27 March 2012 Accepted 11 May 2012
Michael J. Glade h.D., F.A.C.N., C.N.S. the_nutrition_doctor at yahoo.com.
The Nutrition Doctor, Skokie, Illinois, USA

Vitamin D deficiency, diagnosed when the serum 25-hydroxyvitamin D (25-OHD3) concentration is less than 20 ng/mL, has joined vitamin A deficiency as two of the most common nutrition-responsive medical conditions worldwide. There have been more scientific articles published about vitamin D in the 21st century than about any other vitamin, reflecting the massive expansion of the field of vitamin D research. Adequate vitamin D status has been linked to decreased risks of developing

  • specific cancers, including cancers of the esophagus, stomach, colon, rectum, gallbladder, pancreas, lung, breast, uterus, ovary, prostate, urinary bladder, kidney, skin, thyroid, and
  • hematopoietic system (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma);
  • bacterial infections;
  • rheumatoid arthritis;
  • Crohn's disease;
  • periodontal disease;
  • multiple sclerosis; a
  • sthma;
  • type 2 diabetes;
  • cardiovascular disease;
  • stroke;
  • peripheral artery disease;
  • hypertension;
  • chronic kidney disease;
  • muscle weakness;
  • cognitive impairment;
  • Alzheimer's disease;
  • clinical depression; and
  • premature death.

On the other hand, inadequate vitamin D status during human pregnancy may be associated with increased risk for the development of type 1 diabetes in the offspring. However, this point of view may be excessively optimistic. There also is evidence that despite the current heavy reliance on serum 25-OHD3 concentration for the diagnosis of an individual's vitamin D status, local tissue vitamin D intoxication may be present in individuals with much lower serum 25-OHD3 concentrations than are currently appreciated. Only rarely are the symptoms of local tissue vitamin D intoxication associated with vitamin D status or intake. An individual's serum 25-OHD3 concentration may appear to be "low" for reasons totally independent of sunlight exposure or vitamin D intake. Serum 25-OHD3 concentration is only poorly responsive to increases in vitamin D intake, and the prolonged routine consumption of thousands of international units of vitamin D may interfere with the regulation of phosphate homeostasis by fibroblast growth factor-23 (FGF23) and the Klotho gene product, with consequences that are detrimental to human health. In light of these counterbalancing observations, curbing excessive enthusiasm for universally increasing vitamin D intake recommendations may be in order.


There have been more scientific articles published about vitamin D in the 21st century than about any other vitamin (25 724 listed in MedLine between January 1, 2000 and April 30, 2012), reflecting the massive expansion of the field of vitamin D research. A recognized leader in this field, Michael F. Holick, Ph.D., M.D., has published innovative studies that have inspired hundreds of researchers around the globe to join the quest to identify and understand the roles of vitamin D in subcellular, cellular, tissue, and organ physiology, and human nutrition and nutritional therapeutics. This storm of scientific activity has been collated and summarized in the second edition of Dr. Holick's comprehensive textbook, Vitamin D: Physiology, Molecular Biology, and Clinical Applications (Humana Press, 2010). As Dr. Holick explains, vitamin D deficiency, diagnosed when blood 25-hydroxyvitamin D (25-OHD3) concentration is less than 20 ng/mL, has joined vitamin A deficiency as two of the most common nutrition-responsive medical conditions worldwide.

With classical clinical expression as poor skeletal development and bone and joint deterioration, vitamin D deficiency often begins with inadequate exposure to sunlight and is compounded by insufficient consumption of naturally occurring vitamin D and its precursors [1,2]. According to D. Holick, the biochemistry of vitamin D within the human body drives its physiology and ensures a wide margin of safety. He and his colleagues cite evidence that supports the argument that the chronic daily intake of 10 000 IU of vitamin D by adults in the absence of significant exposure to sunlight approximates the daily production of vitamin D in response to full-body exposure to sunlight and does not alter whole-body calcium metabolism or produce kidney stones and therefore is safe. In practice, Dr. Holick recommends adult daily vitamin D intakes of 1000 IU to 2000 IU, although he considers 10 000 IU to be completely safe for long-term daily consumption. Dr. Holick also recommends the therapeutic use of much larger amounts of vitamin D in the adjunctive treatment of several diseases that impair vitamin D absorption or utilization, including the nephritic syndrome, chronic renal disease, hyperparathyroidism, and granulomatous disorders in which the conversion of 25-OHD3 to 1,25-dihydroxyvitamin D (1,25-(OH)2D3) by CYP27B1 (formerly 1 a-hydroxylase) is accelerated within macrophages.

The diversity of vitamin D target genes is almost universal and the effects of vitamin D-induced gene activation affect nearly every cell in the body [3-5]. As explained by Carsten Carlberg of the University of Kuopio (Kuopio, Finland), the vitamin D receptor is a ligand-inducible transcription factor with target genes that are involved in cellular metabolism, bone formation, cellular development, and inflammation [6]. The ability to convert 25-OHD3 to 1,25-(OH)2D3 is not a strict prerequisite for vitamin D responsiveness; for example, human adipocytes lack CYP27B1 activity yet express the vitamin D receptor (VDR), with vitamin D response element (VDRE)-responsive genes suppressing the expression of uncoupling protein-2 and the induction of futile energy cycling [7,8]. In contrast to the many beneficial cellular responses to vitamin D, many of the genes containing VDRE are involved in dysregulated pathways that can produce cancer, osteoporosis, or the metabolic syndrome [6].

According to Dr. Holick and his colleagues, the extrarenal activation of vitamin D links vitamin D status to many aspects of human health. The discovery of extrarenal conversion of25-OHD3 to 1,25-(OH)2D3 by CYP27B1 in many tissues and of tissue-specific regulation of CYP27B1 expression is receiving increasing emphasis in current medical research [9]. For example, the roles played by extrarenal CYP27B1 activity and vitamin D in the differentiation and regulation of the immune system and in human defense mechanisms against tuberculosis have been examined in detail [10]. In another example of the critical roles played by tissue-specific regulation of local vitamin D activation, the human colo-nocyte expression of CYP27B1 activity suggests that the induction of this activity by dietary factors, coupled with concurrent suppression of vitamin D-deactivating CYP24A1 (formerly 25-OHD3-24-hydroxylase), may be truly chemopreventive by inhibiting the uncontrolled proliferation of human colonic epithelial cells while promoting their differentiation and normal apoptotic death [11]. In contrast, overexpression of CYP24A1 and of several VDR corepressors along with the cosuppression of CYP27B1 and the VDR may explain the resistance to vitamin D exhibited by human colon cancer cells [12].

The interactions between exposure to sunlight, vitamin D status, and cancer have been receiving serious examination in the post melanoma-panic era. It is now established that adequate vitamin D status is linked to decreased risks of developing specific cancers, including cancers of the esophagus, stomach, colon, rectum, gallbladder, pancreas, lung, breast, uterus, ovary, prostate, urinary bladder, kidney, skin, thyroid and hematopoietic system (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma) [3-5,13-34]. Similar data associate adequate vitamin D status with reduced risks for bacterial infections, rheumatoid arthritis, Crohn's disease, periodontal disease, multiple sclerosis, asthma, type 2 diabetes, cardiovascular disease, stroke, peripheral artery disease, hypertension, chronic kidney disease, muscle weakness, cognitive impairment, Alzheimer's disease, clinical depression, and premature death [3-5,13-16,18-21,35-75].Emerging data also link inadequate vitamin D status during human pregnancy with increased risk for the development of type 1 diabetes in the offspring [76].

Many of these putative benefits have been deduced from observed relationships between vitamin D intake, sunlight exposure, and the serum 25-OHD3 concentration. However, according to a series of lectures presented by H.L. Sam Queen, M.S., of the Institute for Health Realities, Colorado Springs, CO, USA (available from http://www.healthrealities.com ), although a direct correspondence between vitamin D exposure and serum 25-OHD3 concentration does appear to characterize healthy individuals, an individual's serum 25-OHD3 concentration may be low for reasons other than a lack of exposure to vitamin D. According to Queen, the existing data contain a perplexing anomaly: as many as 40% of men and women over the age of 85 y exhibit a serum 25-OHD3 concentration consistent with a diagnosis of long-standing vitamin D deficiency (serum 25-OHD3 concentration <20 ng/mL) [77]. Queen suggests that, taken together, these reports indicate that there may be an age at which vitamin D deficiency (as currently defined) may be life-sustaining, not life-threatening.

The explanation for this apparent paradox may be found in the emerging data regarding the interactions between the Klotho gene product and osteocyte-secreted FGF23 [78-82]. The Klotho gene product, a transmembrane protein with local glucosidase and hypocalciuric activities synthesized locally within renal tissue [79,83-86], is a required coactivator of FGF23[82,87,88].The rate of FGF23 secretion is correlated with the serum 1,25-(OH)2D3 concentration (and, therefore, with the serum 25-OHD3 concentration) [89,90]. Klotho gene product binding to the renal tubule FGF receptor (FGF receptor-1; FGFR1) increases the affinity of the receptor for FGF23 [83,85,91,92]. Coactivation of renal tubule FGFR1 by the Klotho gene product and FGF23 produces inhibition of renal reabsorption of phosphate via suppression of the activity of sodium-phosphate cotransporter type IIa on the apical brush-border membrane of renal tubules [82,86,88,93,94].FGFR1 activation also produces concurrent down-regulation of renal CYP27B1 [95] and up-regulation of the expression of CYP24A1 [88], reducing the renal content of active 1,25-(OH)2D3 and reducing further the efficiency of renal phosphate reabsorption [78,79, 82-84,88-90].

Klotho-deficient mice develop hypervitaminosis D at an early age and exhibit increased incidence of hyperphosphatemia, osteoporosis, ectopic calcifications, arteriosclerosis, hair loss, dermal thinning, emphysema, pituitary atrophy, infertility, and premature death [79,80]. In contrast, genetically altered mice that overexpress the Klotho gene exhibit increased resistance to oxidative stress and prolonged lifespan [79,81]. FGF23-deficient animals also develop hypervitaminosis D, hyperphosphatemia, and ectopic calcifications [96-98], while in humans early kidney disease is associated with decreased expression of the Klotho gene product, abnormally elevated serum FGF23 concentrations (that further down-regulate the Klotho gene) and hypovitaminosis D [99], hypophosphatemia [100,101], secondary hyperparathyroidism [99], cardiac dysfunction [102,103], and premature death [103,104].

Interestingly, when an across-species comparison of average longevity and average serum phosphate concentration was conducted, it was found that the average longevity per species (in years) was significantly inversely correlated with the average within-species serum phosphate concentration [78], suggesting (according to Queen) that excessive 1,25-(OH)2D3-induced stimulation of FGF23 secretion may not be consistent with maximum longevity.

In humans, the only known influences on Klotho expression are age and 1,25-(OH)2D3. Among the elderly, Klotho gene expression appears to become increasingly sensitive to negative feedback suppression by 1,25-OH2D3 [79]. In addition, genetic polymorphisms, toxic insults, autoimmune disease, gradually accumulating oxidative damage, or chronic mineral imbalances may result in dysfunctional vitamin D receptors with reduced affinity for 1,25-OH2D3 and reduced ability of 1,25-OH2D3 to induce the activity of renal CYP24A1, allowing 1,25-OH2D3 concentration to rise while relieving some of the negative feedback inhibition of the conversion of 25-OHD3 to 1,25-OH2D3 [105,106].When anexcess of dietary vitamin D is present, elevated systemic and local concentrations of 1,25-OH2D3 can occur. When an excess of 1,25-OH2D3 is present within a tissue, local hypervitaminosis D can be produced. In the mildly compromised kidney, local hypervitaminosis D can produce hyperphosphatemia, triggering increased FGF23 secretion, whereas elevated 1,25-OH2D3 concentration can inhibit hepatic 25-hydroxylation of ingested vitamin D, resulting in concurrent renal hypervitaminosis D and low serum 25-OHD3 concentration [100]. A desire to establish a higher serum 25-OHD3 concentration may encourage undue clinical reliance on potentially counterproductive dietary supplementation with increasing amounts of vitamin D.

In such a scenario, local vitamin D toxicosis can occur and produce renal atrophy and calcification that may go unrecognized until clinical signs of "idiopathic" renal disease appear [107]. Although Queen acknowledges that vitamin D plays important preventive and therapeutic roles in supporting human health, he cautions that renal and cardiovascular toxicity and increased mortality can be caused by covert physiologic vitamin D toxicosis [107]. For example, in the presence of age-associated reduction in Klotho expression, prolonged supplementation with large Klotho-suppressing amounts of vitamin D may produce 1,25-OH2D3 excess and low serum 25-OHD3 concentration while increasing the risk of the expression of an aberrant FGF23 gene product that fails to regulate renal phosphate reabsorption, resulting in hyperphosphatemic tumoral calcinosis with carotid artery calcification [108,109].

Queen also expresses concerns that the current interpretation of vitamin D requirements and contributions to human health results from an excessive reliance on epidemiologic evidence (the science of association) that has become dissociated from the basic science of vitamin D and mineral homeostasis. He suggests that rather than reflecting inadequate exposure to vitamin D, a low serum 25-OHD3 concentration may reflect, in some individuals, a set of internal homeostatic attempts to correct an excess of free calcium ions and therefore, viewed from a basic science perspective, a strong argument can be made for the conclusion that in some individuals, a low serum 25-OHD3 concentration results from disease rather than produces disease.

In cautioning against excessive enthusiasm for increasing vitamin D intake recommendations,
Queen emphasizes the following key points:

  • Despite the current heavy reliance on serum 25-OHD3 concentration for the diagnosis of an individual's vitamin D status, local tissue vitamin D intoxication may be present in individuals with much lower serum 25-OHD3 concentrations than are currently appreciated.
  • Only rarely are the symptoms of local tissue vitamin D associated with vitamin D status or intake.
  • A serum 25-OHD3 concentration may appear to be "low" for reasons totally independent of sunlight exposure or vitamin D intake.
  • Serum 25-OHD3 concentration is only poorly responsive to increases in vitamin D intake.
  • The prolonged routine consumption of megadoses of vitamin D may interfere with Klotho and FGF23 regulation of phosphate homeostasis with consequences that are detrimental to health.

The recent rush to elevate serum 25-OHD3 concentrations universally may benefit from a brief pause to reflect on the actual merits (and potential pitfalls) of doing so. Despite the detailed and persuasive data presented by Holick and his colleagues, reconsideration of the paradigm that a single or even a few biochemical markers can provide meaningful insight into the health status of an individual may be appropriate. This may be an area in which the modern reductionist approach to medical nutrition can benefit from an organismal reassessment.


  • [1] Glade MJ. A 21st century evaluation of the safety of oral vitamin D. Nutrition 2012;28:344-56.
  • [2] Norman AW. From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health .Am J Clin Nutr 2008;88:491S-9S.
  • [3] Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 2006;81:353-73.
  • [4] Nagpal S, Na S, Rathnachalam R. Noncalcemic actions of vitamin D receptor ligands. Endocr Rev 2005;26:662-87.
  • [5] Bikle D. Nonclassic actions of vitamin D. J Clin Endocrinol Metab 2009;94:26-34.
  • [6] Carlberg C, Molnar F. Current status of vitamin D signaling and its therapeutic applications. Curr Top Med Chem 2012;12:528-47.
  • [7] Wong KE, Szeto FL, Zhang W, Ye H, Kong J, Zhang Z, et al. Involvement of the vitamin D receptor in energy metabolism: regulation of uncoupling proteins. Am J Physiol Endocrinol Metab 2009;296:E820-8.
  • [8] Wong KE, Kong J, Zhang W, Szeto FL, Ye H, Deb DK, et al. Targeted expression of human vitamin D receptor in adipocytes decreases energy expenditure and induces obesity in mice. J Biol Chem 2011;286: 33804-10.
  • [9] Adams JS, Hewison M. Extrarenal expression of the 25-hydroxyvitamin D-1-hydroxylase. Arch Biochem Biophys 2012;523:95-102.
  • [10] Nnoaham KE, Clarke A. Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis. Int J Epidemiol 2008;37:113-9.
  • [11] Murillo G, Matusiak D, Benya RV, Mehta RG. Chemopreventive efficacy of 25-hydroxyvitamin D3 in colon cancer. J Steroid Biochem Mol Biol 2007;103:763-7.
  • [12] Bai YH, Lu H, Hong D, Lin CC, Yu Z, Chen BC. Vitamin D receptor gene polymorphisms and colorectal cancer risk: A systematic meta-analysis. World J Gastroenterol 2012;18:1672-9.
  • [13] Bischoff-Ferrari HA, Giovannucci E, WillettWC, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr 2006;84:18-28.
  • [14] Haussler MR, Haussler CA, Bartik L, Whitfield GK, Hsieh JC, Slater S, et al. Vitamin D receptor: Molecular signaling and actions of nutritional ligands in disease prevention. Nutr Rev 2008;66(suppl 2):S98-112.
  • [15] Jurutka PW, Bartik L, Whitfield GK, Mathern DR, Barthel TK, Gurevich M, et al. Vitamin D receptor: key roles in bone mineral pathophysiology, molecular mechanism of action, and novel nutritional ligands. J Bone Miner Res 2007;22(suppl 2):V2-10.
  • [16] Holick MF. The vitamin D epidemic and its health consequences. J Nutr 2005;135:2739S-48S.
  • [17] Knight JA, Lesosky M, Barnett H, Raboud JM, Vieth R. Vitamin D and reduced risk of breast cancer: a population-based case-control study. Cancer Epidemiol Biomarkers Prev 2007;16:422-9.
  • [18] Khazai N, Judd SE, Tangpricha V. Calcium and vitamin D: skeletal and extraskeletal health. Curr Rheumatol Rep 2008;10:110-7.
  • [19] Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266-81.
  • [20] Freedman DM, Looker AC, Chang SC, Graubard BI. Prospective study of serum vitamin D and cancer mortality in the United States. J Natl Cancer Inst 2007;99:1594-602.
  • [21] Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ, et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 2006;98:451-9.
  • [22] Garland CF, Comstock GW, Garland FC, Helsing KJ, Shaw EK, Gorham ED. Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study. Lancet 1989;2:1176-8.
  • [23] Gandini S, Raimondi S, Gnagnarella P. Dor_e JF, Maisonneuve P, Testori A. Vitamin D and skin cancer: a meta-analysis. Eur JCancer 2009;45:634-41.
  • [24] Vuolo L, Di Somma C, Faggiano A, Colao A. Vitamin D and cancer. Front Endocrinol (Lausanne) 2012;3:58. [25] Shin MH, Holmes MD, Hankinson SE, Wu K, Colditz GA, WillettWC. Intake of dairy products, calcium, and vitamin D and risk of breast cancer. J Natl Cancer Inst 2002;94:1301-11.
  • [26] Theodoratou E, Palmer T, Zgaga L, Farrington SM, McKeigue P, Din FV. Instrumental variable estimation of the causal effect of plasma 25-hydroxy-vitamin D on colorectal cancer risk: a mendelian randomization analysis. PLoS One 2012;7:e37662.
  • [27] Ng K, Wolpin BM, Meyerhardt JA, Wu K, Chan AT, Hollis BW, et al. Prospective study of predictors of vitamin D status and survival in patients with colorectal cancer. Br J Cancer 2009;101:916-23.
  • [28] Gorham ED, Garland CF, Garland FC, Grant WB, Mohr SB, Lipkin M, et al. Optimal vitamin D status for colorectal cancer prevention: a quantitative meta analysis. Am J Prev Med 2007;32:210-6.
  • [29] Wei MY, Garland CF, Gorham ED, Mohr SB, Giovannucci E. Vitamin D and prevention of colorectal adenoma: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2008;17:2958-69.
  • [30] Lee JE, Li H, Chan AT, Hollis BW, Lee IM, Stampfer MJ, et al. Circulating levels of vitamin D and colon and rectal cancer: the Physicians' Health Study and a meta-analysis of prospective studies. Cancer Prev Res 2011;4:735-43.
  • [31] Ma Y, Zhang P, Wang F, Yang J, Liu Z, Qin H. Association between vitamin D and risk of colorectal cancer: a systematic review of prospective studies.J Clin Oncol 2011;29:3775-82.
  • [32] Li H, Stampfer MJ, Hollis JB, Mucci LA, Gaziano JM, Hunter D, et al. A prospective study of plasma vitamin D metabolites, vitamin D receptor polymorphisms, and prostate cancer. PLoS Med 2007;4:e103.
  • [33] Tretli S, Hernes E, Berg JP, Hestvik UE, Robsahm TE. Association between serum 25(OH)D and death from prostate cancer. Br J Cancer 2009;100:450-4.
  • [34] Fang F, Kasperzyk JL, Shui I, Hendrickson W, Hollis BW, Fall K, et al. Pre-diagnostic plasma vitamin D metabolites and mortality among patients with prostate cancer. PLoS One 2011;6:e18625.
  • [35] Mathieu C, Gysemans C, Giulietti A, Bouillon R. Vitamin D and diabetes. Diabetologia 2005;48:1247-57.
  • [36] Williams S, Malatesta K, Norris K. Vitamin D and chronic kidney disease. Ethn Dis 2009;19(suppl 5). S5-8-11.
  • [37] Wilkins CH, Sheline YI, Roe CM, Birge SJ, Morris JC. Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults. Am J Geriatr Psychiatry 2006;14:1032-40.
  • [38] Mastaglia SR, Seijo M, Muzio D, Somoza J, Nunez M, Oliveri B. Effect of vitamin D nutritional status on muscle function and strength in healthy women aged over sixty-five years. J Nutr Health Aging 2011;15:349-54.
  • [39] Visser M, Deeg DJ, Lips P. Longitudinal Aging Study Amsterdam. Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): the Longitudinal Aging Study Amsterdam. J Clin Endocrinol Metab 2003;88:5766-72.
  • [40] Wilkins CH, Birge Sj, Sheline YI, Morris JC. Vitamin D deficiency is associated with worse cognitive performance and lower bone density in older African Americans. J Natl Med Assoc 2009;101:349-54.
  • [41] Bertone-Johnson ER, Powers SI, Spangler L, Brunner RL, Michael YL, Larson JC, et al. Vitamin D intake from foods and supplements and depressive symptoms in a diverse population of older women. Am J Clin Nutr 2011;94:1104-12.
  • [42] Michaelsson K, Baron JA, Snellman G, Gedeborg R, Byberg L, Sundstrom J, et al. Plasma vitamin D and mortality in older men: a community-based prospective cohort study. Am J Clin Nutr 2010;92:841-8.
  • [43] Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation 2008;117:503-11.
  • [44] Melamed ML, Muntner P, Michos ED, Uribarri J, Weber C, Sharma J, et al. Serum 25-hydroxyvitamin D levels and the prevalence of peripheral arterial disease: results from NHANES 2001 to 2004. Arterioscler Thromb Vasc Biol 2008;28:1179-85.
  • [45] Birge SJ, Haddad JG. 25-Hydroxycholecalciferol stimulation of muscle metabolism. J Clin Invest 1975;56:1100-7.
  • [46] Melamed ML, Michos ED, Post W, Astor B. 25-Hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med

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Comment by VitaminDWiki

Cannot deduce the point of this article

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