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Rapid Responses: Rapid Responses published:
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Vitamin D may be Harmful in Rheumatic Disease
- Trevor G Marshall, Frances E. Marshall (13 January 2003)
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Vitamin D deficiency may be mediating rotavirus diarrhoea
- Rajendra P Deolankar (13 March 2004)
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Rheumatic Disease is Th1, Viral Infections are (generally) Th2
- Trevor G Marshall (4 April 2004)
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Rotavirus linked Type 1 diabetes: 1,25-dihydroxyvitamin-D or molecular mimicry?
- Rajendra P Deolankar (21 April 2004)
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Diabetes is a Th1 Disease, Most Probably Bacterial in Pathogenesis
- Trevor G Marshall, Frances E. Marshall (21 April 2004)
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? Fractures = abuse ?
- Lisa C Blakemore-Brown (21 April 2004)
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Re: Rheumatic Disease is Th1, Viral Infections are (generally) Th2
- Peter Vanlandschoot (6 December 2004)
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Vitamin D is benefical in Rheumatic and Autoimmune Disease
- Ken M Lassesen, M.S. (26 January 2005)
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elevated levels of 1,25 (OH)2D3 and bone resorption
- Graham Chiu (29 May 2006)
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Trevor G Marshall, Research Director, SarcInfo 3423 Hill Canyon Ave, Thousand Oaks, CA 91360 USA, Frances E. Marshall
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We read with surprise the report from Ganapati Mudur that pressure was being brought on the Indian Government to supplement the food chain with Vitamin D. We would urge restraint, as we believe the risks to Public Health from such an action are not yet fully understood. Supplementation of the food chain in the USA has increased the suffering of many patients with chronic inflammatory disease, and may even be responsible for the increasing incidence of Arthritis in this country. Ingested Vitamin D is converted in the body to its active form, the secosteroid hormone 1,25-dihydroxyvitamin D (1,25-D). In addition to its well-known calcitropic activity, this hormone is active in the thyroid, the parathyroid, the lungs, the kidneys, the liver, the pancreas, the intestines and the muscles. Too much Vitamin D intake is not necessarily a good thing, even for the skeleton, where 1,25-D stimulates osteoclasts [1] and elevated levels of 1,25-D lead to bone resorption [2]. Yet the studies which are being used to urge supplementation of the Indian food chain have apparently not been based on assays of the active hormone, only on assays of an inactive intermediate, a metabolite called 25-hydroxyvitamin D (25-D). The incorrect assumption that the concentration of serum 25-D is 'the best index of vitamin D nutrition' is pervasive, and even if 1,25-D data is available, it has often been ignored [3]. In our opinion, that has been a terrible mistake. There is a radioimmunoassay which can measure the active hormone, so why aren't we doing that? It is incorrect to assume that a lowered serum level of 25-D is solely an indicator of an inadequate level of Vitamin D intake. We have found that some common disease processes can depress serum 25-D while maintaining an adequate level of the active hormone.
One of the most serious of those diseases is Sarcoidosis. The data above shows the interrelationship between serum 1,25-D (pmol/L) and serum 25-D (nmol/L) in the small, heterogeneous, subset of the population with which we have been working. These Sarcoidosis patients have a widely varying disease severity, and our results show there is no fixed relationship between the concentrations of the inactive and active D metabolites. Merck [4] suggests using 48-108 pmol/L as the normal range for serum 1,25-D. It is evident from Figure 1 that most of our cohort are presenting with significantly elevated concentrations of the active hormone. Many presented with the common symptoms of Hypervitaminosis D: fatigue, somnolence and asthenia. Those patients all received symptomatic relief after they had eliminated Vitamin D from their diets and returned their 1,25-D levels into the lower end of the normal range. But the raw data in Figure 1 is difficult to interpret, so we have devised a metric called the "D-Ratio". It is calculated by taking the ratio of serum 1,25-D (pmol/L) to serum 25-D (nmol/L). In a healthy population, where 1,25-D is produced primarily in the kidneys, the mean D-Ratio is 1.3, with an approximate standard deviation of 0.5 (based on data from Brot, et al, [5]). An increase in the inflammatory nonrenal conversion [6] will result in an elevation of the D-ratio. That is to say, an elevated D-ratio indicates that a lower serum 25-D concentration is capable of producing an adequate concentration of the active hormone. Figure 2 shows that our patients with the higher D-Ratios actually produce excessive concentrations of 1,25-D But it is Figure 3 that I want to focus upon. Here we have the 25-D concentrations of these patients plotted against the D-ratio. We can see that the most seriously ill patients (high D-Ratios) are presenting with the lowest values of 25-D. Yet supplementation of these patients is a totally incorrect therapy, as Figure 2 shows they already are producing excessive amounts of 1,25-D. Supplementation brings the likelihood of bone resorption and Hypervitaminosis D. We would respectfully submit that Vitamin D supplementation of the food chain might well be based on a flawed hypothesis. It has been assumed that when low values of serum 25-D are present in a population, then we must supplement that population. We would submit that this hypothesis cannot be accepted until studies showing that the alternate hypothesis, "that the depressed levels of 25-D are the result of disease processes, not inadequate intake", has been rejected. Sarcoidosis is a disease with low incidence, and a Public Health decision to ignore the well-being of this population subset might be justifiable. However, data is now becoming available which indicates that the same anomalous D metabolism has also been observed in Rheumatoid Arthritis, which, in the USA, has an incidence approaching 6% of the population [7]. Oelzner, et al [8], demonstrated that the average D-Ratio from 74 German post-menopausal women was 1.88, significantly elevated from the 1.3 of the healthy Danish adults [5]. British studies have also noted non-renal synthesis of 1,25-D in Arthritis [6] Serum 25-D levels were found to be elevated in South Indian patients with Ischemic Heart Disease (IHD) [9]. So the question has to be asked: "Is the excess Vitamin D possibly a causative factor in IHD?" We believe it is, and have described the likely biochemical pathway [10]. Is it really a good idea to supplement a food chain and increase the activity of this Vitamin D hormone? Finally we would note that it has become very difficult for our U.S. Sarcoid patients to avoid milk, and the other basic foodstuffs which have now been heavily supplemented with Vitamin D. We cannot understand how it could be in the best interests of Public Health to discuss "exposure to sunlight" and "fortification of dairy products" in the same sentence. The concentration of the former can be controlled by the individual, while the latter is forced upon all sectors of the population, exacerbating disease pathways that we still don't fully understand. References: 1. Manolagas SC: Birth and Death of Bone Cells: Basic Regulatory Mechanisms and Implications for the Pathogenesis and Treatment of Osteoporosis. Endocrine Reviews 2000; 21(2): 115-137 [Full Text] 2. Adams JS, Lee G: Gains in bone mineral density with resolution of vitamin D intoxication.Ann Intern Med 1997; 127(3): 203-6 [Full Text] 3. Marshall TG: Puzzling 1,25-dihydroxyvitamin D statistics. CMAJ 2002; 167(8): 849 [Full Text] 4. Merck. The Merck Manual of Diagnosis and Therapy - Vitamin D Deficiency and Dependency. 17th Edition, Section 1, Chapter 3 [Publisher Full Text] 5. Brot C, Jorgensen NR, Sorensen OH: The influence of smoking on vitamin D status and calcium metabolism. Eur J Clin Nutr Dec 1999; 53(12): 920-6 [ Abstract] 6. Mawer EB, Hayes ME, Still PE, Davies M, Lumb GA, Palit J, Holt PJ: Evidence for nonrenal synthesis of 1,25-dihydroxyvitamin D in patients with inflammatory arthritis. J Bone Miner Res 1991; 6(7): 733-9 [ Abstract] 7. Tennessee Dept of Health. Tennessee Arthritis Report, 2001. Nashville Tennessee [Full Text] 8. Oelzner P, Franke S, Muller A, Hein G, Stein G: Relationship between soluble markers of immune activation and bone turnover in post-menopausal women with rheumatoid arthritis. Rheumatology (Oxford) 1999; 38(9): 841-7 [Full Text] 9. Rajasree S, Rajpal K, Kartha CC, Sarma PS, Kutty VR, Iyer CS, Girija G: Serum 25-hydroxyvitamin D3 levels are elevated in South Indian patients with ischemic heart disease. Eur J Epidemiol 2001; 17(6): 567-71 [ Abstract] 10. Marshall TG, Marshall FE: Remission in Sarcoidosis. clinmed 2002 Aug 22;2002080004 [Full Text] ----------------------------- Competing interests: None declared |
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Rajendra P Deolankar, Assistant Director National Institute of Virology, Pune 411 001, India
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The rotavirus diarrhoea is widely prevalent in India (Jain et al, 2001 and Parashar et al, 2003). Winter (Aggarwal et al, 1988), Weaning (Motarjemi et al, 1993) and Weakening (Anderson and Weber, 2004) are major confounders of this diarrhoea. The risk factors related with the winter and thereby low exposures to the Sun are poorly understood. A functional NSP4 enterotoxin peptide secreted from rotavirus-infected intestinal cells causes intracellular calcium mobilization that leads to the diarrhoea (Zhang et al, 2000). Effect of vitamin D in prevention of the bone calcium mobilization is well known (Abrams, 2001) and monitoring of the calcium mobilization and interaction with the NSP4 enterotoxin peptide in the intestinal cells is obviously expected. This area is yet to be explored. Dr Kochupillai has suggested health education about exposure to sunlight and fortification of dairy products with vitamin D as simple preventive measures for vitamin D deficiency in India. His statements are based upon clinical experience and limited studies. He put forward that vitamin D deficiency is widespread in northern India (Mudur, 2003). It is also mentioned that a survey by paediatricians at New Delhi’s Kasturba Hospital earlier last year showed the presence of rickets among city children. The winter peak of incidence of rotavirus diarrhoea shown by Aggarwal et al, 1988 also happens to be in the same city. Mudur, 2003 also mentions that over 50% of healthy people surveyed in studies by Dr Ambrish Mithal have poor vitamin D levels. Marshall et al, 2003 have pointed out that assuming by Indian scientist that a lowered serum level of 25-hydroxyvitamin D (25- D) as a sole indicator of an inadequate level of Vitamin D intake is not correct and 1,25-dihydroxyvitamin D (1,25-D) should be assayed. However, he has not denied clinical picture presented by Indian authors. Summarily, the status of Vitamin D might mediate the rotavirus diarrhoea; an important point to be considered in the future laboratory and epidemiological studies. References: Abrams SA. Calcium turnover and nutrition through the life cycle. Proc Nutr Soc. 2001 May;60(2):283-9. Aggarwal P, Srivastav VK, Singh M, Khanna KK. Rotavirus shown to be the main cause of acute childhood diarrhoea in a New Delhi hospital with a high prevalence in winter. J Diarrhoeal Dis Res. 1988 Mar;6(1):39-40. Anderson EJ, Weber SG. Rotavirus infection in adults. Lancet Infect Dis. 2004 Feb;4(2):91-9. Jain V, Parashar UD, Glass RI, Bhan MK. Epidemiology of rotavirus in India. Indian J Pediatr. 2001 Sep;68(9):855-62. Motarjemi Y, Kaferstein F, Moy G, Quevedo F. Contaminated weaning food: a major risk factor for diarrhoea and associated malnutrition. Bull World Health Organ. 1993;71(1):79-92. Mudur Ganapati. Indian endocrinologists warn of vitamin D deficiency. BMJ 2003; 326:12 (4 January). Parashar UD, Hummelman EG, Bresee JS, Miller MA, Glass RI. Global illness and deaths caused by rotavirus disease in children. Emerg Infect Dis. 2003 May;9(5):565-72. Trevor G Marshall, Frances E. Marshall. Vitamin D may be Harmful in Rheumatic Disease. BMJ 2003; (13 January).Rapid response. Zhang M, Zeng CQ, Morris AP, Estes MK. A functional NSP4 enterotoxin peptide secreted from rotavirus-infected cells. J Virol. 2000 Dec;74(24):11663-70. Competing interests: None declared |
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Trevor G Marshall, Director Autoimmunity Research Foundation
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Rheumatic disease is associated with a vigorous Th1 immune reaction, almost certainly fueled by bacterial pathogens [1,2]. The active hormone resulting from 'Vitamin D' ingestion, 1,25-dihydroxyvitamin-D, is intimately associated with Th1 immune reactions, being responsible (inter alia) for differentiation of mast cells into monocytes and differentiation of monocytes into mature macrophages and dendritic cells [3]. Viral infections, on the other hand, typically elicit a Th2 immune response. Indeed, many viruses actively suppress the Th1 activity. An excellent explanation of how the non-infectious surface antigen of Hepatitis B (HBsAg) works to directly oppose the differentiation activity of 1,25-dihydroxyvitamin-D is expounded by Vanlandschoot, et al [4]. HIV has also been extensively studied, and found to similarly directly block the actions of 1,25-dihydroxyvitamin-D. In other words, bacterial pathogens (rheumatic disease) produce an excess of 1,25-dihydroxyvitamin-D in the inflamed tissues while viral infections actively counteract any 1,25-dihydroxyvitamin-D in those tissues. The concentration of serum 1,25-dihydroxyvitamin-D is also vitally important in cancers [5,6]. Further, there is a direct association between the levels of 1,25-dihydroxyvitamin-D and the prognosis of those cancers [5,6]. It is obvious that we are not dealing with the classical nutrient activities of a vitamin. 'Vitamin D' is the precursor of a steroid hormone which fuels an essential component of the body's Th1 immune response. Any calcemic activity is of far lesser importance. Indeed, it is the parathyroid hormone acting in concert with the calcium sensing receptors in the kidney which primarily determine calcemia in man [7,8]. As Dr Deolankar reminds us [9], there is a wealth of historical clinical observations which purport to describe the actions of Vitamin D on the human body. Unfortunately most of these studies are misguided, and many draw incorrect conclusions. One cannot accurately comprehend of the actions of 'Vitamin D' on the body without a comprehensive understanding of the (unfortunately complex) underlying molecular medicine. If a decision is made to supplement the food chain with 'Vitamin D', then one group of individuals (those with an under-active Th1 immune response) will be favored, while another group (those whose rheumatic disease has led to an overactive Th1 immune response) will be prejudiced. We would submit that public health officials should stay away from making such decisons until they fully understand all the implications of their actions.
1. Berger A: Th1 and Th2 responses: what are they? BMJ
2000;321:424 2. Marshall TG, Marshall FE: Sarcoidosis succumbs to antibiotics -
implications for autoimmune disease.
Autoimmunity Reviews, in press, doi:10.1016/j.autrev.2003.10.001 3. Hewison M, Gacad MA, Lemire J, Adams JS: Vitamin D as a cytokine and hematopoetic factor. Rev Endocr Metab Disord 2001, 2(2):217-27 PMID: 11705327 4. Vanlandschoot P, Van Houtte F, Roobrouck A, Farhoudi A, Leroux-Roels
G: Hepatitis B virus surface antigen suppresses the activation of
monocytes through interaction with a serum protein and a monocyte-specific
receptor. Journal of General Virology (2002), 83, 1281-1289 5. Mawer EB, Walls J, Howell A, Davies M, Ratcliffe WA, Bundred NJ: Serum 1,25-dihydroxyvitamin D may be related inversely to disease activity in breast cancer patients with bone metastases. J Clin Endocrinol Metab. 1997 Jan;82(1):118-22 PMID: 8989244 6. Lauerova L, Dusek L, Simickova M, Kocak I, Vagundova M, Zaloudik J, Kovarik J: Malignant melanoma associates with Th1/Th2 imbalance that coincides with disease progression and immunotherapy response. Neoplasma. 2002;49(3):159-66 PMID: 12098001 7. Watanabe T, Minagawa M: Familial hypoparathyroidism due to activating mutations in the calcium-sensing receptor gene. Nippon Rinsho. 2002 Feb;60(2):331-7 PMID: 11857922 8. Thakker RV: Disorders of the calcium-sensing receptor. Biochim Biophys Acta. 1998 Dec 10;1448(2):166-70 PMID: 9920407 9.Deolankar RP: Vitamin D deficiency may be mediating rotavirus diarrhoea. BMJ
Rapid Response, 2004 March 13; #53146 Competing interests: None declared |
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Rajendra P Deolankar, Assistant Director National Institute of Virology, Pune 411 001, INDIA
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Two
possibilities, rotavirus infection may (as observed by Honeyman et al, 2000) or
may not (as observed by Blomqvist et al, 2002) trigger or exacerbate islet
autoimmunity in genetically susceptible children to type 1 diabetes. The
remarks of Marshall et al, 2004 are important. He ascertains that the bacterial
pathogens (rheumatic disease) produce an excess of 1,25-dihydroxyvitamin-D
(1,25-D) in the inflamed tissues. On the other hand, the viral infections
(generally) actively counteract any 1,25-D in those tissues. These should be
time-honored. On this basis, latter of the two aforementioned possibilities
weigh better, and inference applies to the population studied. Molecular
mimicry, as suggested by Honeyman et al, 2000, could be a cause of autoimmunity
due to the virus in the former study. The inflammation of pancreatic islets may
be caused due to rotavirus growth. This clue is thought to be because pancreatic
islets from nonobese diabetic mice, nonobese diabetes-resistant mice, fetal
pigs, and macaque monkeys, in vitro, supported various degrees of
growth of rhesus rotavirus and also pancreatic islets of monkey, in vitro,
supported replication of human rotaviruses (Coulson et al, 2002). The said
inflammation could be independent of production of 1,25-D in the inflamed
tissues as the agent is the virus and not the bacteria (rheumatic disease)
unless complication occurs. Is
it not a high time for the scientists working on acute pediatric diarrhea or
pediatric diabetes associated with rotavirus to link their disease observations
with the level of serum 1,25-D or D-Ratio devised by Marshall et al, 2004? It is
also necessary to answer the question whether the levels of serum 1,25-D or D
ratios are risk factors or the effect of the diseases and how the different risk
factors and/or preventive measures work together. Most of the Indians are
traditionally Sun worshippers and believe that exposure to the morning Sun is
beneficial for prevention of the diseases. Could members of diurnal species like
human stay away completely from Sun? Regular
exposure of kids of Delhi to the morning sunlight at Delhi latitude shall
prevent rickets. It may also be hypothesized that optimal sunbath at least
partially contributes to build up resistance to rotavirus diarrhea in the
pediatric subjects of Delhi. The pathogenesis of acute infectious pediatric
diarrhea is due to rotavirus causing intracellular calcium mobilization in
intestinal cells (Zhang (M) et al, 2000) and increased permeability of intestine
due to rotavirus infection (Zhang (Y) et al, 2000) are the bases for making this
hypothesis. Unfortunately, regular exposure of kids (most of them in Delhi are
dark skinned) to the morning sunlight -- a free gift of nature -- is rather
difficult in this crowded and air-polluted city. If
the aforementioned hypothesis is accepted as a result of proposed clinical
study, then the pathogenesis far-off from intestine may also be curbed if the
virus is checked in the intestine itself by the life style providing an optimal
sunbath and thereby not allowed to cross the intestinal barrier and so also not
allowing translocation of bacteria (Duffy, 2000), toxins and antigens. Fortification
of foods with vitamin D may not be agreeable at this juncture as suggested by
Marshall, 2004 as the entire population consumes such food. The diarrhea and the
suspected autoimmunity due to rotavirus may or may not be the two sides of the
same coin and should be investigated in future laboratory and epidemiological
studies. References: Honeyman
MC, Coulson BS, Stone NL, Gellert SA, Goldwater PN, Steele CE, Couper JJ, Tait
BD, Colman PG, Harrison LC. Association between rotavirus infection and
pancreatic islet autoimmunity in children at risk of developing type 1 diabetes.
Diabetes. 2000 Aug;49(8):1319-24. [Abstract] Blomqvist
M, Juhela S, Erkkila S, Korhonen S, Simell T, Kupila A, Vaarala O, Simell O,
Knip M, Ilonen J. Rotavirus infections and development of diabetes-associated
autoantibodies during the first 2 years of life. Clin Exp Immunol. 2002
Jun;128(3):511-5.[Abstract] Marshall,
TG. Rheumatic Disease is Th1, Viral Infections are (generally) Th2. BMJ 2004; (4
April).Rapid response.[Full
text] Coulson
BS, Witterick PD, Tan Y, Hewish MJ, Mountford JN, Harrison LC, Honeyman MC.
Growth of rotaviruses in primary pancreatic cells. J Virol. 2002
Sep;76(18):9537-44.[Abstract] Zhang
M, Zeng CQ, Morris AP, Estes MK. A functional NSP4 enterotoxin peptide secreted
from rotavirus-infected cells. J Virol. 2000 Dec;74(24):11663-70. [Abstract] Zhang
Y, Lee B, Thompson M, Glass R, Cama RI, Figueroa D, Gilman R, Taylor D,
Stephenson C. Lactulose-mannitol intestinal permeability test in children with
diarrhea caused by rotavirus and cryptosporidium. Diarrhea Working Group, Peru.
J Pediatr Gastroenterol Nutr. 2000 Jul;31(1):16-21. Erratum in: J Pediatr
Gastroenterol Nutr 2000 Nov;31(5):578.[Abstract] Duffy
LC. Interactions mediating bacterial translocation in the immature intestine. J
Nutr. 2000 Feb;130(2S Suppl):432S-436S.[Abstract] Competing interests: None declared |
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Trevor G Marshall, Research Director Autoimmunity Research Foundation, California 91360, Frances E. Marshall
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Diabetes is a Th1 immune process , both Type 2 diabetes [1] and Type 1 [2]. The immune system's Th1 response is typically induced by intracellular pathogens, particularly pathogens which have invaded the phagocytes themselves [3]. It been shown that rotavirus can use molecular mimcry to elicit a Th1 response [6], and may therefore contribute to the pathogenesis of diabetes as described by Deolankar [7]. However, we consider it far more likely that the rotaviral antibodies are more easily observed in the bloodstream than antibodies to the bacterial pathogens precisely because those viruses are not actively involved in the pathogenesis of diabetes. We suggest that the rotavirus is merely a readily observable bystander, not the instigator of the disease process. Intra-cellular bacterial pathogens enter the immune system through a defect in the protective surface proteins of immature macrophages and subsequently inhibit phagocytosis, leading to a viable and stable symbiotic relationship. Such long-term stability is essential to maintain the continuity of the disease process. Further, there is an increasing volume of studies demonstrating that bacteria, including Mycobacterium Bovis (used in BCG vaccinations) can both induce diabetes [4] and provide protection from diabetes [5]. These are not observations which should be considered mutually exclusive. We would suggest that the dichotomy results from variability in genetics between individuals. The genetic susceptibilty which predisposes individuals to allow intra-cellular pathogens to parasitize their immune systems leads to 'autoimmune' disease, including diabetes. The majority of the population, those whose immune systems correctly produce antibiodies against those same bacteria, are actually innoculated against harmful parasites by the identical bacterial exposure. The 'autoimmune' or 'rheumatic' diseases have remained an enigma for a century. Louis Pasteur said "Chance favors the prepared mind" and we were fortunate to find well-documented examples of parasitization of phagocytes in (arguably) the most chronic of these diseases, Sarcodiosis [3]. Once their function was elucidated in that disease it became much simpler to understand the remaining Th1 disease processes. The steroid-hormone/cytokine 1,25-dihydroxyvitamin-D appears to be capable of alternately weakening the surface proteins protecting phagocytes from parasitization, or protecting against that parasitization, depending on individual's genetic susceptibilities. We suggest that it is important not to look at the viral antibodies (which represent failure of the viral pathogen in its parasitization attempt), but to focus on the pathogens which have actually managed to safely make their homes within the phagocytes themselves - a true success story for any parasite. We believe that these bacteria, which are not killed by the immune system (and therefore don't form antibodies), carry the secrets of the Th1 diseases. 1. Yang Z, Chen M, Ellett JD, Fialkow LB, Carter JD, McDuffie M, Nadler JL: Autoimmune diabetes is blocked in Stat4-deficient mice. J Autoimmun. 2004 May;22(3):191-200. PMID: 15041039 2. Oikawa Y, Shimada A, Kasuga A, Morimoto J, Osaki T, Tahara H, Miyazaki T, Tashiro F, Yamato E, Miyazaki J, Saruta T: Systemic administration of IL-18 promotes diabetes development in young nonobese diabetic mice. J Immunol. 2003 Dec 1;171(11):5865-75.PMID: 14634096 3. Marshall TG, Marshall FE: Sarcoidosis succumbs to antibiotics - implications for autoimmune disease.Autoimmunity Reviews, in press, doi:10.1016/j.autrev.2003.10.001 4. Guo YX, Luo ML, Lin ZB: Establishment of immune insulin resistance model in the rats by i.v. injection of BCG. Yao Xue Xue Bao. 2002 May;37(5):321-5. PMID: 12579832 5. Silveira PA, Baxter AG: The NOD mouse as a model of SLE. Autoimmunity. 2001;34(1):53-64.PMID: 11681493 6. Vancott JL, McNeal MM, Choi AH, Ward RL: The role of interferons in rotavirus infections and protection. J Interferon Cytokine Res. 2003 Mar;23(3):163-70. PMID: 12716489 7. Deolankar RP: Rotavirus linked Type 1 diabetes: 1,25-dihydroxyvitamin-D or molecular mimicry. BMJ Rapid Response #57269, 21 April 2004. Available from URL http://bmj.bmjjournals.com/cgi/eletters/326/7379/12/b#57269 Accessed Apr 21, 2004 Competing interests: None declared |
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Lisa C Blakemore-Brown, Psychologist Based in UK
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Perhaps there will now be some serious attempts to ascertain why these vitamin deficiences are occurring and leading to bone deformities and fractures, especially as in the UK, if the latter are found, particularly in children, physical abuse is laid at the door of the carer. Even when no evidence can be found to attach that blame, the very existence of fractures is deemed synonymous with abuse. The system of professionals needs to be trained to understand that there can be other causes for what are deemed to be fractures. If, however, it transpires that some iatrogenic process is leading to these unexpected and unusual findings of fractures, rickets etc., then I am sure all responsible professionals, Judges and politicians will recognise that this is very serious iatrogenic child abuse on a grand scale and will immediately seek to prevent such abuse continuing in the system, and will put in place funding for the research to prevent and ameliorate such damage. This is all the more crucial and urgent a task for Governments as it appears the problems are widespread in the Western world, affecting whole generations, and undoubtedly underreported and misrepresented. Competing interests: None declared |
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Peter Vanlandschoot, Group leader Center for Vaccinology, Ghent University, 9000 Ghent, Belgium
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I noticed that Trevor G Marshall refers to a paper I published (Vanlandschoot P, Van Houtte F, Roobrouck A, Farhoudi A, Leroux-Roels G: Hepatitis B virus surface antigen suppresses the activation of monocytes through interaction with a serum protein and a monocyte-specific receptor. Journal of General Virology (2002), 83, 1281-1289). According to Trevor Marshall I provided in this paper an excellent explanation of how the non- infectious surface antigen of Hepatitis B (HBsAg) works to directly oppose the differentiation activity of 1,25-dihydroxyvitamin-D. I wish to point out that in my paper I do not demonstrate such activity of hepatitis B surface antigen. I only used 1,25-dihydroxyvitamin-D to induce expression of CD14 on THP-1 pre-monocytic cells and such more matured cells were subsequently used to demonstrate that Hepatitis B surface antigen inhibited lipopolysaccharide-induced activation of the cells. Competing interests: None declared |
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Ken M Lassesen, M.S., Consultant Kingston, 98346
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Vitamin D is an important immune system regulator[1]. Its impact on Multiple Sclerosis, an autoimmune disease, has been well studied with the following generally accepted:
Vitamin D has been identified as a significant factor for incidence of several autoimmune illnesses such as multiple sclerosis, rheumatoid arthritis, insulin-dependent diabetes mellitus, and inflammatory bowel disease[5]. Significant improve from taking vitamin D has been reported for several autoimmune illnesses, for example rheumatoid arthritis[6] and lupus[7]. Studies of fibromyalgia and persistent, nonspecific musculoskeletal pain have found that low levels of vitamin D is common[9]. The literature strongly suggests vitamin D supplementation. [1] Zhu, Monica Froicu, and Anja Wittke Vitamin D status, 1,25-dihydroxyvitamin D3 and the Immune System, Margherita T Cantorna, Yan Am J Clin Nutr 2004;80(suppl):1717S–20S. http://www.ajcn.org/cgi/content/full/80/6/1717S
[2] Goldberg, P., Multiple Sclerosis: vitamin D and calcium as environmental determinants of prevalence. Part 1: Sunlight, dietary factors and epidemiology. Intern. J. Environmental Studies, v. 6, p. 19-27, 1974. Goldberg, P., Multiple Sclerosis: vitamin D and calcium as environmental determinants of prevalence. Part 2: Biochemical and genetic factors. Intern. J. Environmental Studies, v. 6, p.121-129, 1974. [3] Lemire, J. and Archer, D., 1991, 1,25-dehydroxyvitamin D3 prevents the in vivo induction of murine experimental autoimmune encephalomyelitis. J. Clin. Invest., v. 87, p. 1103-1107. [4] D Michal Freedmana, Mustafa Dosemecib, Michael C R Alavanjab Mortality from multiple sclerosis and exposure to residential and occupational solar radiation: a case-control study based on death certificates. Occup Environ Med 2000;57:418-421 http://oem.bmjjournals.com/cgi/content/full/57/6/418 [5] Cantorna MT. Vitamin D and autoimmunity: is vitamin D status an environmental factor affecting autoimmune disease prevalence? Proc Soc Exp Biol Med. 2000 Mar;223(3):230-3. http://www.ebmonline.org/cgi/content/full/223/3/230 Cantorna MT, Mahon BD. Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence. Exp Biol Med (Maywood). 2004 Dec;229(11):1136-42. http://www.ebmonline.org/cgi/content/full/229/11/1136 [6] Cantorna, M., Hayes, C. and DeLuca, H., 1,25-Dihydroxycholecalciferol inhibits the progression of arthritis in murine models of human arthritis. Journal of Nutrition, v. 128, p. 68-72. 1998 http://www.nutrition.org/cgi/content/full/128/1/68 [7] Lemire JM, Ince A, Takashima M. 1,25-Dihydroxyvitamin D3 attenuates the expression of experimental murine lupus of MRL/l mice. Autoimmunity. 1992;12(2):143-8.
[9] Al-Allaf AW, Mole PA, Paterson CR, Pullar T. Bone health in patients with fibromyalgia. Rheumatology (Oxford). 2003 Oct;42(10):1202-6. Epub 2003 Jun 16. http://rheumatology.oupjournals.org/cgi/content/full/42/10/1202 Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain Mayo Clin Proc. 2003 Dec;78(12):1463-70. Competing interests: None declared |
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Graham Chiu, Rheumatologist Capital Sports Medicine, Wellington, New Zealand
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Marshall refers to [1] as a paper indicating that increased levels of 1,25(OH)2D3 can cause increased bone resorption. However, the paper clearly states "All four patients with elevated 25-hydroxyvitamin D levels were hypercalciuric, but none was hypercalcemic or had an elevated 1,25- dihydroxyvitamin D level. " Veith [2] has also been critical of the diagnosis of the vitamin D intoxication as reported in [1]. The diagnosis of vitamin D intoxication normally requires the presence of hypercalcaemia, and this was not present. 1. Adams JS, Lee G: Gains in bone mineral density with resolution of vitamin D intoxication.Ann Intern Med 1997; 127(3): 203-6 2. Veith, R: Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. American Journal of Clinical Nutrition, Vol. 69, No. 5, 842-856, May 1999 Competing interests: None declared |
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