Vitamins

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Yvonne
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Re: Vitamins

Post by Yvonne » Tue 24 Nov 2009 10:10

http://www.medicalnewstoday.com/articles/171536.php

Women At Risk From Vitamin A Deficiency
Almost half of UK women could be suffering from a lack of vitamin A due to a previously undiscovered genetic variation, scientists at Newcastle University have found.

The team, led by Dr Georg Lietz, has shown that almost 50 per cent of women have a genetic variation which reduces their ability to produce sufficient amounts of vitamin A from beta-carotene.

Vitamin A - also known as retinol- plays a vital role in strengthening our immune system, protecting us against common infections such as flu and winter vomiting.

Vitamin A also helps to maintain healthy skin and mucus linings such as inside the nose and the lungs

In 1987, an American study found that excessive use of vitamin A during pregnancy was associated with certain birth defects. Beta-carotene, however, was deemed to be safe and this led to the general advice that we should eat more of this nutrient, allowing the body to convert what it needs into vitamin A.

However, Dr Lietz' latest research - published in the FASEB Journal and presented this month at the 2nd Hohenheim Nutrition Conference in Stuttgart - shows that for many women, beta-carotene is not an effective substitute for vitamin A.

Dr Lietz explained: "Vitamin A is incredibly important - particularly at this time of year when we are all trying to fight off the winter colds and flu.

"It boosts our immune system and reduces the risk of inflammation such as that associated with chest infections.

"What our research shows is that many women are simply not getting enough of this vital nutrient because their bodies are not able to convert the beta-carotene."

From a volunteer group of 62 women, the team found that 29 of them - 47 per cent - carried the genetic variation which prevented them from being able to effectively convert beta-carotene into vitamin A.

The study also showed that all volunteers consumed only about a third of their recommended intake from 'preformed' vitamin A - the form found in dairy products such as eggs and milk - indicating that those volunteers carrying the genetic variation were not eating enough vitamin A-rich foods to reach the optimum level their body required to function.

"Worryingly, younger women are at particular risk," explained Dr Lietz, who is based in the School of Agriculture, Food and Rural Development at Newcastle University.

"The older generations tend to eat more eggs, milk and liver which are naturally rich in vitamin A whereas the health-conscious youngsters on low-fat diets are relying heavily on the beta-carotene form of the nutrient."

The next step in the study is to assess whether the effect of the genetic variation can also be observed in men and whether our body composition will influence our ability to absorb and convert beta-carotene into vitamin A.

Source: Dr. Georg Lietz
Newcastle University
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Re: Vitamins

Post by Yvonne » Mon 4 Jan 2010 9:39

http://ajprenal.physiology.org/cgi/cont ... l/289/1/F8

ABSTRACT

The vitamin D endocrine system plays an essential role in calcium homeostasis and bone metabolism, but research during the past two decades has revealed a diverse range of biological actions that include induction of cell differentiation, inhibition of cell growth, immunomodulation, and control of other hormonal systems. Vitamin D itself is a prohormone that is metabolically converted to the active metabolite, 1,25-dihydroxyvitamin D [1,25(OH)2D]. This vitamin D hormone activates its cellular receptor (vitamin D receptor or VDR), which alters the transcription rates of target genes responsible for the biological responses. This review focuses on several recent developments that extend our understanding of the complexities of vitamin D metabolism and actions: the final step in the activation of vitamin D, conversion of 25-hydroxyvitamin D to 1,25(OH)2D in renal proximal tubules, is now known to involve facilitated uptake and intracellular delivery of the precursor to 1-hydroxylase. Emerging evidence using mice lacking the VDR and/or 1-hydroxylase indicates both 1,25(OH)2D3-dependent and -independent actions of the VDR as well as VDR-dependent and -independent actions of 1,25(OH)2D3. Thus the vitamin D system may involve more than a single receptor and ligand. The presence of 1-hydroxylase in many target cells indicates autocrine/paracrine functions for 1,25(OH)2D3 in the control of cell proliferation and differentiation. This local production of 1,25(OH)2D3 is dependent on circulating precursor levels, providing a potential explanation for the association of vitamin D deficiency with various cancers and autoimmune diseases.
CONCLUDING REMARKS

Critical findings in the last five years have improved our understanding of vitamin D bioactivation and actions and the relevance of the vitamin D endocrine system in disease prevention.

In relation to vitamin D bioactivation to 1,25(OH)2D, CYP2R1, a nonexclusively hepatic cytochrome P-450, was identified as the critical 25-hydroxylase, suggesting that hepatic and extrahepatic 25-hydroxyvitamin D synthesis could contribute to vitamin D status. In the kidney, 25-hydroxyvitamin D uptake by proximal tubular cells was shown to require receptor-mediated endocytosis by megalin, a protein not ubiquitously distributed and induced by 1,25(OH)2D3, whereas intracellular vitamin D binding proteins mediate the final transport of 25(OH)D to mitochondrial 1-hydroxylase. Cell-specific differences in the expression of the proteins mediating active substrate uptake and delivery to renal 1-hydroxylase in kidney disease and to the extrarenal 1-hydroxylases of DC and numerous other cell types should affect not only serum 1,25(OH)2D3 levels but local 1,25(OH)2D3 production and, therefore, 1,25(OH)2D3 autocrine control of immune responses, cell growth, differentiation, and secretory function.

Of great importance in 1,25(OH)2D3-VDR regulation of gene transcription were the findings that the 1,25(OH)2D3-VDR complex controls the gene expression of critical nuclear coregulator molecules and splicing by the splicesome, thus regulating not only the cell competence in inducing or repressing VDR transcriptional activity but also the splicing of transcripts of vitamin D-responsive genes.

Several VDR-dependent and -independent mechanisms were characterized as critical in bone remodeling and renal and intestinal calcium uptake, or parathyroid and chondrocyte growth, respectively. Also, a novel cross talk emerged between extracellular calcium and 1,25(OH)2D3-VDR. The 1,25(OH)2D3-VDR complex not only controls extracellular calcium levels but the cellular responses to calcium as well, through modulation of the expression of the calcium sensor in the parathyroid glands and in several other tissues, including the kidney. In turn, extracellular calcium modulates the response to 1,25(OH)2D3-VDR, in a cell-specific manner, through the selective recruitment to the nuclear VDR of coregulator molecules that affect VDR transactivation potency.

The link between a defective vitamin D endocrine system and hypertension, cancer, and noncarcinogenic hyperproliferative disorders, autoimmune diseases, and susceptibility to infections has been further characterized. The 1,25(OH)2D3-VDR complex was found to 1) suppress the renin-angiotensin system; 2) induce C/EBP, a potent suppressor of the cyclin D1 oncogene in epithelial carcinomas in humans, and an inducer of macrophage differentiation and immune function; 3) promote and/or prevent apoptosis as required for normal tissue development; 4) inhibit growth signals from activated EGFR in EGFR-driven carcinomas and secondary hyperparathyroidism; and 5) modulate the immunogenic or tolerogenic state of DC, the main determinants of the susceptibility to infections, autoimmune diseases, or the development of tolerance after transplantation.

The strong epidemiological association between vitamin D status [rather than serum 1,25(OH)2D levels] and susceptibility to infections, autoimmune diseases, and cancer suggests an advantage for local 1,25(OH)2D3 production over systemic 1,25(OH)2D3 administration in growth arrest, immunomodulation, and cell secretory functions. Future studies in this area should help optimize the use of the vitamin D endocrine system in disease prevention
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Re: Vitamins

Post by Yvonne » Sun 7 Feb 2010 11:28

http://www.medicalnewstoday.com/articles/177496.php

Low Vitamin D Levels Linked To Poorer Lung Function In Asthmatics
Asthmatics with higher blood levels of vitamin D have better lung function than those with lower levels, according to new research from National Jewish Health, in Denver.

The findings have been published online ahead of print publication in the American Thoracic Society's American Journal of Respiratory and Critical Care Medicine.

E. Rand Sutherland, M.D., M.P.H, the lead author and his colleagues enrolled 54 nonsmoking asthmatics, assessed their levels of serum vitamin D [25(OH)D] and tested their lung function and airway hyper-responsiveness (both hallmarks of asthma.) They also tested the subjects' response to steroid treatment.

"Our goal was to assess whether vitamin D levels were associated with asthma severity in adults," said Dr. Sutherland, who is chief of the pulmonary division at National Jewish Heath.

They found that with decreasing levels of vitamin D, subjects performed more poorly on tests of lung function and airway hyper-responsiveness

"We showed that in adults with asthma, lower vitamin D levels were associated with lower lung function, an increased propensity for bronchospasm and poorer steroid response," said Dr. Sutherland.

Furthermore, the effect seemed to be dose dependent: The lower the vitamin D level, the worse the subjects tended to perform on tests of lung function and airway hyperresponsiveness. Airway hyper-responsiveness nearly doubled in subjects with serum levels of vitamin D below the "sufficient" threshold level of 30ng/ml, when compared to subjects with higher levels.

In addition to its association with lower lung function, increased airway hyper-responsiveness, and poorer response to steroids, a lower level of vitamin D was associated with increased production of the pro-inflammatory cytokine, TNF-α, by immune cells in the blood, raising the possibility that low vitamin D levels could be linked to enhanced inflammation in asthma.

Vitamin D levels were also inversely correlated with body mass index (BMI)-the higher the BMI of a subject, the lower their vitamin D levels tended to be. "Asthma is known to be associated with obesity. The lower levels of vitamin D in obese subjects may illuminate one factor that ties obesity and asthma together," said Dr. Sutherland.

"Our findings suggest that vitamin D levels influence a number of important features of asthma, including lung function, bronchospasm and therapeutic response to steroids," said Dr. Sutherland. "The next question to answer is whether giving supplemental vitamin D will lead to clinical improvements in patients with asthma, highlighting the need for clinical trials in this area."

Source
American Thoracic Society
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Re: Vitamins

Post by Yvonne » Tue 9 Mar 2010 19:48

http://www.medicalnewstoday.com/articles/181501.php

Low Levels Of Vitamin D Linked To Muscle Fat, Decreased Strength In Young People
There's an epidemic in progress, and it has nothing to do with the flu. A ground-breaking study published in the March 2010 Journal of Clinical Endocrinology and Metabolism found an astonishing 59 per cent of study subjects had too little Vitamin D in their blood. Nearly a quarter of the group had serious deficiencies (less than 20 ng/ml) of this important vitamin. Since Vitamin D insufficiency is linked to increased body fat, decreased muscle strength and a range of disorders, this is a serious health issue.

"Vitamin D insufficiency is a risk factor for other diseases," explains principal investigator, Dr. Richard Kremer, co-director of the Musculoskeletal Axis of the Research Institute of the MUHC. "Because it is linked to increased body fat, it may affect many different parts of the body. Abnormal levels of Vitamin D are associated with a whole spectrum of diseases, including cancer, osteoporosis and diabetes, as well as cardiovascular and autoimmune disorders

The study by Dr. Kremer and co-investigator Dr. Vincente Gilsanz, head of musculoskeletal imaging at the Children's Hospital Los Angeles of the University of Southern California, is the first to show a clear link between Vitamin D levels and the accumulation of fat in muscle tissue - a factor in muscle strength and overall health. Scientists have known for years that Vitamin D is essential for muscle strength. Studies in the elderly have showed bedridden patients quickly gain strength when given Vitamin D.

The study results are especially surprising, because study subjects - all healthy young women living in California - could logically be expected to benefit from good diet, outdoor activities and ample exposure to sunshine - the trigger that causes the body to produce Vitamin D.

"We are not yet sure what is causing Vitamin D insufficiency in this group," says Dr. Kremer who is also Professor of Medicine at McGill University. High levels of Vitamin D could help reduce body fat. Or, fat tissues might absorb or retain Vitamin D, so that people with more fat are likely to also be Vitamin D deficient."

The results extend those of an earlier study by Dr. Kremer and Dr. Gilsanz, which linked low levels of Vitamin D to increased visceral fat in a young population. "In the present study, we found an inverse relationship between Vitamin D and muscle fat," Dr. Kremer says. "The lower the levels of Vitamin D the more fat in subjects' muscles."

While study results may inspire some people to start taking Vitamin D supplements, Dr. Kremer recommends caution. "Obviously this subject requires more study," he says. "We don't yet know whether Vitamin D supplementation would actually result in less accumulation of fat in the muscles or increase muscle strength. We need more research before we can recommend interventions. We need to take things one step at a time
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Re: Vitamins

Post by Yvonne » Tue 9 Mar 2010 19:49

http://www.medicalnewstoday.com/articles/181515.php

Vitamin D Crucial To Activating Immune Defenses
Scientists at the University of Copenhagen have discovered that Vitamin D is crucial to activating our immune defenses and that without sufficient intake of the vitamin, the killer cells of the immune system - T cells - will not be able to react to and fight off serious infections in the body.

For T cells to detect and kill foreign pathogens such as clumps of bacteria or viruses, the cells must first be 'triggered' into action and 'transform' from inactive and harmless immune cells into killer cells that are primed to seek out and destroy all traces of a foreign pathogen.

The researchers found that the T cells rely on vitamin D in order to activate and they would remain dormant, 'naïve' to the possibility of threat if vitamin D is lacking in the blood

Chemical Reaction that Enables Activation

In order for the specialized immune cells (T cells) to protect the body from dangerous viruses or bacteria, the T cells must first be exposed to traces of the foreign pathogen. This occurs when they are presented by other immune cells in the body (known as macrophages) with suspicious 'cell fragments' or 'traces' of the pathogen. The T cells then bind to the fragment and divide and multiply into hundreds of identical cells that are all focused on the same pathogen type. The sequence of chemical changes that the T cells undergo enables them to both be 'sensitized to' and able to deliver a targeted immune response.

Professor Carsten Geisler from the Department of International Health, Immunology and Microbiology explains that "when a T cell is exposed to a foreign pathogen, it extends a signaling device or 'antenna' known as a vitamin D receptor, with which it searches for vitamin D. This means that the T cell must have vitamin D or activation of the cell will cease. If the T cells cannot find enough vitamin D in the blood, they won't even begin to mobilize."

T cells that are successfully activated transform into one of two types of immune cell. They either become killer cells that will attack and destroy all cells carrying traces of a foreign pathogen or they become helper cells that assist the immune system in acquiring "memory". The helper cells send messages to the immune system, passing on knowledge about the pathogen so that the immune system can recognize and remember it at their next encounter. T cells form part of the adaptive immune system, which means that they function by teaching the immune system to recognize and adapt to constantly changing threats.

Activating and Deactivating the Immune System

For the research team, identifying the role of vitamin D in the activation of T cells has been a major breakthrough. "Scientists have known for a long time that vitamin D is important for calcium absorption and the vitamin has also been implicated in diseases such as cancer and multiple sclerosis, but what we didn't realize is how crucial vitamin D is for actually activating the immune system - which we know now. "

The discovery, the scientists believe, provides much needed information about the immune system and will help them regulate the immune response. This is important not only in fighting disease but also in dealing with anti-immune reactions of the body and the rejection of transplanted organs. Active T cells multiply at an explosive rate and can create an inflammatory environment with serious consequences for the body. After organ transplants, e.g. T cells can attack the donor organ as a "foreign invader". In autoimmune disease, hypersensitive T cells mistake fragments of the body's own cells for foreign pathogens, leading to the body launching an attack upon itself.

The research team was also able to track the biochemical sequence of the transformation of an inactive T cell to an active cell, and thus would be able to intervene at several points to modulate the immune response. Inactive or 'naïve' T cells crucially contain neither the vitamin D receptor nor a specific molecule (PLC-gamma1) that would enable the cell to deliver an antigen specific response

The findings, continues Professor Geisler "could help us to combat infectious diseases and global epidemics. They will be of particular use when developing new vaccines, which work precisely on the basis of both training our immune systems to react and suppressing the body's natural defenses in situations where this is important - as is the case with organ transplants and autoimmune disease."

Most Vitamin D is produced as a natural byproduct of the skin's exposure to sunlight. It can also be found in fish liver oil, eggs and fatty fish such as salmon, herring and mackerel or taken as a dietary supplement. No definitive studies have been carried out for the optimal daily dosage of vitamin D but as a large proportion of the population have very low concentrations of vitamin D in the blood, a number of experts recommend between 25-50mg micrograms a day.

The findings will be published in the latest edition of Nature Immunology, (Vitamin D controls T cell antigen receptor signaling and activation of human T cells ) 10.1038/ni.1851, on 07 March 1800 London Time/1300 Us Eastern Time.
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Re: Vitamins

Post by Yvonne » Fri 19 Mar 2010 18:35

http://www.medicalnewstoday.com/articles/182425.php

Treating Vitamin D Deficiency Significantly Reduces Heart Disease Risk
Preventing and treating heart disease in some patients could be as simple as supplementing their diet with extra vitamin D, according to two new studies at the Intermountain Medical Center Heart Institute in Murray, Utah.

Researchers at the Intermountain Medical Center Heart Institute last fall demonstrated the link between vitamin D deficiency and increased risk for coronary artery disease. These new studies show that treating vitamin D deficiency with supplements may help to prevent or reduce a person's risk for cardiovascular disease and a host of other chronic conditions. They also establish what level of vitamin D further enhances that risk reduction.

Study findings was presented at the American College of Cardiology 59th annual scientific session in Atlanta on March 15, 2010

"Vitamin D replacement therapy has long been associated with reducing the risk of fractures and diseases of the bone," says Dr. J. Brent Muhlestein, MD, director of cardiovascular research at the Intermountain Medical Center Heart Institute. "But our findings show that vitamin D could have far greater implications in the treatment and reduction of cardiovascular disease and other chronic conditions than we previously thought."

For the first study, researchers followed two groups of patients for an average of one year each. In the first study group, over 9,400 patients, mostly female, reported low initial vitamin D levels, and had at least one follow up exam during that time period. Researchers found that 47 percent of the patients who increased their levels of vitamin D between the two visits showed a reduced risk for cardiovascular disease.

In the second study, researchers placed over 31,000 patients into three categories based on their levels of vitamin D. The patients in each category who increased their vitamin D levels to 43 nanograms per milliliter of blood or higher had lower rates of death, diabetes, cardiovascular disease, myocardial infarction, heart failure, high blood pressure, depression, and kidney failure. Currently, a level of 30 nanograms per milliliter is considered "normal."

Heidi May, PhD, a cardiovascular clinical epidemiologist with the Intermountain Medical Center Heart Institute, and one of the study's authors, says the link between low levels of vitamin D and increased risk for a variety of diseases is significant.

"It was very important to discover that the 'normal' levels are too low. Giving physicians a higher level to look for gives them one more tool in identifying patients at-risk and offering them better treatment," says Dr. May.

Dr. Muhlestein says the results of these studies will change the way he treats his patients.

"Although randomized trials would be useful and are coming, I feel there is enough information here for me to start treatment based on these findings," he says.

Treatment options in this case are simple, starting with a blood test to determine a patient's vitamin D level. If low levels are detected, supplements and/or increased exposure to sunlight may be prescribed.

Increasing vitamin D intake by 1000 to 5000 international units (IU) a day may be appropriate, depending on a patient's health and genetic risk, says Dr. Muhlestein. He says supplements are the best source of vitamin D because they are relatively inexpensive and can be found at almost any supermarket or drug store. Most supplements provide an average of 400 IU per tablet.

While exposure to 20-30 minutes of sunlight can provide up to 10,000 IU, Dr. Muhlestein says it is important to use sunscreen and avoid the hottest parts of the day in order to avoid sunburn and the harmful UV rays associated with skin cancer
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Re: Vitamins

Post by Yvonne » Fri 19 Mar 2010 18:38

http://www.medicalnewstoday.com/articles/182304.php

Vitamin D Levels Have Different Effects On Atherosclerosis In Blacks And Whites
Vitamin D is quickly becoming the "go-to" remedy for treating a wide range of illnesses, from osteoporosis to atherosclerosis. However, new evidence from a Wake Forest University School of Medicine study suggests that supplementing vitamin D in those with low levels may have different effects based on patient race and, in black individuals, the supplement could actually do harm.


The study is the first to show a positive relationship between calcified plaque in large arteries, a measure of atherosclerosis or "hardening of the arteries," and circulating vitamin D levels in black patients. It appears in the March issue of the Journal of Clinical Endocrinology and Metabolism.

"In black patients, lower levels of vitamin D may not signify deficiency to the same extent as in whites," said the study's lead investigator, Barry I. Freedman, M.D., John H. Felts III Professor and chief of the section on nephrology at the School of Medicine "We should use caution when supplementing vitamin D in black patients while we investigate if we are actually worsening calcium deposition in the arteries with treatment."

Vitamin D is widely used to treat patients with osteoporosis and/or low vitamin D levels based on a medically accepted normal range. This "normal" range is typically applied to all race groups, although it was established predominantly in whites. It is thought that as low vitamin D levels rise to the normal range with supplementation, protection from bone and heart disease (atherosclerosis) may increase, as well.


Blacks generally have lower vitamin D levels than whites, partly because their darker skin pigmentation limits the amount of the vitamin produced by sunlight. Blacks also consume fewer dairy products and ingest less dietary calcium than whites, said Freedman, an affiliate of the Maya Angelou Center for Health Equity, part of the School of Medicine. Despite these lower vitamin D levels and dietary calcium ingestion, blacks naturally experience lower rates of osteoporosis and have far less calcium in their arteries. Studies further reveal that black patients with diabetes have half the rate of heart attack as whites, when provided equal access to health care. This shows that lower levels of calcified atherosclerotic plaque in blacks are associated with a lower risk of heart disease. However, blacks in the general community have higher rates of heart attack than whites, potentially due to unequal access to medical care, Freedman said.

The research team determined the relationship between circulating vitamin D levels and arterial calcium in 340 black men and women with type 2 diabetes. Calcium can deposit in blood vessel walls forming a bone-like material called "calcified atherosclerotic plaque" and this plaque can be detected by computed tomography (CT) scans. Calcified atherosclerotic plaque is a reliable predictor of risk for heart attack and stroke. The investigators measured vitamin D levels in all study participants and then performed a CT scan to detect calcium in the heart and major arteries.

"We found that higher circulating levels of vitamin D in blacks were associated with more calcium in the artery walls," Freedman said. "This is the opposite effect of what is felt to occur in white patients and shows that the accepted "normal" range of vitamin D may be different between blacks and whites.

"Many of these study patients would be placed on supplemental vitamin D by their physicians simply because their levels were felt to be in the low range." Freedman added that physicians should use caution in supplementing vitamin D levels in blacks - especially if they do not have weak bones or other reasons to take this vitamin - until the effects of supplementing vitamin D on blood vessels and heart disease are better understood.

"Doctors frequently prescribe supplemental vitamin D," Freedman said. "However, we do not know all of its effects and how they may differ between the races. The bottom line is that racial differences in calcium handling are seen and black and white patients have differing risk for bone and heart disease. We should more clearly determine the effects of supplementing vitamin D in black patients with low levels based on existing criteria and should not assume that the effects of supplementation will be the same between the races
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Re: Vitamins

Post by Yvonne » Sun 25 Apr 2010 10:30

http://tinyurl.com/379r22e

The journal of Pediatrics Volume 156, Issue 5, Pages 698-703 (May 2010)


Vitamin D and the Magic Mountain: The Anti-Infectious Role of the Vitamin
Vitamin D status has become a “hot topic” in human nutrition.1, 2, 3, 4, 5, 6, 7 In part, the concept of osseous and non-osseous effects of the active form of the vitamin underlies this expanded emphasis on vitamin D nutrition.

There are 2 mechanisms by which human beings acquire vitamin D: ingestion from the diet and synthesis after exposure to sunlight. The discovery that appreciable segments of human populations are vitamin D-deficient or -insufficient,3, 8 with the finding that essentially all human tissues contain a vitamin D receptor (VDR), has led to new interest in the vitamin D system and the mechanisms of its hormonal action.1, 2, 4, 5, 6, 9, 10, 11, 12, 13, 14, 15 Although the role of this secosteroid hormone on skeletal status has long been recognized,6, 11, 16 recent and mounting evidence suggests that it affects immune function and can protect against cancer, cardiovascular disease, infection, and autoimmune disorders such as multiple sclerosis and type 1 diabetes mellitus.2, 6, 11, 14, 17

Vitamin D status is best assessed by measuring circulating 25-hydroxyvitamin D (25[OH]D) values.1, 4, 5, 10, 12, 13, 14, 15 Large population surveys, such as the National Health and Nutrition Examination Survey, indicate that substantial segments of infant, child, and pregnant women populations are vitamin D-deficient or -insufficient.3, 7, 12, 13 Parenthetically, the association of infection and vitamin D deficiency has long been noted, and some of these biologic effects were described more than a century ago, even before the concept of vitamins had been surmised.

Recently, it has been hypothesized that subjects' vitamin D status can be divided into ranges of serum 25(OH)D concentrations termed deficient, insufficient, or sufficient. One study defined 25(OH)D values <15 ng/mL as deficient, those 15 to 30 ng/mL as insufficient, and those >30 ng/mL as sufficient. Traditionally, a serum 25(OH)D value <10 ng/mL has been considered the cutoff point for deficiency.2, 18 A division into “deficient” and “sufficient” with a cutoff point of 20 ng/mL has been proposed, but many people have serum 25(OH)D levels this low.1, 2, 3, 4, 5, 6, 7 These concentrations should be viewed as approximate guides to vitamin D status and may vary slightly with the season or latitude.

There can be concern about vitamin D toxicity from overdosing. Current guidelines from the Section on Breastfeeding and the Committee on Nutrition of the American Academy of Pediatrics recommend “that all infants and children, including adolescents, have a minimum daily intake of 400 IU (10 μg) of vitamin D beginning soon after birth.”19 Because of northern latitudes, the Canadian Paediatric Society recommends increasing vitamin D intake from 400 IU/day to 800 IU/day between October and April above the 55th parallel. These doses are felt to be safe and effective in preventing vitamin D deficiency.19, 20

Although mineral balance is regulated by the calcium-vitamin D-parathyroid hormone (PTH)-endocrine system,6 many of the non-skeletal effects of vitamin D appear to operate outside this tight feedback-controlled endocrine loop,5, 6, 18, 21, 22 and thus are independent of regulation by serum calcium, phosphorus, and PTH levels.

Ultimately, our understanding of the complex clinical effects of the vitamin and implications of its insufficiency rests on 3 degrees of evidence. This is especially relevant for the immunomodulation roles of vitamin D and its skeletal effects. The first is observation and association, such as children with rickets are more likely to develop pneumonia or tuberculosis (TB) than children without rickets.2, 6, 11, 16 Second, on the basis of epidemiologic studies of defined populations, gradations of vitamin D status have clinical implications. For example, deficiency or insufficiency can be associated with infection after dental procedures, other infections,2, 6, 9, 11, 15 or pneumonia.16 Third, vitamin D and its metabolites operate at tissue, cellular, and nuclear sites6, 9, 22 and likely alter immune function at a subcellular level.21, 22 Again, we now know more about the anti-infectious role of vitamin D; this level of function is not under the tight feedback control of the vitamin D endocrine system.22

The association of vitamin D with infectious disorders has actually been recognized for more than a century, but clinicians believed that infections caused rickets.16, 23, 24, 25 It is timely to examine infections during the epidemic of rickets that occurred from 1650 to 1930. This review will examine some of the infectious complications of vitamin D deficiency with a historical perspective and the currently understood anti-infectious mechanisms of action of activated vitamin D. This story is still unfolding and forms a fascinating chapter in the story of vitamin D.
Historical Context
Circumstances in the social and geographical features of Glasgow, Scotland, in the late 19th and early 20th centuries provide a window into the full scope of rickets, which was common in Europe and North America. Not only was the prevalence of rickets high,26 it was so common that it was actually difficult to find enough non-rachitic children to conduct clinical trials on the etiology of rickets in Glasgow.27 In 1908, >1000 osteotomies were performed on rachitic children at the Royal Hospital for Sick Children.26, 27 The mortality rate from TB and pneumonia was approximately 30% to 40% higher in Glasgow and environs than in the remainder of Scotland.26, 28

Glasgow sits at 55.858°N and has limited sunlight from October to April. It was also a large urban center for heavy manufacturing (iron, railway engine, and ship building), all fueled by coal and coke. Because of conditions of extreme crowding, the smog of coal fires, children living in some of the worst slums in Europe, and the high prevalence of TB and pneumonia, it was only natural to attribute rickets to infection caused by crowding.25 However, there was also a great deal of crowding in the tiny plots and hovels (bothies) of Highland crofters in Scotland, where both rickets and lung infection rates were lower.28 It is probable that children of crofters had greater sun exposure and ate some fish that contained vitamin D.

Why should vitamin D influence the occurrence or severity of infections? The concept of rickets as an infection was “seductive” and initially difficult to disprove.23 The similarity of the conditions under which infections (eg, typhus and TB) occur contributed to this hypothesis.

An association between infection and the prototypical disorder of vitamin D deficiency, nutritional rickets, has its origins in observations from the 17th to 19th centuries.6, 11, 18 Indeed, many clinical scholars of the 19th century postulated that infection actually caused rickets. Robert Koch sought an infectious agent as the primary etiologic factor of rickets.16 Sir William Jenner, a founder of the Great Ormond Street Hospital for children, described the association of rickets with TB.29 Howland and Holt, major scholars of rickets, noted that rachitic lung often was found to be interstitial pneumonitis.30 However, by the mid 1920s, the concept of an “antirachitic factor” in cod liver oil was secure. Manville wrote that fat-soluble vitamin deficiency “leads to infections of the respiratory tract and very frequently [to] pyogenic involvement.”16 Fatal rickets often involved an infection as a factor in a downward spiral toward death. The infection hypothesis became less secure, and it was appreciated that it was vitamin D deficiency that led to infection. We need to understand how these anti-infectious effects occur
Vitamin D as an Immune Modulator
In the past 15 years, we have sought mechanisms to account for the non-osseous effects of vitamin D. Vitamin D, particularly in its active form, 1,25(OH)2D, is appreciated as a secosteroid that functions as a gene transcription factor. After binding to a VDR, this complex is then translocated to an intranuclear site.6, 17 VDRs are found in >30 tissue types, including the heart, intestine, liver, kidney, lungs, and various immune cells, such as thymic and bone marrow T and B cells.6, 11, 17 After binding of 1,25(OH)2D to VDRs, a heterodimerization with a retinoid X receptor (RXR; eg, 9-cis retinoic acid) occurs, and after translocation into the nucleus and binding to DNA, the transcriptional regulation of >200 proteins occurs. These proteins not only influence calcium and phosphate homeostasis, but also cell proliferation, cell differentiation, and immune function.6, 17, 21, 31

The various cells of the immune system—antigen-presenting cells (dendritic cells), macrophages, and T and B cells—express VDRs. This expression may be constitutive or induced post-stimulation.31 Expression of 25(OH)D vitamin D 1α-hydroxylase (CYP27b1) is found in monocytic and dendritic cells after immune stimulus.32 1,25(OH)2D appears to act on all immune-related cells.6, 22, 31 This active form of vitamin D blocks dendritic cell maturation. In addition, 1,25(OH)2D influences T cell gene expression of an impressive set of cytokines (interleukin [IL]1, lL2, IL I2, IL 17, interferon gamma [INFγ]) required for antigen presentation to T cells. Additional immunomodulating features include anti-proliferative and pro-differentiative actions, with both immune enhancement and suppression.17, 21 An effect of 1,25(OH)2D action is to reduce activation of the acquired immune system, especially in dampening the development of or enhancement of autoimmune disorders (eg, multiple sclerosis or type 1 diabetes mellitus).6, 17, 18, 31, 33 Treatment with 1,25(OH)2D can also ameliorate either experimental or spontaneous autoimmune disorders in rodent models of experimental allergic encephalitis, nephritis, inflammatory bowel disease, and diabetes mellitus.6, 17, 31, 32 Epidemiologic studies in humans indicate that vitamin D intake early in life may reduce risk of type 1 diabetes mellitus, with risk reduction of 78% with 2000 IU/day.32 Although these studies strongly suggest a role of optimizing perinatal and neonatal vitamin D status in the prevention of type 1 diabetes mellitus, randomized prospective trials are only now being conducted. However, examination of this vast array of immune disorders is beyond the scope of this review. Hence, we will focus on innate immunity and respiratory infections.
Influence on Innate Immunity
Although 1,25(OH)2D action dampens the effects of activation of the acquired immune system relative to autoimmunity, this hormone has key actions that enhance the innate immune system.6, 17, 21, 33 The influence of vitamin D on innate immunity is dependent on tissue concentrations of 1,25(OH)2D and is regulated by 2 enzymes: the activating 25(OH)D 1α-hydroxylase (CYP27b1) and its catabolic counterpart, 25(OH)D 24-hydroxylase (CYP24).6 The entry of 25(OH)D, the main substrate for CYP27b1 and CYP24, into the cell depends on 25(OH) binding to D-binding protein (DBP) and subsequent recognition, internalization, and intracellular release of this molecule.17, 33, 34, 35

The innate immune system begins with the epithelial barrier between the bacteria abundant in the outside environment and the effectively sterile host. When bacterial products gain entry to the host, they are recognized by a class of receptors in the plasma membrane of macrophages known as Toll-like receptors (TLRs). These TLRs recognize a panoply of antigens, including nucleic acids, lipids, and peptides.17, 36 When bound, these TLRs recruit various adaptor proteins (eg, MyD88) that turn on signaling pathways, many of which terminate in the transaction of NFκB. This innate immune response is activated by antigens that result in up-regulation of the VDR and activation by 1,25(OH)2D.37 The VDR promotes antigen processing, phagocytosis, and IL-1β and tumor necrosis factor α production,21, 36, 37, 38 which form the mechanisms by which foreign antigens are ultimately eliminated.

The macrophage is capable of accumulating 25(OH)D and locally producing 1,25(OH)2D. Adams and his group21 have postulated this forms “a primitive, non-endocrine biological system designed to control immune responsiveness to invading antigens.” They opine that this primitive immune system may phylogenetically pre-date the vitamin D endocrine system that controls divalent mineral balance, because 1,25(OH)2D production is not feedback regulated by prevailing serum mineral concentrations

The metabolism of 25(OH)D to 1,25(OH)2D as a local event appears to differ in the innate (macrophage) and acquired (dendritic cell) immune cells. The macrophage expresses CYP27b1, necessary for 1,25(OH)2D synthesis, but not 25(OH)D 24 hydroxylase.21 In part this is because infection/inflammation results in INFγ-induced STAT1α (signal transducer and activators of transcription-1α) activity, which down-regulates CYP24 expression (Figure).17 Hence, 1,25(OH)2D levels in the cell remain high. Activation of the TLR system in the macrophage can also work through this STAT1α pathway. This might explain why patients with an extrarenal macrophage or granulomatous source of active vitamin D lack the ability to down-regulate further synthesis of this molecule after exposure to exogenous 1,25(OH)2D. If macrophages in pleural effusions die and then leak 1,25(OH)2D into the extracellular milieu (which results in increased calcium absorption by the intestine), these patients may become hypercalcemic and hypercalciuric.39 As mentioned, there is no feedback regulation of macrophage vitamin D metabolism.

Activation by TLR type 2/1 ligand (TLR2/1L) binding results in vitamin D-dependent induction of fundamental antimicrobial peptides (AMPs). It also has been shown that IL-15 and IL-4 can stimulate macrophage differentiation, but only IL-15 can induce CYP27b1, resulting in VDR activation, and induce the synthesis of a specific AMP, namely cathelicidin.40 It is theorized that 25(OH)D in sufficient concentrations within the macrophage can trigger IL-15-differentiated macrophages to induce specific AMPs that act against intracellular Mycobacterium tuberculosis.21, 38, 39, 40 IL-15 links TLR2/1-induced macrophage differentiation to the vitamin D-dependent pathway. Although IL-15 classically promotes differentiation and activation of lymphocytes (for example, NK, B and T cells) and induces T cell memory, it also activates monocytes/macrophages.40 The picture that is emerging is that vitamin D acts through cytokine pathways to form defensins, endogenous AMPs that result in intracellular killing of organisms that have invaded the cell.21

As aforementioned, another aspect of inflammation and infection is that the up-regulation of CYP24 is hampered by INFγ-sustained STAT1α, which results in sustained elevated 1,25(OH)2D levels and continuing production of AMPs.17 This VDR-related action to combat infection may have an intracrine effect within the same cell or a paracrine effect on a neighboring cell.

TB is a prototypical infection that is influenced by vitamin D status41 and by the innate immune response.17, 21, 39, 40 Macrophages stimulated by live M tuberculosis produce large amounts of 1,25(OH)2D. In particular, TLR1/2-primed macrophages kill M tuberculosis, whereas the bacterium survives inside TLR1/2-primed dendritic cells.33 When macrophages are infected with fluorescein-labeled BCG (tuberculosis vaccine—“bacillus of Calmette and Guerin”) both cathelicidin and the organism are co-localized to the macrophage cell membrane.22, 33

Consistent with these fundamental cellular mechanisms defining the importance of adequate 25(OH)D values is the finding that reduced serum 25(OH)D is associated with a higher risk for active tuberculosis, as discerned by meta-analysis.41
Vitamin D Status and Implications for Infection
The role of vitamin D status in innate immunity helps explain some of long-held views on the role of sunlight in the clinical course of TB. Both clinical observations and epidemiologic studies exist that show that M tuberculosis is suppressed by sunlight exposure and by habitation at higher elevations.42 TB is more common in patients with rickets and vitamin D deficiency per se6, 22; it is also more prevalent in dark-skinned individuals whose melanin blocks out the UV wavelength necessary for cutaneous vitamin D synthesis.6, 9 What is now understood is that innate immunity against M tuberculosis is influenced by serum 25(OH)D concentration, and the organism is killed by cathelicidin, synthesized after macrophage production of 1,25(OH)D.33 Thus, in essence, the autocrine immune action of macrophages is positively influenced by vitamin D sufficiency.

The practice of treating subjects with TB in a sun-exposed open air mountainous location (a “sanatorium”) has been impressively described in Thomas Mann's Nobel Prize-winning bildungsroman The Magic Mountain (Der Zauberberg).43 A Nobel prize was given to Niels Finsen in 1903 for his observation that sun exposure was an effective treatment for cutaneous tuberculosis. We now understand the dual influence of high altitude, which has lower concentrations of ozone, an element that absorbs photons of light, and of sunlight, which results in greater photocutaneous synthesis of vitamin D. Higher serum 25(OH)D values are achieved per unit of time and more substrate is available for pulmonary macrophage synthesis of 1,25(OH)2D. This in turn enhances cathelicidin synthesis. In essence, the effect of sunlight exposure at higher elevation is to enhance innate immunity.

Epidemiologic evidence also suggests that vitamin D may be involved in the seasonality of influenza. In 1981, Hope-Simpson proposed that “a seasonal stimulus” for the onset of influenza was associated with a reduction in solar radiation.44 It had long been known that clinical influenza is clustered during the winter regardless of the hemisphere. However, for the modern indoor worker, the extent of crowding does not differ by the season.45 In experimental attenuated influenza infection in volunteers, a proof of hypothesis is that infection occurs predominantly in winter.46 Recent epidemiologic evidence suggests that for many areas of the world, influenza occurs during the months after the winter solstice, when circulating 25(OH)D concentrations are their lowest, and disappears after the summer solstice.47 This raises the question whether the seasonal decline in circulating 25(OH)D concentrations might represent the “seasonal stimulus factor” at latitudes above 40°, which is associated with increased case rates for influenza.47 Recall that sunlight-related photocutaneous synthesis of vitamin D in late fall and winter is virtually absent at such latitudes.6, 9

Vitamin D status appears to influence the risk of developing both upper and lower respiratory tract infections, including pneumonia. Clinical vitamin D deficiency was associated with a 13-fold increased risk of pneumonia in Ethiopian children younger than 5 years. 48 In Yemen, half the children admitted for lower respiratory tract infections were rachitic,49 and 43% of children in Kuwait with rickets had pneumonia.50 Subclinical vitamin D deficiency and non-exclusive breast feeding in the first 4 months formed a risk for lower respiratory tract infections in Indian children.51 These reports from 1989 to 2004 are reminiscent of the high rates of pneumonia in rachitic children in Glasgow23, 25, 26, 27, 28 and in the reports of Park and Howland.16, 30 Although it has long been presumed that vitamin D deficiency induces muscle weakness, especially of the diaphragm and intercostal muscles, which leads to impaired clearance of respiratory secretions and can lead to lower respiratory tract infections, the immunologic impairment of vitamin D deficiency is probably also important. Consistent with this idea is a recent study that showed that serum 25(OH)D levels are significantly and inversely associated with upper respiratory infection.52 The percent of subjects with a recent upper respiratory infection and a serum 25(OH)D level <10 ng/mL was higher in winter than in summer. Controlling for all variables, serum 25(OH)D levels <10 ng/mL in patients with asthma were associated with 5.67 higher odds of upper respiratory infections compared with patients with asthma with levels >30 ng/mL.
Conclusion
The risk of respiratory infections, including TB, influenza, pneumonia, and other upper and lower respiratory tract infections, is much greater in children with vitamin D deficiency (serum 25(OH)D <10 ng/mL). This inverse relationship between vitamin D status (low in winter and high in summer) and infection is what was found when rickets was epidemic. Recent experiments have shed light on the immune-enhancing properties of vitamin D, especially involving innate immunity and localized monocyte production of vitamin D-dependent antimicrobial proteins (cathelicidin) that combat M tuberculosis and other infectious agents. The concept prevalent in the late 19th century that infections caused rickets can now be reversed, because mechanisms exist by which vitamin D deficiency leads to increased infection rates
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Yvonne
Posts: 2421
Joined: Fri 27 Jul 2007 16:02

Re: Vitamins

Post by Yvonne » Sun 2 May 2010 11:46

J Am Acad Dermatol. 2010 Apr 2. [Epub ahead of print]

Estimated equivalency of vitamin D production from natural sun exposure versus oral vitamin D supplementation across seasons at two US latitudes.

Terushkin V, Bender A, Psaty EL, Engelsen O, Wang SQ, Halpern AC.

Memorial Sloan-Kettering Cancer Center, New York, New York.

Abstract
BACKGROUND: The relationship between oral vitamin D supplementation and cutaneous photosynthesis is not well understood. OBJECTIVE: We sought to provide estimates of the equivalency of vitamin D production from natural sun exposure versus oral supplementation. METHODS: Using the FastRT simulation tool, we determined sun exposure times needed to achieve serum vitamin D(3) concentrations equivalent to 400 or 1000 IU vitamin D for individuals of various Fitzpatrick skin types living in Miami, FL, and Boston, MA, during the months of January, April, July, and October. RESULTS: Peak ultraviolet B irradiation for vitamin D synthesis occurs around 12 PM Eastern Standard Time (EST). In Boston, MA, from April to October at 12 pm EST an individual with type III skin, with 25.5% of the body surface area exposed, would need to spend 3 to 8 minutes in the sun to synthesize 400 IU of vitamin D. It is difficult to synthesize vitamin D during the winter in Boston, MA. For all study months in Miami, FL, an individual with type III skin would need to spend 3 to 6 minutes at 12 pm EST to synthesize 400 IU. Vitamin D synthesis occurs faster in individuals with lighter Fitzpatrick skin types. The duration to attain 1000 IU of vitamin D is longer in all scenarios. LIMITATIONS: Results of the computer model are only approximations. In addition, calculations were made based on the assumption that (1/4) of 1 minimal erythema dose directed at (1/4) body surface area is equal to 1000 IU of oral vitamin D. CONCLUSIONS: Although it may be tempting to recommend intentional sun exposure based on our findings, it is difficult, if not impossible to titrate one's exposure. There are well-known detrimental side effects of ultraviolet irradiation. Therefore, oral supplementation remains the safest way for increasing vitamin D status. Copyright © 2009 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

PMID: 20363523
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plucking a feather from every passing goose,
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User avatar
Yvonne
Posts: 2421
Joined: Fri 27 Jul 2007 16:02

Re: Vitamins

Post by Yvonne » Sun 2 May 2010 11:47

Curr Opin Pharmacol. 2010 Apr 26. [Epub ahead of print]

Vitamin D: modulator of the immune system.

Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C.

Laboratory of Experimental Medicine and Endocrinology (LEGENDO), Katholieke Universiteit Leuven (KUL), Herestraat 49 - O&N1 - bus 902, 3000 Leuven, Belgium.

Abstract
1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the active form of vitamin D, is known to regulate calcium and phosphorus metabolism, thus being a key-player in bone-formation. However 1,25(OH)(2)D(3) also has a physiological role beyond its well-known role in skeletal homeostasis. Here, we describe 1,25(OH)(2)D(3) as an immunomodulator targeting various immune cells, including monocytes, macrophages, dendritic cells (DCs), as well as T-lymphocytes and B-lymphocytes, hence modulating both innate and adaptive immune responses. Besides being targets, immune cells express vitamin D-activating enzymes, allowing local conversion of inactive vitamin D into 1,25(OH)(2)D(3) within the immune system. Taken together, these data indicate that 1,25(OH)(2)D(3) plays a role in maintenance of immune homeostasis. Several epidemiological studies have linked inadequate vitamin D levels to a higher susceptibility of immune-mediated disorders, including chronic infections and autoimmune diseases. This review will discuss the complex immune-regulatory effects of 1,25(OH)(2)D(3) on immune cells as well as its role in infectious and autoimmune diseases, more in particular in tuberculosis and type 1 diabetes (T1D). Copyright © 2010 Elsevier Ltd. All rights reserved.

PMID: 20427238
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