http://journals.sagepub.com/doi/full/10 ... 8512472754
Multiple Sclerosis Relapsing-Remitting rate reduced 30 percent by addition of 14,000 IU vitamin D daily – RCT Nov 2016
A Phase II Study of the Efficacy and Safety of High-Dose Cholecalciferol (Vitamin D3) Oil as Add-on Therapy in Subjects with Relapsing-Remitting Multiple Sclerosis Receiving Subcutaneous Interferon β-1a: SOLAR
• SOLAR is the largest (to date), placebo-controlled, randomised, double-blind study of vitamin D3 as an
add-on therapy for MS patients.
• Compared with placebo, high-dose vitamin D did not demonstrate an effect on the NEDA primary
endpoint at Week 48.
• High-dose vitamin D significantly improved MRI outcomes compared with placebo.
• Relapse rates were reduced with high-dose vitamin D, although statistical significance was not reached.
• There were no additional safety issues with highdose vitamin D treatment.
• SOLAR did not show a significant effect on the primary endpoint, although the MRI findings (CUA
lesions, change from baseline in total volume of T2 lesions) and the ARR suggest a benefit of high-dose
https://www.vitamindwiki.com/tiki-downl ... download=y
Vitamin D receptor gene is epigenetically altered and transcriptionally up-regulated in multiple sclerosis
Vitamin D deficiency has been linked to increased risk of multiple sclerosis (MS) and poor outcome. However, the specific role that vitamin D plays in MS still remains unknown. In order to identify potential mechanisms underlying vitamin D effects in MS, we profiled epigenetic changes in vitamin D receptor (VDR) gene to identify genomic regulatory elements relevant to MS pathogenesis.
Human T cells derived from whole blood by negative selection were isolated in a set of 23 relapsing-remitting MS (RRMS) patients and 12 controls matched by age and gender. DNA methylation levels were assessed by bisulfite cloning sequencing in two regulatory elements of VDR. mRNA levels were measured by RT-qPCR to assess changes in VDR expression between patients and controls.
An alternative VDR promoter placed at exon 1c showed increased DNA methylation levels in RRMS patients (median 30.08%, interquartile range 19.2%) compared to controls (18.75%, 9.5%), p-value<0.05. Moreover, a 6.5-fold increase in VDR mRNA levels was found in RRMS patients compared to controls (p-value<0.001).
An alternative promoter of the VDR gene shows altered DNA methylation levels in patients with multiple sclerosis, and it is associated with VDR mRNA upregulation. This locus may represent a candidate regulatory element in the genome relevant to MS pathogenesis.
http://journals.plos.org/plosone/articl ... ne.0174726
http://www.msard-journal.com/article/S2 ... 4/abstract
Vitamin D discovery could prove key to new treatments for metabolic disorders and certain cancers
Date: February 1, 2017
Source: Kyoto University
Researchers have identified a new way vitamin D helps control the balance of lipids in the body. This key finding could advance development of new treatments for metabolic disorders and certain cancers.
Abstract: http://www.cell.com/cell-chemical-biolo ... 16)30478-0
Full Article: http://sci-hub.cc/10.1016/j.chembiol.2016.12.017
Immune regulatory effects of high dose vitamin D3
supplementation in a randomized controlled trial in
relapsing remitting multiple sclerosis patients
receiving IFNβ; the SOLARIUM study.
Multiple sclerosis (MS) is characterized by a disturbed immune homeostasis and low serum vitamin D levels are associated with an increased disease activity. While vitamin D has been hypothesized to promote the maintenance of immune homeostasis, vitamin D supplementation could be of benefit to patients with MS. The SOLAR study investigated the effects of high dose vitamin D3 supplementation on clinical outcomes in a randomized controlled trial. Here we present the immune regulatory effects, investigated in the SOLARIUM sub-study. Thirty Dutch relapsing remitting (RR) MS patients treated with IFNβ-1a received high dose vitamin D3 supplementation and 23 patients received placebo during a period of 48weeks. Lymphocytes were phenotypically characterized by flow cytometry and in vitro cytokine secretion was assessed in the presence or absence of 1,25(OH)2D3 using Luminex technology. Changes in immune regulatory parameters were determined within subjects as well as between treatment groups. The proportion of cells in the immune regulatory cell compartment (nTreg, iTreg and Breg) was not altered upon high dose vitamin D3 supplementation. Proportions of T helper subsets were not affected by vitamin D3, except for the proportion of IL4+ Th cells, which decreased in the placebo but not in the vitamin D3 group. T cell cytokine secretion increased, most pronounced for IL5 and latency activated protein of TGFβ, in the placebo group but not in the vitamin D3 group. Lymphocytes remained equally reactive to in vitro 1,25(OH)2D3. In conclusion, high dose vitamin D3 supplementation did not result in a relative increase in lymphocytes with a regulatory phenotype. However, this study supports the hypothesis that vitamin D contributes to the maintenance of immune homeostasis by preventing further disturbance of the T cell compartment early in the disease course of MS.
Full Article: http://sci-hub.cc/10.1016/j.jneuroim.2016.09.018
Effect of Vitamin D Replacement on Cognition in Multiple Sclerosis Patients
Multiple Sclerosis is associated with deficient serum 25 hydroxyvitamin D (25 (OH)D) level and cognitive impairment. The aim of this study is to evaluate cognitive performance in MS patients with deficient 25 (OH)D (<25 ng/ml) compared to patients with sufficient levels (>35 ng/ml), then to evaluate the change in cognitive performance after 3 months of vitamin D3 oral replacement. Eighty-eight MS patients with relapsing remitting and clinically isolated type of MS, older than 18 years treated with interferon beta were enrolled. Cognitive testing was performed at baseline and at 3 months using the Montreal Cognitive Assessment (MoCA), Stroop, Symbol Digit Modalities (SDMT) and Brief Visuospatial Memory Test (BVMT-R). Serum 25 (OH)D was measured at baseline and at the end of the study. Vitamin D3 replacement improved the MS patients’ cognitive performance after 3 months on the MoCA and BVMT-Delayed Recall (DR). Sufficient serum 25 (OH)D level predicted better cognitive performance on the BVMT-DR at baseline (β: 1.74, p: <0.008) and 3 months (β: 1.93, p: <0.01) after adjusting for all measured confounding variables. Vitamin D3 replacement could improve cognitive performance in MS patients and make a significant difference in the patient’s quality of life.
Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system that is linked to environmental factors such as smoking and vitamin D level. Low serum 25 hydroxyvitamin D (25 (OH) D) is associated with increased risk of MS1,2 and increased disease activity in patients with MS3,4. Vitamin D supplementation protects from disease in MS animal models5,6,7. Furthermore, Vitamin D levels appear to be lower in MS patients than controls8,9.
Cognitive impairment is a common symptom of MS that impacts quality of life, and affects up to 65% of patients10,11,12. The impairment affects a wide range of cognitive functions including verbal and non-verbal memory, and information processing speed12. Studies in humans provide support for a role of the vitamin D in cognitive functioning, and recent studies have linked low serum 25 (OH)D levels to cognitive dysfunction in adults13,14,15. Vitamin D receptors are expressed by neurons and glial cells16,17 supporting a role for vitamin D beyond bone homeostasis. Based on prevalence of hypovitaminosis D in our clinical population9, we hypothesized that low serum 25 (OH)D has a negative effect on cognitive performance. This study aim was to measure cognitive performance in patients with serum 25 (OH)D deficiency (<25 ng/ml) compared to patients with sufficient levels (>35 ng/ml), then evaluate the change in cognitive performance in 25 (OH)D deficient subjects after supplementation with oral vitamin D3 (Cholecalciferol, Euro-D 10000, Montreal, Quebec, Canada).
A total of 111 participants were recruited, of whom 23 had 25 (OH)D levels between 25 and 35 ng/ml (inclusive) and were thus excluded from the study. Of the remaining 88 participants, 40 were males (45.4%) and the average age of all the participants was 36.3 ± 12.2 years. At baseline, there were 47 (53.4%) patients with sufficient and 41 (46.6%) with deficient 25 (OH)D. Of those, 84 participants underwent cognitive tests (39 in deficient group and 45 in sufficient group). After 3 months, 22 patients were lost to follow up; 66 had their serum 25 (OH)D level tested; 61 of them completed the study and underwent cognitive tests (31started in deficient group and 30 in sufficient group) (Fig. 1 and Table 1).
https://www.nature.com/articles/srep459 ... _supported
Vitamin D: not just bone, but also immunity.
Vitamin D should not be considered only as a vitamin. It has a relevant role in many functions of body regulation, both skeletal and extra skeletal and this makes vitamin D an essential element for a healthy status. This is well explained by a ubiquitous presence of vitamin D receptors. Nowadays extra skeletal effects have a more interesting impact in medical practice. The paracrine and autocrine action of vitamin D has a pivotal role for these effects. The activation of the cellular transcriptional process leads to the expression of beta-defensin and cathelicidin, activating the Th1 pathway, related to innate immunity against bacteria. The action of vitamin D is also related to adaptive immunity with a Th2 response and production of anti-inflammatory cytokines like interleukins 4 and 5, and with Th17 and B-lymphocyte suppression. Vitamin D deficiency could have an unfavorable effect on both healthy and ill subjects. It is well-known that many autoimmune diseases like systemic lupus erythematosus and rheumatoid arthritis are influenced by vitamin D deficiency, and this is especially true for disease activity. Several other pathologies are influenced by the levels of vitamin D, such as diabetes mellitus type 1: an adequate intake of vitamin D can reduce the risk to develop this disease. The same applies to asthma and multiple sclerosis. It is very important to make a point about the deficiency state and their correction, especially in those people at higher risk.
[Repairing the spinal cord with vitamin D: a promising strategy].
In 2014, a phase II randomised, double blind clinical trial assessing the efficacy of cholecalciferol (vitamin D3) in patients with a cervical trauma will be set up. This trial stems from previous studies showing that vitamin D supplementation improves functional recovery in rat models of peripheral or central nerve injury. In a first series of experiments, we used a rat model of peripheral nerve trauma to demonstrate the therapeutic efficiency of vitamin D. We first demonstrated that ergocalciferol (vitamin D2) increases the number and the diameter of newly formed axons and improves the response of metabosensitive fibers from tibialis muscle, in a model of transected peroneal nerve. Then, we compared vitamin D2 and vitamin D3 and observed that the latter is more efficient. At the dose of 500 IU/kg/day, vitamin D3 induces a dramatic functional recovery. We also demonstrated that vitamin D3 increases the number of preserved or newly formed axons in the proximal end, the mean axon diameter in the distal end, neurite myelination in both the distal and proximal ends as well as the expression of genes involved in axogenesis and myelination. In parallel, we assessed the therapeutic role of vitamin D on the central nervous system. In a first study, using a rat model of spinal cord compression at the T10 thoracic level, we delivered vitamin D3 (cholecalciferol) orally at the dose of 50 IU/kg/day or 200 IU/kg/day. When compared to control animals, vitamin D-treated rats displayed, three months after injury, a significant improvement of ventilatory frequency and a reduction of H reflex indicating functional improvements at three months post-injury. In a second study, we used a rat model of cervical hemisection (C2) with a higher dose of oral vitamin D3 (500 IU/kg/day) delivered weekly, during 12 weeks. We observed an improved locomotor recovery, a reduced spasticity and a significantly higher rate of axons crossing the lesion site in treated animals. However, it must be pointed out that the functional improvement is reduced when vitamin D is provided one week after the trauma.
https://www.ncbi.nlm.nih.gov/pubmed/249 ... t=Abstract
Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS
''One more recently published study connecting vitamin D to multiple sclerosis. It's worth noting that Dr. Coimbra has always considered Body Mass Index one of the factors that influence resistance to vitamin D.''
To utilize Mendelian randomization to estimate the causal association between low serum vitamin D concentrations, increased body mass index (BMI), and pediatric-onset multiple sclerosis (MS) using genetic risk scores (GRS).
We constructed an instrumental variable for vitamin D (vitD GRS) by computing a GRS for 3 genetic variants associated with levels of 25(OH)D in serum using the estimated effect of each risk variant. A BMI GRS was also created that incorporates the cumulative effect of 97 variants associated with BMI. Participants included non-Hispanic white individuals recruited from over 15 sites across the United States (n = 394 cases, 10,875 controls) and Sweden (n = 175 cases, 5,376 controls; total n = 16,820).
Meta-analysis findings demonstrated that a vitD GRS associated with increasing levels of 25(OH)D in serum decreased the odds of pediatric-onset MS (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.55, 0.94; p = 0.02) after controlling for sex, genetic ancestry, HLA-DRB1*15:01, and over 100 non-human leukocyte antigen MS risk variants. A significant association between BMI GRS and pediatric disease onset was also demonstrated (OR 1.17, 95% CI 1.05, 1.30; p = 0.01) after adjusting for covariates. Estimates for each GRS were unchanged when considered together in a multivariable model.
We provide evidence supporting independent and causal effects of decreased vitamin D levels and increased BMI on susceptibility to pediatric-onset MS.
https://www.ncbi.nlm.nih.gov/pubmed/283 ... t=Abstract
Evaluation of vitamin D3 intakes up to 15,000 international units/day and serum 25-hydroxyvitamin D concentrations up to 300 nmol/L on calcium metabolism in a community setting
S. M. Kimball, N. Mirhosseini & M. F. Holick
Article: e1300213 | Received 19 Dec 2016, Accepted 23 Feb 2017, Accepted author version posted online: 13 Apr 2017, Published online: 13 Apr 2017
Supplementation by the general public with vitamin D at doses above the Tolerable Upper Level of Intake (UL) is becoming quite common. The objective of the current analysis was to characterize the effect of vitamin D supplementation at doses up to 15,000 IU/d in a community-based program on vitamin D status, calcium homeostasis as well as on kidney, liver and immune function. We evaluated data collected for 3,882 participants in a community program for whom there were blood measurements at program entry and at follow-up within 6–18 months between 2013 and 2015. Participants were supplemented with a wide range of vitamin D doses (1,000 – 15,000 IU/d) aimed at achieving serum 25-hydroxyvitamin D [25(OH)D] levels of at least 100 nmol/L. Serum 25(OH)D concentrations up to 300 nmol/L were achieved without perturbation of calcium homeostasis or incidence of toxicity. Hypercalcemia and hypercalciuria were not related to an increase in 25(OH)D concentrations nor vitamin D dose. To achieve serum 25(OH)D levels >100 nmol/L on average, required vitamin D intakes of 6,000 IU/d for normal Body Mass Index (BMI), 7,000 IU/d for overweight and 8,000 IU/d for obese. Doses of vitamin D in excess of 6,000 IU/d were required to achieve serum 25(OH)D concentrations above 100 nmol/L, especially in individuals who were overweight or obese without any evidence of toxicity. Serum 25(OH)D concentrations up to 300 nmol/L were found to be safe.
http://www.tandfonline.com/doi/full/10. ... 17.1300213
Vitamin-D Deficiency As a Potential Environmental Risk Factor in Multiple Sclerosis, Schizophrenia, and Autism.
In this short review, we want to summarize the current findings on the role of vitamin-D in multiple sclerosis (MS), schizophrenia, and autism. Many studies have highlighted hypovitaminosis-D as a potential environmental risk factor for a variety of conditions such as MS, asthma, cardiovascular disease, and, more recently, psychiatric diseases. However, whether hypovitaminosis-D is a potential causative factor for the development or activity in these conditions or whether hypovitaminosis-D may be due to increased vitamin-D consumption by an activated immune system (reverse causation) is the focus of intense research. Here, we will discuss current evidence exploring the role of vitamin-D in MS, schizophrenia, and autism and its impact on adaptive and innate immunity, antimicrobial defense, the microbiome, neuroinflammation, behavior, and neurogenesis. More work is needed to gain insight into its role in the underlying pathophysiology of these conditions as it may offer attractive means of intervention and prevention.
Fatigue reduced by a single dose of vitamin D (100,000 IU) – RCT Dec 2016
Effect of vitamin D3 on self-perceived fatigue: A double-blind randomized placebo-controlled trial.
Medicine (Baltimore). 2016 Dec;95(52):e5353. doi: 10.1097/MD.0000000000005353.
Nowak A1, Boesch L, Andres E, Battegay E, Hornemann T, Schmid C, Bischoff-Ferrari HA, Suter PM, Krayenbuehl PA.
aDepartment of Internal Medicine
bInstitute for Clinical Chemistry, University Hospital Zurich and University of Zurich
cDivision of Endocrinology, Diabetology and Clinical Nutrition
dDepartment of Geriatrics, University Hospital Zurich, Zurich
eDepartment of Internal Medicine, Spital Linth, Uznach, Switzerland.
Vitamin D deficiency is frequent and has been associated with fatigue in uncontrolled trials.
This is the first double-blind placebo-controlled clinical trial to investigate the efficacy of per os vitamin D3 (cholecalciferol) in treating fatigue among otherwise healthy persons with low serum 25-hydroxyvitamin D (25(OH)D) levels. We enrolled 120 individuals (mean age 29 ± 6 years, 53% women) presenting with fatigue and vitamin D deficiency (serum 25(OH)D < 20 µg/L). Participants were randomized to a single oral dose of 100,000 units of vitamin D or placebo. The primary endpoint was intra-individual change in the fatigue assessment scale (FAS) at 4 weeks after treatment.
The mean age of the participants was 29 ± 6 years, 53% were women. Mean FAS decreased significantly more in the vitamin D group (-3.3 ± 5.3; 95% confidence interval [CI] for change -14.1 to 4.1) compared with placebo (-0.8 ± 5.3; 95% CI for change -9.0 to 8.7); (P = 0.01). Amelioration of fatigue was reported more frequently in vitamin D than in placebo group (42 [72%] vs. 31 [50%]; P = 0.01; odds ratio [OR] 2.63, 95% CI for OR 1.23-5.62). Among all participants, improvement in fatigue score correlated with the rise in 25(OH)D level (R = -0.22, P = 0.02).
Vitamin D treatment significantly improved fatigue in otherwise healthy persons with vitamin D deficiency.
This study was registered at the http://www.ClinicalTrials.gov Protocol ID NCT02022475.
PMID: 28033244 DOI: 10.1097/MD.0000000000005353
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