Skeletal muscle is a direct target for the group of seco-steroids collectively termed Vitamin D. Skeletal muscle expresses both CYP27A1 and CYP27B1 encoding for the hydroxylases required to convert Vitamin D to 25[OH]D and subsequently the bioactive 1α-25-dihydroxyvitamin D3 (1α-25[OH]2D3) (Girgis et al., 2014b). Crucially, the Vitamin D receptor (VDR) is also present in skeletal muscle (Srikuea, Zhang, Park-Sarge, & Esser, 2012) and upon exposure, binds to its ligand 1α-25[OH]2D3 and initiates genomic and non-genomic rapid signalling responses. At present there is a global prevalence of low serum Vitamin D (25[OH]D) concentrations due to a lack of sun exposure (the primary route for Vitamin D synthesis) as a function of latitude and/or an indoor lifestyle coupled with few dietary sources of Vitamin D (Chen et al., 2007). Accumulating data are now suggestive that low 25[OH]D may be associated with perturbations in contractile activity and the regeneration of human skeletal muscle (Owens, Fraser, & Close, 2014), although a definitive causal relationship is yet to be established. Therefore, this thesis aimed to establish a more precise role for Vitamin D in human skeletal muscle function and regeneration. There were four overarching aims: 1. Explore the role of Vitamin D in human skeletal muscle contractile properties in humans in vivo. 2. Identify the role of Vitamin D in human skeletal muscle contractile properties ex vivo. 3. Investigate the role of Vitamin D in skeletal muscle regeneration following eccentric exercise induced muscle damage in vivo. 4. Elucidate cellular mechanisms of the muscle regeneration process that are responsive to Vitamin D in vitro. The main findings from this work imply that serum 25[OH]D concentrations across a broad range from 18 → 100 nmol.L-1 do not affect skeletal muscle contractile properties. Conversely elevating serum 25[OH]D from < 50 nmol.L-1 to > 75 nmol.L-1 resulted in significant improvements in the recovery of maximal voluntary contraction force following a bout of eccentric exercise. Implementing an in vitro model of muscle regeneration also identified potential cellular mechanisms for these observations: Muscle derived cells treated with a total amount of 10 nmol 1α-25[OH]2D3 following a mechanical scrape improved migration dynamics and fusion capability of skeletal muscle derived cells. Taken together, low Vitamin D concentrations are highly prevalent but can be easily corrected with supplementation of Vitamin D3. This may have the advantage of optimising the regenerative capacity of skeletal muscle amongst other health benefits previously characterised by others.

No description available.

4 p. / Originally published: 2000. / Osteoporosis means “porous bones.” It is a condition where the skeleton becomes fragile and results in broken bones under normal use. Osteoporosis is a “silent” condition that happens slowly over years. The rate of bone loss (“resorption”) exceeds the rate of new bone formation (“acretion”). Many times neither a person nor a doctor is aware of weakened bones until one breaks unexpectedly. Originally published: 2000

Class of 2017 Abstract / Objectives: To assess the general public’s knowledge of the benefits and sources of calcium and vitamin D dietary and supplemental intake and to identify any pertinent demographic characteristics that influence such knowledge. Methods: Participants were convenience sampled from Walmart locations in Safford, Arizona and Tucson, Arizona. Each participant completed a brief survey assessing their knowledge about the benefits and sources of calcium and vitamin D and optional questions regarding demographics. Results: 51 participants in Safford and 51 participants in Tucson completed the questionnaire. Of the 51 responders in Safford, 18 were men and 24 were women with a mean age of 49.52 (SD = 14.53, 80.49% white). Of the 51 responders in Tucson, 22 were men and 17 were women with a mean age of 50.97 (SD = 17.32, 71.79% white). Baseline demographics were equivalent. Statistical significant was observed when the mean total scores from Tucson and Safford were compared. On average, the participants in Tucson scored higher when compared to participants in Safford with mean scores of 55.5% and 49.0% respectively (p= 0.0412). Conclusions: Tucson participants scored statistically significantly higher when compared to Safford participants. This may be due to the health disparity between urban and rural populations. Gender, ethnicity, supplement use, personal or family history of osteoporosis, and education level did not appear to affect response scores on the questionnaire.

Introduction: Patients with Systemic Lupus Erythematosus (SLE) have increased cardiovascular risk, endothelial dysfunction, and abnormal endothelial repair mechanisms. Vitamin D deficiency is common in SLE and has been associated with active disease and increased vascular stiffness. Myeloid angiogenic cells (MACs) repair damaged vessels by secretion of angiogenic factors and may be a target for vitamin D. Vitamin D may therefore be a novel therapy to improve cardiovascular risk in SLE patients. This study aimed to determine the effects of vitamin D on endothelial function and repair in patients with SLE. Methods: The effects of the active form of vitamin D (1,25(OH)2D3) were studied on MACs from vitamin D deficient SLE patients ex vivo. Functional models were developed to study MAC migration, adhesion and interaction with endothelial cells. Additional experiments used a model of healthy MACs treated with IFN-alpha. An observational study of clinically stable vitamin D deficient SLE patients being treated with high dose vitamin D over 3 months was used to investigate the effects of vitamin D on endothelial function as measured by flow-mediated dilatation (FMD). Results: MACs expressed markers consistent with an M2 macrophage phenotype and they enhanced endothelial network formation in vitro. SLE patients had an increased number of MACs; however, these were dysfunctional compared to healthy controls. Vitamin D increased the number, changed the phenotype and improved the functional capacity of SLE MACs ex vivo. In addition, the angiogenic capacity of SLE MACs was restored toward that of healthy controls via a reduction in the anti-angiogenic cytokine IP10. Vitamin D-treated MACs were also more able to protect endothelial cells against TNF-mediated down-regulation of endothelial nitric oxide synthase (eNOS). In SLE patients treated with vitamin D, there was a strong correlation between the change in serum 25(OH)D and the change in the ratio of endothelium-dependent:independent dilatation (r=-0.650, p=0.006). This was accompanied by an increase in the number of MACs at 3 months (p=0.015). These observations were independent of changes in serum PTH, calcium or lupus disease activity. Conclusions: Vitamin D can target MACs and therefore offers a novel approach to improve endothelial repair in patients with SLE. In addition, vitamin D treatment in lupus patients resulted in an improvement in endothelial function, related to the change in vitamin D status. These results suggest that vitamin D could improve surrogate markers of cardiovascular disease and thus reduce cardiovascular risk in this patient group.

Vitamin D is a fat-soluble vitamin that has proven to be extremely important for human health. Vitamin D has important functions that regulate calcium and phosphate absorption from the gastrointestinal tract. The regulation of calcium and phosphorus metabolism is extremely important for the maintenance of the structural integrity of the human skeleton, neuromuscular function and a wide variety of metabolic processes. A major source of vitamin D for most children and adults if exposure to sunlight. During sun exposure 7-dehydrocholesterol in the epidermis and dermis absorb solar ultraviolet B radiation with wavelengths of 290-315nm. This results in it being converted to previtamin D. Once formed, the thermodynamically unstable previtamin D is isomerized to vitamin D. Vitamin D is then hydroxylated in the liver and the kidneys to its active form before it can act as a homeostatic regulator of calcium and phosphorus metabolism. There are certain patients who do not respond well to vitamin D supplements because they suffer from fat malabsorption syndromes such as cystic fibrosis, Crohn’s disease and ulcerative colitis. In addition, gastric bypass patients have difficulty in absorbing dietary and supplemental vitamin D. One approach for treating vitamin D deficiency in these patients is to recommend that they be exposed to artificial UVB radiation either from a tanning bed or from a Sperti vitamin D producing lamp. Novel ultraviolet emitting light emitting diodes (LED) have emerged as a promising solution because of their size, efficiency, and ability to use narrow band UV radiation. A LED has been developed to emit narrowband UVB radiation with a peak wavelength of that 295nm. This thesis provides evidence that this novel UVB-LED is able to cause the photo-conversion of 7-deyhdrocholesterol to previtamin D3 in vitro, using 7-dehydrocholesterol containing borosilicate ampoules as positive controls, as well as produce vitamin D3 in surgically obtained type II human skin. Results from this study suggest that vitamin D producing LEDs can be developed for the treatment of vitamin D deficiency, especially in patients with fat malabsorption syndromes.

Rising rates of urbanization and the global trend towards a more Western lifestyle correlates with increased incidence of both Vitamin D deficiency and Inflammatory Bowel Disease (IBD). The Vitamin D Hypothesis is the most current and prevalent theory that explains the rising cases of IBD. This hypothesis postulates that decreased ultraviolet radiation and dietary variety predispose certain populations to develop IBD. Vitamin D has an active role within the immune system, suppressing the development and function of pro-inflammatory T helper cells while promoting the development and action of immunotolerant regulatory T cells. IBD patients receive pharmaceutical immunotherapies that antagonize pro-inflammatory markers. Though Vitamin D is typically prescribed to support skeletal development, it may also be considered an adjunct therapy to prevent gastrointestinal flares in patients with IBD. However, the current standard of care for treating Vitamin D deficiency is prescribing daily Vitamin D supplements. On average, children exhibit poor compliance when prescribed a daily dosing regimen, especially when they do not experience a clear, direct benefit after taking their daily dose. An alternative to the daily dosing regimen is a high-dose, interval regimen of Vitamin D supplementation. Recent studies have demonstrated that high doses of Vitamin D are safe and effective at raising serum Vitamin D levels to optimal levels (40-60 ng/mL) in the pediatric population. Moreover, IBD patients with optimal Vitamin D levels appear to experience significantly fewer gastrointestinal flare-ups and hospitalizations. There is little existing research reporting on the use of high-dose, interval Vitamin D supplementation. As such, more longitudinal studies need to be performed to assess not only patients’ Vitamin D status but also their levels of relevant immunological markers in their serum, such as pro-inflammatory cytokines and regulatory T cells. These efforts would enable researchers to definitively conclude the effectiveness of high dose interval Vitamin D supplementation to raise serum Vitamin D levels and assess the impact of Vitamin D supplementation on the immune system in patients with IBD.

La vitamine D (D3 ou cholécalciférol du règne animal et D2 ou ergostérol du règne végétal) est une hormone pléiotrope qui possède de nombreux effets biologiques incluant la régulation du métabolisme du calcium et du phosphate. Chez l’Homme, ce composé est synthétisé au niveau cutané sous forme inactive. On décrit ainsi le métabolisme de la vitamine D qui conduit à la production de métabolites actifs (par les vitamine D 25- et 1α-hydroxylases codées par les gènes CYP2R1 et CYP27B1) et à leur dégradation par la vitamine D 24-hydroxylase (gène CYP24A1). L’expression des vitamine 1α- et 24-hydroxylases est finement et inversement régulée afin de maintenir l’homéostasie phosphocalcique, grâce à plusieurs boucles de rétrocontrôle impliquant entre autres la forme 1,25-dihydroxylée de la vitamine D et son récepteur VDR, la calcémie et la parathormone, la phosphatémie et le FGF23. La carence en vitamine D et les défauts de son activation sont associés à un phénotype de rachitisme, tandis que les excès en vitamine D sont associés à un phénotype d’hypercalcémie-hypercalciurie par intoxication (surdosage) ou hypersensibilité à la vitamine D (excès d’activation ou défaut de dégradation).L’objectif de ce travail de thèse est d’identifier des causes génétiques de dérégulation du métabolisme de la vitamine D et de préciser leurs mécanismes physiopathologiques par une description précise du phénotype associé. Pour ce faire, nous avons utilisé de façon conjointe les outils de la génétique (séquençage nouvelle génération et Sanger) et de la biochimie (dosage des métabolites) dans une cohorte de patients recrutés grâce au centre de référence maladies rares du métabolisme du calcium et du phosphate.Ce travail a permis de préciser le rôle de deux gènes dans les maladies liées à la dérégulation métabolisme de la vitamine D, CYP2R1 et CYP24A1, par la mise en évidence de mutations perte de fonction chez des patients avec un phénotype de rachitisme à 25-hydroxyvitamine D basse et d’hypersensibilité à la vitamine D respectivement. Notre étude a permis aussi de préciser le phénotype de ces affections. Dans la cohorte des patients étudiés, l’identification de mutations de gènes impactant le métabolisme du phosphate (SLC34A1 et SLC34A3), souligne l’intérêt de l’étude des facteurs régulateurs des activités vitamine D 1α- et 24-hydroxylases.Aucune variation significative dans les régions promotrices proximales de CYP27B1 et CYP24A1 n’a été identifiée. Le peu de connaissances sur l’ensemble des éléments régulateurs chez l’Homme n’a pas permis d’approfondir notre étude. L’identification et l’étude de ces éléments régulateurs distaux permettra de déterminer leur implication dans les maladies rares du métabolisme de la vitamine D. / The vitamin D (D3 or cholecalciferol from animal kingdom and D2 or ergosterol from plan kingdom) is a pleiotropic hormone who has numerous biological effects including the regulation of calcium and phosphate metabolism. In humans, this compound is synthetized in skin in an inactive form. Thus, we call vitamin D metabolism the biological process which leads to the production of active metabolites (by enzymes 25- and 1α-hydroxylases encoded by CYP2R1 and CYP27B1 genes) and its degradation by vitamin D 24-hydroxylase (gene CYP24A1). The expression of 1α- and 24-hydroxylases is tightly and inversely regulated to maintain calcium and phosphate homeostasis, thanks to several feedback loops including 1,25-dihydroxyvitamin D and its receptor VDR, serum calcium and parathormone, serum phosphate and FGF23. Vitamin D deficiency and vitamin D activation deficiency are associated with rickets, while vitamin D excess are associated with hypercalcemia-hypercalciuria due to vitamin D intoxication (overdose) or hypersensitivity to vitamin D (activation excess or degradation deficiency).Our aim is to identify genetic causes of vitamin D metabolism deregulation and to specify pathophysiologic mechanisms describing phenotype. Thus, we jointly used the tools of genetics (next-generation and Sanger sequencing) and biochemistry (vitamin D metabolites assay) in a cohort of human patients ascertained thanks to the national center for rare diseases of calcium and phosphate metabolism.This work allowed us to specify the role of two genes in diseases of vitamin D metabolism, CYP2R1 and CYP24A1, showing loss of function mutations in patients with rickets and low 25-hydroxyvitamin D and hypersensitivity to vitamin D, respectively. Our study brought new phenotypic elements in these affections. In our cohort of patients, the identification of mutations leading to phosphate deregulation (in SLC34A1 and SLC34A3) highlights the putative role of regulators of vitamin D 1α- and 24-hydroxylases activities in pathophysiology.No significant variation have been identified in the proximal promoting regions of CYP27B1 and CYP24A1. We could not go further considering the lack of knowledge in regulating regions and factors in humans. Identifying distal regulators will allow to study their implication in rare diseases of vitamin D metabolism.

Vitamin D3 (cholecalciferol) (Vit D3) is a form of vitamin D (Vit D) that is essential for normal body function in humans. Vit D is a fat-soluble vitamin used to prevent osteoporosis in adults, prevent rickets in children, and supplement Vit D deficiencies which are seen worldwide. Physicians usually recommend 2,000 International Units (IU) Vit D3 for these deficiencies, but due to the poor aqueous solubility of Vit D3, this dose can be insufficient for patients. It would be more beneficial to recommend 5,000 IU. In 1994, the Dietary Supplement Health and Education Act was passed defining vitamins as “dietary supplements” and no longer required FDA registration prior to marketing. Dissolution results are expressed as the percent of the content released into solution, with a target of 85 to 125%. There is not an effective dissolution test existing for Vit D3 product evaluation, so an optimized dissolution test for Vit D3 was developed and used to evaluate non-prescription Vit D3 products. The current FDA guideline for Vit D3 dissolution is USP Apparatus II with 500 mL of 0.3% sodium dodecyl sulfate (SDS) in water. Since Vit D3 is not very water soluble, a surfactant is required for it to go into solution. The research was started with a larger volume (1 L) and with commonly used pharmaceutical grade surfactants: Triton X-100, Tween 80, Span 20, and sodium lauryl sulfate (SLS). SDS was eliminated due to interference with the HPLC analysis. Using two Vit D3 test products, which previous research found to have consistent drug content, each of these surfactants were tested at 0.8%. After evaluating the HPLC results, Triton and Tween were eliminated due to too much interference with the analysis process. The interference consisted of a large initial solvent front peak, elevated baseline, overlap with the drug peak, and required significant decrease in the mobile phase flow rate. Changing the mobile phase to 50/50 methanol/1-propanol solved the flow rate issue and peak separation overlap, but not the large solvent peak or elevated baseline. Dissolution testing continued using SLS and Span using 0.6%. Dissolution of the two test products, designated A and B, with 2 representing 2000 IU and 5 being 5000 IU, yielded higher values using SLS (A2 75.5%; A5 152.8%; B2 30.9%; B5 36.6%) compared to Span (A2 15%; A5 136%; B2 20.3%; B5 63%). Additional work continued to determine the best concentration of SLS. Better dissolution results were obtained using 1.2% (A2 88.1%; A5 156.7%) when compared to 0.3% (A2 87.4%; A5 153.2%), 0.6% (A2 70.7%; A5 132.2%), and 0.9% (A2 79.7%; A5 150.5%). Use of 1.5% did not yield a significant improvement (A2 84% vs 86.8%; A5 146.4% vs 144.6%), so 1.2% was chosen as this would minimize the amount of surfactant in the samples. The final dissolution method was created using a USP Apparatus II in 1000 mL containing 1.2% SLS in water. Based upon these characteristics, SLS 1.2% gave a good balance of minimizing surfactant concentration and analytical interference while maximizing Vit D3 dissolution.

Evidence exists that vitamin D has a potential antimicrobial activity and its deficiency has deleterious effects on general well-being and longevity. Vitamin D may reduce the risk of infection through multiple mechanisms. Vitamin D boosts innate immunity by modulating production of anti-microbial peptides (AMPs) and cytokine response. Vitamin D and its analogues via these mechanisms are playing an increasing role in the management of atopic dermatitis, psoriasis, vitiligo, acne and rosacea. Vitamin D may reduce susceptibility to infection in patients with atopic dermatitis and the ability to regulate local immune and inflammatory responses offers exciting potential for understanding and treating chronic inflammatory dermatitides. Moreover, B and T cell activation as well as boosting the activity of monocytes and macrophages also contribute to a potent systemic anti-microbial effect. The direct invasion by pathogenic organisms may be minimized at sites such as the respiratory tract by enhancing clearance of invading organisms. A vitamin D replete state appears to benefit most infections, with the possible noteworthy exception of Leishmaniasis. Antibiotics remain an expensive option and misuse of these agents results in significant antibiotic resistance and contributes to escalating health care costs. Vitamin D constitutes an inexpensive prophylactic option and possibly therapeutic product either by itself or as a synergistic agent to traditional antimicrobial agents. This review outlines the specific antimicrobial properties of vitamin D in combating a wide range of organisms. We discuss the possible mechanisms by which vitamin D may have a therapeutic role in managing a variety of infections.