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1.  Correction of vitamin D deficiency in critically ill patients - VITdAL@ICU study protocol of a double-blind, placebo-controlled randomized clinical trial 
Vitamin D deficiency is associated with multiple adverse health outcomes including increased morbidity and mortality in the general population and in critically ill patients. However, no randomized controlled trial has evaluated so far whether treatment with sufficiently large doses of vitamin D can improve clinical outcome of patients in an intensive care setting.
The VITdAL@ICU trial is an investigator-initiated, non-commercial, double-blind, placebo-controlled randomized clinical trial. This study compares high-dose oral cholecalciferol (vitamin D3) versus placebo treatment in a mixed population of 480 critically ill patients with low 25-hydroxyvitamin-D levels at study enrollment (≤ 20ng/ml). Following an initial loading dose of 540,000 IU of vitamin D3, patients receive 90,000 IU of vitamin D3 on a monthly basis for 5 months. The study is designed to compare clinical outcome in the two study arms with the primary endpoint being length of hospital stay. Secondary endpoints include among others length of ICU stay, the percentage of patients with 25(OH)D levels > 30 ng/ml at day 7, ICU and hospital mortality and duration of mechanical ventilation. We describe here the VITdAL@ICU study protocol for the primary report.
This trial is designed to evaluate whether high-dose vitamin D3 is able to improve morbidity and mortality in a mixed population of adult critically ill patients and correct vitamin D deficiency safely.
Trial registration
ClinicalTrials: NCT01130181
PMCID: PMC3534412  PMID: 23134762
Critical Illness; Vitamin D deficiency; Cholecalciferol; Vitamin D; Critical care; Intensive care; Vitamin D3
2.  Seasonal variation of serum 25-hydroxyvitamin D levels in adult patients with inflammatory bowel disease 
Osteoporosis International  2010;22(11):2857-2867.
Patients with inflammatory bowel disease (IBD) are at risk of osteoporosis. Vitamin D (vitD) deficiency is known as a risk factor of osteoporosis. We observed low vitD blood levels in adult IBD patients both at the end of summer and winter. Furthermore, effects of oral vitD supplementation in (generally low) daily dosages were poor.
Patients with IBD are at risk of osteoporosis. This study evaluates seasonal vitD status, determinants of vitD deficiency and effects of vitD supplementation in adult IBD patients.
Patients were screened for vitD deficiency at the end of summer and winter using serum 25OHD3 (cut-off point, <50 nmol/L) combined with routine laboratory tests. A standardized questionnaire was used for demographic/lifestyle data i.e. IBD activity, health behaviour and vitD intake through diet and ultraviolet light.
Late-summer, 39% of the included 316 patients were vitD deficient. Late-winter, 57% of the follow-up patients (n = 281) were deficient. Independent protective determinants of vitD deficiency were oral vitD supplementation (summer/winter: odds ratio [OR], 0.52 [95% confidence interval [CI], 0.29–0.94]/OR, 0.44 [95% CI, 0.26–0.75]), recent sun holiday (summer: OR, 0.42 [95% CI, 0.24–0.74]) and regular solarium visits (summer/winter: OR, 0.28 [95% CI, 0.13–0.63]/OR, 0.17 [0.06–0.50]). IBD activity (p = 0.031), red blood cell distribution width (RDW; p = 0.04) and erythrocyte sedimentation rate (p = 0.03) were associated with low vitD levels using univariate analyses of the extreme 25OHD quartiles. In a subgroup with vitD supplementation, still 30% (late-summer) and 44% (late-winter) were vitD deficient.
VitD deficiency is common in IBD patients, but prevalence might be comparable with the general population. Ultraviolet light is essential for adequate vitD levels. Effects of oral vitD supplementation in (generally low) daily dosages are poor. Determinants for low vitD levels were IBD activity and elevated inflammatory markers, suggesting that increased risk of osteoporosis in IBD might be more related to the inflammation than to vitD deficiency.
PMCID: PMC3186887  PMID: 21113577
Inflammatory bowel disease; Osteoporosis; Pathophysiology; Prevalence; Seasonal variation; Serum 25-hydroxyvitamin D
3.  Decreased Serum Vitamin D Levels in Children with Asthma are Associated with Increased Corticosteroid Usage 
There is little knowledge about clinical variables associated with vitamin D (vitD) insufficiency in asthmatic children.
To investigate disease variables associated with vitD insufficiency in childhood asthma and interaction of vitD with corticosteroid-mediated anti-inflammatory responses.
We analyzed 25-hydroxyvitamin D serum levels in 100 asthmatic children to investigate relationships between 25-hydroxyvitamin D levels and patient characteristics. We determined vitD effects on dexamethasone (DEX) induction of mitogen-activated protein kinase phosphatase-1 (MKP-1) and IL-10 in peripheral blood mononuclear cells (PBMC).
The median 25-hydroxyvitamin D serum level was 31 ng/mL. 47% of subjects had vitD levels in the insufficient range (<30 ng/mL), while 17% were vitD deficient (<20 ng/mL). Log10 IgE (p=0.01, ρ=−0.25) and the number of positive aeroallergen skin prick tests (p=0.02, ρ=−0.23) showed a significant inverse correlation with vitD, whereas FEV1% predicted (p =0.004, ρ=0.34) and FEV1/FVC ratio (p=0.01, ρ=0.30) showed a significant positive correlation with vitD. The use of inhaled steroids (p=0.0475), oral steroids (p=0.02), and total steroid dose (p=0.001), all showed significant inverse correlations with vitD. The amount of MKP-1 and IL-10 mRNA induced by vitD plus DEX was significantly greater than that induced by DEX alone (p<0.01). In an experimental model of steroid resistance where DEX alone did not inhibit T cell proliferation, addition of vitD to DEX resulted in significant dose dependent suppression of cell proliferation.
Corticosteroid use and worsening airflow limitation is associated with lower vitD serum levels in asthmatics. VitD enhances glucocorticoid action in asthmatic PBMC and enhances the immunosuppressive function of DEX in vitro.
Clinical Implications
Our study suggests that vitD supplementation may potentiate anti-inflammatory function of corticosteroids in asthmatics and thereby improve asthma control.
PMCID: PMC2866800  PMID: 20381849
vitamin D; children; asthma
4.  Vitamin D deficiency is associated with increased mortality in critically ill patients especially in those requiring ventilatory support 
Vitamin D (VitD) classically recognized for its role in the musculoskeletal system, has been implicated in myriad of conditions such as diabetes, immune dysfunction, cancers, heart disease, metabolic syndrome, etc. We studied the role of VitD in acute care setting and its correlation with mortality.
Materials and Methods:
A total of 85 consecutive consenting patients admitted in medical intensive care unit of tertiary care hospital who fulfilled the inclusion criteria were included. All patients were evaluated clinically, and blood samples were collected for hemogram, biochemical investigations including serum calcium, phosphorus, alkaline phosphatase, magnesium, along with 25(OH) VitD, 1,25(OH) VitD and intact parathormone levels. Simplified acute physiology score (SAPS II) was calculated for all patients.
VitD was deficient (<30 ng/ml) in 27 patients (32%). The overall mortality was more in VitD deficient group as compared to VitD sufficient group (74 vs. 41%; P < 0.05). The actual mortality in VitD deficient group was higher than the mortality predicted by SAPS II score (50 vs. 74%; P < 0.0507). VitD deficiency was also associated with more mortality among those requiring ventilator support (95% vs. 40%; P < 0.05) as well as with higher blood glucose (124.5 ± 29.7 vs. 94.8 ± 19.8: P < 0.01) levels.
VitD deficiency was associated with increased mortality, poor ventilator outcomes, and increased blood glucose in critically ill patients.
PMCID: PMC4138907  PMID: 25143908
Blood glucose; mortality; vitamin D
5.  L-arginine and Vitamin D Adjunctive Therapies in Pulmonary Tuberculosis: A Randomised, Double-Blind, Placebo-Controlled Trial 
PLoS ONE  2013;8(8):e70032.
Vitamin D (vitD) and L-arginine have important antimycobacterial effects in humans. Adjunctive therapy with these agents has the potential to improve outcomes in active tuberculosis (TB).
In a 4-arm randomised, double-blind, placebo-controlled factorial trial in adults with smear-positive pulmonary tuberculosis (PTB) in Timika, Indonesia, we tested the effect of oral adjunctive vitD 50,000 IU 4-weekly or matching placebo, and L-arginine 6.0 g daily or matching placebo, for 8 weeks, on proportions of participants with negative 4-week sputum culture, and on an 8-week clinical score (weight, FEV1, cough, sputum, haemoptysis). All participants with available endpoints were included in analyses according to the study arm to which they were originally assigned. Adults with new smear-positive PTB were eligible. The trial was registered at NCT00677339.
200 participants were enrolled, less than the intended sample size: 50 received L-arginine + active vitD, 49 received L-arginine + placebo vit D, 51 received placebo L-arginine + active vitD and 50 received placebo L-arginine + placebo vitD. According to the factorial model, 99 people received arginine, 101 placebo arginine, 101 vitamin D, 99 placebo vitamin D. Results for the primary endpoints were available in 155 (4-week culture) and 167 (clinical score) participants. Sputum culture conversion was achieved by week 4 in 48/76 (63%) participants in the active L-arginine versus 48/79 (61%) in placebo L-arginine arms (risk difference −3%, 95% CI −19 to 13%), and in 44/75 (59%) in the active vitD versus 52/80 (65%) in the placebo vitD arms (risk difference 7%, 95% CI −9 to 22%). The mean clinical outcome score also did not differ between study arms. There were no effects of the interventions on adverse event rates including hypercalcaemia, or other secondary outcomes.
Neither vitD nor L-arginine supplementation, at the doses administered and with the power attained, affected TB outcomes.
Registry Registry number: NCT00677339
PMCID: PMC3743888  PMID: 23967066
6.  Prevalence of 25-OH Vitamin D Deficiency in a Population of Hemodialysis Patients and Efficacy of an Oral Ergocalciferol Supplementation Regimen 
American journal of nephrology  2013;37(6):568-574.
Optimal dosing regimens for 25-OH vitamin D (VitD) deficiency are unknown in hemodialysis (HD) patients. Our aim was to evaluate the efficacy of prescribing ergocalciferol supplementation based on KDOQI guidelines for chronic kidney disease (CKD) stages III–IV in HD patients.
We conducted a retrospective study of 96 urban, predominately African-American HD patients at a single-center dialysis unit with VitD insufficiency or deficiency treated with ergocalciferol. Patients were classified as either compliant or non-compliant with supplementation as determined by review of pharmacy records. The primary outcome was VitD levels 6 months after initiation of treatment and secondary outcomes were VitD levels at 11 months, bone/mineral and anemia parameters.
The population was predominately African-American (69%) and Hispanic (28%). There were 61 individuals in the compliant group and 35 individuals in the non-compliant group. The compliant group was older but otherwise similar in demographics and co-morbid conditions to the non-compliant group. After 6 months of treatment, the compliant group had a significant increase in VitD level (14.7 ± 6.0 to 28.7 ± 10.0 ng/ml, p < 0.0001) compared to the non-compliant group (14.7 ± 5.5 to 14.8 ± 7.1 ng/ml, p = 0.95). There were no differences in the incidence of hypercalcemia between the two groups. Except for a decrease in phosphorus in the compliant group (5.6 ± 1.6 to 4.9 ± 1.7 mg/dl, p = 0.004), there were no significant difference in bone/mineral or anemia parameters including dosing of darbepoetin.
An ergocalciferol-prescribing strategy using the KDOQI guidelines for stage III–IV kidney disease in HD patients with VitD deficiency or insufficiency is inadequate to achieve repletion or maintenance of normal VitD levels.
PMCID: PMC4109679  PMID: 23735861
Vitamin D deficiency; End-stage renal disease; Hemodialysis
7.  Vitamin D Status and Related Factors in Newborns in Shanghai, China 
Nutrients  2014;6(12):5600-5610.
With the increasing recognition of the importance of the non-skeletal effects of vitamin D (VitD), more and more attention has been drawn to VitD status in early life. However, the VitD status of newborns and factors that influence VitD levels in Shanghai, China, remain unclear. A total of 1030 pregnant women were selected from two hospitals in Shanghai, one of the largest cities in China located at 31 degrees north latitude. Umbilical cord serum concentrations of 25-hydroxy vitamin D [25(OH)D] were measured by LC-MS-MS, and questionnaires were used to collect information. The median cord serum 25(OH)D concentration was 22.4 ng/mL; the concentration lower than 20 ng/mL accounted for 36.3% of the participants, and the concentration lower than 30 ng/mL for 84.1%. A multivariable logistic regression model showed that the determinants of low 25(OH)D status were being born during autumn or winter months and a lack of VitD-related multivitamin supplementation. The relative risk was 1.7 for both autumn (95% CI, 1.1–2.6) and winter (95% CI, 1.1–2.5) births (p < 0.05). VitD-related multivitamin supplementation more than once a day during pregnancy reduced the risk of VitD deficiency [adjusted OR (aOR) = 0.6, 95% CI (0.45–1.0) for VitD supplementation] (p < 0.05). VitD deficiency and insufficiency are common in newborns in Shanghai, China, and are independently associated with season and VitD supplementation. Our findings may assist future efforts to correct low levels of 25(OH)D in Shanghai mothers and their newborn children.
PMCID: PMC4276986  PMID: 25486368
vitamin D; related factors; newborn
8.  Ribavirin induced anaemia: the effect of vitamin D supplementation on erythropoietin and erythrocyte indices in normal Wistar rat 
Objectives: To measure the effect of vitamin D3 (VitD) supplementation on erythrocyte indices, serum and kidney erythropoietin (EPO) in normal rats treated with Pegylated interferon-α (Peg-INF-α) and ribavirin (RBV). Materials and methods: Eighty male Wistar rats were divided equally into 8 groups. ‘Control’; ‘P’: only received Peg-INF-α; ‘PD’: Peg-INF-α/VitD; ‘PR’: Peg-INF-α/RBV; ‘PRD’: Peg-INF-α/RBV/VitD; ‘R’: only received RBV; ‘RD’: RBV/VitD and ‘VitD’: only received vitamin D3. Peg-INF-α-2a was injected subcutaneously (6 µg/rat/week) for 4 weeks. RBV (4 mg/rat/day) and VitD (500 IU/rat/day) were given orally for 5 weeks. Blood samples were collected to measure erythrocyte indices and serum 25(OH) vitamin D. EPO was measured in serum samples and kidney specimens by ELISA. Results: Peg-INF-α alone did not affect the RBCs count, haemoglobin, serum and kidney EPO compared to control (P > 0.05). RBV significantly decreased (P < 0.05) the erythrocyte count, haemoglobin and EPO levels in kidney and serum, either individually (R group) or combined with Peg-INF-α (PR group), compared to ‘Control’ and ‘P’ groups. VitD prevented the development of anaemia and significantly increased the concentrations of EPO at serum and kidney levels in the ‘RD’ and ‘PRD’ groups compared to ‘R’ and ‘PR’ groups. There was a significant positive correlation between blood levels of VitD with serum and kidney EPO, Red cell count and haemoglobin concentrations. Conclusion: VitD could have a potential beneficial role in the prevention of ribavirin-induced anaemia by promoting endogenous EPO. Further studies are needed to explore the role of vitamin D in the prevention of ribavirin associated anaemia.
PMCID: PMC4211774  PMID: 25356124
Anaemia; erythropoietin hormone; pegylated interferon-α; ribavirin and vitamin D
9.  A Prospective Randomized Controlled Trial of the Effects of Vitamin D Supplementation on Cardiovascular Disease Risk 
PLoS ONE  2012;7(5):e36617.
Vitamin D (VitD) supplementation has been advocated for cardiovascular risk reduction; however, supporting data are sparse. The objective of this study was to determine whether VitD supplementation reduces cardiovascular risk. Subjects in this prospective, randomized, double-blind, placebo-controlled trial of post-menopausal women with serum 25-hydroxyvitamin D concentrations >10 and <60 ng/mL were randomized to Vitamin D3 2500 IU or placebo, daily for 4 months. Primary endpoints were changes in brachial artery flow-mediated vasodilation (FMD), carotid-femoral pulse wave velocity (PWV), and aortic augmentation index (AIx). The 114 subjects were mean (standard deviation) 63.9 (3.0) years old with a 25-hydroxyvitamin D level of 31.3 (10.6) ng/mL. Low VitD (<30 ng/mL) was present in 47% and was associated with higher body-mass index, systolic blood pressure, glucose, CRP, and lower FMD (all p<0.05). After 4 months, 25-hydroxyvitamin D levels increased by 15.7 (9.3) ng/mL on vitamin D3 vs. −0.2 (6.1) ng/mL on placebo (p<0.001). There were no significant differences between groups in changes in FMD (0.3 [3.4] vs. 0.3 [2.6] %, p = 0.77), PWV (0.00 [1.06] vs. 0.05 [0.92] m/s, p = 0.65), AIx (2.7 [6.3] vs. 0.9 [5.6] %, p = 0.10), or CRP (0.3 [1.9] vs. 0.3 [4.2] mg/L, p = 0.97). Multivariable models showed no significant interactions between treatment group and low VitD status (<30 ng/mL) for changes in FMD (p = 0.65), PWV (p = 0.93), AIx (p = 0.97), or CRP (p = 0.26).In conclusion, VitD supplementation did not improve endothelial function, arterial stiffness, or inflammation. These observations do not support use of VitD supplementation to reduce cardiovascular disease risk.
Trial Registration NCT00690417
Trial Registration NCT01049048
PMCID: PMC3346736  PMID: 22586483
10.  Effects of vitamin D supplementation on intestinal permeability, cathelicidin and disease markers in Crohn’s disease: Results from a randomised double-blind placebo-controlled study 
Vitamin D (vitD) supplementation may prolong remission in Crohn’s disease (CD); however, the clinical efficacy and mechanisms are unclear.
To determine changes in intestinal permeability (IP), antimicrobial peptide (AMP) concentrations and disease markers in CD, in response to vitD supplementation.
In a double-blind randomised placebo-controlled study, we assigned 27 CD patients in remission to 2000 IU/day vitD or placebo for 3 mos. We determined IP, plasma cathelicidin (LL-37 in ng/mL), human-beta-defensin-2 (hBD2 in pg/mL), disease activity (Crohn’s Disease Activity Index (CDAI)), C-reactive protein (CRP in mg/L), fecal calprotectin (µg/g), Quality of Life (QoL) and serum 25-hydroxyvitamin D (25(OH)D in nmol/L) at 0 and 3 mos.
At 3 mos., 25(OH)D concentrations were significantly higher in those whom were treated (p < 0.001). Intra-group analysis showed increased LL-37 concentrations (p = 0.050) and maintenance of IP measures in the treated group. In contrast, in the placebo group, the small bowel (p = 0.018) and gastro-duodenal permeability (p = 0.030) increased from baseline. At 3 mos., patients with 25(OH)D ≥ 75 nmol/L had significantly lower CRP (p = 0.019), higher QoL (p = 0.037), higher LL-37 concentrations (p < 0.001) and non-significantly lower CDAI scores (p = 0.082), compared to those with levels <75 nmol/L.
Short-term treatment with 2000 IU/day vitD significantly increased 25(OH)D levels in CD patients in remission and it was associated with increased LL-37 concentrations and maintenance of IP. Achieving 25(OH)D ≥ 75 nmol/l was accompanied by higher circulating LL-37, higher QoL scores and reduced CRP. Registered at (NCT01792388).
PMCID: PMC4480538  PMID: 26137304
Barrier function; calprotectin; cathelicidin; Crohn’s disease; human beta defensin 2; intestinal permeability; quality of life; vitamin D
11.  Vitamin D3 Decreases Parathyroid Hormone in HIV-Infected Youth Being Treated With Tenofovir: A Randomized, Placebo-Controlled Trial 
In this randomized, double-blind, placebo-controlled trial of human immunodeficiency virus–infected youths aged 18–25, vitamin D3, 50000 IU once monthly for 3 months decreased parathyroid hormone in participants treated with tenofovir-containing antiretroviral regimens but not in those participants whose regimens did not contain tenofovir.
Background. The study goal was to determine the effect of vitamin D (VITD) supplementation on tubular reabsorption of phosphate (TRP), parathyroid hormone (PTH), bone alkaline phosphatase (BAP), and C-telopeptide (CTX) in youth infected with human immunodeficiency virus (HIV) receiving and not receiving combination antiretroviral therapy (cART) containing tenofovir disoproxil fumarate (TDF).
Methods. This randomized, double-blind, placebo-controlled multicenter trial enrolled HIV-infected youth 18–25 years based on stable treatment with cART containing TDF (n = 118) or no TDF (noTDF; n = 85), and randomized within those groups to vitamin D3, 50 000 IU (n = 102) or placebo (n = 101), administered at 0, 4, and 8 weeks. Outcomes included change in TRP, PTH, BAP, and CTX from baseline to week 12 by TDF/noTDF; and VITD/placebo.
Results. At baseline, VITD and placebo groups were similar except those on TDF had lower TRP and higher PTH and CTX. At week 12, 95% in the VITD group had sufficient serum 25-hydroxy vitamin D (25-OHD; ≥20 ng/mL), increased from 48% at baseline, without change in placebo (P < .001). PTH decreased in the TDF group receiving VITD (P = .031) but not in the noTDF group receiving VITD, or either placebo group. The decrease in PTH with VITD in those on TDF occurred with insufficient and sufficient baseline 25-OHD (mean PTH change, −7.9 and −6.2 pg/mL; P = .031 and .053, respectively).
Conclusions. In youth on TDF, vitamin D3 supplementation decreased PTH, regardless of baseline 25-OHD concentration.
Clinical Trials Registration. NCT00490412.
PMCID: PMC3297650  PMID: 22267714
12.  Vitamin D3 inhibits lipopolysaccharide-induced placental inflammation through reinforcing interaction between vitamin D receptor and nuclear factor kappa B p65 subunit 
Scientific Reports  2015;5:10871.
It is increasingly recognized that vitamin D3 (VitD3) has an anti-inflammatory activity. The present study investigated the effects of maternal VitD3 supplementation during pregnancy on LPS-induced placental inflammation and fetal intrauterine growth restriction (IUGR). All pregnant mice except controls were intraperitoneally injected with LPS (100 μg/kg) daily from gestational day (GD)15–17. In VitD3 + LPS group, pregnant mice were orally administered with VitD3 (25 μg/kg) before LPS injection. As expected, maternal LPS exposure caused placental inflammation and fetal IUGR. Interestingly, pretreatment with VitD3 repressed placental inflammation and protected against LPS-induced fetal IUGR. Further analysis showed that pretreatment with VitD3, which activated placental vitamin D receptor (VDR) signaling, specifically suppressed LPS-induced activation of nuclear factor kappa B (NF-κB) and significantly blocked nuclear translocation of NF-κB p65 subunit in trophoblast gaint cells of the labyrinth layer. Conversely, LPS, which activated placental NF-κB signaling, suppressed placental VDR activation and its target gene expression. Moreover, VitD3 reinforced physical interaction between placental VDR and NF-κB p65 subunit. The further study demonstrates that VitD3 inhibits placental NF-κB signaling in VDR-dependent manner. These results provide a mechanistic explanation for VitD3-mediated anti-inflammatory activity. Overall, the present study provides evidence for roles of VDR as a key regulator of placental inflammation.
PMCID: PMC4464284  PMID: 26065916
13.  Very High-dose Cholecalciferol and Arteriovenous Fistula Maturation in ESRD: A Randomized, Double-Blind, Placebo-Controlled Pilot Study 
The journal of vascular access  2013;15(2):88-94.
While vitamin D is critical for optimal skeletal health, it also appears to play a significant role in vascular homeostasis. This pilot study compared arteriovenous access outcomes following cholecalciferol supplementation compared to placebo in end-stage renal disease patients preparing to undergo AV access creation.
52 adult hemodialysis patients preparing for AVF creation were randomized to receive peri-operative high dose cholecalciferol vs. placebo in this double-blind, randomized placebo-controlled pilot study. The primary outcome was mean response to high-dose oral cholecalciferol vs. placebo, and secondary outcome arteriovenous access maturation at 6 months. Logistic regression was used to assess the association between AV access maturation and baseline, post-treatment and overall change in vitamin D concentration.
45% of cholecalciferol-treated and 54% of placebo-treated patients were successfully using their AVF or AVG at 6 months (p= 0.8). Baseline serum concentrations of 25(OH)D and 1,25(OH)2D did not differ between those who experienced AVF or AVG maturation and those who did not (p=0.22 and p=0.59, respectively). Similarly, there was no relationship between AVF or AVG maturation and post-treatment serum 25(OH)D and 1,25(OH)2D concentration (p=0.24 and 0.51, respectively).
Peri-operative high dose vitamin D3 therapy does correct 25(OH)D level but does not appear to have an association with AV access maturation rates. Future research may include extended pre-operative vitamin D3 therapy in a larger population or in certain sub-populations at high risk for AVF failure.
PMCID: PMC3979512  PMID: 24101420
AVF; Dialysis access; ESRD; Vitamin D
14.  Vitamin D deficiency reduces the benefits of progesterone treatment after brain injury in aged rats 
Neurobiology of aging  2009;32(5):864-874.
Administration of the neurosteroid progesterone (PROG) has been shown to be beneficial in a number of brain injury models and in two recent clinical trials. Given widespread vitamin D deficiency and increasing traumatic brain injuries (TBIs) in the elderly, we investigated the interaction of vitamin D deficiency and PROG with cortical contusion injury in aged rats. Vitamin D deficient (VitD-deficient) animals showed elevated inflammatory proteins (TNFα, IL-1β, IL-6, NFκB p65) in the brain even without injury. VitD-deficient rats with TBI, whether given PROG or vehicle, showed increased inflammation and greater open-field behavioral deficits compared to VitD-normal animals. Although PROG was beneficial in injured VitD-normal animals, in VitD-deficient subjects neurosteroid treatment conferred no improvement over vehicle. A supplemental dose of 1,25-dihydroxyvitamin D3 (VDH) given with the first PROG treatment dramatically improved results in VitD-deficient rats, but treatment with VDH alone did not. Our results suggest that VitD-deficiency can increase baseline brain inflammation, exacerbate the effects of TBI, and attenuate the benefits of PROG treatment; these effects may be reversed if the deficiency is corrected.
PMCID: PMC3586224  PMID: 19482377
Aging; Inflammation; Progesterone; 1,25-Dihydroxyvitamin D3; Traumatic brain injury; Vitamin D deficiency
15.  Vitamin D3 enhances the tumouricidal effects of 5-Fluorouracil through multipathway mechanisms in azoxymethane rat model of colon cancer 
Vitamin D3 and its analogues have recently been shown to enhance the anti-tumour effects of 5- Fluorouracil (5-FU) both in vitro and in xenograft mouse model of colon cancer. This study measured the potential mechanism(s) by which vitamin D3 could synergise the tumouricidal activities of 5-FU in azoxymethane (AOM) rat model of colon cancer.
Seventy-five male Wistar rats were divided equally into 5 groups: Control, AOM, AOM-treated by 5-FU (5-FU), AOM-treated by vitamin D3 (VitD3), and AOM-treated by 5-FU + vitamin D3 (5-FU/D). The study duration was 15 weeks. AOM was injected subcutaneously for 2 weeks (15 mg/kg/week). 5-FU was injected intraperitoneally in the 9th and 10th weeks post AOM (8 total injections were given: 12 mg/kg/day for 4 successive days, then 6 mg/kg every other day for another 4 doses) and oral vitamin D3 (500 IU/rat/day; 3 days/week) was given from week 7 post AOM till the last week of the study. The colons were collected following euthanasia for gross and histopathological examination. The expression of β-catenin, transforming growth factor-β1 (TGF-β1), TGF-β type 2 receptor (TGF-βR2), smad4, inducible nitric oxide synthase (iNOS), and heat shock protein-90 (HSP-90) proteins was measured by immunohistochemistry. In colonic tissue homogenates, quantitative RT-PCR was used to measure the mRNA expression of Wnt, β-catenin, Dickkopf-1 (DKK-1) and cyclooxygenase-2 (COX-2) genes, while ELISA was used to measure the concentrations of TGF-β1, HSP-90 and COX-2 proteins.
Monotherapy with 5-FU or vitamin D3 significantly decreased the number of grown tumours induced by AOM (P < 0.05); however, their combination resulted in more significant tumouricidal effects (P < 0.05) compared with monotherapy groups. Mechanistically, vitamin D3/5-FU co-therapy significantly decreased the expression of Wnt, β-catenin, iNOS, COX-2 and HSP-90 and significantly increased the expression of DKK-1, TGF-β1, TGF-βR2, smad4 (P < 0.05), in comparison with their corresponding monotherapy groups.
Vitamin D3 and 5-FU synergise together and exhibit better anticancer effects by modulating Wnt/β-catenin pathway, TGF-β1 signals, iNOS, COX-2 and HSP-90. Further studies are required to illustrate the clinical value of vitamin D supplementation during the treatment of colon cancer with 5-FU in human patients.
PMCID: PMC4513788  PMID: 26205949
Colon cancer; Vitamin D3; β-catenin; TGF-β; iNOS; HSP-90; COX-2; Therapeutic efficacy
16.  Vitamin D2 Supplementation Amplifies Eccentric Exercise-Induced Muscle Damage in NASCAR Pit Crew Athletes 
Nutrients  2013;6(1):63-75.
This study determined if 6-weeks vitamin D2 supplementation (vitD2, 3800 IU/day) had an influence on muscle function, eccentric exercise-induced muscle damage (EIMD), and delayed onset of muscle soreness (DOMS) in National Association for Stock Car Auto Racing (NASCAR) NASCAR pit crew athletes. Subjects were randomized to vitD2 (n = 13) and placebo (n = 15), and ingested supplements (double-blind) for six weeks. Blood samples were collected and muscle function tests conducted pre- and post-study (leg-back and hand grip dynamometer strength tests, body weight bench press to exhaustion, vertical jump, 30-s Wingate test). Post-study, subjects engaged in 90 min eccentric-based exercise, with blood samples and DOMS ratings obtained immediately after and 1- and 2-days post-exercise. Six weeks vitD2 increased serum 25(OH)D2 456% and decreased 25(OH)D3 21% versus placebo (p < 0.001, p = 0.036, respectively), with no influence on muscle function test scores. The post-study eccentric exercise bout induced EIMD and DOMS, with higher muscle damage biomarkers measured in vitD2 compared to placebo (myoglobin 252%, 122% increase, respectively, p = 0.001; creatine phosphokinase 24 h post-exercise, 169%, 32%, p < 0.001), with no differences for DOMS. In summary, 6-weeks vitD2 (3800 IU/day) significantly increased 25(OH)D2 and decreased 25(OH)D3, had no effect on muscle function tests, and amplified muscle damage markers in NASCAR pit crew athletes following eccentric exercise.
PMCID: PMC3916849  PMID: 24362707
delayed onset of muscle soreness (DOMS); myoglobin; creatine phosphokinase; muscle function testing; eccentric exercise; LC-MS/MS
17.  Effect of Vitamin D Supplementation on Glucose Control and Inflammatory Response in Type II Diabetes: A Double Blind, Randomized Clinical Trial 
Diabetes mellitus (DM) and vitamin D deficiency are major health concerns around the world. Evidence suggests a possible role of vitamin D in improvement of insulin secretion and sensitivity.
We assessed whether vitamin D supplementation could be used in vitamin D deficient-type II diabetes to improve glucose metabolism, components of metabolic syndrome (MetS) and specific inflammatory biomarkers.
Patients and Methods:
A double blind, randomized clinical trial was conducted in King Khalid University Hospital, Saudi Arabia to evaluate the effect of cholecalciferol supplementation on glycemic control, MetS components and specific inflammatory biomarkers including tumor necrosis factor-alpha (TNF-α), Interleukin (IL-6), leptin, adiponectin and vascular cell adhesion molecule-1 (VCAM-1). Twenty-two patients with type II diabetes with insulin resistance, glycated hemoglobin (HbA1c) ≥ 6 (42 mmol/mol) and serum 25(OH)D < 50 nmol/L were randomized using a computer program to receive either supplementation with cholecalciferol (5000 IU/day) or placebo for 12 weeks. The primary outcome was change in HbA1c levels from baseline.
Median [IQR] 25(OH)D levels increased significantly in the vitamin D group as 58.1 [48, 67.3] nmol/L (P = 0.002). There was no significant difference in the change of HbA1c between the groups (P = 0.5) with a decrease of -0.1% [-1, 0.5] in the vitamin D group and an increase of 0.15% [0.1, 0.2] in the placebo group. A significant improvement was observed in the homeostasis model of assessment of β-cell activity (HOMA-%B) (P = 0.03) with vitamin D supplementation compared to baseline.
Vitamin D repletion for 12 weeks increased serum vitamin D concentrations and improved β-cell activity in vitamin D-deficient type II diabetes with no significant changes in HbA1c or insulin sensitivity.
PMCID: PMC4338666  PMID: 25745497
Diabetes Mellitus; Insulin Resistance; Vitamin D
18.  Pilot study of vitamin D supplementation in adults with cystic fibrosis pulmonary exacerbation 
Dermato-endocrinology  2012;4(2):191-197.
Background: Vitamin D insufficiency is common in cystic fibrosis (CF) and vitamin D repletion may have an important role in improving clinical outcomes in CF. This randomized, placebo-controlled, pilot study examined the feasibility and impact of a single, large dose of cholecalciferol on vitamin D status and clinical outcomes in subjects with CF.
Methods: Thirty adults with were randomized in a double-blinded, pilot study to receive 250,000 IU cholecalciferol or placebo within 48 h of hospital admission for a pulmonary exacerbation. Concentrations of 25-hydroxyvitamin D (25(OH)D), clinical outcomes and potential adverse events were assessed up to one year after randomization. Mixed effects linear regression models were used to evaluate the difference in mean serum concentrations and log-rank analyses were used to evaluate survival.
Results: Data from all subjects was analyzed. Serum 25(OH)D concentrations increased from a mean of 30.6 ± 3.2 ng/mL to 58.1 ± 3.5 ng/mL (p < 0.001) at one week and 36.7 ± 2.6 ng/mL by 12 weeks (p = 0.06) in the vitamin D group; in contrast, serum 25(OH)D concentrations remained unchanged in the placebo group. Unadjusted, one-year survival and hospital-free days were increased in the vitamin D group (p = 0.029, p = 0.036; respectively). There was also a trend toward increased IV antibiotic therapy-free days in the vitamin D group (p = 0.073). There were no signs of hypervitaminosis D or adverse events. Serum PTH and calcium concentrations were similar across both groups.
Conclusions: In this pilot study, a single, oral bolus of cholecalciferol increased serum 25(OH)D concentrations and was associated with a trend toward improved clinical outcomes in CF subjects hospitalized for a pulmonary exacerbation. Further investigation is needed into the clinical impact of improved vitamin D status in patients with CF.
PMCID: PMC3427199  PMID: 22928076
vitamin D; cystic fibrosis; parathyroid hormone; anti-microbial peptide; pulmonary exacerbation
19.  Impact of vitamin D supplementation during a resistance training intervention on body composition, muscle function, and glucose tolerance in overweight and obese adults 
Background & Aims
The impact of vitamin D supplementation in overweight and obese adults during resistance training on body composition, muscle function, and glucose tolerance was investigated.
Twenty-three overweight and obese (age: 26.1±4.7 y; BMI: 31.3±3.2 kg/m2; 25-hydroxyvitamin D: 19.3±7.2 ng/mL) adults were recruited for participation in a double-blind, placebo-controlled trial. Participants were randomly divided into vitamin D (VitD, 4000 IU/d; 5 female, 5 male) and placebo (PL; 7 female, 6 male) groups. Both groups completed 12 wks of resistance training. 25-hydroxyvitamin D, parathyroid hormone, body composition, and glucose tolerance were assessed at baseline and 12 wks. Muscle function (strength and power) was assessed at baseline, 4, 8, and 12 wks.
During the intervention, 25-hydroxyvitamin D increased and parathyroid hormone decreased in the VitD group (P<0.05). Peak power was significantly increased at 4 wks in the VitD group only (P<0.05). Regression analysis revealed an inverse association between the change in 25-hydroxyvitamin D with the change in waist-to-hip ratio (R2=0.205, P=0.02). No other improvements were observed with supplementation.
Vitamin D supplementation in overweight and obese adults during resistance training induced an early improvement in peak power, and elevated vitamin D status was associated with reduced waist-to-hip ratio.
Clinical trial registration number
PMCID: PMC4365291  PMID: 23034474
25-hydroxyvitamin D; parathyroid hormone; lean mass; muscular strength; muscular power
20.  Calcium and vitamin D intakes in children: a randomized controlled trial 
BMC Pediatrics  2013;13:86.
Calcium (Ca2+) and vitamin D (VitD) play an important role in child health. We evaluated the daily intake of Ca2+ and VitD in healthy children. Moreover, we demonstrate the efficacy of Ca2+ and VitD supplementation.
Daily Ca2 + and VitD intake was evaluated in consecutive healthy children through a validated questionnaire. Subjects with <70% of dietary reference intakes (DRIs) of Ca2+ and VitD were invited to participate in a prospective randomized trial with 2 groups of nutritional intervention: Group 1, dietary counseling aiming to optimize daily Ca2+ and VitD intake plus administration of a commercially available Ca2 + and VitD supplementation product; Group 2, dietary counseling alone. At the enrollment (T0) and after 4 months (T1) serum 25(OH) Vitamin D levels were assessed.
We evaluated 150 healthy children (male 50%, mean age 10 years); at baseline a low VitD intake was observed in all subjects (median 0.79 μg/die, IQR 1.78; range 0.01-5.02); this condition was associated with Ca2+ intake <70% of the DRIs in 82 subjects (55%). At baseline serum 25(OH)D levels were low (<30 ng/ml) in all study subjects and after 4 months of nutritional intervention, a normalization of serum 25(OH)D levels (≥30 ng/ml) was observed in all children in Group 1 and in only one subject in Group 2 [Group 1: T1 33.8 ng/ml (IQR 2.5) vs Group 2: T1 24.5 ng/ml (IQR 5.2), p <0.001].
Adequate Ca2+ and VitD intakes are difficult to obtain through dietary counseling alone in pediatric subjects. Oral supplementation with of Ca2+ and VitD is a reliable strategy to prevent this condition.
Trial registration
The study was registered in Clinical Trials Protocol Registration System (ID number: NCT01638494).
PMCID: PMC3665520  PMID: 23702146
25-hydroxyvitamin D; Dietary counseling; Pediatrics; Ca2+ intake; VitD intake; Bone metabolism; Nutritional intervention; Vitamin D supplement; Vitamin D deficiency
21.  Prognostic Role of Vitamin D Status and Efficacy of Vitamin D Supplementation in Cancer Patients: A Systematic Review 
The Oncologist  2011;16(9):1215-1227.
Whether or not hypovitaminosis D can influence the prognosis of cancer patients and whether or not vitamin D supplementation improves outcome were examined through a literature review. It was concluded that the currently available evidence is insufficient to recommend vitamin D supplementation in cancer patients in clinical practice.
Whether or not hypovitaminosis D can influence the prognosis of cancer patients and whether or not vitamin D (vitD) supplementation improves outcome remain controversial.
Studies evaluating the prognostic role of vitD and vitD receptor (VDR) in cancer patients and trials evaluating the efficacy of vitD administration on patient outcome were identified by a search of MEDLINE, EMBASE, ISI Web of Knowledge, and the Cochrane Library through June 2010.
Twenty-five studies were included. A negative prognostic role for low serum vitD level was observed in five cohort studies including patients with breast cancer (one study), colon cancer (two studies), prostate cancer (one study), and melanoma (one study), but not in two studies on non-small cell lung cancer and one study on breast cancer. Three of four studies showed that VDR+ tumors carry a better prognosis than VDR− tumors, whereas VDR polymorphisms were significantly associated with prognosis in five of 10 studies. A significant interaction between serum vitD level and VDR polymorphism was observed in one study. Three randomized trials involving advanced prostate cancer patients explored the prognostic role of vitD supplementation. A meta-analysis of these trials showed no effect on survival (pooled risk ratio, 1.07; 95% confidence interval, CI, 0.93–1.23), with strong heterogeneity among studies.
Hypovitaminosis D seems to be associated with a worse prognosis in some cancers, but vitD supplementation failed to demonstrate a benefit in prostate cancer patients. The currently available evidence is insufficient to recommend vitD supplementation in cancer patients in clinical practice.
PMCID: PMC3228169  PMID: 21835895
Vitamin D; Vitamin D receptor; Neoplasm; Prognosis
22.  Alveolar Macrophage Cathelicidin Deficiency in Severe Sarcoidosis 
Journal of innate immunity  2012;4(5-6):569-578.
Dysfunctional immune responses characterize sarcoidosis but the status of cathelicidin, a potent immunoregulatory and anti-microbial molecule has not been established in clinical disease activity. Alveolar macrophage cathelicidin expression was determined in biopsy-proven sarcoidosis patients classified clinically as “severe” (requiring systemic treatment) or “non-severe” (never requiring treatment). Sarcoidosis and healthy control bronchoalveolar lavage (BAL) cells were analyzed for mRNA expression of cathelicidin, vitamin D receptor (VDR), and the VDR co-activator, steroid receptor co-activator-3 (SRC3) by quantitative PCR. Cathelicidin-derived peptide LL-37 was determined by immunocytochemistry. Serum calcidiol [25(OH)vitD2] (vitD2) and calcitriol [1,25(OH)2vitD3] (vitD3) were quantified. Results indicated reduced BAL cell expression of cathelicidin and SRC3 in severe but not non-severe sarcoidosis compared to controls. Serum levels of biologically active vitD3 in both severe and non-severe patients were within control range even though vitD2 levels in both groups were below recommended level (30ng/ml). Sarcoidosis and control alveolar macrophages were studied in vitro to determine cathelicidin responses to vitD3 and tumor necrosis factor-alpha (TNFα), a vitD3 antagonist elevated in active sarcoidosis. Alveolar macrophage cathelicidin was stimulated by vitD3 but repressed by TNFα which also repressed SRC3. Findings suggest that TNFα-mediated repression of SRC3 contributes to alveolar macrophage cathelicidin deficiency in severe sarcoidosis despite healthy vitD3 levels. Deficiency of cathelicidin, a multifunctional regulator of immune cells and pro-inflammatory cytokines, may impede resolution of inflammation in severe sarcoidosis lung.
PMCID: PMC3472801  PMID: 22759465
alveolar macrophage; sarcoidosis; cathelicidin; vitamin D; cytokines; steroid receptor co-activators
23.  The effect of a combined oral calcium and vitamin D supplement for treating mild to moderate vitamin D deficiency in postmenopausal women 
Clinical Interventions in Aging  2008;3(1):183-186.
To evaluate the efficacy of a combined calcium and vitamin D (Ca-D3) supplement for vitamin D deficiency in a small group of postmenopausal women.
A prospective open label 3 month-study.
23 postmenopausal women (mean age 61.2 yrs) with vitamin D deficiency were given a combined oral Ca-D3 supplement called “Osteoblast”. The supplement comprises 500 mg elemental calcium and 500 IU of cholecalciferol. The dosing regimen comprised a loading dose of 1000 IU of cholecalciferol per day for one month (two tablets) and thereafter a maintenance dose of 500 IU of cholecalciferol per day for 2 months (one tablet).
Outcome measure
Serum was collected for calcium, 25 hydroxyvitamin D3 (25OHD3), and PTH measurements, as well as early morning 2-hour urine calcium/creatinine excretion index (Uca/creat). Specimens were collected at baseline and after 3 months of therapy. Data are reported as mean ± 1 standard error and 95% confidence intervals.
Data was available for the 21 subjects who completed the study. Two subjects (9%) withdrew because of gastrointestinal intolerance. There were 3 subjects with moderate (12.5–24 nmol/L) and 18 with mild (25–49 nmol/L) vitamin D deficiency. Ten subjects (48%) had secondary hyperparathyroidism. Following the oral Ca-D3 combination, serum 25OHD3 levels normalised in all subjects with 18 (86%) subjects achieving values of greater than 70 nmol/L. Serum 25OHD3 levels increased from 36 (31–41) to 91 (79–102) nmol/L (p = 0.0001), increasing by an average of 152% over the 3-month period. There was a corresponding 38% decrease in serum PTH concentrations at 3 months (5.1 + 0.6 pmol/L), compared with baseline (8.0 + 1 pmol/L) (p = 0.001). No subject developed hypercalcemia, but an elevated Uca/creat excretion index occurred in one subjects.
A combined oral Ca-D3 product (Osteoblast) is effective for treating vitamin D deficiency and is adequately tolerated.
PMCID: PMC2544364  PMID: 18488888
24.  Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials 
Objective To test the efficacy of supplemental vitamin D and active forms of vitamin D with or without calcium in preventing falls among older individuals.
Data sources We searched Medline, the Cochrane central register of controlled trials, BIOSIS, and Embase up to August 2008 for relevant articles. Further studies were identified by consulting clinical experts, bibliographies, and abstracts. We contacted authors for additional data when necessary.
Review methods Only double blind randomised controlled trials of older individuals (mean age 65 years or older) receiving a defined oral dose of supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)) or an active form of vitamin D (1α-hydroxyvitamin D3 (1α-hydroxycalciferol) or 1,25-dihydroxyvitamin D3 (1,25-dihydroxycholecalciferol)) and with sufficiently specified fall assessment were considered for inclusion.
Results Eight randomised controlled trials (n=2426) of supplemental vitamin D met our inclusion criteria. Heterogeneity among trials was observed for dose of vitamin D (700-1000 IU/day v 200-600 IU/day; P=0.02) and achieved 25-hydroxyvitamin D3 concentration (25(OH)D concentration: <60 nmol/l v ≥60 nmol/l; P=0.005). High dose supplemental vitamin D reduced fall risk by 19% (pooled relative risk (RR) 0.81, 95% CI 0.71 to 0.92; n=1921 from seven trials), whereas achieved serum 25(OH)D concentrations of 60 nmol/l or more resulted in a 23% fall reduction (pooled RR 0.77, 95% CI 0.65 to 0.90). Falls were not notably reduced by low dose supplemental vitamin D (pooled RR 1.10, 95% CI 0.89 to 1.35; n=505 from two trials) or by achieved serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l (pooled RR 1.35, 95% CI 0.98 to 1.84). Two randomised controlled trials (n=624) of active forms of vitamin D met our inclusion criteria. Active forms of vitamin D reduced fall risk by 22% (pooled RR 0.78, 95% CI 0.64 to 0.94).
Conclusions Supplemental vitamin D in a dose of 700-1000 IU a day reduced the risk of falling among older individuals by 19% and to a similar degree as active forms of vitamin D. Doses of supplemental vitamin D of less than 700 IU or serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l may not reduce the risk of falling among older individuals.
PMCID: PMC2755728  PMID: 19797342
25.  Vitamin D3 supplementation increases fibroblast growth factor-23 in HIV-infected youth treated with tenofovir disoproxil fumarate 
Antiviral therapy  2014;19(6):613-618.
Tenofovir (TDF) is associated with phosphaturia and elevated 1,25 dihydroxy vitamin D (1,25-OH(2)D). Fibroblast growth factor 23 (FGF23) causes phosphaturia and increases in response to elevated 1,25-OH(2)D. Vitamin D binding protein (VDBP) binds to 1,25-OH(2)D, decreasing its biologic activity, and is elevated in persons with higher plasma tenofovir concentrations. We compared FGF23 and VDBP before and after vitamin D3 (VITD) supplementation in youth treated with combination antiretroviral therapy (cART) containing or not containing TDF.
A randomized controlled trial in HIV+ youth ages 18–25 years enrolled participants based on cART treatment with TDF (TDF, N=118) or without TDF (no-TDF, N=85) and randomized within those groups to VITD (50,000 IU every four weeks) or placebo (PL). We measured FGF23 and VDBP and calculated free 1,25-OH(2)D at baseline and week 12, and compared changes by TDF treatment and VITD randomized group.
At baseline, serum FGF23 concentration showed a quadratic relationship with 1,25-OH(2)D most pronounced in the TDF group. At week 12, total and free 1,25-OH(2)D increased in the VITD but not PL groups, independent of TDF use. FGF23 increased in the TDF group receiving VITD, but there was no FGF23 change in the no-TDF group receiving VITD or the PL groups. The adjusted mean change in FGF23 from baseline to week 12 was +7.7 pg/mL in the TDF/VITD group, compared to −1.7 (no-TDF/VITD, p=0.010); −1.3 (TDF/PL, p=0.006); and +1.1 (no-TDF/PL, p=0.035).
These results suggest that TDF-containing cART may alter the FGF23 response to vitamin D supplementation in HIV-infected youth.
PMCID: PMC4135028  PMID: 24535626

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