Prospective, Randomized, Double-Blind, Parallel-Group, Comparative Effectiveness Clinical Trial Comparing a Powder Vehicle Compound of Vitamin D With an Oil Vehicle Compound in Adults With Cystic Fibrosis.

BACKGROUND: There is little consensus on the most efficacious vehicle substance for vitamin D supplements. Fat malabsorption may impede the ability of patients with cystic fibrosis (CF) to absorb vitamin D in an oil vehicle. We hypothesized that vitamin D contained in a powder vehicle would be absorbed more efficiently than vitamin D contained in an oil vehicle in patients with CF. METHODS: In this double-blind, randomized controlled trial, hospitalized adults with CF were given a one-time bolus dose of 100,000 IU of cholecalciferol (D3) in a powder-based or oil-based vehicle. Serum D3, 25-hydroxyvitamin D, and parathyroid hormone concentrations were analyzed at 0, 12, 24, and 48 hours posttreatment. The area under the curve for serum D3 and the 12-hour time point were also assessed as indicators of D3 absorption. RESULTS: This trial was completed by 15 patients with CF. The median (interquartile range) age, body mass index, and forced expiratory volume in 1 second were 23.7 (19.9-33.2) years, 19.9 (18.6-22.6) kg/m2, and 63% (37%-80%), respectively. The increase in serum D3 and the area under the curve was greater in the powder group ( P = .002 and P = .036, respectively). Serum D3 was higher at 12 hours in the powder group compared with the oil group ( P = .002), although levels were similar between groups by 48 hours. CONCLUSIONS: In adults with CF, cholecalciferol is more efficiently absorbed in a powder compared with an oil vehicle. Physicians should consider prescribing vitamin D in a powder vehicle in patients with CF to improve the absorption of vitamin D from supplements.

Vitamin D Status and Virologic Response to HCV Therapy in the HALT-C and VIRAHEP-C Trials.

CONCLUSION: Higher vitamin D status was not beneficially associated with responses to therapy; if anything, patients with higher vitamin D concentrations were less likely to attain SVR. Our data do not support a role for vitamin D supplementation as an adjuvant therapy for HCV.

Genomics Virtual Laboratory: A Practical Bioinformatics Workbench for the Cloud.

BACKGROUND: Analyzing high throughput genomics data is a complex and compute intensive task, generally requiring numerous software tools and large reference data sets, tied together in successive stages of data transformation and visualisation. A computational platform enabling best practice genomics analysis ideally meets a number of requirements, including: a wide range of analysis and visualisation tools, closely linked to large user and reference data sets; workflow platform(s) enabling accessible, reproducible, portable analyses, through a flexible set of interfaces; highly available, scalable computational resources; and flexibility and versatility in the use of these resources to meet demands and expertise of a variety of users. Access to an appropriate computational platform can be a significant barrier to researchers, as establishing such a platform requires a large upfront investment in hardware, experience, and expertise. RESULTS: We designed and implemented the Genomics Virtual Laboratory (GVL) as a middleware layer of machine images, cloud management tools, and online services that enable researchers to build arbitrarily sized compute clusters on demand, pre-populated with fully configured bioinformatics tools, reference datasets and workflow and visualisation options. The platform is flexible in that users can conduct analyses through web-based (Galaxy, RStudio, IPython Notebook) or command-line interfaces, and add/remove compute nodes and data resources as required. Best-practice tutorials and protocols provide a path from introductory training to practice. The GVL is available on the OpenStack-based Australian Research Cloud (http://nectar.org.au) and the Amazon Web Services cloud. The principles, implementation and build process are designed to be cloud-agnostic. CONCLUSIONS: This paper provides a blueprint for the design and implementation of a cloud-based Genomics Virtual Laboratory. We discuss scope, design considerations and technical and logistical constraints, and explore the value added to the research community through the suite of services and resources provided by our implementation.

Vitamin D, pregnancy, breastfeeding, and postpartum multiple sclerosis relapses.

OBJECTIVE: To determine whether low levels of 25-hydroxyvitamin D (25[OH]D) contribute to the increased risk of postpartum multiple sclerosis (MS) relapses. DESIGN: Prospective cohort study. SETTING: Outpatients identified through membership records of Kaiser Permanente Northern California or Stanford University outpatient neurology clinics. PATIENTS: Twenty-eight pregnant women with MS. INTERVENTIONS: We prospectively followed up patients through the postpartum year and assessed exposures and symptoms through structured interviews. Total serum 25(OH)D levels were measured using the DiaSorin Liaison Assay during the third trimester and 2, 4, and 6 months after giving birth. The data were analyzed using longitudinal multivariable methods. MAIN OUTCOME MEASURES: Levels of 25(OH)D and relapse rate. RESULTS: Fourteen (50%) women breastfed exclusively, and 12 women (43%) relapsed within 6 months after giving birth. During pregnancy, the average 25(OH)D levels were 25.4 ng/mL (range, 13.7-42.6) and were affected only by season (P=.009). In contrast, in the postpartum period, 25(OH)D levels were significantly affected by breastfeeding and relapse status. Levels of 25(OH)D remained low in the exclusive breastfeeding group, yet rose significantly in the nonexclusive breastfeeding group regardless of season (P=.007, unadjusted; P=.02, adjusted for season). By 4 and 6 months after childbirth, 25(OH)D levels were, on average, 5 ng/mL lower in the women who breastfed exclusively compared with the nonbreastfeeding group (P=.001). CONCLUSIONS: Pregnancy and exclusive breastfeeding are strongly associated with low 25(OH)D levels in women with MS. However, these lower vitamin D levels were not associated with an increased risk of postpartum MS relapses. These data suggest that low vitamin D in isolation is not an important risk factor for postpartum MS relapses.

Serum vitamin D and risk of pancreatic cancer in the prostate, lung, colorectal, and ovarian screening trial.

Experimental evidence suggests that vitamin D has anticarcinogenic properties; however, a nested case-control study conducted in a population of male Finnish smokers found that higher 25-hydroxyvitamin D [25(OH)D], the best indicator of vitamin D status as determined by the sun and diet, was associated with a significant 3-fold increased risk for pancreatic cancer. We conducted a nested case-control study in the Prostate, Lung, Colorectal, and Ovarian Screening Trial cohort of men and women 55 to 74 years of age at baseline to test whether prediagnostic serum 25(OH)D concentrations were associated with pancreatic cancer risk. Between 1994 and 2006, 184 incident cases of pancreatic adenocarcinoma occurred (follow-up to 11.7 years). Two controls (n = 368) who were alive at the time the case was diagnosed were selected for each case and matched by age, race, sex, and calendar date of blood draw (to control for seasonal variation). We calculated odds ratios (OR) and 95% confidence intervals (95% CI) using conditional logistic regression, adjusting for smoking and body mass index. Vitamin D concentrations were not associated with pancreatic cancer overall (highest versus lowest quintile, >82.3 versus <45.9 nmol/L: OR, 1.45; 95% CI, 0.66-3.15; P trend = 0.49). However, positive associations were observed among subjects with low estimated annual residential solar UBV exposure, but not among those with moderate to high annual exposure (P interaction = 0.015). We did not confirm the previous strong positive association between 25(OH)D and pancreatic cancer; however, the increased risk among participants with low residential UVB exposure is similar.

The effect of high-dose vitamin D supplementation on serum vitamin D levels and milk calcium concentration in lactating women and their infants.

OBJECTIVE: Improve vitamin D status in lactating women and their recipient infants, and measure breast milk calcium concentration [Ca] as a function of vitamin D regimen. DESIGN/METHODS: Fully breastfeeding mothers were randomized at 1 month postpartum to 2000 (n = 12) or 4000 (n = 13) IU/day vitamin D for 3 months to achieve optimal vitamin D status [serum 25(OH)D > or =32 ng/mL (80 nmol/L)]. Breast milk [Ca], maternal and infant serum 25(OH)D and serum Ca, and maternal urinary Ca/Cr ratio were measured monthly. RESULTS: Mothers were similar between groups for age, race, gestation, and birth weight. 25(OH)D increased from 1 to 4 months in both groups (mean +/- SD): +11.5 +/- 2.3 ng/mL for group 2000 (p = 0.002) and +14.4 +/- 3.0 ng/mL for group 4000 (p = 0.0008). The 4000 IU/day regimen was more effective in raising both maternal and infant serum levels and breast milk antirachitic activity than the 2000 IU/day regimen. Breast milk [Ca] fell with continued lactation through 4 months in the 2000 and 4000 IU groups. Decline in breast milk [Ca] was not associated with vitamin D dose (p = 0.73) or maternal 25(OH)D (p = 0.94). No mother or infant experienced vitamin D-related adverse events, and all laboratory parameters remained in the normal range. CONCLUSION: High-dose vitamin D was effective in increasing 25(OH)D levels in fully breastfeeding mothers to optimal levels without evidence of toxicity. Breast milk [Ca] and its decline in both groups during 1 to 4 months were independent of maternal vitamin D status and regimen. Both the mother and her infant attained improved vitamin D status and maintained normal [Ca].

Evidence for abnormal translational regulation of renal 25-hydroxyvitamin D-1alpha-hydroxylase activity in the hyp-mouse.

Hyp-mice exhibit abnormal regulation of 25-hydroxyvitamin D [25(OH)D]-1alpha-hydroxylase activity. Previous observations suggest such aberrant modulation is posttranscriptional. To investigate this possibility further, we examined whether hyp-mice manifest abnormal translation of 25(OH)D-1alpha-hydroxylase mRNA. We compared phosphate, parathyroid, and calcitonin effects on renal 25(OH)D-1alpha-hydroxylase protein as well as mRNA and enzyme activity in normal and hyp-mice. We assayed protein by Western blots, mRNA by real-time RT-PCR, and enzyme activity by measuring 1,25-dihydroxyvitamin D production. Although phosphate-depleted mice exhibited enhanced enzyme function, with significantly increased mRNA and protein expression, hyp-mice comparably increased mRNA but failed to augment enzyme activity, concordant with an inability to increase protein expression. PTH stimulation increased mRNA and protein expression as well as enzyme activity in normal mice but in hyp-mice, despite effecting mRNA enhancement, did not increment enzyme function or protein. The inability of hypophosphatemia and PTH to increase 25(OH)D-1alpha-hydroxylase activity and protein expression in hyp-mice was not universal because calcitonin stimulation was normal, suggesting proximal convoluted tubule localization of the defect. These data, in accord with absent undue enhancement of protein expression in hyp-mice treated with protease inhibitors, establish that abberrant regulation of vitamin D metabolism results from abnormal translational activity.

Abnormal regulation of renal 25-hydroxyvitamin D-1alpha-hydroxylase activity in X-linked hypophosphatemia: a translational or post-translational defect.

The hyp mouse exhibits abnormal metabolic/hormonal regulation of renal 25(OH)D-1alpha-hydroxylase activity. Whether this results from aberrant transcriptional regulation of the 1alpha-hydroxylase gene, CYP27B1, remains unknown. To investigate this possibility, we compared phosphate and parathyroid hormone effects on renal proximal convoluted tubule and thyrocalcitonin effects on proximal straight tubule enzyme activity and mRNA expression in normal and hyp mice. We assayed 25(OH)D-1alpha-hydroxylase activity by measuring 1,25(OH)2D production and mRNA by ribonuclease protection. Phosphate-depleted mice exhibited a 3-fold increment of 25(OH)D-1alpha-hydroxylase activity compared with normals, whereas hyp mice displayed no enhanced enzyme function. Phosphate-depleted mice concurrently displayed a 2-fold increase in mRNA transcripts; in contrast, despite failure to alter enzyme activity, hyp mice exhibited a similar increment in mRNA transcripts. Parathyroid hormone stimulation of normal mice increased 25(OH)D-1alpha-hydroxylase activity 10-fold, while eliciting only a 2-fold increment in hyp mouse enzyme function. This disparity occurred despite increments of mRNA transcripts to comparable levels (22.2 +/- 3.5- vs. 19.9 +/- 1.8-fold). The dissociation between phosphate- and parathyroid hormone-mediated transcriptional activity and protein function was not universal. Thus, thyrocalcitonin stimulation of normal and hyp mice resulted in comparable enhancement of mRNA transcripts and enzyme activity. These observations indicate that abnormal regulation of vitamin D metabolism in hyp mice occurs in the proximal convoluted tubule and results, not from aberrant transcriptional regulation, but from a defect in translational or post-translational activity.