Risk Factors for Vitamin D Deficiency among Veterans with and without HIV Infection

Objectives

We aimed to describe and compare the prevalence of vitamin D deficiency between HIV-negative and HIV-infected veterans in the southern United States, and to determine risk factors for vitamin D deficiency for HIV infected patients.

Methods

Cross-sectional, retrospective study including all patients followed at the Atlanta VA Medical Center with the first 25-hydroxyvitamin D [25(OH)D] level determined between January 2007 and August 2010. Multivariate logistic regression analysis was used to determine risk factors associated with vitamin D deficiency (< 20 ng/ml).

Results

There was higher prevalence of 25(OH)D deficiency among HIV-positive compared to HIV-negative patients (53.2 vs. 38.5%, p <0.001). Independent risk factors for vitamin D deficiency in HIV + patients included black race (OR 3.24, 95% CI 2.28–4.60), winter season (OR 1.39, 95% CI 1.05–1.84) and higher GFR (OR 1.01, CI 1.00–1.01); increasing age (OR 0.98, 95% CI 0.95–0.98), and tenofovir use (OR 0.72, 95% CI 0.54–0.96) were associated with less vitamin D deficiency.

Conclusions

Vitamin D deficiency is a prevalent problem that varies inversely with age and affects HIV-infected patients more than other veterans in care. In addition to age, tenofovir and kidney disease seem to confer a protective effect from vitamin D deficiency in HIV-positive patients.     

Complementary expression patterns of retinoid acid-synthesizing and -metabolizing enzymes in pre-natal mouse inner ear structures

Retinoic acid (RA) plays a pivotal role in patterning and differentiation of the embryonic inner ear. Despite its documented effects during embryonic development, the cellular sites that synthesize or metabolize RA in the inner ear have yet to be determined. Here we describe the distribution of three synthesizing enzymes, retinaldehyde dehydrogenases 1, 2 and 3 (RALDH1, RALDH2 and RALDH3) and two catabolizing enzymes (CYP26A1 and CYP26B1) in the mouse inner ear at embryonic day 18.5 when active cell differentiation is underway. Two detection methods, radioactive and non-radioactive in situ hybridization, were employed to elucidate the tissue distribution and cellular localization of these enzymes, respectively. All of the five enzymes examined, with the exception of CYP26A1, were expressed in both vestibular and cochlear end organs. While expression of the three RALDHs was observed in various cell types, CYP26B1 expression was found only in supporting cells of the vestibular and cochlear end organs. In the cochlea, expression domains of RALDH1-3 and CYP26B1 were complementary to one another. These results reveal specific tissue- and cellular expression patterns of RA synthesizing and catabolizing enzymes in the pre-natal inner ear, and suggest that a precise control of RA concentrations in various cell types of the inner ear is achieved by the balance between RALDHs and CYP26B1 activities.     

Impact of ABCB1 and CYP2B6 Genetic Polymorphisms on Methadone Metabolism,Dose and Treatment Response in Patients with Opioid Addiction: A Systematic Review and Meta-Analysis

Background

Genetic variability may influence methadone metabolism, dose requirements, and risk of relapse.

Objectives

To determine whether the CYP2B6*6 or ABCB1 (rs1045642) polymorphisms are associated with variation in methadone response (plasma concentration, dose, or response to treatment).

Methods

Two independent reviewers searched Medline, EMBASE, CINAHL, PsycINFO, and Web of Science databases. We included studies that reported methadone plasma concentration, methadone response, or methadone dose in relation to the CYP2B6*6 or ABCB1 polymorphisms.

Results

We screened 182 articles and extracted 7 articles for inclusion in the meta-analysis. Considerable agreement was observed between the two independent raters on the title (kappa, 0.82), abstract (kappa, 0.43), and full text screening (kappa, 0.43). Trough (R) methadone plasma concentration was significantly higher in CYP2B6*6 homozygous carriers when compared to non-carriers (standardized mean difference [SMD] = 0.53, 95% confidence interval [CI], 0.05–1.00, p = 0.03) with minimal heterogeneity (I² = 0%). Similarly, trough (S) methadone plasma concentration was higher in homozygous carriers of the *6 haplotype when compared to non-carriers, (SMD = 1.44, 95% CI 0.27–2.61, p = 0.02) however significant heterogeneity was observed (I² = 69%). Carriers of the CYP2B6*6 haplotype were not found to be significantly different from non-carriers with respect to dose or response to treatment. We found no significant association between the ABCB1 polymorphism and the trough (R), (S) plasma concentrations, methadone dose, or methadone response.

Conclusion

Although the number of studies included and sample size were modest, this is the first meta analysis to show participants homozygous for the CYP2B6*6 genotype have higher trough (R) and (S) methadone plasma concentrations, suggesting that methadone metabolism is significantly slower in *6 homozygous carriers.     

Late‐life rapamycin treatment reverses age‐related heart dysfunction

Rapamycin has been shown to extend lifespan in numerous model organisms including mice, with the most dramatic longevity effects reported in females. However, little is known about the functional ramifications of this longevity‐enhancing paradigm in mammalian tissues. We treated 24‐month‐old female C57BL/6J mice with rapamycin for 3 months and determined health outcomes via a variety of noninvasive measures of cardiovascular, skeletal, and metabolic health for individual mice. We determined that while rapamycin has mild transient metabolic effects, there are significant benefits to late‐life cardiovascular function with a reversal or attenuation of age‐related changes in the heart. RNA‐seq analysis of cardiac tissue after treatment indicated inflammatory, metabolic, and antihypertrophic expression changes in cardiac tissue as potential mechanisms mediating the functional improvement. Rapamycin treatment also resulted in beneficial behavioral, skeletal, and motor changes in these mice compared with those fed a control diet. From these findings, we propose that late‐life rapamycin therapy not only extends the lifespan of mammals, but also confers functional benefits to a number of tissues and mechanistically implicates an improvement in contractile function and antihypertrophic signaling in the aged heart with a reduction in age‐related inflammation.     

Trends in tuna carbon isotopes suggest global changes in pelagic phytoplankton communities

Considerable uncertainty remains over how increasing atmospheric CO₂ and anthropogenic climate changes are affecting open‐ocean marine ecosystems from phytoplankton to top predators. Biological time series data are thus urgently needed for the world's oceans. Here, we use the carbon stable isotope composition of tuna to provide a first insight into the existence of global trends in complex ecosystem dynamics and changes in the oceanic carbon cycle. From 2000 to 2015, considerable declines in δ¹³C values of 0.8‰–2.5‰ were observed across three tuna species sampled globally, with more substantial changes in the Pacific Ocean compared to the Atlantic and Indian Oceans. Tuna recorded not only the Suess effect, that is, fossil fuel‐derived and isotopically light carbon being incorporated into marine ecosystems, but also recorded profound changes at the base of marine food webs. We suggest a global shift in phytoplankton community structure, for example, a reduction in ¹³C‐rich phytoplankton such as diatoms, and/or a change in phytoplankton physiology during this period, although this does not rule out other concomitant changes at higher levels in the food webs. Our study establishes tuna δ¹³C values as a candidate essential ocean variable to assess complex ecosystem responses to climate change at regional to global scales and over decadal timescales. Finally, this time series will be invaluable in calibrating and validating global earth system models to project changes in marine biota.     

Planar Cell Polarity Pathway Regulates Nephrin Endocytosis in Developing Podocytes

The noncanonical Wnt/planar cell polarity (PCP) pathway controls a variety of cell behaviors such as polarized protrusive cell activity, directional cell movement, and oriented cell division and is crucial for the normal development of many tissues. Mutations in the PCP genes cause malformation in multiple organs. Recently, the PCP pathway was shown to control endocytosis of PCP and non-PCP proteins necessary for cell shape remodeling and formation of specific junctional protein complexes. During formation of the renal glomerulus, the glomerular capillary becomes enveloped by highly specialized epithelial cells, podocytes, that display unique architecture and are connected via specialized cell-cell junctions (slit diaphragms) that restrict passage of protein into the urine; podocyte differentiation requires active remodeling of cytoskeleton and junctional protein complexes. We report here that in cultured human podocytes, activation of the PCP pathway significantly stimulates endocytosis of the core slit diaphragm protein, nephrin, via a clathrin/β-arrestin-dependent endocytic route. In contrast, depletion of the PCP protein Vangl2 leads to an increase of nephrin at the cell surface; loss of Vangl2 functions in Looptail mice results in disturbed glomerular maturation. We propose that the PCP pathway contributes to podocyte development by regulating nephrin turnover during junctional remodeling as the cells differentiate.     

Effect of C-Terminal S-Palmitoylation on D2 Dopamine Receptor Trafficking and Stability

We have used bioorthogonal click chemistry (BCC), a sensitive non-isotopic labeling method, to analyze the palmitoylation status of the D2 dopamine receptor (D2R), a G protein-coupled receptor (GPCR) crucial for regulation of processes such as mood, reward, and motor control. By analyzing a series of D2R constructs containing mutations in cysteine residues, we found that palmitoylation of the D2R most likely occurs on the C-terminal cysteine residue (C443) of the polypeptide. D2Rs in which C443 was deleted showed significantly reduced palmitoylation levels, plasma membrane expression, and protein stability compared to wild-type D2Rs. Rather, the C443 deletion mutant appeared to accumulate in the Golgi, indicating that palmitoylation of the D2R is important for cell surface expression of the receptor. Using the full-length D2R as bait in a membrane yeast two-hybrid (MYTH) screen, we identified the palmitoyl acyltransferase (PAT) zDHHC4 as a D2R interacting protein. Co-immunoprecipitation analysis revealed that several other PATs, including zDHHC3 and zDHHC8, also interacted with the D2R and that each of the three PATs was capable of affecting the palmitoylation status of the D2R. Finally, biochemical analyses using D2R mutants and the palmitoylation blocker, 2-bromopalmitate indicate that palmitoylation of the receptor plays a role in stability of the D2R.