Vasodilator effects of estrogen are not diminished by androgen in postmenopausal women

Objective: To compare the effects of estrogen with estrogen-androgen treatment on vaginal blood flow velocity and fingertip postocclusive hyperemic blood flow response.

Design: Prospective, randomized, parallel, double-blind study.

Setting: Healthy human volunteers in an academic research environment.

Patient(s): Postmenopausal women receiving estrogen replacement therapy for at least 12 months and treated with placebo before this investigation.

Intervention(s): Esterified estrogens or esterified estrogen + methyltestosterone were administered orally; laser Doppler velocimetry was used to determine vaginal and fingertip blood flow responses at baseline and after 4 and 8 weeks of daily drug administration.

Main Outcome Measure(s): Fingertip postocclusive area under curve (AUC); vaginal blood flow velocities.

Result(s): The AUC for postocclusive fingertip blood flow and vaginal blood flow increased to a greater extent in the estrogen-androgen group, but changes were not statistically significant between groups.

Conclusion(s): Estrogen-androgen treatment does not diminish the vasodilator effects of estrogen treatment in postmenopausal women.     

Long-term effects of a standardized complex mixture of urban dust particulate on the metabolic activation of carcinogenic polycyclic aromatic hydrocarbons in human cells in culture.

Humans are exposed to complex mixtures of polycyclic aromatic hydrocarbons in the atmosphere. We examined the long term effects of a standard reference material (SRM) 1649a over time on the metabolic activation and DNA adduct formation by two carcinogenic PAHs, benzo[a]pyrene (BP) and dibenzo[a,l]pyrene (DBP) in the human mammary carcinoma derived cell line MCF-7. PAH-DNA adduct analysis, cytochrome P450 (CYP) enzyme activity, CYP1A1 and CYP1B1 protein expression were determined in cells treated with SRM 1649a alone or SRM 1649a with either BP or DBP for 24 to 120 h. Averaging over time, significantly higher levels of DNA adducts were observed in cells treated with BP or DBP alone than in co-treatments with SRM 1649a and BP or DBP. Ethoxyresorufin O-deethylase assay indicated a significant increase in activity in cells treated with BP alone and co-treated with SRM1649a in comparison to other treatment groups. Induction of CYP1A1 and CYP1B1 protein expression was observed by immunoblots in cells treated with BP alone or in co-treatments of SRM 1649a and BP or DBP. These data demonstrate the influence of the components of SRM 1649a in inhibiting the activation of BP or DBP by CYP enzymes in the formation of DNA adducts. It also suggests that the carcinogenic activity of PAH within a complex mixture may vary with composition and activation of the components present in the complex mixture.     

Discovery of common human genetic variants of GTP cyclohydrolase 1 (GCH1) governing nitric oxide, autonomic activity, and cardiovascular risk

GTP cyclohydrolase 1 (GCH1) is rate limiting in the provision of the cofactor tetrahydrobiopterin for biosynthesis of catecholamines and NO. We asked whether common genetic variation at GCH1 alters transmitter synthesis and predisposes to disease. Here we undertook a systematic search for polymorphisms in GCH1, then tested variants' contributions to NO and catecholamine release as well as autonomic function in twin pairs. Renal NO and neopterin excretions were significantly heritable, as were baroreceptor coupling (heart rate response to BP fluctuation) and pulse interval (1/heart rate). Common GCH1 variant C+243T in the 3'-untranslated region (3'-UTRs) predicted NO excretion, as well as autonomic traits: baroreceptor coupling, maximum pulse interval, and pulse interval variability, though not catecholamine secretion. In individuals with the most extreme BP values in the population, C+243T affected both diastolic and systolic BP, principally in females. In functional studies, C+243T decreased reporter expression in transfected 3'-UTRs plasmids. We conclude that human NO secretion traits are heritable, displaying joint genetic determination with autonomic activity by functional polymorphism at GCH1. Our results document novel pathophysiological links between a key biosynthetic locus and NO metabolism and suggest new strategies for approaching the mechanism, diagnosis, and treatment of risk predictors for cardiovascular diseases such as hypertension.     

Evaluation of an ultra‐lightweight,single‐patient‐use negative pressure wound therapy system over dermal regeneration template and skin grafts

As the use of negative pressure wound therapy (NPWT) over skin grafts has increased, traditional methods of NPWT system reimbursement and application are increasingly being challenged. A simplified method of accessing and operating NPWT in the outpatient setting is needed, particularly in cases where immediate outpatient use of NPWT is optimal. We evaluated use of a new ultra‐lightweight, off‐the‐shelf, disposable, single‐patient‐use NPWT system (SP‐NPWT; V.A.C.Via? Therapy, KCI USA, Inc., San Antonio, TX) over dermal regeneration template (DRT) and/or skin grafts. SP‐NPWT was initiated over a DRT and/or skin graft in 33 patients with 41 graft procedures. Endpoints were recorded and compared to a historical control group of 25 patients with 28 grafts bolstered with traditional rental NPWT (V.A.C.® Therapy, KCI USA, Inc.). Average length of inpatient hospital stay was 0·0 days for the SP‐NPWT group and 6·0 days for the control group (P < 0·0001). The average duration of SP‐NPWT post‐DRT or skin graft was 5·6 days for the SP‐NPWT group and 7·0 days for the control (P < 0·0001). Preliminary data suggest that, compared to traditional NPWT, off‐the‐shelf SP‐NPWT may provide a quicker, seamless transition to home, resulting in decreased hospital stay and potential cost savings.     

Lead and Trace Element Levels in Milk and Blood of Buffaloes (Bubalus bubalis) from Hyderabad,India

The presence of lead (Pb) in milk and its interaction with trace elements is a serious health concern. Present study is aimed at determining Pb and trace element (Fe, Zn and Mg) levels in milk and blood/serum samples of lactating buffaloes (Bubalus bubalis) living in a market-area (Group-A) and a dairy-experimental station (Group-B), Hyderabad, India. In addition, kidney and liver function tests were assessed. Fodder, milk and blood Pb levels were significantly (p < 0.01) higher in Group-B. Elevated Pb levels correlated positively with reduced Fe and Zn levels in both serum and milk. A significant (p < 0.01) positive correlation between blood Pb and milk Pb levels was observed. Kidney and liver function markers were significantly higher in Group-B buffaloes. The results suggest that contaminated fodder might be one of the responsible factors for elevated Pb levels. In addition, lower levels of Fe and Zn might have led to bioaccumulation of Pb in blood and milk.     

Evaluation of OPRM1 variants in heroin dependence by family-based association testing and meta-analysis

OPRM1, which codes for the μ-opioid receptor, is the most frequently studied candidate gene for opioid dependence. Despite numerous allelic association studies, no definitive conclusion has been reached regarding the role of OPRM1 polymorphisms in determining risk for opioid dependence. We attempted to resolve this by conducting a family-based association study and meta-analysis which may be more robust and powerful, respectively, than traditional case–control analyses. First, we genotyped three single nucleotide polymorphisms (SNPs) of OPRM1 in 1208 individuals from 473 Han Chinese families ascertained on the basis of having two or more siblings with DSM-IV-defined opioid dependence. The Val6Ala and Arg111His SNPs were detected, but with low minor allele frequencies (0.002 and 0.001, respectively). The Asn40Asp SNP was more informative (minor allele frequency: 0.419), but no significant evidence was observed for either a dominant (p = 0.810) or additive (p = 0.406) effect of this polymorphism on risk for opioid dependence. In addition, a meta-analysis of case–control studies of opioid dependence was performed, and found a similar lack of evidence for an association with the Asn40Asp SNP (p = 0.859). Although a role of OPRM1 polymorphisms in determining risk for opioid dependence cannot be entirely discounted, a major contribution of the Asn40Asp polymorphism seems unlikely. Further analysis is warranted in samples from specific ancestral groups. In addition, it is critical that other OPRM1 variants, including all haplotype-tagging and amino-acid-coding SNPs, be tested for an influence on risk for opioid dependence, since the Asn40Asp polymorphism is only one of several hundred known mutations in the gene.