Disruption of adult expression of sexually selected traits by developmental exposure to bisphenol A

Exposure to endocrine disrupting compounds (EDCs), such as bisphenol A (BPA), may cause adverse health effects in wildlife and humans, but controversy remains as to what traits are most sensitive to EDCs and might serve as barometers of exposure. Expression of sexually selected traits that have evolved through intrasexual competition for mates and intersexual choice of mating partner are more dependent on developmental and physical condition of an animal than naturally selected traits and thus might be particularly vulnerable to disruption by developmental exposure to EDCs. We have used the deer mouse (Peromyscus maniculatus) as a model to test this hypothesis. Adult male-male competition for mates in this species is supported by enhanced spatial navigational and exploratory abilities, which enable males to search for prospective, widely dispersed females. Male deer mice exposed to BPA or ethinyl estradiol (EE) through maternal diet showed no changes in external phenotype, sensory development, or adult circulating concentrations of testosterone and corticosterone, but spatial learning abilities and exploratory behaviors were severely compromised compared with control males. Because these traits are not sexually selected in females, BPA exposure predictably had no effect, although EE-exposed females demonstrated enhanced spatial navigational abilities. Both BPA-exposed and control females preferred control males to BPA-exposed males. Our demonstration that developmental exposure to BPA compromises cognitive abilities and behaviors essential for males to reproduce successfully has broad implications for other species, including our own. Thus, sexually selected traits might provide useful biomarkers to assess risk of environmental contamination in animal and human populations.     

Lenalidomide maintenance after nonmyeloablative allogeneic stem cell transplantation in multiple myeloma is not feasible: results of the HOVON 76 Trial

To improve the outcome of allogeneic stem cell transplantation (allo-SCT) in multiple myeloma as part of first-line treatment, we prospectively investigated the feasibility and efficacy of lenalidomide maintenance. Patients started maintenance 1 to 6 months after nonmyeloablative allo-SCT. Lenalidomide was dosed 10 mg on days 1 to 21 of a 28-day schedule for a total of 24 cycles. Peripheral blood samples were taken to evaluate immune modulating effects. Thirty-five eligible patients were enrolled, and 30 started with lenalidomide. After 2 cycles, 14 patients (47%) had to stop treatment, mainly because of the development of acute graft versus host disease (GVHD). In total, 13 patients (43%) stopped treatment because of development of GVHD, 5 patients (17%) because of other adverse events, and 5 patients (17%) because of progression. Responses improved in 37% of patients, and the estimated 1-year progression-free survival from start of maintenance was 69% (90% confidence interval, 53%-81%). Lenalidomide increased the frequency of human leukocyte antigen-DR(+) T cells and regulatory T cells, without correlation with clinical parameters. In conclusion, lenalidomide maintenance 10 mg daily after nonmyeloablative allo-SCT with unmanipulated graft in multiple myeloma patients is not feasible, mainly because of the induction of acute GVHD. This trial was registered at www.trialregister.nl as #NTR1645.     

The prevalence and molecular basis of hemoglobinopathies in Cambodia

Blood counts, hemoglobin (Hb) high performance liquid chromatography (HPLC), and DNA analyses were performed on 260 children, aged 5 months to 16 years, at Siem Reap to assess the prevalence of thalassemia and other hemoglobinopathies in regional Cambodia. Hemoglobinopathies were present in 134 children (51.5%) with 20 abnormal genotypes identified. alpha-Thalassemia (thal) (35.4%) was the most prevalent disorder and the -alpha3.7 gene deletion was the most common alpha-globin gene abnormality. The - -SEA deletion and nondeletional forms of alpha-thal, Hb Constant Spring [Hb CS, alpha142, Term-->Gln, TAA-->CAA (alpha2)], Hb Paksé [alpha142, Term-->Tyr, TAA-->TAT (alpha2)] and triplicated alpha genes, were also present but at low frequencies. Hb E [beta26(B8)Glu-->Lys, GAG-->AAG] (28.8%) was the most common beta-globin gene abnormality, whilst beta-thal was only detected in two children (0.8% of cases). Although hemoglobinopathies were common, the majority of abnormalities detected (heterozygous -alpha3.7 and Hb E) were not clinically significant. On the basis of these findings, and with the majority of abnormalities being mild, it seems improbable that thalassemia represents a major health burden in this region of Cambodia.     

Mutations in herpes simplex virus glycoprotein D that prevent cell entry via nectins and alter cell tropism

Glycoprotein D (gD) determines which cells can be infected by herpes simplex virus (HSV) by binding to one of the several cell surface receptors that can mediate HSV entry or cell fusion. These receptors include the herpesvirus entry mediator (HVEM), nectin-1, nectin-2, and sites in heparan sulfate generated by specific 3-O-sulfotransferases. The objective of the present study was to identify residues in gD that are critical for physical and functional interactions with nectin-1 and nectin-2. We found that double or triple amino acid substitutions at positions 215, 222, and 223 in gD caused marked reduction in gD binding to nectin-1 and a corresponding inability to function in cell fusion or entry of HSV via nectin-1 or nectin-2. These substitutions either enhanced or did not significantly inhibit functional interactions with HVEM and modified heparan sulfate. These and other results demonstrate that different domains of gD, with some overlap, are critical for functional interactions with each class of entry receptor. Viral entry assays, using gD mutants described here and previously, revealed that nectins are the principal entry receptors for selected human cell lines of neuronal and epithelial origin, whereas HVEM or nectins could be used to mediate entry into a T lymphocyte line. Because T cells and fibroblasts can be infected via HVEM, HSV strains carrying gD mutations that prevent entry via nectins may establish transient infections in humans, but perhaps not latent infections of neurons, and are therefore candidates for development of safe live virus vaccines and vaccine vectors.     

Usefulness of microvolt T-wave alternans to predict outcomes in patients with ischemic cardiomyopathy beyond one year

Previous studies have demonstrated that microvolt T-wave alternans (MTWA) screening effectively risk-stratifies patients with ischemic cardiomyopathy. Whether the prognostic utility of MTWA diminishes over 3 years of follow-up remains unknown. In this study, a prospective cohort of 768 patients with ischemic cardiomyopathy (left ventricular ejection fraction <35%) and no previous sustained ventricular arrhythmia was developed, of whom 514 (67%) screened MTWA nonnegative (positive and indeterminate). The mean follow-up period was 18 +/- 11 months. The primary end point was all-cause mortality and appropriate implantable cardioverter-defibrillator shocks. Stratified Cox regression analyses (by implantable cardioverter-defibrillator status) estimated the predictive power of MTWA within each year of follow-up and determined whether this diminished over time. There were 99 deaths (MTWA negative: 21 [8.3%]; MTWA nonnegative: 78 [15.2%]) and 33 appropriate implantable cardioverter-defibrillator shocks (MTWA negative: 3 [4.0%]; MTWA nonnegative: 30 [9.5%]). After multivariate adjustment, a nonnegative MTWA test result was associated with a greater than twofold increased risk for events in each of the 3 years of follow-up (year 1: stratified hazard ratio 2.19, 95% confidence interval 1.10 to 4.34, p = 0.03; year 2: stratified hazard ratio 3.36, 95% confidence interval 1.28 to 8.83, p = 0.01; year 3: stratified hazard ratio 2.06, 95% confidence interval 0.81 to 5.22, p = 0.13). There were no significant interactions between the time periods (year 1 vs year 2: p = 0.47; year 1 vs year 3: p = 0.92). In conclusion, MTWA reliably and consistently predicts mortality and arrhythmic risk throughout the first 2 to 3 years of follow-up. Although these findings need further validation, they suggest that rescreening with MTWA may not need to be performed more frequently than once every 2 years.     

Comparison of Oxycodone and Hydrocodone for the Treatment of Acute Pain Associated with Fractures: A Double-blind, Randomized, Controlled Trial

Background: Previous studies have demonstrated the efficacy of oxycodone and hydrocodone for the treatment of acute pain. However, to the best of the authors' knowledge, no previous reports have compared the efficacies of these commonly prescribed agents. Objectives: To compare the efficacies of oxycodone and hydrocodone for the treatment of acute pain associated with fractures in emergency department (ED) patients. Methods: This prospective, double‐blind, randomized, controlled trial was conducted at an urban trauma center with an annual census of 65,000. Eligible participants included ED patients over the age of 12 years with fractures who consented to participate. Subjects were randomized to receive either oxycodone (5 mg orally [po]) with acetaminophen, or hydrocodone (5 mg po) with acetaminophen. Measurements included demographic information; pain scores on a verbal numeric rating scale at baseline and at 30 and 60 minutes; vital signs at baseline and at 30 and 60 minutes; and adverse effects. Ninety‐five‐percent confidence intervals (95% CIs) constructed about means and proportions were used to assess differences between the oxycodone and hydrocodone groups in analgesic efficacy and side effects. Results: Seventy‐three subjects were randomized to receive oxycodone or hydrocodone. Sixty‐seven subjects completed the ED study period (n= 35, oxycodone; n= 32, hydrocodone). There was no difference between the two groups in age, weight, gender, ethnicity, diagnoses, baseline pain scores, or vital signs. Patients in both groups had pain relief from baseline to 30 minutes (oxycodone mean change 3.7, 95% CI = 2.9 to 4.6; hydrocodone mean change 2.5, 95% CI = 1.7 to 3.3), and from baseline to 60 minutes (oxycodone mean change 4.4, 95% CI = 3.2 to 5.6; hydrocodone mean change 3.0, 95% CI = 2.1 to 3.9). There was no difference in pain between the patients treated with oxycodone and hydrocodone at 30 minutes (mean difference between groups ?0.6, 95% CI =?1.8 to 0.5) or at 60 minutes (mean difference ?0.5, 95% CI =?2.0 to 1.0). There was no difference between the groups in nausea, vomiting, itching, or drowsiness; however, the hydrocodone patients had a higher incidence of constipation (oxycodone 0%, hydrocodone 21%, difference in proportions 21%, 95% CI = 3% to 39% more with hydrocodone). Conclusions: Treatment with acetaminophen and either oxycodone, 5 mg po, or hydrocodone, 5 mg po, resulted in pain relief among ED patients with acute fractures, and there was no difference between the two agents at 30 and 60 minutes. Adverse effect profiles were similar, with the exception of a higher incidence of subsequent constipation with the use of hydrocodone. These results suggest that oxycodone and hydrocodone have similarly potent analgesic effects in the first hour of treatment for ED patients with acute fractures.     

Obstructive sleep apnea and modifications in sedation

Obstructive sleep apnea is a common problem affecting all ages, particularly in conjunction with other pre-existing conditions. Compounding the disorder with the added insult of surgery, anesthesia, analgesia, and sedation requires the medical team continuously to re-evaluate this particular patient population. Physicians and nurses have recognized an increase in morbidity and mortality in patients with obstructive sleep apnea when they are administered anesthesia in conjunction with sedation. There are few reports of sedation alone and obstructive sleep apnea; most studies have been in relation to anesthesia, surgery, patient-controlled analgesia, and sleep-disordered breathing.     

Platelet microparticles and soluble P selectin in peripheral artery disease: relationship to extent of disease and platelet activation markers

BACKGROUND: There is increased platelet activation in many cardiovascular diseases. This observation may explain the presence of increased levels of platelet microparticles (PMP) in these diseases. However, whether or not levels of PMPs inter-relate with other markers of platelet activation, such as soluble P-selectin, or with disease severity, is unknown. We therefore hypothesized raised PMP levels in stable peripheral artery disease (PAD) intermittent claudication (IC), with an additional increase in severe PAD critical limb ischaemia (CLI). Furthermore, we tested the hypothesis that PMP levels are correlated with other markers of platelet activation, such as soluble P-selectin, membrane bound P-selectin (CD62P) and 63. METHODS: Patients with PAD were recruited from the vascular outpatient and inpatient facilities at a teaching hospital. Age- and sex-matched controls were also recruited from healthy volunteers. Venous blood was obtained from 23 patients with severe disease (CLI), 36 with moderate disease (IC), and from 30 healthy controls. The percentage of platelets positive for CD62P and CD63, as well as the numbers of PMPs were defined by flow cytometry. Plasma soluble P selectin was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: PMPs were increased relative to healthy controls in patients with IC, with a further increase in CLI (P<0.001). Soluble P selectin and CD62+ve platelets were raised in both patient groups, but there was no difference amongst the two patient groups. CD63+ve cells were raised only in CLI compared to healthy controls. In multivariate analysis, only PMP and soluble P selectin independently predicted disease severity, and the two markers correlated modestly (r=0.345, P<0.001). CONCLUSION: Increased PMP and soluble P selectin are both related to the severity of symptomatic PAD. However, it is uncertain if this relationship is a cause or effect of atherosclerosis. This finding may have clinical implications as PMPs have the potential to influence the progression of atheroma as well as promote thrombosis.     

Endothelin-aldosterone interaction and proteinuria in low-renin hypertension

OBJECTIVE: To investigate whether endothelin and aldosterone participate in the increased prevalence and severity of nephrosclerosis in human low-renin hypertension, analogous to observations in experimental hypertension. DESIGN: Comparison of endothelin, aldosterone and their relationships with proteinuria, in hypertensive patients with high aldosterone : renin ratios (HARR group, n = 14) or normal aldosterone : renin ratios (NARR group, n = 15). METHODS: Urine protein and radioimmunoassay measurements of plasma renin activity, endothelin and aldosterone were carried out in individuals taking their usual diet, and after salt loading and salt depletion. RESULTS: Compared with the NARR group, patients in the HARR group had higher blood pressure, greater salt sensitivity of their blood pressure, significantly greater urine protein and lower serum potassium concentrations, lower renin activities [0.14 +/- 0.03 ng AngiotensinI (AI)/l per s compared with 0.76 +/- 0.16 ng AI/l per s; P < 0.005], blunted renin-aldosterone responses to salt loading and salt depletion, enhanced catecholamine responses to salt depletion, and increased plasma endothelin (5.1 +/- 0.5 fmol/ml compared with 3.7 +/- 0.3 fmol/ml; P < 0.03). In the HARR group, endothelin and aldosterone concentrations were highly correlated, and both correlated with blood pressure and urine protein. In contrast, in the NARR group, endothelin and aldosterone did not correlate between them or with blood pressure, and only endothelin, not aldosterone, correlated with urine protein. Multivariate regression confirmed that the interaction between aldosterone and endothelin was the major predictor of urine protein in the HARR group (r = 0.442), whereas endothelin, renin and their interaction were predictors in the NARR group (r = 0.467). CONCLUSIONS: Our results concur with experimental evidence for participation of endothelin in renal damage of angiotensin-dependent hypertension and for that of an endothelin-aldosterone interaction in low-renin hypertension. We propose that combined pharmacological antagonism of endothelin and aldosterone may confer renal protection beyond blood pressure reduction in patients with low-renin hypertension, a population at high risk for hypertensive nephrosclerosis.