Heteromultimers of DEG/ENaC subunits form H+-gated channels in mouse sensory neurons

Acidic extracellular solution activates transient H(+)-gated currents in dorsal root ganglion (DRG) neurons. The biophysical properties of three degenerin/epithelial sodium (DEG/ENaC) channel subunits (BNC1, ASIC, and DRASIC), and their expression in DRG, suggest that they might underlie these H(+)-gated currents and function as sensory transducers. However, it is uncertain which of these DEG/ENaC subunits generate the currents, and whether they function as homomultimers or heteromultimers. We found that the biophysical properties of transient H(+)-gated currents from medium to large mouse DRG neurons differed from BNC1, ASIC, or DRASIC expressed individually, but were reproduced by coexpression of the subunits together. To test the contribution of each subunit, we studied DRG from three strains of mice, each bearing a targeted disruption of BNC1, ASIC, or DRASIC. Deletion of any one subunit did not abolish H(+)-gated currents, but altered currents in a manner consistent with heteromultimerization of the two remaining subunits. These data indicate that combinations of two or more DEG/ENaC subunits coassemble as heteromultimers to generate transient H(+)-gated currents in mouse DRG neurons.     

Clinical evaluation of music perception,appraisal and experience in cochlear implant users

Objectives: The objectives were to evaluate the relationships among music perception, appraisal, and experience in cochlear implant users in multiple clinical settings and to examine the viability of two assessments designed for clinical use. Design: Background questionnaires (IMBQ) were administered by audiologists in 14 clinics in the United States and Canada. The CAMP included tests of pitch-direction discrimination, and melody and timbre recognition. The IMBQ queried users on prior musical involvement, music listening habits pre and post implant, and music appraisals. Study sample: One-hundred forty-five users of Advanced Bionics and Cochlear Ltd cochlear implants. Results: Performance on pitch direction discrimination, melody recognition, and timbre recognition tests were consistent with previous studies with smaller cohorts, as well as with more extensive protocols conducted in other centers. Relationships between perceptual accuracy and music enjoyment were weak, suggesting that perception and appraisal are relatively independent for CI users. Conclusions: Perceptual abilities as measured by the CAMP had little to no relationship with music appraisals and little relationship with musical experience. The CAMP and IMBQ are feasible for routine clinical use, providing results consistent with previous thorough laboratory-based investigations.     

Rankings versus reality in pancreatic cancer surgery: a real-world comparison

Background

Patients are increasingly confronted with systems for rating hospitals. However, the correlations between publicized ratings and actual outcomes after pancreatectomy are unknown.

Methods

The Massachusetts Division of Health Care Finance and Policy Hospital Inpatient Discharge Database was queried to identify pancreatic cancer resections carried out during 2005–2009. Hospitals performing fewer than 10 pancreatic resections in the 5-year period were excluded. Primary outcomes included mortality, complications, median length of stay (LoS) and a composite outcomes score (COS) combining primary outcomes. Ranks were determined and compared for: (i) volume, and (ii) ratings identified from consumer-directed hospital ratings including the US News & World Report (USN), Consumer Reports, Healthgrades and Hospital Compare. An inter-rater reliability analysis was performed and correlation coefficients (r) between outcomes and ratings, and between rating systems were calculated.

Results

Eleven hospitals in which a total of 804 pancreatectomies were conducted were identified. Surgical volume correlated with overall outcome, but was not the strongest indicator. The highest correlation referred to that between USN rank and overall outcome. Mortality was most strongly correlated with Healthgrades ratings (r = 0.50); however, Healthgrades ratings demonstrated poorer correlations with all other outcomes. Consumer Reports ratings showed inverse correlations.

Conclusions

The plethora of publicly available hospital ratings systems demonstrates heterogeneity. Volume remains a good but imperfect indicator of surgical outcomes. Further systematic investigation into which measures predict quality outcomes in pancreatic cancer surgery will benefit both patients and providers.     

Rare copy number variation in cerebral palsy

Recent studies have established the role of rare copy number variants (CNVs) in several neurological disorders but the contribution of rare CNVs to cerebral palsy (CP) is not known. Fifty Caucasian families having children with CP were studied using two microarray designs. Potentially pathogenic, rare (<1% population frequency) CNVs were identified, and their frequency determined, by comparing the CNVs found in cases with 8329 adult controls with no known neurological disorders. Ten of the 50 cases (20%) had rare CNVs of potential relevance to CP; there were a total of 14 CNVs, which were observed in <0.1% (<8/8329) of the control population. Eight inherited from an unaffected mother: a 751-kb deletion including FSCB, a 1.5-Mb duplication of 7q21.13, a 534-kb duplication of 15q11.2, a 446-kb duplication including CTNND2, a 219-kb duplication including MCPH1, a 169-kb duplication of 22q13.33, a 64-kb duplication of MC2R, and a 135-bp exonic deletion of SLC06A1. Three inherited from an unaffected father: a 386-kb deletion of 12p12.2-p12.1, a 234-kb duplication of 10q26.13, and a 4-kb exonic deletion of COPS3. The inheritance was unknown for three CNVs: a 157-bp exonic deletion of ACOX1, a 693-kb duplication of 17q25.3, and a 265-kb duplication of DAAM1. This is the first systematic study of CNVs in CP, and although it did not identify de novo mutations, has shown inherited, rare CNVs involving potentially pathogenic genes and pathways requiring further investigation.     

Prenatal exposure to PCBs in Cyp1a2 knock‐out mice interferes with F1 fertility,impairs long‐term potentiation,reduces acoustic startle and impairs conditioned freezing contextual memory with minimal transgenerational effects

Polychlorinated biphenyls (PCBs) are toxic environmental pollutants. Humans are exposed to PCB mixtures via contaminated food or water. PCB exposure causes adverse effects in adults and after exposure in utero. PCB toxicity depends on the congener mixture and CYP1A2 gene activity. For coplanar PCBs, toxicity depends on ligand affinity for the aryl hydrocarbon receptor (AHR). Previously, we found that perinatal exposure of mice to a three‐coplanar/five‐noncoplanar PCB mixture induced deficits in novel object recognition and trial failures in the Morris water maze in Cyp1a2^?/?::Ahr^b1 C57BL6/J mice compared with wild‐type mice (Ahr^b1 = high AHR affinity). Here we exposed gravid Cyp1a2^?/?::Ahr^b1 mice to a PCB mixture on embryonic day 10.5 by gavage and examined the F₁ and F₃ offspring (not F₂). PCB‐exposed F₁ mice exhibited increased open‐field central time, reduced acoustic startle, greater conditioned contextual freezing and reduced CA1 hippocampal long‐term potentiation with no change in spatial learning or memory. F₁ mice also had inhibited growth, decreased heart rate and cardiac output, and impaired fertility. F₃ mice showed few effects. Gene expression changes were primarily in F₁ PCB males compared with wild‐type males. There were minimal RNA and DNA methylation changes in the hippocampus from F₁ to F₃ with no clear relevance to the functional effects. F₀ PCB exposure during a period of rapid DNA de‐/remethylation in a susceptible genotype produced clear F₁ effects with little evidence of transgenerational effects in the F₃ generation. While PCBs show clear developmental neurotoxicity, their effects do not persist across generations for effects assessed herein.     

Abnormal cardiac and metabolic measures correlate significantly with lower performance and activity in overweight chronic liver disease

People with Hepatitis C (HCV) and non‐alcoholic fatty liver disease (NAFLD) in the United States follow national trends toward a sedentary lifestyle and are increasingly at risk for hypertension. The intent of this study was to identify potential correlates of exercise tolerance in people with two types of chronic liver disease (CLD)‐NAFLD and HCV. Measures included cardiac output, oxygen consumption and stroke volume, blood pressure, distance walked in 6 minutes, clinical laboratory tests, and medications influencing the autonomic nervous system, patient self‐reports of activity, fatigue, and health‐related quality of life (HRQL). A total of 67 patients completed the 6‐minute walk test [45.1% Female, Age 51.7 ± 8.0 years, Body Mass Index 32.8 ± 5.9, 60% HCV]. At baseline, 70% had either diastolic (DBP) or systolic blood pressure outside normal range. Performance and cardiorespiratory measures correlated strongly with one another, but not with activity. Patients with abnormal DBP reported significantly lower maximum activity (MAS; r = −.254, P = .041, CI = −0.51 to −0.010; MAS 70.6 vs 82.5), significantly higher DBP post‐6‐minute walk test (r = .524, P = .0001, CI = 0.287‐0.762) and significantly lower overall HRQL items related to physical domains (r = .273, P = .029, CI = −0.518 to −0.029). Mental‐domain HRQL and depression measures did not correlate significantly with blood pressure. This study reports a significant correlation between both pre‐hypertensive and hypertensive DBP, poor physical‐domain self‐reports, HRQL, and performance in CLD patients.