State-dependent GABAergic inhibition of sciatic nerve-evoked responses of dorsal spinocerebellar tract neurons

Peripheral nerve-evoked potentials recorded in the cerebellum 35 yr ago inferred that sensory transmission via the dorsal spinocerebellar tract (DSCT) is reduced occasionally and only during eye movements of active sleep compared with wakefulness or quiet sleep. A reduction or withdrawal of primary afferent input and/or ongoing inhibition of individual lumbar DSCT neurons may underlie this occurrence. This study distinguished between these possibilities by examining whether peripheral nerve-evoked responses recorded from individual DSCT neurons are suppressed specifically during active sleep, and if so, whether GABA mediates this phenomenon. Synaptic responses to threshold stimuli applied to the sciatic nerve were characterized by a single spike response at short latency and/or a longer latency burst of action potentials. During the state of quiet wakefulness, response magnitude did not differ from that observed during quiet sleep. During active sleep, short and long latency responses were suppressed by 26 and 14%, respectively, and returned to pre-active sleep levels following awakening from active sleep. Sciatic nerve-evoked early and late responses were further analyzed in a paired fashion around computer-tagged eye movement events that hallmark the state of active sleep. Response magnitude was suppressed by 14.4 and 11.5%, respectively, during eye movement events of active sleep. The GABA_A antagonist bicuculline, applied juxtacellularly by microiontophoresis, abolished response suppression during non–eye movement periods and eye movement events of active sleep. In conclusion, synaptic transmission via DSCT neurons is inhibited by GABA tonically during non–eye movement periods and phasically during eye movement events of active sleep.     

Properties of an oncornavirus glycoprotein: evidence for its presence on the surface of virions and infected cells

The surface proteins of a lymphoblast line (SCRF 60_A) from an NZB mouse were studied. Iodination of the cell surface followed by solubilization and immunoprecipitation with antisera prepared against various MuLVs and cells produced a precipitate which gave a single peak in SDS-PAGE and comprised about 5% of the incorporated iodide. The antigen is a glycoprotein of apparent molecular weight (MW_app) of approximately 70,000 daltons and comprises about 0.1% of the total cellular amino acids and about 10% of the cellular glucosamine. Studies on the oncogenic C type virus produced by SCRF 60_A, Scripps leukemia virus (SLV), showed that a glycoprotein of identical radioactive labeling properties and SDS-PAGE mobility is present on the surface of the virions. It constitutes about 10% of the virion amino acids and about 50% of the glucosamine. This protein reacts with sera which neutralize Moloney, Kirsten, Rauscher, AKR, and, of course, Scripps viruses. These data suggest that this is the antigen detected when murine leukemia cells are studied by immunofluorescence and that this antigen may be involved in virus neutralization.     

Antibody response detected by immunoblot in respiratory tract washings of chickens after infection with Mycoplasma gallisepticum.

Two experiments were conducted to test the sensitivity of Western blotting for detection of M. gallisepticum antibodies in respiratory washings and sera of infected chickens by mouse monoclonal antibodies to chicken IgG, IgM and IgA. In the first experiment, birds infected at 10 days of age were examined 2 weeks later. In the respiratory washings, IgA antibodies reacted with eight polypeptides of M. gallisepticum, while IgM and IgG reacted with three. In the serum IgA antibodies were not detected but IgM antibodies reacted with eight polypeptides and IgG with 16. In the second experiment birds were infected at 3 weeks of age and a subgroup was examined every week for 3 weeks post-infection. In the respiratory washings IgA was the principle immunoglobulin detected in the first week and it reacted to six major polypeptides of M. gallisepticum (p72, p64-67, p60, p56, p45, p40). In serum IgM was predominant in the first week and reacted to nine polypeptides. From the second week IgG antibodies were the most important as they reacted to 13 polypeptides in respiratory washings and to 11 polypeptides in the serum, while they reacted to nine polypeptides in respiratory washings and to 13 in the serum in the third week.     

Age‐ and Sex‐Dependent Changes of Intra‐articular Cortical and Trabecular Bone Structure and the Effects of Rheumatoid Arthritis

The objective of this cross‐sectional study was to define normal sex‐ and age‐dependent values of intra‐articular bone mass and microstructures in the metacarpal heads of healthy individuals by high‐resolution peripheral quantitative computed tomography (HR‐pQCT) and test the effect of rheumatoid arthritis (RA) on these parameters. Human cadaveric metacarpal heads were used to exactly define intra‐articular bone. Healthy individuals of different sex and age categories and RA patients with similar age and sex distribution received HR‐pQCT scans of the second metacarpal head and the radius. Total, cortical, and trabecular bone densities as well as microstructural parameters were compared between 1) the different ages and sexes in healthy individuals; 2) between metacarpal heads and the radius; and 3) between healthy individuals and RA patients. The cadaveric study allowed exact definition of the intra‐articular (intracapsular) bone margins. These data were applied in measuring intra‐articular and radial bone parameters in 214 women and men (108 healthy individuals, 106 RA patients). Correlations between intra‐articular and radial bone parameters were good (r = 0.51 to 0.62, p < 0.001). In contrast to radial bone, intra‐articular bone remained stable until age 60 years (between 297 and 312 mg HA/cm³) but decreased significantly (p < 0.001) in women thereafter (237.5 ± 44.3) with loss of both cortical and trabecular bone. Similarly, RA patients showed significant (p < 0.001) loss of intra‐articular total (263.0 ± 44.8), trabecular (171.2 ± 35.6), and cortical bone (610.2 ± 62.0) compared with sex‐ and age‐adjusted controls. Standard sex‐ and age‐dependent values for physiological intra‐articular bone were defined. Postmenopausal state and RA led to significant decrease of intra‐articular bone. © 2016 American Society for Bone and Mineral Research.     

Blood cell DNA methylation biomarkers in preclinical malignant pleural mesothelioma: The EPIC prospective cohort

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer mainly caused by asbestos exposure. Specific and sensitive noninvasive biomarkers may facilitate and enhance screening programs for the early detection of cancer. We investigated DNA methylation (DNAm) profiles in MPM prediagnostic blood samples in a case-control study nested in the European Prospective Investigation into Cancer and nutrition (EPIC) cohort, aiming to characterise DNAm biomarkers associated with MPM. From the EPIC cohort, we included samples from 135 participants who developed MPM during 20 years of follow-up and from 135 matched, cancer-free, controls. For the discovery phase we selected EPIC participants who developed MPM within 5 years from enrolment (n = 36) with matched controls. We identified nine differentially methylated CpGs, selected by 10-fold cross-validation and correlation analyses: cg25755428 (MRI1), cg20389709 (KLF11), cg23870316, cg13862711 (LHX6), cg06417478 (HOOK2), cg00667948, cg01879420 (AMD1), cg25317025 (RPL17) and cg06205333 (RAP1A). Receiver operating characteristic (ROC) analysis showed that the model including baseline characteristics (age, sex and PC1wbc) along with the nine MPM-related CpGs has a better predictive value for MPM occurrence than the baseline model alone, maintaining some performance also at more than 5 years before diagnosis (area under the curve [AUC] < 5 years = 0.89; AUC 5-10 years = 0.80; AUC >10 years = 0.75; baseline AUC range = 0.63-0.67). DNAm changes as noninvasive biomarkers in prediagnostic blood samples of MPM cases were investigated for the first time. Their application can improve the identification of asbestos-exposed individuals at higher MPM risk to possibly adopt more intensive monitoring for early disease identification.     

An Economic Evaluation of Sacubitril/Valsartan for Heart Failure Patients in the Netherlands

Background

In September 2014, the PARADIGM-HF trial showed the heart failure drug combination sacubitril/valsartan to be superior to enalapril for patients with a reduced ejection fraction.