An assessment of the effects of neurokinin₁ receptor antagonism against nausea and vomiting: Relative efficacy, sites of action and lessons for future drug development.

A ‘broad-spectrum’ anti-vomiting effect of neurokinin1 receptor antagonists (NK1RA), shown in preclinical animal studies, has been supported by a more limited range of clinical studies in different indications. However, this review suggests that compared with vomiting, the self-reported sensation of nausea is less affected or possibly unaffected (depending on the stimulus) by NK1 receptor antagonism, a common finding for ‘anti-emetics’. The stimulus-independent effects of NK1RAs against vomiting are explicable by actions within the central pattern generator (CPG; ventral brainstem) and the nucleus tractus solitarius (NTS; dorsal brainstem), with additional effects on vagal afferent activity for certain stimuli (e.g., highly emetogenic chemotherapy). The CPG and NTS neurones are multifunctional so the notable lack of obvious effects of NK1RAs on other reflexes mediated by the same neurones suggests that their anti-vomiting action is dependent on the activation state of the pathway leading to vomiting. Nausea requires activation of cerebral pathways by projection of information from the NTS. Although NK1 receptors are present in cerebral nuclei implicated in nausea, and imaging studies show very high receptor occupancy at clinically used doses, the variable or limited ability of NK1RAs to inhibit nausea emphasises (a) our inadequate understanding of the mechanisms of nausea and (b) that classification of a drug as an “anti-emetic” may give a false impression of efficacy against nausea versus vomiting. We discuss the potential mechanisms for the differential efficacy of NK1RA and the implications for future development of drugs which can effectively treat nausea, an area of unmet clinical need

Interaction between oxytocin receptor DNA methylation and genotype is associated with risk of postpartum depression in women without depression in pregnancy

Postpartum depression (PPD) affects up to 19% of women, negatively impacting maternal and infant health. Reductions in plasma oxytocin levels have been associated with PPD and heritability studies have established a genetic contribution. Epigenetic regulation of the oxytocin receptor gene (OXTR) has been demonstrated and we hypothesized that individual epigenetic variability at OXTR may impact the development of PPD and that such variability may be central to predicting risk. This case-control study is nested within the Avon Longitudinal Study of Parents and Children and included 269 cases with PPD and 276 controls matched on age group, parity, and presence or absence of depressive symptoms in pregnancy as assessed by the Edinburgh Postnatal Depression Scale. OXTR DNA methylation (CpG site -934) and genotype (rs53576 and rs2254298) were assayed from DNA extracted from blood collected during pregnancy. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association of elevated symptoms of PPD with genotype, methylation, and their interaction adjusted for psychosocial factors (n=500). There was evidence of an interaction between rs53576 and methylation in the OXTR gene amongst women who did not have depression prenatally but developed PPD (p interaction=0.026, adjusted for covariates, n=257). Those women with GG genotype showed 2.63 greater odds of PPD for every 10% increase in methylation level (95% CI: 1.37, 5.03), whereas methylation was unrelated to PPD amongst A carriers (OR=1.00, 95%CI: 0.58, 1.73). There was no such interaction among women with PPD and prenatal depression. These data indicate that epigenetic variation that decreases expression of OXTR in a susceptible genotype may play a contributory role in the etiology of postpartum depression

Diaryl- and triaryl-pyrrole derivatives:Inhibitors of the MDM2-p53 and MDMX-p53 protein-protein interactions

Screening identified 2-(3-((4,6-dioxo-2-thioxotetrahydropyrimidin-5(2H)-ylidene)methyl)-2,5-dimethyl-1H-pyrrol-1-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile as an MDM2–p53 inhibitor (IC(50) = 12.3 μM). MDM2–p53 and MDMX–p53 activity was seen for 5-((1-(4-chlorophenyl)-2,5-diphenyl-1H-pyrrol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (MDM2 IC(50) = 0.11 μM; MDMX IC(50) = 4.2 μM) and 5-((1-(4-nitrophenyl)-2,5-diphenyl-1H-pyrrol-3-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-trione (MDM2 IC(50) = 0.15 μM; MDMX IC(50) = 4.2 μM), and cellular activity consistent with p53 activation in MDM2 amplified cells. Further SAR studies demonstrated the requirement for the triarylpyrrole moiety for MDMX–p53 activity but not for MDM2–p53 inhibition

Vestibular Perception following Acute Unilateral Vestibular Lesions.

Little is known about the vestibulo-perceptual (VP) system, particularly after a unilateral vestibular lesion. We investigated vestibulo-ocular (VO) and VP function in 25 patients with vestibular neuritis (VN) acutely (2 days after onset) and after compensation (recovery phase, 10 weeks). Since the effect of VN on reflex and perceptual function may differ at threshold and supra-threshold acceleration levels, we used two stimulus intensities, acceleration steps of 0.5°/s(2) and velocity steps of 90°/s (acceleration 180°/s(2)). We hypothesised that the vestibular lesion or the compensatory processes could dissociate VO and VP function, particularly if the acute vertiginous sensation interferes with the perceptual tasks. Both in acute and recovery phases, VO and VP thresholds increased, particularly during ipsilesional rotations. In signal detection theory this indicates that signals from the healthy and affected side are still fused, but result in asymmetric thresholds due to a lesion-induced bias. The normal pattern whereby VP thresholds are higher than VO thresholds was preserved, indicating that any 'perceptual noise' added by the vertigo does not disrupt the cognitive decision-making processes inherent to the perceptual task. Overall, the parallel findings in VO and VP thresholds imply little or no additional cortical processing and suggest that vestibular thresholds essentially reflect the sensitivity of the fused peripheral receptors. In contrast, a significant VO-VP dissociation for supra-threshold stimuli was found. Acutely, time constants and duration of the VO and VP responses were reduced - asymmetrically for VO, as expected, but surprisingly symmetrical for perception. At recovery, VP responses normalised but VO responses remained shortened and asymmetric. Thus, unlike threshold data, supra-threshold responses show considerable VO-VP dissociation indicative of additional, higher-order processing of vestibular signals. We provide evidence of perceptual processes (ultimately cortical) participating in vestibular compensation, suppressing asymmetry acutely in unilateral vestibular lesions

Counter and Complicit Masculine Discourse Among Men’s Shed Members

Men’s Sheds is a growing international movement aimed at providing men with places and activities that facilitate social connectedness. Despite Men’s Sheds’ focus on males, little attention has been paid to masculinities within the specific context of these settings. The current study used a gender relations framework to explore the ways in which attendees discussed Men’s Sheds, with particular attention to discussions that were complicit and counter to traditional, hegemonic views of masculinity, and diverse positions in between these binaries. The data consisted of transcripts and field notes from four focus groups comprised of mostly older, White, retired male members of a Canadian shed (N = 22). The analysis revealed three overall themes: (1) focus on work, (2) independence, and (3) need for male-focused spaces. These themes and associated subthemes suggest that shed members ascribe to dominant masculine values and ideals, but also support more fluid and flexible views of masculinity. Implications are discussed for how working with an array of masculinities within the Men’s Sheds movement will be helpful with respect to their future growth in Canada and internationally

Evaluation of quality of life in adults with neurofibromatosis 1 (NF1) using the Impact of NF1 on Quality Of Life (INF1-QOL) questionnaire

Background Neurofibromatosis 1 (NF1) is an inherited, multi-system, tumour suppressor disorder with variable complications that cause psychological distress and social isolation. The study aim was to develop and validate a disease-specific questionnaire to measure quality of life (QOL) in NF1 that is suitable both as an assessment tool in clinical practice and in clinical trials of novel therapy. Methods The Impact of NF1 on Quality of Life (INF1-QOL) questionnaire was developed by a literature search for common terms, focus group (n=6), semi-structured interviews (n=21), initial drafts (n =50) and final 14 item questionnaire (n=50). Bivariate correlations between items, exploratory factor analysis, correlations with severity and EuroQol were employed. Results INF1-QOL showed good internal reliability (Cronbach’s alpha 0.87), mean total INF1-QOL score was 8.64 (SD 6.3), median 7.00, range 0-30 (possible range 0-42); no significant correlations with age or gender. The mean total EuroQol score was 7.38 (SD 2.87), median 6.5, mean global EuroQol score was 76.34 (SD 16.56), median 80. Total INF1-QOL score correlated with total EuroQol r=0.82, p<0.0001. The highest impact on QOL was moderate or severe problems with anxiety and depression (32%) and negative effects of NF1 on role and outlook on life (42%). The mean inter-relater reliability for grading of clinical severity scores was 0.71 (range 0.65-0.79), and intra-class correlation was 0.92. The mean clinical severity score was 1.95 (SD 0.65) correlating r=0.34 with total INF1-QOL score p<0.05 and correlated 0.37 with total EuroQol score p<0.01. The clinical severity score was mild in 17 (34%), moderate in 16 (32%) and 17 (34%) individuals had severe disease. Conclusions INF1-QOL is a validated, reliable disease specific questionnaire that is easy and quick to complete. Role and outlook on life and anxiety and depression have the highest impact on QOL indicating the variability, severity and unpredictability of NF1. INFI-QOL correlates moderately with clinical severity. The moderate relationship between INF1-QOL and physician rated severity emphasizes the difference between clinical and patient perception. INFI-QOL will be useful in individual patient assessment and as an outcome measure for clinical trials

American Mastodon Mitochondrial Genomes Suggest Multiple Dispersal Events in Response to Pleistocene Climate Oscillations

Pleistocene glacial-interglacial cycles are correlated with dramatic temperature oscillations. Examining how species responded to these natural fluctuations can provide valuable insights into the impacts of present-day anthropogenic climate change. Here we present a phylogeographic study of the extinct American mastodon (Mammut americanum), based on 35 complete mitochondrial genomes. These data reveal the presence of multiple lineages within this species, including two distinct clades from eastern Beringia. Our molecular date estimates suggest that these clades arose at different times, supporting a pattern of repeated northern expansion and local extirpation in response to glacial cycling. Consistent with this hypothesis, we also note lower levels of genetic diversity among northern mastodons than in endemic clades south of the continental ice sheets. The results of our study highlight the complex relationships between population dispersals and climate change, and can provide testable hypotheses for extant species expected to experience substantial biogeographic impacts from rising temperatures

Longitudinal evaluation of quality of life in 288 patients with Neurofibromatosis 2

Advances in molecular biology have resulted in novel therapy for neurofibromatosis 2-related (NF2) tumours, highlighting the need for robust outcome measures. The disease-focused NF2 impact on quality of life (NFTI-QOL) patient questionnaire was assessed as an outcome measure for treatment in a multi-centre study. NFTI-QOL was related to clinician-rated severity (ClinSev) and genetic severity (GenSev) over repeated visits. Data were evaluated for 288 NF2 patients (n = 464 visits) attending the English national NF2 clinics from 2010 to 2012. The male-to-female ratio was equal and the mean age was 42.2 (SD 17.8) years. The analysis included NFTI-QOL eight-item score, ClinSev graded as mild, moderate, or severe, and GenSev as a rank order of the number of NF2 mutations (graded as mild, moderate, severe). The mean (SD) 8.7 (5.4) score for NFTI-QOL for either a first visit or all visits 9.2 (5.4) was similar to the published norm of 9.4 (5.5), with no significant relationships with age or gender. NFTI-QOL internal reliability was good, with a Cronbach’s alpha score of 0.85 and test re-test reliability r = 0.84. NFTI related to ClinSev (r = 0.41, p < 0.001; r = 0.46 for all visits), but weakly to GenSev (r = 0.16, p < 0.05; r = 0.15 for all visits). ClinSev related to GenSev (r = 0.41, p < 0.001; r = 0.42 for all visits). NFTI-QOL showed a good reliability and ability to detect significant longitudinal changes in the QOL of individuals. The moderate relationships of NFTI-QOL with clinician- and genetic-rated severity suggest that NFTI-QOL taps into NF2 patient experiences that are not encompassed by ClinSev rating or genotype