An in vitro analysis of neuronal survival in response to hormones and photoperiod in the HVc of the songbird Junco hyemalis

Thesis (M.S.) University of Alaska Fairbanks, 2003The ability of songbirds to sing is essential for their survival, proper reproductive behavior, and territorial establishment. Male and female juvenile passerine songbirds learn their song through the formation of a song template in their earliest days of life, first by listening to their parents, and then followed by auditory feedback against their own templates to crystallize their individual songs. However, in most passerine species, only the adult males actually sing on a seasonal basis with little to no singing during winter, followed by a phase of song production in the spring in correlation with increased plasma testosterone concentration and extended photoperiods. While the production of new neurons in the song system of adult males is continuous throughout the year, a counterbalancing turnover of these neurons must exist until the spring, when a three- to four-fold decrease in dying HVc (hyperstriatum pars ventralis caudale or higher vocal center) neurons in males initiates song production. We hypothesized that testosterone, under the influence of increased photoperiod, attenuates the rate of programmed cell death (apoptosis) of newly generated neurons migrating into the HVc song nucleus in the wild arctic songbird Junco hyemalis. Using an organotypic culture system, we examined the effect of testosterone and [beta]-estradiol on the degree of apoptosis in the HVc obtained from photo stimulated and non-photo stimulated male and female juncos. We employed a TUNEL assay and BrdU-labeling to detect and quantify apoptosis. We found that hormonal treatment with testosterone, and [beta]-estradiol in photostimulated birds only, extends the lifespan of cells within the HVc compared to controls, as shown by BrdU labeling, and decreasing apoptosis, as shown by TUNEL assay

An in vitro analysis of neuronal survival in response to hormones and photoperiod in the HVc of the songbird Junco hyemalis

Thesis (M.S.) University of Alaska Fairbanks, 2003The ability of songbirds to sing is essential for their survival, proper reproductive behavior, and territorial establishment. Male and female juvenile passerine songbirds learn their song through the formation of a song template in their earliest days of life, first by listening to their parents, and then followed by auditory feedback against their own templates to crystallize their individual songs. However, in most passerine species, only the adult males actually sing on a seasonal basis with little to no singing during winter, followed by a phase of song production in the spring in correlation with increased plasma testosterone concentration and extended photoperiods. While the production of new neurons in the song system of adult males is continuous throughout the year, a counterbalancing turnover of these neurons must exist until the spring, when a three- to four-fold decrease in dying HVc (hyperstriatum pars ventralis caudale or higher vocal center) neurons in males initiates song production. We hypothesized that testosterone, under the influence of increased photoperiod, attenuates the rate of programmed cell death (apoptosis) of newly generated neurons migrating into the HVc song nucleus in the wild arctic songbird Junco hyemalis. Using an organotypic culture system, we examined the effect of testosterone and [beta]-estradiol on the degree of apoptosis in the HVc obtained from photo stimulated and non-photo stimulated male and female juncos. We employed a TUNEL assay and BrdU-labeling to detect and quantify apoptosis. We found that hormonal treatment with testosterone, and [beta]-estradiol in photostimulated birds only, extends the lifespan of cells within the HVc compared to controls, as shown by BrdU labeling, and decreasing apoptosis, as shown by TUNEL assay

Association of circulating metabolites with healthy diet and risk of cardiovascular disease : analysis of two cohort studies

Diet may modify metabolomic profiles towards higher or lower cardiovascular disease (CVD) risk. We aimed to identify metabolite profiles associated with high adherence to dietary recommendations-the Alternative Healthy Eating Index (AHEI) - and the extent to which metabolites associated with AHEI also predict incident CVD. Relations between AHEI score and 80 circulating lipids and metabolites, quantified by nuclear magnetic resonance metabolomics, were examined using linear regression models in the Whitehall II study (n = 4824, 55.9 +/- 6.1 years, 28.0% women) and were replicated in the Cardiovascular Risk in Young Finns Study (n = 1716, 37.7 +/- 5.0 years, 56.3% women). We used Cox models to study associations between metabolites and incident CVD over the 15.8-year follow-up in the Whitehall II study. After adjustment for confounders, higher AHEI score (indicating healthier diet) was associated with higher degree of unsaturation of fatty acids (FA) and higher ratios of polyunsaturated FA, omega-3 and docosahexaenoic acid relative to total FA in both Whitehall II and Young Finns studies. A concordance of associations of metabolites with higher AHEI score and lower CVD risk was observed in Whitehall II. Adherence to healthy diet seems to be associated with specific FA that reduce risk of CVD.Peer reviewe

Preliminary assessment of the feasibility of using AB words to assess candidacy in adults

Background: Adult cochlear implant (CI) candidacy is assessed in part by the use of speech perception measures. In the United Kingdom the current cut-off point to fall within the CI candidacy range is a score of less than 50% on the BKB sentences presented in quiet (presented at 70 dBSPL). Goal: The specific goal of this article was to review the benefit of adding the AB word test to the assessment test battery for candidacy. Results: The AB word test scores showed good sensitivity and specificity when calculated based on both word and phoneme scores. The word score equivalent for 50% correct on the BKB sentences was 18.5% and it was 34.5% when the phoneme score was calculated; these scores are in line with those used in centres in Wales (15% AB word score). Conclusion: The goal of the British Cochlear Implant Group (BCIG) service evaluation was to determine if the pre-implant assessment measures are appropriate and set at the correct level for determining candidacy, the future analyses will determine whether the speech perception cut-off point for candidacy should be adjusted and whether other more challenging measures should be used in the candidacy evaluation

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

A Comparison of Scent Marking between a Monogamous and Promiscuous Species of Peromyscus: Pair Bonded Males Do Not Advertise to Novel Females

Scent marking can provide behavioral and physiological information including territory ownership and mate advertisement. It is unknown how mating status and pair cohabitation influence marking by males from different social systems. We compared the highly territorial and monogamous California mouse (Peromyscus californicus) to the less territorial and promiscuous white-footed mouse (P. leucopus). Single and mated males of both species were assigned to one of the following arenas lined with filter paper: control (unscented arena), male scented (previously scent-marked by a male conspecific), or females present (containing females in small cages). As expected, the territorial P. californicus scent marked and overmarked an unfamiliar male conspecific's scent marks more frequently than P. leucopus. Species differences in responses to novel females were also found based on mating status. The presence of unfamiliar females failed to induce changes in scent marking in pair bonded P. californicus even though virgin males increased marking behavior. Pair bonding appears to reduce male advertisement for novel females. This is in contrast to P. leucopus males that continue to advertise regardless of mating status. Our data suggest that communication through scent-marking can diverge significantly between species based on mating system and that there are physiological mechanisms that can inhibit responsiveness of males to female cues

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Abstract: Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate

Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe