Redefining Gonadotropin-Releasing Hormone (GnRH) Cell Groups in the Male Syrian Hamster: Testosterone Regulates GnRH mRNA in the Tenia Tecta

Gonadotropin-releasing hormone (GnRH) regulates the production of testosterone via the hypothalamic-pituitary-gonadal axis and testosterone, in turn, regulates the GnRH system via negative feedback. We compared testosterone regulation of GnRH mRNA expression in four anatomically defined GnRH cell groups in juvenile and adult male Syrian hamsters, including a rostral population of GnRH cells in the tenia tecta. In situ hybridization histochemistry (ISHH) was used to measure GnRH mRNA in brains from castrated juveniles and adults treated with 0 mg or 2.5 mg testosterone pellets for one week. ISHH was performed on coronal sections using a 35 S-cRNA probe generated from Syrian hamster GnRH cDNA. Testosterone treatment resulted in a significant reduction in mean area of GnRH neurones covered by silver grains within the tenia tecta, but only a trend toward decreased GnRH mRNA in the diagonal band of Broca/organum vasculosum of the lamina terminalis (DBB/OVLT), medial septum (MS), and caudal preoptic area (cPOA). The effects of testosterone were independent of age. Frequency distribution analyses unveiled a significant reduction in the number of heavily labelled cells following testosterone treatment within the tenia tecta and MS. Simple regression analyses revealed a significant positive correlation between plasma luteinizing hormone concentrations and GnRH mRNA only in the tenia tecta. These data indicate that, overall, GnRH mRNA is modestly reduced by testosterone, and the most robust attenuation of GnRH mRNA occurs within the tenia tecta. This is the first report to link mechanisms of steroid negative feedback with tenia tecta GnRH neurones, providing a new focus for investigating brain region-specific steroidal regulation of GnRH synthesis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75357/1/j.0007-1331.2002.00787.x.pd

Open AccessArticle Sex Differences in the Effect of Alcohol Drinking on Myelinated Axons in the Anterior Cingulate Cortex of Adolescent Rats

Cognitive deficits associated with teenage drinking may be due to disrupted myelination of prefrontal circuits. To better understand how alcohol affects myelination, male and female Wistar rats (n = 7–9/sex/treatment) underwent two weeks of intermittent operant self-administration of sweetened alcohol or sweetened water early in adolescence (postnatal days 28–42) and we tested for macro- and microstructural changes to myelin. We previously reported data from the males of this study showing that alcohol drinking reduced myelinated fiber density in layers II–V of the anterior cingulate division of the medial prefrontal cortex (Cg1); herein, we show that myelinated fiber density was not significantly altered by alcohol in females. Alcohol drinking patterns were similar in both sexes, but males were in a pre-pubertal state for a larger proportion of the alcohol exposure period, which may have contributed to the differential effects on myelinated fiber density. To gain more insight into how alcohol impacts myelinated axons, brain sections from a subset of these animals (n = 6/sex/treatment) were used for microstructural analyses of the nodes of Ranvier. Confocal analysis of nodal domains, flanked by immunofluorescent-labeled contactin-associated protein (Caspr) clusters, indicated that alcohol drinking reduced nodal length-to-width ratios in layers II/III of the Cg1 in both sexes. Despite sex differences in the underlying cause (larger diameter axons after alcohol in males vs. shorter nodal lengths after alcohol in females), reduced nodal ratios could have important implications for the speed and integrity of neural transmission along these axons in both males and females. Alcohol-induced changes to myelinated axonal populations in the Cg1 may contribute to long-lasting changes in prefrontal function associated with early onset drinking

Resolving the contributions of the membrane-bound and periplasmic nitrate reductase systems to nitric oxide and nitrous oxide production in Salmonella enterica serovar Typhimurium

The production of cytotoxic nitric oxide (NO) and conversion into the neuropharmacological agent and potent greenhouse gas nitrous oxide (N2O) is linked with anoxic nitrate catabolism by Salmonella enterica serovar Typhimurium. Salmonella can synthesize two types of nitrate reductase: a membrane-bound form (Nar) and a periplasmic form (Nap). Nitrate catabolism was studied under nitrate-rich and nitrate-limited conditions in chemostat cultures following transition from oxic to anoxic conditions. Intracellular NO production was reported qualitatively by assessing transcription of the NO-regulated genes encoding flavohaemoglobin (Hmp), flavorubredoxin (NorV) and hybrid cluster protein (Hcp). A more quantitative analysis of the extent of NO formation was gained by measuring production of N2O, the end-product of anoxic NO-detoxification. Under nitrate-rich conditions, the nar, nap, hmp, norV and hcp genes were all induced following transition from the oxic to anoxic state, and 20% of nitrate consumed in steady-state was released as N2O when nitrite had accumulated to millimolar levels. The kinetics of nitrate consumption, nitrite accumulation and N2O production were similar to those of wild-type in nitrate-sufficient cultures of a nap mutant. In contrast, in a narG mutant, the steady-state rate of N2O production was ~30-fold lower than that of the wild-type. Under nitrate-limited conditions, nap, but not nar, was up-regulated following transition from oxic to anoxic metabolism and very little N2O production was observed. Thus a combination of nitrate-sufficiency, nitrite accumulation and an active Nar-type nitrate reductase leads to NO and thence N2O production, and this can account for up to 20% of the nitrate catabolized

A pilot feasibility trial of alcohol screening and brief intervention in the police custody setting (ACCEPT): study protocol for a cluster randomised controlled trial

BACKGROUND: There is evidence of an association between alcohol use and offending behaviour and around a quarter of police time is spent on alcohol-related incidents. Police custody, therefore, provides an important opportunity to intervene. This pilot trial aims to investigate whether a definitive evaluation of screening and brief interventions aimed at reducing risky drinking in arrestees is acceptable and feasible in the custody suite setting. METHODS: Screening will be carried out by trained detention officers or drug and alcohol workers in four police forces across two geographical areas (North East and South West England). Detention officers (or drug and alcohol workers) will be cluster randomised to one of three conditions: screening only (control group), screening followed immediately by 10 min of manualised brief structured advice delivered by the individual responsible for screening (intervention 1) or screening followed by 10 min of manualised brief structured advice delivered by the individual responsible for screening plus the offer of a subsequent 20-min session of behaviour change counselling delivered by a trained alcohol health worker (intervention 2). Participants will be arrestees aged 18+ who screen positive on the Alcohol Use Disorders Identification Test. Participants will be followed up at 6 and 12 months post-intervention. An embedded qualitative process evaluation will explore acceptability of alcohol screening and brief intervention to staff and arrestees as well as facilitators and barriers to the delivery of such approaches in this setting. RESULTS: Recruitment is currently underway and due to end May 2015. CONCLUSION: Results from this pilot trial will determine if a definitive evaluation is possible in the future and will provide stakeholder input to its design. TRIAL REGISTRATION: Reference number: ISRCTN89291046

The remote diet intervention to reduce Long COVID symptoms trial (ReDIRECT): protocol for a randomised controlled trial to determine the effectiveness and cost-effectiveness of a remotely delivered supported weight management programme for people with Long COVID and excess weight, with personalised improvement goals

Objectives: The Remote Diet Intervention to Reduce Long COVID Symptoms Trial (ReDIRECT) evaluates whether the digitally delivered, evidence-based, cost-effective Counterweight-Plus weight management programme improves symptoms of Long COVID in people with overweight/obesity. Methods: Baseline randomised, non-blinded design with 240 participants allocated in a 1:1 ratio either to continue usual care or to add the remotely delivered Counterweight-Plus weight management programme, which includes a Counterweight dietitian supported delivery of 12 weeks total diet replacement, food reintroduction, and long-term weight loss maintenance. Randomisation is achieved by accessing a web-based randomisation system incorporated into the study web portal developed by a registered Clinical Trials Unit. We are using an innovative approach to outcome personalisation, with each participant selecting their most dominant Long COVID symptom as their primary outcome assessed at six months. Participants in the control arm enter the weight management programme after six months. We are recruiting participants from social media and existing networks (e.g., Long COVID Scotland groups), through newspaper advertisements and from primary care. Main inclusion criteria: people with Long COVID symptoms persisting > three months, aged 18 years or above, body mass index (BMI) above 27kg/m2 (>25kg/m2 for South Asians). The trial includes a process evaluation (involving qualitative interviews with participants and analysis of data on dose, fidelity and reach of the intervention) and economic evaluation (within-trial and long-term cost-utility analyses). Anticipated results: The recruitment for this study started in December 2021 and ended in July 2022. Project results are not yet available and will be shared via peer-reviewed publication once the six-months outcomes have been analysed. Trial registration: Current Controlled Trials ISRCTN1259552

Adolescent Binge Drinking Leads to Changes in Alcohol Drinking, Anxiety, and Amygdalar Corticotropin Releasing Factor Cells in Adulthood in Male Rats

Heavy episodic drinking early in adolescence is associated with increased risk of addiction and other stress-related disorders later in life. This suggests that adolescent alcohol abuse is an early marker of innate vulnerability and/or binge exposure impacts the developing brain to increase vulnerability to these disorders in adulthood. Animal models are ideal for clarifying the relationship between adolescent and adult alcohol abuse, but we show that methods of involuntary alcohol exposure are not effective. We describe an operant model that uses multiple bouts of intermittent access to sweetened alcohol to elicit voluntary binge alcohol drinking early in adolescence (∼postnatal days 28–42) in genetically heterogeneous male Wistar rats. We next examined the effects of adolescent binge drinking on alcohol drinking and anxiety-like behavior in dependent and non-dependent adult rats, and counted corticotropin-releasing factor (CRF) cell in the lateral portion of the central amygdala (CeA), a region that contributes to regulation of anxiety- and alcohol-related behaviors. Adolescent binge drinking did not alter alcohol drinking under baseline drinking conditions in adulthood. However, alcohol-dependent and non-dependent adult rats with a history of adolescent alcohol binge drinking did exhibit increased alcohol drinking when access to alcohol was intermittent. Adult rats that binged alcohol during adolescence exhibited increased exploration on the open arms of the elevated plus maze (possibly indicating either decreased anxiety or increased impulsivity), an effect that was reversed by a history of alcohol dependence during adulthood. Finally, CRF cell counts were reduced in the lateral CeA of rats with adolescent alcohol binge history, suggesting semi-permanent changes in the limbic stress peptide system with this treatment. These data suggest that voluntary binge drinking during early adolescence produces long-lasting neural and behavioral effects with implications for anxiety and alcohol use disorders

The Alcohol Intervention Training Program (AITP): A response to alcohol misuse in the farming community

Background Farm men and women in Australia have higher levels of problematic alcohol use than their urban counterparts and experience elevated health risks associated with excessive alcohol consumption. The Sustainable Farm Families (SFF) program has worked successfully with farm men and women to address health, well- being and safety and has identified that further research and training is required to understand and address alcohol misuse behaviours. This project will add an innovative component to the program by training health professionals working with farm men and women to discuss and respond to alcohol-related physical and mental health problems. Methods/Design A mixed method design with multi-level evaluation will be implemented following the development and delivery of a training program (The Alcohol Intervention Training Program {AITP}) for Sustainable Farm Families health professionals. Pre-, post- and follow-up surveys will be used to assess both the impact of the training on the knowledge, confidence and skills of the health professionals to work with alcohol misuse and associated problems, and the impact of the training on the attitudes, behaviour and mental health of farm men and women who participate in the SFF project. Evaluations will take a range of forms including self-rated outcome measures and interviews. Discussion The success of this project will enhance the health and well-being of a critical population, the farm men and women of Australia, by producing an evidence-based strategy to assist them to adopt more positive alcohol-related behaviours that will lead to better physical and mental health

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

The pre-history of health psychology in the UK: From natural science and psychoanalysis to social science, social cognition and beyond

Health psychology formally came of age in the United Kingdom in the 1980s, but it was prefigured by much discussion about challenges to the dominance of biomedicine in healthcare and debates. This articles focuses on what could be termed the pre-history of health psychology in the UK. This was the period in the earlier 20th century when psychological approaches were dominated by psychoanalysis which was followed by behaviourism and then cognitivism. Review of this pre-history provides the backdrop for the rise of health psychology in the UK and also reveals the tensions between the different theoretical perspectives

Dose Frequency Ranging Pharmacokinetic Study of Tenofovir-Emtricitabine After Directly Observed Dosing in Healthy Volunteers to Establish Adherence Benchmarks (HPTN 066)

Oral preexposure prophylaxis (PrEP) trials report disparate efficacy attributed to variable adherence. HPTN 066 was conducted to establish objective, quantitative benchmarks for discrete, regular levels of adherence using directly observed dosing of tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC). Healthy, HIV-uninfected men and women were randomized to one of four oral regimens of fixed-dose TDF 300 mg/FTC 200 mg tablet for 5 weeks with all doses observed: one tablet weekly (one/week), one tablet twice weekly (two/week), two tablets twice weekly (four/week), or one tablet daily (seven/week). Trough serum TFV and FTC, peripheral blood mononuclear cell (PBMC), and CD4+ TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) concentrations were determined throughout dosing and 2 weeks after the last dose. Rectosigmoidal, semen, and cervicovaginal samples were collected for drug assessment at end of dosing and 2 weeks later in a subset of participants. The 49 enrolled participants tolerated the regimens well. All regimens achieved steady-state concentrations by the second dose for serum TFV/FTC and by 7 days for PBMC TFV-DP/FTC-TP. Steady-state median TFV-DP predose concentrations demonstrated dose proportionality: one/week 1.6 fmol/106 PBMCs, two/week 9.1, four/week 18.8, seven/week, 36.3. Further, TFV-DP was consistently quantifiable 2 weeks after the last dose for the ≥4/week regimens. Adherence benchmarks were identified using receiver operating characteristic curves, which had areas under the curve ≥0.93 for all analytes in serum and PBMCs. Intersubject and intrasubject coefficients of variation (%CV) ranged from 33% to 63% and 14% to 34%, respectively, for all analytes in serum and PBMCs. Steady-state PBMC TFV-DP was established earlier and at lower concentrations than predicted and was the only analyte demonstrating predose concentration dose proportionality. Steady-state daily dosing serum TFV and PBMC TFV-DP was consistent with highly effective PrEP clinical trials. HPTN 066 provides adherence benchmarks for oral TFV/FTC regimens to assist interpreting study outcomes