Isotocin neuronal phenotypes differ among social systems in cichlid fishes

Social living has evolved numerous times across a diverse array of animal taxa. An open question is how the transition to a social lifestyle has shaped, and been shaped by, the underlying neurohormonal machinery of social behaviour. The nonapeptide neurohormones, implicated in the regulation of social behaviours, are prime candidates for the neuroendocrine substrates of social evolution. Here, we examined the brains of eight cichlid fish species with divergent social systems, comparing the number and size of preoptic neurons that express the nonapeptides isotocin and vasotocin. While controlling for the influence of phylogeny and body size, we found that the highly social cooperatively breeding species (n = 4) had fewer parvocellular isotocin neurons than the less social independently breeding species (n = 4), suggesting that the evolutionary transition to group living and cooperative breeding was associated with a reduction in the number of these neurons. In a complementary analysis, we found that the size and number of isotocin neurons significantly differentiated the cooperatively breeding from the independently breeding species. Our results suggest that isotocin is related to sociality in cichlids and may provide a mechanistic substrate for the evolution of sociality

Evidence-based care of older people with suspected cognitive impairment in general practice: protocol for the IRIS cluster randomised trial

Background: Dementia is a common and complex condition. Evidence-based guidelines for the management of people with dementia in general practice exist; however, detection, diagnosis and disclosure of dementia have been identified as potential evidence-practice gaps. Interventions to implement guidelines into practice have had varying success. The use of theory in designing implementation interventions has been limited, but is advocated because of its potential to yield more effective interventions and aid understanding of factors modifying the magnitude of intervention effects across trials. This protocol describes methods of a randomised trial that tests a theory-informed implementation intervention that, if effective, may provide benefits for patients with dementia and their carers. Aims: This trial aims to estimate the effectiveness of a theory-informed intervention to increase GPs’ (in Victoria, Australia) adherence to a clinical guideline for the detection, diagnosis, and management of dementia in general practice, compared with providing GPs with a printed copy of the guideline. Primary objectives include testing if the intervention is effective in increasing the percentage of patients with suspected cognitive impairment who receive care consistent with two key guideline recommendations: receipt of a i) formal cognitive assessment, and ii) depression assessment using a validated scale (primary outcomes for the trial). Methods: The design is a parallel cluster randomised trial, with clusters being general practices. We aim to recruit 60 practices per group. Practices will be randomised to the intervention and control groups using restricted randomisation. Patients meeting the inclusion criteria, and GPs’ detection and diagnosis behaviours directed toward these patients, will be identified and measured via an electronic search of the medical records nine months after the start of the intervention. Practitioners in the control group will receive a printed copy of the guideline. In addition to receipt of the printed guideline, practitioners in the intervention group will be invited to participate in an interactive, opinion leader-led, educational face-to-face workshop. The theory-informed intervention aims to address identified barriers to and enablers of implementation of recommendations. Researchers responsible for identifying the cohort of patients with suspected cognitive impairment, and their detection and diagnosis outcomes, will be blind to group allocation. Trial registration: Australian New Zealand Clinical Trials Registry: ACTRN12611001032943 (date registered 28 September, 2011)

Gestational weight gain and group prenatal care: A systematic review and meta-analysis

Abstract Background Group visits for chronic medical conditions in non-pregnant populations have demonstrated successful outcomes including greater weight loss compared to individual visits for weight management. It is plausible that group prenatal care can similarly assist women in meeting gestational weight gain goals. The purpose of this study was to evaluate the effect of group vs. traditional prenatal care on gestational weight gain. Methods A keyword search of Medline, Embase, Scopus, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, clinicaltrials.gov, and Google Scholar was performed up to April 2017. Studies were included if they compared gestational weight gain in a group prenatal care setting to traditional prenatal care in either randomized controlled trials, cohort, or case-control studies. The primary and secondary outcomes were excessive and adequate gestational weight gain according to the Institute of Medicine guidelines. Heterogeneity was assessed with the Q test and I2 statistic. Pooled relative risks (RRs) and confidence intervals (CI) were reported with random-effects models from the randomized controlled trials (RCT) and cohort studies. Results One RCT, one secondary analysis of an RCT, one study with “random assignment”, and twelve cohort studies met the inclusion criteria for a total of 13,779 subjects. Thirteen studies used the CenteringPregnancy model, defined by 10 sessions that emphasize goal setting and self-monitoring. Studies targeted specific populations such as adolescents, African-Americans, Hispanics, active-duty military or their spouses, and women with obesity or gestational diabetes. There were no significant differences in excessive [7 studies: pooled rates 47% (1806/3582) vs. 43% (3839/8521), RR 1.09, 95% CI 0.97–1.23] or adequate gestational weight gain [6 studies: pooled rates 31% (798/2875) vs. 30% (1410/5187), RR 0.92, 95% CI 0.79–1.08] in group and traditional prenatal care among the nine studies that reported categorical gestational weight gain outcomes in the meta-analysis. Conclusions Group prenatal care was not associated with excessive or adequate gestational weight gain in the meta-analysis. Since outcomes were overall inconsistent, we propose that prenatal care models (e.g., group vs. traditional) should be evaluated in a more rigorous fashion with respect to gestational weight gain

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

SHANK3 controls maturation of social reward circuits in the VTA.

Haploinsufficiency of SHANK3, encoding the synapse scaffolding protein SHANK3, leads to a highly penetrant form of autism spectrum disorder. How SHANK3 insufficiency affects specific neural circuits and how this is related to specific symptoms remains elusive. Here we used shRNA to model Shank3 insufficiency in the ventral tegmental area of mice. We identified dopamine (DA) and GABA cell-type-specific changes in excitatory synapse transmission that converge to reduce DA neuron activity and generate behavioral deficits, including impaired social preference. Administration of a positive allosteric modulator of the type 1 metabotropic glutamate receptors mGluR1 during the first postnatal week restored DA neuron excitatory synapse transmission and partially rescued the social preference defects, while optogenetic DA neuron stimulation was sufficient to enhance social preference. Collectively, these data reveal the contribution of impaired ventral tegmental area function to social behaviors and identify mGluR1 modulation during postnatal development as a potential treatment strategy

Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

It is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complex induced by infections and immune trauma and mediated by pro-inflammatory cytokines. It is an adaptive response that enhances recovery by conserving energy to combat acute inflammation. There are considerable phenomenological similarities between sickness behavior and depression, for example, behavioral inhibition, anorexia and weight loss, and melancholic (anhedonia), physio-somatic (fatigue, hyperalgesia, malaise), anxiety and neurocognitive symptoms. In clinical depression, however, a transition occurs to sensitization of immuno-inflammatory pathways, progressive damage by oxidative and nitrosative stress to lipids, proteins, and DNA, and autoimmune responses directed against self-epitopes. The latter mechanisms are the substrate of a neuroprogressive process, whereby multiple depressive episodes cause neural tissue damage and consequent functional and cognitive sequelae. Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology. Inflammation may provoke a Janus-faced response with a good, acute side, generating protective inflammation through sickness behavior and a bad, chronic side, for example, clinical depression, a lifelong disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well defined triggers

Discovery of novel GPVI receptor antagonists by structure-based repurposing.

Inappropriate platelet aggregation creates a cardiovascular risk that is largely managed with thienopyridines and aspirin. Although effective, these drugs carry risks of increased bleeding and drug 'resistance', underpinning a drive for new antiplatelet agents. To discover such drugs, one strategy is to identify a suitable druggable target and then find small molecules that modulate it. A good and unexploited target is the platelet collagen receptor, GPVI, which promotes thrombus formation. To identify inhibitors of GPVI that are safe and bioavailable, we docked a FDA-approved drug library into the GPVI collagen-binding site in silico. We now report that losartan and cinanserin inhibit GPVI-mediated platelet activation in a selective, competitive and dose-dependent manner. This mechanism of action likely underpins the cardioprotective effects of losartan that could not be ascribed to its antihypertensive effects. We have, therefore, identified small molecule inhibitors of GPVI-mediated platelet activation, and also demonstrated the utility of structure-based repurposing

Impact of optical coherence tomography on diagnostic decision-making by UK community optometrists: a clinical vignette study.

PURPOSE: In recent years, there has been widespread investment in imaging technologies by community optometrists in the UK, most notably optical coherence tomography (OCT). The aim of the current study was to determine the value of OCT in the diagnosis of posterior segment diseases in a representative sample of community optometrists using a clinical vignette methodology. METHODS: A group of community optometrists (n = 50) initially completed a standardised training package on OCT interpretation followed by a computer-based assessment featuring 52 clinical vignettes, containing images of healthy (n = 8) or glaucomatous (n = 18) discs or healthy (n = 8) or diseased (n = 18) fundi. Each vignette featured either a single fundus/disc photographic image, or a combination of a fundus/disc image with the corresponding OCT scan. An expert panel confirmed that the fundus images presented alone and those in combination with OCT data were of a similar level of difficulty and that the cases were typical of those seen in primary care. For each case, the optometrist selected their diagnosis from a pull-down list and reported their confidence in their decision using a 10-point Likert scale. Pairwise comparisons of the fundus image alone and fundus image/OCT combination were made for both diagnostic performance and confidence. RESULTS: The mean percentage of correct diagnoses using fundus imaging alone was 62% (95% CI 59-64%) and for the combination of fundus image/OCT was 80% (95% CI 77-82%). The mean false negative rate with fundus alone was 27% reducing to 13% with the OCT combination. Median confidence scores for fundus imaging alone was 8.0 (IQR 7.0-8.0) and 8.3 (IQR 8.0-9.0) for the combination. Improvements in performance and confidence were statistically significant (p < 0.001). CONCLUSION: The results from this vignette study suggests that OCT improves optometrists' diagnostic performance compared to fundus observation alone. These initial results suggest that OCT provides valuable additional data that could augment case-finding for glaucoma and retinal disease; however, further research is needed to assess its diagnostic performance in a routine clinical practice setting

Resistance to paclitaxel in a cisplatin-resistant ovarian cancer cell line is mediated by P-glycoprotein

The IGROVCDDP cisplatin-resistant ovarian cancer cell line is also resistant to paclitaxel and models the resistance phenotype of relapsed ovarian cancer patients after first-line platinum/taxane chemotherapy. A TaqMan low-density array (TLDA) was used to characterise the expression of 380 genes associated with chemotherapy resistance in IGROVCDDP cells. Paclitaxel resistance in IGROVCDDP is mediated by gene and protein overexpression of P-glycoprotein and the protein is functionally active. Cisplatin resistance was not reversed by elacridar, confirming that cisplatin is not a P-glycoprotein substrate. Cisplatin resistance in IGROVCDDP is multifactorial and is mediated in part by the glutathione pathway and decreased accumulation of drug. Total cellular glutathione was not increased. However, the enzyme activity of GSR and GGT1 were up-regulated. The cellular localisation of copper transporter CTR1 changed from membrane associated in IGROV-1 to cytoplasmic in IGROVCDDP. This may mediate the previously reported accumulation defect. There was decreased expression of the sodium potassium pump (ATP1A), MRP1 and FBP which all have been previously associated with platinum accumulation defects in platinum-resistant cell lines. Cellular localisation of MRP1 was also altered in IGROVCDDP shifting basolaterally, compared to IGROV-1. BRCA1 was also up-regulated at the gene and protein level. The overexpression of P-glycoprotein in a resistant model developed with cisplatin is unusual. This demonstrates that P-glycoprotein can be up-regulated as a generalised stress response rather than as a specific response to a substrate. Mechanisms characterised in IGROVCDDP cells may be applicable to relapsed ovarian cancer patients treated with frontline platinum/taxane chemotherapy

Evaluation of a Theory-Informed Implementation Intervention for the Management of Acute Low Back Pain in General Medical Practice: The IMPLEMENT Cluster Randomised Trial

Introduction: This cluster randomised trial evaluated an intervention to decrease x-ray referrals and increase giving advice to stay active for people with acute low back pain (LBP) in general practice. Methods: General practices were randomised to either access to a guideline for acute LBP (control) or facilitated interactive workshops (intervention). We measured behavioural predictors (e.g. knowledge, attitudes and intentions) and fear avoidance beliefs. We were unable to recruit sufficient patients to measure our original primary outcomes so we introduced other outcomes measured at the general practitioner (GP) level: behavioural simulation (clinical decision about vignettes) and rates of x-ray and CT-scan (medical administrative data). All those not involved in the delivery of the intervention were blinded to allocation. Results: 47 practices (53 GPs) were randomised to the control and 45 practices (59 GPs) to the intervention. The number of GPs available for analysis at 12 months varied by outcome due to missing confounder information; a minimum of 38 GPs were available from the intervention group, and a minimum of 40 GPs from the control group. For the behavioural constructs, although effect estimates were small, the intervention group GPs had greater intention of practising consistent with the guideline for the clinical behaviour of x-ray referral. For behavioural simulation, intervention group GPs were more likely to adhere to guideline recommendations about x-ray (OR 1.76, 95%CI 1.01, 3.05) and more likely to give advice to stay active (OR 4.49, 95%CI 1.90 to 10.60). Imaging referral was not statistically significantly different between groups and the potential importance of effects was unclear; rate ratio 0.87 (95%CI 0.68, 1.10) for x-ray or CT-scan. Conclusions: The intervention led to small changes in GP intention to practice in a manner that is consistent with an evidence-based guideline, but it did not result in statistically significant changes in actual behaviour. Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN01260600009853