Functional inhibition of deep brain non-visual opsins facilitates acute long day induction of reproductive recrudescence in male Japanese quail :Deep brain photoreceptors in birds

For nearly a century, we have known that brain photoreceptors regulate avian seasonal biology. Two photopigments, vertebrate ancient opsin (VA) and neuropsin (OPN5), provide possible molecular substrates for these photoreceptor pathways. VA fulfills many criteria for providing light input to the reproductive response, but a functional link has yet to be demonstrated. This study examined the role of VA and OPN5 in the avian photoperiodic response of Japanese quail (Coturnix japonica). Non-breeding male quail were housed under short days (6L:18D) and received an intracerebroventricular infusion of adeno-associated viral vectors with shRNAi that selectively inhibited either VA or OPN5. An empty viral vector acted as a control. Quail were then photostimulated (16L:8D) to stimulate gonadal growth. Two long days significantly increased pituitary thyrotrophin-stimulating hormone β-subunit (TSHβ) and luteinizing hormone β-subunit (LHβ) mRNA of VA shRNAi treated quail compared to controls. Furthermore, at one week there was a significant increase, compared to controls, in both hypothalamic gonadotrophin releasing hormone-I (GnRH-I) mRNA and paired testicular mass in VA shRNAi birds. Opn5 shRNAi facilitated the photoinduced increase in TSHβ mRNA at 2 days, but no other differences were identified compared to controls. Contrary to our expectations, the silencing of deep brain photoreceptors enhanced the response of the reproductive axis to photostimulation rather than preventing it. In addition, we show that VA opsin plays a dominant role in the light-dependent neuroendocrine control of seasonal reproduction in birds. Together our findings suggest the photoperiodic response involves at least two photoreceptor types and populations working together with VA opsin playing a dominant role

Effects of the pattern of glucocorticoid replacement on neural processing, emotional reactivity and well-being in healthy male individuals:study protocol for a randomised controlled trial

BACKGROUND: Deviation from the physiological glucocorticoid dynamics (circadian and underlying ultradian rhythmicity) is a common characteristic of various neuropsychiatric and endocrine disorders as well as glucocorticoid-based therapeutics. These states may be accompanied by neuropsychiatric symptomatology, suggesting continuous dynamic glucocorticoid equilibrium is essential for brain homeostasis. METHODS/DESIGN: The study consists of two parts. The preliminary stage of the study aims to validate (technically and pharmacologically) and optimise three different patterns of systemic cortisol administration in man. These patterns are based on the combinatory administration of metyrapone, to suppress endogenous cortisol production, and concurrent hydrocortisone replacement. The second, subsequent, core part of the study is a randomised, double-blinded, placebo-controlled, crossover study, where participants (healthy male individuals aged 18–60 years) will undergo all three hydrocortisone replacement schemes. During these infusion regimes, we plan a number of neurobehavioural tests and imaging of the brain to assess neural processing, emotional reactivity and perception, mood and self-perceived well-being. The psychological tests include: ecological momentary assessment, P1vital Oxford Emotional Test Battery and Emotional Potentiated Startle Test, Leeds Sleep Evaluation Questionnaire and the visual working memory task (n-back). The neuroimaging protocol combines magnetic resonance sequences that capture data related to the functional and perfusion status of the brain. DISCUSSION: Results of this clinical trial are designed to evaluate the impact (with possible mechanistic insights) of different patterns of daily glucocorticoid dynamics on neural processing and reactivity related to emotional perception and mood. This evidence should contribute to the optimisation of the clinical application of glucocorticoid-based therapeutics. TRIAL REGISTRATION: UK Clinical Research Network, IRAS Ref: 106181, UKCRN-ID-15236 (23 October 2013

Using observational data to estimate an upper bound on the reduction in cancer mortality due to periodic screening

BACKGROUND: Because randomized cancer screening trials are very expensive, observational cancer screening studies can play an important role in the early phases of screening evaluation. Periodic screening evaluation (PSE) is a methodology for estimating the reduction in population cancer mortality from data on subjects who receive regularly scheduled screens. Although PSE does not require assumptions about natural history of cancer it requires other assumptions, particularly progressive detection – the assumption that once a cancer is detected by a screening test, it will always be detected by the screening test. METHODS: We formulate a simple version of PSE and show that it leads to an upper bound on screening efficacy if the progressive detection assumption does not hold (and any effect of birth cohort is minimal) To determine if the upper bound is reasonable, for three randomized screening trials, we compared PSE estimates based only on screened subjects with PSE estimates based on all subjects. RESULTS: In the three randomized screening trials, PSE estimates based on screened subjects gave fairly close results to PSE estimates based on all subjects. CONCLUSION: PSE has promise for obtaining an upper bound on the reduction in population cancer mortality rates based on observational screening data. If the upper bound estimate is found to be small and any birth cohort effects are likely minimal, then a definitive randomized trial would not be warranted

Marburg Virus Infection Detected in a Common African Bat

Marburg and Ebola viruses can cause large hemorrhagic fever (HF) outbreaks with high case fatality (80–90%) in human and great apes. Identification of the natural reservoir of these viruses is one of the most important topics in this field and a fundamental key to understanding their natural history. Despite the discovery of this virus family almost 40 years ago, the search for the natural reservoir of these lethal pathogens remains an enigma despite numerous ecological studies. Here, we report the discovery of Marburg virus in a common species of fruit bat (Rousettus aegyptiacus) in Gabon as shown by finding virus-specific RNA and IgG antibody in individual bats. These Marburg virus positive bats represent the first naturally infected non-primate animals identified. Furthermore, this is the first report of Marburg virus being present in this area of Africa, thus extending the known range of the virus. These data imply that more areas are at risk for MHF outbreaks than previously realized and correspond well with a recently published report in which three species of fruit bats were demonstrated to be likely reservoirs for Ebola virus

The Elicitation and Management of Multiple Health Concerns in GP Consultations

OBJECTIVE: To describe the nature of patient concerns and to explore if, when and how they are addressed by GPs in the UK. // METHODS: Detailed coding and descriptive analysis of 185 video recordings from the EPaC study (Elicitation of Patient Concerns, EPaC) // RESULTS: An average of 2.1 concerns were raised per consultation and the most common concerns were musculoskeletal, administrative (e.g. test results and medication related issues), and skin symptoms. GPs who had been trained as part of the EPaC intervention to solicit for additional concerns in the opening phase of the consultation did so 92.6% of the time. In contrast, those in the control arm did so only 7% of the time. However, the particular formulation of the GP soliciting question does not seem to be associated with the likelihood of the patient volunteering an additional concern. // CONCLUSIONS: GP consultations are complex encounters in which multiple concerns are dealt with across a wide range of disease areas. GPs can be trained to solicit for problems/concerns early in the consultation. // PRACTICE IMPLICATIONS: Soliciting for additional concerns is not routinely done. But very brief training can substantially help in eliciting concerns early in the consultation, which may help with organising the consultation

Legal determinants of external finance revisited : the inverse relationship between investor protection and societal well-being

This paper investigates relationships between corporate governance traditions and quality of life as measured by a number of widely reported indicators. It provides an empirical analysis of indicators of societal health in developed economies using a classification based on legal traditions. Arguably the most widely cited work in the corporate governance literature has been the collection of papers by La Porta et al. which has shown, inter alia, statistically significant relationships between legal traditions and various proxies for investor protection. We show statistically significant relationships between legal traditions and various proxies for societal health. Our comparative evidence suggests that the interests of investors may not be congruent with the interests of wider society, and that the criteria for judging the effectiveness of approaches to corporate governance should not be restricted to financial metrics

The Elicitation and Management of Multiple Health Concerns in GP Consultations

Objective To describe the nature of patient concerns and to explore if, when and how they are addressed by GPs in the UK. Methods Detailed coding and descriptive analysis of 185 video recordings from the EPaC study (Elicitation of Patient Concerns, EPaC) Results An average of 2.1 concerns were raised per consultation and the most common concerns were musculoskeletal, administrative (e.g. test results and medication related issues), and skin symptoms. GPs who had been trained as part of the EPaC intervention to solicit for additional concerns in the opening phase of the consultation did so 92.6% of the time. In contrast, those in the control arm did so only 7% of the time. However, the particular formulation of the GP soliciting question does not seem to be associated with the likelihood of the patient volunteering an additional concern. Conclusions GP consultations are complex encounters in which multiple concerns are dealt with across a wide range of disease areas. GPs can be trained to solicit for problems/concerns early in the consultation. Practice Implications Soliciting for additional concerns is not routinely done. But very brief training can substantially help in eliciting concerns early in the consultation, which may help with organising the consultation

PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia

The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. Fully exploiting this finding will require unraveling the molecular genetics underlying phenotypic variability in mitochondrial priming. Here, we report that mitochondria) apoptosis resistance in T cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2). In T-ALL clinical specimens, loss-of-function mutations of PRC2 core components (EZH2, FED, or SUZ12) were associated with mitochondrial apoptosis resistance. In T-ALL cells, PRC2 depletion induced resistance to apoptosis induction by multiple chemotherapeutics with distinct mechanisms of action. PRC2 loss induced apoptosis resistance via transcriptional up-regulation of the LIM domain transcription factor CRIP2 and downstream up-regulation of the mitochondrial chaperone TRAP1. These findings demonstrate the importance of mitochondrial apoptotic priming as a prognostic factor in T-ALL and implicate mitochondrial chaperone function as a molecular determinant of chemotherapy response