Molecular and functional mapping of the neuroendocrine hypothalamus: a new era begins.

BACKGROUND: Recent advances in neuroscience tools for single-cell molecular profiling of brain neurons have revealed an enormous spectrum of neuronal subpopulations within the neuroendocrine hypothalamus, highlighting the remarkable molecular and cellular heterogeneity of this brain area. RATIONALE: Neuronal diversity in the hypothalamus reflects the high functional plasticity of this brain area, where multiple neuronal populations flexibly integrate a variety of physiological outputs, including energy balance, stress and fertility, through crosstalk mechanisms with peripheral hormones. Intrinsic functional heterogeneity is also observed within classically 'defined' subpopulations of neuroendocrine neurons, including subtypes with distinct neurochemical signatures, spatial organisation and responsiveness to hormonal cues. AIM: The aim of this review is to critically evaluate past and current research on the functional diversity of hypothalamic neuroendocrine neurons and their plasticity. It focuses on how this neuronal plasticity in this brain area relates to metabolic control, feeding regulation and interactions with stress and fertility-related neural circuits. CONCLUSION: Our analysis provides an original framework for improving our understanding of the hypothalamic regulation of hormone function and the development of neuroendocrine diseases.

Suicide prevention during COVID-19: identification of groups with reduced presentations to emergency departments.

OBJECTIVE: Reductions in suicidal and self-harm presentations to emergency departments (EDs) since COVID-19 indicate changes in help-seeking behaviours, but it is unknown if hospital avoidance equally affects all population groups. METHOD: Socio-demographic and clinical information relating to suicidal and self-harm presentations to EDs in Queensland, Australia, were compared for the period before (March-August 2019) and since the COVID-19 outbreak (March-August 2020). RESULTS: Since COVID, Indigenous Australians and persons with less severe suicidal and self-harm presentations had significantly reduced presentations, while persons younger than 18 years had more presentations. Less suicidal presentations resulted in an admission to inpatient care. CONCLUSIONS: Patterns of reduced attendance to ED in some groups suggest the need for innovative and community-based models of care to help prevent suicides during the pandemic.

Implementing a systems approach to suicide prevention in a mental health service using the Zero Suicide Framework.

OBJECTIVE: The Zero Suicide Framework, a systems approach to suicide prevention within a health service, is being implemented across a number of states in Australia, and internationally, although there is limited published evidence for its effectiveness. This paper aims to provide a description of the implementation process within a large health service in Australia and describes some of the outcomes to date and learnings from this process. METHOD: Gold Coast Mental Health and Specialist Services has undertaken an implementation of the Zero Suicide Framework commencing in late 2015, aiming for high fidelity to the seven key elements. This paper describes the practical steps undertaken by the service, the new practices embedded, emphasis on supporting staff following the principles of restorative just culture and the development of an evaluation framework to support a continuous quality improvement approach. RESULTS: Improvements have been demonstrated in terms of processes implementation, enhanced staff skills and confidence, positive cultural change and innovations in areas such as the use of machine learning for identification of suicide presentations. A change to 'business as usual' has benefited thousands of consumers since the implementation of a Suicide Prevention Pathway in late 2016 and achieved reductions in rates of repeated suicide attempts and deaths by suicide in Gold Coast Mental Health and Specialist Services consumers. CONCLUSION: An all-of-service, systems approach to suicide prevention with a strong focus on cultural shifts and aspirational goals can be successfully implemented within a mental health service with only modest additional resources when supported by engaged leadership across the organisation. A continuous quality improvement approach is vital in the relentless pursuit of zero suicides in healthcare.

Inconvenient truths in suicide prevention: Why a Restorative Just Culture should be implemented alongside a Zero Suicide Framework.

OBJECTIVE: The prevailing paradigm in suicide prevention continues to contribute to the nihilism regarding the ability to prevent suicides in healthcare settings and a sense of blame following adverse incidents. In this paper, these issues are discussed through the lens of clinicians' experiences as second victims following a loss of a consumer to suicide, and the lens of health care organisations. METHOD: We discuss challenges related to the fallacy of risk prediction (erroneous belief that risk screening can be used to predict risk or allocate resources), and incident reviews that maintain a retrospective linear focus on errors and are highly influenced by hindsight and outcome biases. RESULTS: An argument that a Restorative Just Culture should be implemented alongside a Zero Suicide Framework is developed. CONCLUSIONS: The current use of algorithms to determine culpability following adverse incidents, and a linear approach to learning ignores the complexity of the healthcare settings and can have devastating effects on staff and the broader healthcare community. These issues represent 'inconvenient truths' that must be identified, reconciled and integrated into our future pathways towards reducing suicides in health care. The introduction of Zero Suicide Framework can support the much-needed transition from relying on a retrospective focus on errors (Safety I) to a more prospective focus which acknowledges the complexities of healthcare (Safety II), when based on the Restorative Just Culture principles. Restorative Just Culture replaces backward-looking accountability with a focus on the hurts, needs and obligations of all who are affected by the event. In this paper, we argue that the implementation of Zero Suicide Framework may be compromised if not supported by a substantial workplace cultural change. The process of responding to critical incidents implemented at the Gold Coast Mental Health and Specialist Services is provided as an example of a successful implementation of Restorative Just Culture-based principles that has achieved a culture change required to support learning, improving and healing for our consumers, their families, our staff and broader communities.

Trends and repetition of non-fatal suicidal behaviour: analyses of the Gold Coast University Hospital's Emergency Department.

Objective The aim of the current paper is to analyse time trends of non-fatal suicidal behaviour (NFSB) and its repetition at the Gold Coast in 2005-2015. Methods Data on presentations for NFSB were obtained from the Emergency Department (ED) Information System. Potential cases were identified through keyword searches, which were further scrutinised and coded. Annual person-based age-standardised rates for NFSB were calculated. Chi-square test, Poisson regression and Cox proportional hazards regression were used. RESULTS: There was a significant increase in the age-standardised rates of NFSB for males (incidence Rate Ratio = 1.05; 95% confidence interval (CI): 1.04-1.07) and females (iRR = 1.06; 95% CI: 1.04-1.07). Age-specific rates showed significant increases for all age groups, except 25-34 and 55+ for females. Different types of poisoning were the predominant method of NFSB (poisoning only - 61.7% of episodes), followed by cutting (23%). Within the first year after the index episode, 13.4% of subjects repeated NFSB. Multivariate Cox regression model showed that sex, age and method predicted repetition. CONCLUSION: The increasing trends of NFSB and relatively high repetition rates emphasise the need for preventative actions. Monitoring of NFSB at the ED level should be further extended in Australia.

The diversity of zinc-finger genes on human chromosome 19 provides an evolutionary mechanism for defense against inherited endogenous retroviruses.

Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections of the germ line that can remain capable of replication within the host genome. In the soma, DNA methylation and repressive chromatin keep the majority of this parasitic DNA transcriptionally silent. However, it is unclear how the host organism adapts to recognize and silence novel invading retroviruses that enter the germ line. Krueppel-Associated Box (KRAB)-associated protein 1 (KAP1) is a transcriptional regulatory factor that drives the epigenetic repression of many different loci in mammalian genomes. Here, we use published experimental data to provide evidence that human KAP1 is recruited to endogenous retroviral DNA by KRAB-containing zinc-finger transcription factors (TFs). Many of these zinc-finger genes exist in clusters associated with human chromosome 19. We demonstrate that these clusters are located at hotspots for copy number variation (CNV), generating a large and continuing diversity of zinc-finger TFs with new generations. These zinc-finger genes possess a wide variety of DNA binding affinities, but their role as transcriptional repressors is conserved. We also perform a computational study of the different ERVs that invaded the human genome during primate evolution. We find candidate zinc-finger repressors that arise in the genome for each ERV family that enters the genomes of primates. In particular, we show that those repressors that gained their binding affinity to retrovirus sequences at the same time as their targets invaded the human lineage are preferentially located on chromosome 19 (P-value: 3 × 10(-3)).

Las aguas y sedimentos del río tunecino Hamdoun presentan riesgo de disrupción endocrina / Water and sediment waste rejected in Hamdoun’sriver are major endocrine disrupting system

Diversos estudios recientes sostienen que muchos productos químicos antropogénicos, presentes en el medio ambiente, imitan la acción de hormonas endógenas. Estos disruptores endocrinos pueden originar múltiples efectos adversos en la fauna, como la feminización de peces, la pérdida de capacidad reproductiva, defectos congénitos y, a veces, pueden estar en el origen de algunos tipos de cáncer en el ser humano. La aparición de intersexos en peces de varios ríos europeos se ha atribuido a la exposición a sustancias químicas estrogénicas presentes en los efluentes de estaciones de tratamiento de aguas residuales. Para profundizar en el efecto ambiental de estos contaminantes, hemos investigado la actividad estrogénica, de receptor de hidrocarburo arílico y de receptor X de pregnano, de muestras de agua y sedimentos del río Hamdoun, tomadas aguas arriba y aguas abajo de la zona de vertidos procedentes del área industrial de la región central de Túnez. Mediante un ensayo in vitro de células cancerosas bioluminiscentes que expresan el gen de la luciferasa bajo el control de ciertos elementos con acción hormonal, hemos detectado escasa actividad estrogénica en agua y sedimentos por encima de la zona de vertidos; sin embargo, encontram os fuerte actividad es trogénica, de receptor de hidrocarburo arílico y de receptor X de pregnano en agua y s edimentos río abajo. Con experimentos de com petición demostramos que, predominantemente, las muestras de agua y de sedimentos con actividad estrogénica contienen compuestos con alta y baja afinidad con el ER " recombinante, respectivamente. Estos resultados indican que el agua del río y los sedimentos constituyen un importante sumidero y pueden ser fuente potencial de contaminantes disruptores endocrinos(AU)

In recent years, many studies supported that anthropogenic chemicals occurring in the environment have been shown to mimic the action of endogenous hormones. These endocrine-disrupting chemicals can potentially lead to a host of adverse effects on wildlife, such as the feminization of fish, the lack of reproduction success, birth defects and sometimes they can be the origin of some kind of cancers in human. The occurrence of intersex fish in a number of European rivers has been attributed to the exposure to estrogenic chemicals present in sewage treatment work effluents. To further understand the environmental effect of these contaminants, the estrogenic, aryl hydrocarbon receptor and pregnane X receptor activities of water and sediments were investigated in this study. The water and sediment samples were obtained from upstream and downstream outfalls of the Hamdoun River located in proximity of the industrial area in the centre region of Tunisia. Using an in vitro assay with bioluminescent cancer cells expressing luciferase gene under different hormonal responsive element control, we detected a much lower level of estrogenic activity in water and sediment upstream, however, we found out a strong estrogenic, aryl hydrocarbon receptor and pregnane X receptor activities in water and sediment downstream this river. By using competition experiments, we demonstrated that estrogenic activity found contained mainly compounds with a strong and lower affinitiy in water and sediment respectively with the recombinant ER ". These results suggest that the river water and sediments are a major sink and could be a potential source of endocrine-disrupting chemicals contaminants(AU)

[An epidemiological model of genital herpes for assessment of potential impact of therapy and prophylaxis: application to France]. / Un modèle épidémiologique de l'herpès génital pour l'évaluation des interventions thérapeutiques et prophylactiques.

OBJECTIVES: This study was performed to quantify the development of the number of cases of genital herpes and to assess the impact of different treatment strategies in France. METHOD: A model for the natural history of herpes simplex virus genital infection is presented and applied to the French population. The model encompasses infection by herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2), first episodes, recurrences, viral shedding and the effect of treatment on infected individuals. RESULTS: In the Year 2000, 270,000 individuals would have suffered from genital herpes in France. A total annual cumulated number of 1.5 million episodes of recurrence and 23 million days of viral shedding were estimated. Seventy percent of viral shedding occurred in sub-clinical seropositive individuals. The expected number of attributable neonatal deaths remained very low. Systematic treatment of clinical episodes might reduce the number of days with lesions (- 27 p. 100), and is also effective on viral shedding (symptomatic: - 50 p. 100). Continuous treatment of the most severe patients (>or=6 recurrences per Year) might reduce viral shedding slightly more (- 85 p. 100). Antiviral treatment might have a major impact on the quality of life of these patients but would only slightly curb the number of new infections. DISCUSSION: This model tries to integrate the various data currently available at international level on the epidemiology of genital herpes. However, many aspects are still not well documented and remain uncertain. It is therefore necessary to define various assumptions in order to simulate the natural history of the disease in a population. The lack of French data especially on the HSV-1 and HSV-2 seroprevalence profiles reinforces these uncertainties. Our results should hence be considered as exploratory. However, this modeling approach is the only possible way to integrate the multiple parameters describing the pathology and predicting of the public health impact of different interventions. This model is an open tool which may be modified when new data become available.

Estrogenic activity in water and sediments of a French river: contribution of alkylphenols.

Alkylphenols, known to possess estrogenic activity, have been found in the aquatic environment. In this study, we focused on the contribution of alkylphenols to total estrogenic activity in sediment and water extracts of French rivers. Four sites representing rural, agricultural, urban, and industrial watersheds were studied. The concentrations of alkylphenols in water and sediment were quantified by GC/MS. Estrogen-responsive reporter cell lines (MELN) have been used for investigating estrogenic activity at these sites. These observed activities were compared with activities mediated by known concentrations of alkylphenols. In water, the concentration of alkylphenols, from 0.06 to 0.550 microg x L(-1) and from < 0.001 microg x L(-1) to 0.077 microg x L(-1) for nonylphenols and 4t-octylphenol, respectively, were too low to contribute to the observed estrogenic activity. In sediment of the industrial, rural, and urban sites, the observed estrogenic activities could be explained in great part by the alkylphenol concentrations from 0.26 to 2.87 microg x g(-1) and from 0.005 microg x g(-1) to 0.49 microg x g(-1) for nonylphenols and 4t-octylphenol, respectively. In the agricultural site, the alkylphenols (0.022 microg x g(-1) of nonylphenols) poorly contribute to the observed estrogenic activity. Other compounds, such as natural and synthetic hormones, present in water and sediments could act additively in the overall activity.