Osmoadaptive GLP-1R signalling in hypothalamic neurones inhibits antidiuretic hormone synthesis and release.

OBJECTIVES: The excessive release of the antidiuretic hormone vasopressin is implicated in many diseases including cardiovascular disease, diabetes, obesity, and metabolic syndrome. Once thought to be elevated as a consequence of diseases, data now supports a more causative role. We have previously identified CREB3L1 as a transcription factor that co-ordinates vasopressin synthesis and release in the hypothalamus. The objective here was to identify mechanisms orchestrated by CREB3L1 that co-ordinate vasopressin release. METHODS: We mined Creb3l1 knockdown SON RNA-seq data to identify downstream target genes. We proceeded to investigate the expression of these genes and associated pathways in the supraoptic nucleus of the hypothalamus in response to physiological and pharmacological stimulation. We used viruses to selectively knockdown gene expression in the supraoptic nucleus and assessed physiological and metabolic parameters. We adopted a phosphoproteomics strategy to investigate mechanisms that facilitate hormone release by the pituitary gland. RESULTS: We discovered glucagon like peptide 1 receptor (Glp1r) as a downstream target gene and found increased expression in stimulated vasopressin neurones. Selective knockdown of supraoptic nucleus Glp1rs resulted in decreased food intake and body weight. Treatment with GLP-1R agonist liraglutide decreased vasopressin synthesis and release. Quantitative phosphoproteomics of the pituitary neurointermediate lobe revealed that liraglutide initiates hyperphosphorylation of presynapse active zone proteins that control vasopressin exocytosis. CONCLUSION: In summary, we show that GLP-1R signalling inhibits the vasopressin system. Our data advises that hydration status may influence the pharmacodynamics of GLP-1R agonists so should be considered in current therapeutic strategies.

Illicit Drugs and Reversible Cerebral Vasoconstriction Syndrome.

Reversible cerebral vasoconstriction syndrome (RCVS) is a condition characterized by thunderclap headache and associated vasospasm of the cerebral vasculature. A multitude of factors are considered to potentially predispose to the development of RCVS. These potential precipitants include numerous illicit drugs. In this study, we investigated the role of illicit drugs as a precipitating factor for RCVS, through systematic review of the relevant literature. We found the strongest evidence for cannabis, but a relative lack of evidence to support other illicit drugs, particularly as individual precipitating factors. We also identified a lack of the consistent application of diagnostic criteria for RCVS, which undoubtedly hampers advancement of knowledge in this field. Consistent adherence to diagnostic criteria will be important for future studies. Ultimately, a prospective registry of RCVS cases would be advantageous to advance understanding of the condition and its underlying causes.

Environmental and genetic factors determine whether the mosquito Aedes aegypti lays eggs without a blood meal.

Some mosquito strains or species are able to lay eggs without taking a blood meal, a trait named autogeny. This may allow populations to persist through times or places where vertebrate hosts are scarce. Autogenous egg production is highly dependent on the environment in some species, but the ideal conditions for its expression in Aedes aegypti mosquitoes are unknown. We found that 3.2% of females in a population of Ae. aegypti from Kenya were autogenous. Autogeny was strongly influenced by temperature, with many more eggs laid at 28°C compared with 22°C. Good nutrition in larval stages and feeding on higher concentrations of sugar solution during the adult stage both result in more autogenous eggs being produced. The trait also has a genetic basis, as not all Ae. aegypti genotypes can lay autogenously. We conclude that Ae. aegypti requires a favorable environment and a suitable genotype to be able to lay eggs without a blood meal.

"Are you available for the next 18 months?" - methods and aims of a longitudinal birth cohort study investigating a universal developmental surveillance program: the 'Watch Me Grow' study.

BACKGROUND: Universal developmental surveillance programs aimed at early identification and targeted early intervention significantly improve short- and long-term outcomes in children at risk of developmental disorders. However, a significant challenge remains in providing sufficiently rigorous research and robust evidence to inform policy and service delivery. This paper describes the methods of the 'Watch Me Grow' study that aims to maximise accurate early detection of children with developmental disorders through a partnership formed between policy makers, service providers and researchers. METHODS/DESIGN: A mixed methods study design was developed consisting of: (1) a qualitative study of parents and health service providers to investigate barriers and enablers of developmental surveillance; (2) recruitment of a birth cohort and their longitudinal follow-up to 18 months of age to: a) assess risk factors for not accessing existing developmental surveillance programs and b) estimate the prevalence of children identified with developmental risk; (3) comparison of surveillance outcomes with a reference standard at 18 months of age to assess the diagnostic test accuracy of existing and alternative developmental surveillance tools; and (4) comparison of developmental surveillance models to inform policy recommendations. Data linkage will be used to determine the uptake and representativeness of the study participant group versus non-participants. DISCUSSION: The Watch Me Grow study is expected to provide a collaborative opportunity to enhance universal developmental surveillance for early accurate identification of developmental risk. This will also provide quality evidence about identification of developmental risk and access to services to be embedded in existing practice with linkages to policy development.

Da Comissão ao Conselho: a Organização das Nações Unidas conseguiu ou não criar um organismo de direitos humanos confiável? / De la Comisión al Consejo: ¿Las Naciones Unidas han logrado crear un órgano de derechos humanos confiable? / From Commission to Council: has the United Nations succeeded in creating a credible human rights body?

Em 2006 a Organização das Nações Unidas passou pela maior reforma desde sua fundação, em 1945, demonstrando um compromisso renovado com a proteção dos direitos humanos. A substituição da Comissão de Direitos Humanos pelo Conselho de Direitos Humanos representa a força ascendente do regime internacional de proteção dos direitos humanos. Entretanto, essa mudança não transcorreu sem críticas. Particularmente, alega-se que o Conselho é influenciado por diferentes inclinações políticas, em detrimento de sua efetividade: por exemplo, manter foco desproporcional nos territórios ocupados da Palestina enquanto falha em reagir com prontidão aos abusos cometidos em Darfur. Além disso, o Conselho é claramente desabonado por seu fracasso; tanto em implementar mecanismos eficazes de direitos humanos para impedir as ações de seus próprios membros - consistentes em transgressores de direitos humanos reconhecidos mundialmente - como pela contínua inabilidade em angariar apoio dos EUA. Esse artigo analisa essas críticas.

In 2006 the United Nations underwent its greatest reform since its foundation in 1945, showing a renewed commitment to human rights protection. The replacement of the Commission on Human Rights with the Human Rights Council signifies the growing strength of the international human rights regime. However, this change has not been without criticism. In particular it has been alleged that the Council suffers from various political biases to the detriment of its effectiveness: for example, disproportionately focusing on the Occupied Palestinian Territories while failing to swiftly respond to abuses in Darfur. Further, the Council is arguably undermined by both its failure to implement effective mechanisms to prevent its own membership consisting to include acknowledged human rights violator and its continuing inability to harness US support. This paper analyses such criticisms.

En 2006 la Organización de Naciones Unidas sufrió su mayor reforma desde su creación en 1945, mostrando un renovado compromiso de protección de los derechos humanos. La sustitución de la Comisión de Derechos Humanos por el Consejo de Derechos Humanos pone de manifiesto la gran fortaleza del derecho internacional de los derechos humanos. Sin embargo, este cambio no ha estado exento de críticas. En particular se ha sostenido que el Consejo adolece de diversos prejuicios políticos en detrimento de su eficacia: por ejemplo, concentrándose desproporcionadamente en los territorios palestinos ocupados mientras que no responde rápidamente a los abusos en Darfur. Además, el Consejo está, sin duda, debilitado tanto por su fracaso para aplicar mecanismos eficaces para evitar que sus propios miembros sean violadores de los derechos humanos como por su incapacidad para conseguir el apoyo de los Estados Unidos. Este artículo analiza las referidas críticas.

Double-blind, randomized, placebo-controlled trial of the use of topical 10% potassium hydroxide solution in the treatment of molluscum contagiosum.

Molluscum contagiosum is a common viral infection of the skin that frequently affects children. Lesions take between 6 and 18 months to resolve spontaneously and are a source of great embarrassment to both caretakers and children, often affecting attendance at school and limiting social activity. Treatment options to date have been poorly tolerated by children but recent studies have suggested that potassium hydroxide may be beneficial. This double-blind, randomized, placebo-controlled study compared 10% potassium hydroxide with placebo (normal saline). Twenty patients, aged 2 to 12 years, were recruited. Parents applied a solution twice daily to lesional skin until signs of inflammation appeared. Children were examined by the same observer on days 0, 15, 30, 60, and 90. Seventy percent of children receiving topical potassium hydroxide cleared, compared with 20% in the placebo group. Further dosing studies are required to identify whether weaker concentrations of potassium hydroxide are as efficacious, with less irritancy.