A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models

Progressive kidney diseases are often associated with scarring of the kidney’s filtration unit, a condition called focal segmental glomerulosclerosis (FSGS). This scarring is due to loss of podocytes, cells critical for glomerular filtration, and leads to proteinuria and kidney failure. Inherited forms of FSGS are caused by Rac1-activating mutations, and Rac1 induces TRPC5 ion channel activity and cytoskeletal remodeling in podocytes. Whether TRPC5 activity mediates FSGS onset and progression is unknown. We identified a small molecule, AC1903, that specifically blocks TRPC5 channel activity in glomeruli of proteinuric rats. Chronic administration of AC1903 suppressed severe proteinuria and prevented podocyte loss in a transgenic rat model of FSGS. AC1903 also provided therapeutic benefit in a rat model of hypertensive proteinuric kidney disease. These data indicate that TRPC5 activity drives disease and that TRPC5 inhibitors may be valuable for the treatment of progressive kidney diseases.National Institutes of Health (U.S.) (Grant DK095045)National Institutes of Health (U.S.) (Grant DK099465)National Institutes of Health (U.S.) (Grant DK103658)National Institutes of Health (U.S.) (Grant DK083511)National Institutes of Health (U.S.) (Grant DK093746

Weak signal detection: A discrete window of opportunity for achieving ‘Vision 90:90:90’?

INTRODUCTION: UNAIDS’ Vision 90:90:90 is a call to ‘end AIDS’. Developing predictive foresight of the unpredictable changes that this journey will entail could contribute to the ambition of ‘ending AIDS’. There are few opportunities for managing unpredictable changes. We introduce ‘weak signal detection’ as a potential opportunity to fill this void. METHOD: Combining futures and complexity theory, we reflect on two pilot case studies that involved the Archetype Extraction technique and the SenseMakerw CollectorTM tool. RESULTS: Both the piloted techniques have the potentials to surface weak signals but there is room for improvement. DISCUSSION: A management response to a complex weak signal requires pattern management, rather than an exclusive focus on behaviour management. CONCLUSION: Weak signal detection is a window of opportunity to improve resilience to unpredictable changes in the HIV/AIDS landscape that can both reduce the risk that emerges from the changes and increase the visibility of opportunities to exploit the unpredictable changes that could contribute to ‘ending AIDS’.IS

Polymyalgia rheumatica and colon malignacy: case report

Polymyalgia rheumatica (PMR) is a relatively common disorder in the elderly. Whereas the relationship between polymyalgia rheumatica and giant cell arteritis (GCA) is well recognized, there is still controversy about PMR and malignancy. We are presenting a patient with PMR and adenocarcinoma of the sygmoid colon and hypothesize a paraneoplastic relationship

Influence des mécanismes de décomposition de la ferrite sur la résistance à la corrosion d’un acier inoxydable austéno ferritique vieilli

L’effet des modes de décomposition de la ferrite vieillie de la nuance d’acier inoxydable austéno-ferritique type X6 CrNiMoCu 25-6 sur la résistance à la corrosion par piqûres et intercristalline dans l’eau de mer synthétique, a été étudié par des essais électrochimiques de types potentiodynamiques cycliques, potentiocinétiques et DL-EPR (Double Loop Electrochemical Potentiokinetic Reactivation). Il a été établi que le mécanisme de décomposition spinodale gouvernant la démixtion de la ferrite (formation de phases α’ et G) au cours d’un vieillissement de 1000 h à 400 °C, engendre des fluctuations de teneur en chrome à très courtes distances (7 à 13 nm) qui n’affectent pas la résistance à la corrosion de l’acier étudié. Par contre, le vieillissement à 500 °C pendant 1000 h conduit à une décomposition de type eutectoïde de la ferrite en carbures (M23C6) et en phases intermétalliques (I, R, χ et η), par le mécanisme de germination et croissance, mettant en jeu des fluctuations de composition chimique plus importantes et à plus grandes distances, responsables d’un important affaiblissement de la résistance à la corrosion localisée de la nuance étudiée dans l’eau de mer synthétique