Sirtuin inhibition induces apoptosis-like changes in platelets and thrombocytopenia

Sirtuins are evolutionarily conserved NAD+-dependent acetyl-lysine deacetylases that belong to class III type of histone deacetylases. In humans, seven sirtuin isoforms (Sirt1 to Sirt7) have been identified. Sirtinol, a cell permeable lactone ring derived from naphthol, is a dual Sirt1/Sirt2 inhibitor of low potency whereas EX-527 is a potent and selective Sirt1 inhibitor. Here we have demonstrated that Sirt1, Sirt2 and Sirt3 are expressed in enucleate platelets. Both sirtinol or EX-527 induced apoptosis-like changes in platelets as revealed from enhanced annexin V binding, ROS production and drop in mitochondrial transmembrane potential. Above changes were associated with increased phagocytic clearance of the platelets by macrophages. Expression of acetylated p53 and the conformationally active form of Bax were found to be significantly higher in both sirtinol- as well as EX-527-treated platelets, thus implicating p53-Bax axis in apoptosis induced by sirtuin inhibitors. Administration of either sirtinol or EX-527 in mice led to reduction in both platelet count and number of reticulated platelets. Our results, for the first time, implicate sirtuins as a central player in determination of platelet aging. Since sirtuin inhibitors are being evaluated for their anti-tumor activity, this study rekindles attention to potential side effect of sirtuin inhibition in delimiting platelet life span and management of thrombosis

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Testing export-led growth in India, Pakistan and Sri Lanka using a multivariate framework

Most time-series studies in the area of export-led growth adopt a bivariate framework and neglect the role of terms of trade. Because the terms of trade have an important bearing on export earnings and income, the underlying models of these studies may have been misspecified. This study is the first to adopt a multivariate framework for South Asia as a region; and by including the terms of trade as an additional variable it tries to correct the misspecification bias of earlier studies. The evidence suggests bidirectional causality between real exports and real income in India, export-led growth in Pakistan and a no-causality result for Sri Lanka