The perpetuation of inflammation is an important pathophysiological contributor to the global medical burden. Chronic inflammation is promoted by non-programmed cell death1,2; however, how inflammation is instigated, its cellular and molecular mediators, and its therapeutic value are poorly defined. Here we use mouse models of atherosclerosis—a major underlying cause of mortality worldwide—to demonstrate that extracellular histone H4-mediated membrane lysis of smooth muscle cells (SMCs) triggers arterial tissue damage and inflammation. We show that activated lesional SMCs attract neutrophils, triggering the ejection of neutrophil extracellular traps that contain nuclear proteins. Among them, histone H4 binds to and lyses SMCs, leading to the destabilization of plaques; conversely, the neutralization of histone H4 prevents cell death of SMCs and stabilizes atherosclerotic lesions. Our data identify a form of cell death found at the core of chronic vascular disease that is instigated by leukocytes and can be targeted therapeutically.
2328 -2336 DOI 10.1007 /s00125-009-1484 scores 28-30 ('normal', n=8,689), 24-27 ('mild dysfunction', n=2,231) and <24 ('severe dysfunction', n=212). Risks of major cardiovascular events, death and hypoglycaemia and interactions with treatment were assessed using Cox proportional hazards analysis. Results Relative to normal function, both mild and severe cognitive dysfunction significantly increased the multipleadjusted risks of major cardiovascular events (HR 1.27, 95% CI 1.11-1.46 and 1.42, 95% CI 1.01-1.99; both p< 0.05), cardiovascular death (1.41, 95% CI 1.16-1.71 and 1.56, 95% CI 0.99-2.46; both p≤0.05) and all-cause death (1.33, 95% CI 1.16-1.54 and 1.50, 95% CI 1
Background This study assessed the efficacy and safety of the once-daily glucagon-like peptide-1 receptor agonist, lixisenatide, in Asian patients with type 2 diabetes mellitus inadequately controlled on metformin ± sulfonylurea.
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