Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Cellular variability of RpoS expression underlies subpopulation activation of an integrative and conjugative element.

Conjugative transfer of the integrative and conjugative element ICEclc in the bacterium Pseudomonas knackmussii is the consequence of a bistable decision taken in some 3% of cells in a population during stationary phase. Here we study the possible control exerted by the stationary phase sigma factor RpoS on the bistability decision. The gene for RpoS in P. knackmussii B13 was characterized, and a loss-of-function mutant was produced and complemented. We found that, in absence of RpoS, ICEclc transfer rates and activation of two key ICEclc promoters (P(int) and P(inR)) decrease significantly in cells during stationary phase. Microarray and gene reporter analysis indicated that the most direct effect of RpoS is on P(inR), whereas one of the gene products from the P(inR)-controlled operon (InrR) transmits activation to P(int) and other ICEclc core genes. Addition of a second rpoS copy under control of its native promoter resulted in an increase of the proportion of cells expressing the P(int) and P(inR) promoters to 18%. Strains in which rpoS was replaced by an rpoS-mcherry fusion showed high mCherry fluorescence of individual cells that had activated P(int) and P(inR), whereas a double-copy rpoS-mcherry-containing strain displayed twice as much mCherry fluorescence. This suggested that high RpoS levels are a prerequisite for an individual cell to activate P(inR) and thus ICEclc transfer. Double promoter-reporter fusions confirmed that expression of P(inR) is dominated by extrinsic noise, such as being the result of cellular variability in RpoS. In contrast, expression from P(int) is dominated by intrinsic noise, indicating it is specific to the ICEclc transmission cascade. Our results demonstrate how stochastic noise levels of global transcription factors can be transduced to a precise signaling cascade in a subpopulation of cells leading to ICE activation

Mercúrio total em músculo de cação Prionace glauca (Linnaeus, 1758) e de espadarte Xiphias gladius Linnaeus, 1758, na costa sul-sudeste do Brasil e suas implicações para a saúde pública Total mercury in muscle of the shark Prionace glauca (Linnaeus, 1758) and swordfish Xiphias gladius Linnaeus, 1758, from the South-Southeast coast of Brazil and the implications for public health

Foram analisadas as concentrações de mercúrio total (THg) em tecido muscular do tubarão azul Prionace glauca e do teleósteo Xiphias gladius, vulgarmente conhecido como espadarte, provenientes das regiões sul e sudeste da costa brasileira, para verificar se estas se encontram dentro dos padrões legais para consumo humano. As amostras foram obtidas utilizando-se o programa REVIZEE, de agosto a setembro de 2001, e por intermédio de uma empresa de pesca em Itajaí, Santa Catarina. Foi analisado um total de 95 espécimes, testando-se as correlações entre THg, comprimento (cm) e peso (kg). As concentrações de mercúrio total em todas as amostras variaram de 0,13 a 2,26µgg-1 (peso úmido). A média de mercúrio total em P. glauca foi de 0,76 ± 0,48µgg-1 (p.u.), e em X. gladius foi de 0,62 ± 0,31µgg-1 (p.u.) com diferença não significativa (teste Mann-Whitney, p < 0,05). Em cerca de 16% das amostras, o THg excedeu o limite de 1µgg-1 (Agência Nacional de Vigilância Sanitária) e em 62% excedeu o limite de 0,5µgg-1 (Organização Mundial da Saúde - OMS). O consumo regular (100 g.dia-1) de P. glauca e de X. gladius resultaria em uma ingestão diária de THg que excederia em mais de duas vezes o limite diário de ingestão recomendado pela OMS.<br>Total mercury (THg) was analyzed in muscle tissue from the blue shark Prionace glauca and the swordfish Xiphias gladius, obtained from the South and Southeast coast of Brazil, to verify compliance with current limits for human consumption. Samples were obtained through the REVIZEE Program and a commercial fishery in Itajaí, Santa Catarina State. A total of 95 specimens were analyzed (48 X. gladius and 47 P. glauca), and correlations were checked between THg and fish length and weight. THg ranged from 0.13 to 2.26µgg-1 (fresh weight), and there was no significant difference between the means for P. glauca, 0.76 ± 0.48µgg-1 (f.w.) and X. gladius, 0.62 ± 0.31 (Mann-Whitney test, p < 0.05). In 16% of samples, THg was above the limits set by the National Health Surveillance Agency (ANVISA), namely 1µgg-1, and 62% exceeded the World Health Organization (WHO) limit of 0.5µgg-1. The ingestion of 100g/ day-1 of P. glauca or X. gladius would result in a daily THg intake of more than twice the WHO (1990) suggested limit