Direct visualization of the outer membrane of mycobacteria and corynebacteria in their native state.

The cell envelope of mycobacteria, which include the causative agents of tuberculosis and leprosy, is crucial for their success as pathogens. Despite a continued strong emphasis on identifying the multiple chemical components of this envelope, it has proven difficult to combine its components into a comprehensive structural model, primarily because the available ultrastructural data rely on conventional electron microscopy embedding and sectioning, which are known to induce artifacts. The existence of an outer membrane bilayer has long been postulated but has never been directly observed by electron microscopy of ultrathin sections. Here we have used cryo-electron microscopy of vitreous sections (CEMOVIS) to perform a detailed ultrastructural analysis of three species belonging to the Corynebacterineae suborder, namely, Mycobacterium bovis BCG, Mycobacterium smegmatis, and Corynebacterium glutamicum, in their native state. We provide new information that accurately describes the different layers of the mycobacterial cell envelope and challenges current models of the organization of its components. We show a direct visualization of an outer membrane, analogous to that found in gram-negative bacteria, in the three bacterial species examined. Furthermore, we demonstrate that mycolic acids, the hallmark of mycobacteria and related genera, are essential for the formation of this outer membrane. In addition, a granular layer and a low-density zone typifying the periplasmic space of gram-positive bacteria are apparent in CEMOVIS images of mycobacteria and corynebacteria. Based on our observations, a model of the organization of the lipids in the outer membrane is proposed. The architecture we describe should serve as a reference for future studies to relate the structure of the mycobacterial cell envelope to its function.

Biodegradable polymer sirolimus-eluting stents versus durable polymer everolimus-eluting stents for primary percutaneous coronary revascularisation of acute myocardial infarction.

AIMS Our aim was to compare the safety and efficacy of a novel, ultrathin strut, biodegradable polymer sirolimus-eluting stent (BP-SES) with a thin strut, durable polymer everolimus-eluting stent (DP-EES) in a pre-specified subgroup of patients with acute ST-segment elevation myocardial infarction (STEMI) enrolled in the BIOSCIENCE trial. METHODS AND RESULTS The BIOSCIENCE trial is an investigator-initiated, single-blind, multicentre, randomised non-inferiority trial (NCT01443104). Randomisation was stratified according to the presence or absence of STEMI. The primary endpoint, target lesion failure (TLF), is a composite of cardiac death, target vessel myocardial infarction, and clinically indicated target lesion revascularisation within 12 months. Between February 2012 and May 2013, 407 STEMI patients were randomly assigned to treatment with BP-SES or DP-EES. At one year, TLF occurred in seven (3.4%) patients treated with BP-SES and 17 (8.8%) patients treated with DP-EES (RR 0.38, 95% CI: 0.16-0.91, p=0.024). Rates of cardiac death were 1.5% in the BP-SES group and 4.7% in the DP-EES group (RR 0.31, 95% CI: 0.08-1.14, p=0.062); rates of target vessel myocardial infarction were 0.5% and 2.6% (RR 0.18, 95% CI: 0.02-1.57, p=0.082), respectively, and rates of clinically indicated target lesion revascularisation were 1.5% in the BP-SES group versus 2.1% in the DP-EES group (RR 0.69, 95% CI: 0.16-3.10, p=0.631). There was no difference in the risk of definite stent thrombosis. CONCLUSIONS In this pre-specified subgroup analysis, BP-SES was associated with a lower rate of target lesion failure at one year compared to DP-EES in STEMI patients. These findings require confirmation in a dedicated STEMI trial.

Efficacy and safety of a novel bioabsorbable polymer-coated, everolimus-eluting coronary stent: the EVOLVE II Randomized Trial.

BACKGROUND Drug eluting stents with durable polymers may be associated with hypersensitivity, delayed healing, and incomplete endothelialization, which may contribute to late/very late stent thrombosis and the need for prolonged dual antiplatelet therapy. Bioabsorbable polymers may facilitate stent healing, thus enhancing clinical safety. The SYNERGY stent is a thin-strut, platinum chromium metal alloy platform with an ultrathin bioabsorbable Poly(D,L-lactide-co-glycolide) abluminal everolimus-eluting polymer. We performed a multicenter, randomized controlled trial for regulatory approval to determine noninferiority of the SYNERGY stent to the durable polymer PROMUS Element Plus everolimus-eluting stent. METHODS AND RESULTS Patients (n=1684) scheduled to undergo percutaneous coronary intervention for non-ST-segment-elevation acute coronary syndrome or stable coronary artery disease were randomized to receive either the SYNERGY stent or the PROMUS Element Plus stent. The primary end point of 12-month target lesion failure was observed in 6.7% of SYNERGY and 6.5% PROMUS Element Plus treated subjects by intention-to-treat (P=0.83 for difference; P=0.0005 for noninferiority), and 6.4% in both the groups by per-protocol analysis (P=0.0003 for noninferiority). Clinically indicated revascularization of the target lesion or definite/probable stent thrombosis were observed in 2.6% versus 1.7% (P=0.21) and 0.4% versus 0.6% (P=0.50) of SYNERGY versus PROMUS Element Plus-treated subjects, respectively. CONCLUSIONS In this randomized trial, the SYNERGY bioabsorbable polymer everolimus-eluting stent was noninferior to the PROMUS Element Plus everolimus-eluting stent with respect to 1-year target lesion failure. These data support the relative safety and efficacy of SYNERGY in a broad range of patients undergoing percutaneous coronary intervention. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01665053.