Autocatalytic self-propagation of misfolded prion protein

Prions are thought to replicate in an autocatalytic process that converts cellular prion protein (PrP(C)) to the disease-associated misfolded PrP isoform (PrP(Sc)). Our study scrutinizes this hypothesis by in vitro protein misfolding cyclic amplification (PMCA). In serial transmission PMCA experiments, PrP(Sc) was inoculated into healthy hamster brain homogenate containing PrP(C). Misfolded PrP was amplified by rounds of sonication and incubation and reinoculated into fresh brain homogenate every 10 PMCA rounds. The amplification depended on PrP(C) substrate and could be inhibited by recombinant hamster PrP. In serial dilution experiments, newly formed misfolded and proteinase K-resistant PrP (PrPres) catalyzed the structural conversion of PrP(C) as efficiently as PrP(Sc) from brain of scrapie (263K)-infected hamsters, yielding an ≈300-fold total amplification of PrPres after 100 rounds, which confirms an autocatalytic PrP-misfolding cascade as postulated by the prion hypothesis. PrPres formation was not paralleled by replication of biological infectivity, which appears to require factors additional to PrP-misfolding autocatalysis

Meta-Analysis of Efficacy and Safety of Proton Pump Inhibitors with Dual Antiplatelet Therapy for Coronary Artery Disease

Background: There is inconsistency in the literature regarding the clinical effects of proton pump inhibitors (PPI) when added to dual antiplatelet therapy (DAPT) in subjects with coronary artery disease (CAD). We performed meta-analysis stratified by study design to explore these differences. Methods and results: 39 studies [4 randomized controlled trials (RCTs) and 35 observational studies) were selected using MEDLINE, EMBASE and CENTRAL (Inception-January 2018). In 221,204 patients (PPI = 77,731 patients, no PPI =143,473 patients), RCTs restricted analysis showed that PPI did not increase the risk of all-cause mortality (Risk Ratio (RR): 1.35, 95% Confidence Interval (CI), 0.56–3.23, P = 0.50, I2 = 0), cardiovascular mortality (RR: 0.94, 95% CI, 0.25–3.54, P = 0.92, I2 = 56), myocardial infarction (MI) (RR: 0.97, 95% CI, 0.62–1.51, P = 0.88, I2 = 0) or stroke (RR: 1.11, 95% CI, 0.25–5.04, P = 0.89, I2 = 26). However, PPI significantly reduced the risk of gastrointestinal (GI) bleeding (RR: 0.32, 95% CI, 0.20–0.52, P \u3c 0.001, I2 = 0). Conversely, analysis of observational studies showed that PPI significantly increased the risk of all-cause mortality (RR: 1.25, 95% CI, 1.11–1.41, P \u3c 0.001, I2 = 82), cardiovascular mortality (RR: 1.25, 95% CI, 1.03–1.52, P = 0.02, I2 = 71), MI (RR: 1.30, 95% CI, 1.16–1.47, P \u3c 0.001, I2 = 82) and stroke (RR: 1.60, 95% CI, 1.43–1.78, P \u3c 0.001, I2 = 0), without reducing GI bleeding (RR: 0.74, 95% CI, 0.45–1.22, P = 0.24, I2 = 79). Conclusion: Meta-analysis of RCTs endorsed the use of PPI with DAPT for reducing GI bleeding without worsening cardiovascular outcomes. These findings oppose the negative observational data regarding effects of PPI with DAPT