Bactericidal peptidoglycan recognition protein induces oxidative stress in Escherichia coli through a block in respiratory chain and increase in central carbon catabolism.

Mammalian Peptidoglycan Recognition Proteins (PGRPs) kill both Gram-positive and Gram-negative bacteria through simultaneous induction of oxidative, thiol and metal stress responses in bacteria. However, metabolic pathways through which PGRPs induce these bactericidal stress responses are unknown. We screened Keio collection of Escherichia coli deletion mutants and revealed that deleting genes for respiratory chain flavoproteins or for tricarboxylic acid (TCA) cycle resulted in increased resistance of E. coli to PGRP killing. PGRP-induced killing depended on the production of hydrogen peroxide, which required increased supply of NADH for respiratory chain oxidoreductases from central carbon catabolism (glycolysis and TCA cycle), and was controlled by cAMP-Crp. Bactericidal PGRP induced a rapid decrease in respiration, which suggested that the main source of increased production of hydrogen peroxide was a block in respiratory chain and diversion of electrons from NADH oxidoreductases to oxygen. CpxRA two-component system was a negative regulator of PGRP-induced oxidative stress. By contrast, PGRP-induced thiol stress (depletion of thiols) and metal stress (increase in intracellular free Zn2+ through influx of extracellular Zn2+ ) were mostly independent of oxidative stress. Thus, manipulating pathways that induce oxidative, thiol and metal stress in bacteria could be a useful strategy to design new approaches to antibacterial therapy.

No Association of Proton Pump Inhibitor Use with Fasting or Postload Glycaemia in Patients with Cardiovascular Disease: A Cross-Sectional Retrospective Study.

Background: Proton pump inhibitor (PPI) use was reportedly associated with an excess of adverse cardiovascular (CV) events, thus making their systemic effects relevant to public health. PPIs reduce gastric acid secretion, causing increased gastrin release. Gastrin stimulates ß-cell neogenesis and enhances insulin release, exerting an incretin-like effect. Our aim was to assess, if PPI usage is associated with altered glycaemia in patients with CV disease. Methods: We retrospectively analyzed medical records of 102 subjects (80 with ischemic heart disease) who underwent a routine oral glucose tolerance test while hospitalized in a cardiology department. Fasting and 2-h postload glucose levels were compared according to PPI use for ≥1 month prior to admission. Results: Compared to 51 subjects without PPIs, those on a PPI were older, more frequently male, had a lower body-mass index and a tendency to a worse renal function. PPI users and non-users exhibited similar glucose levels at baseline (5.6 ± 0.9 vs. 5.5 ± 1.1 mmol/l, P = 0.5) and 2-hrs post glucose intake (9.8 ± 3.0 vs. 9.9 ± 3.4 mmol/l, P = 0.9). This was consistent across subgroups stratified by gender or diabetes status. The results were substantially unchanged after adjustment for different characteristics of subjects with and without PPIs. Conclusions: PPI use does not appear associated with altered glycaemia in subjects with CV disease. Unchanged glucose tolerance despite PPI usage may result from simultaneous activation of pathways that counteract the putative PPI-induced incretin-like effect.

Platypnea-Orthodeoxia Syndrome With Normal Right Heart Pressures in an Octogenarian.

We describe a case of platypnea-orthodeoxia syndrome in an 88-year-old man who presented with progressive dyspnea. Right-to-left shunting through a patent foramen ovale (PFO) was seen in the setting of normal right-sided heart pressures. He was successfully treated with percutaneous transcatheter PFO closure. (Level of Difficulty: Beginner.).

How does preclinical laboratory training impact physical examination skills during the first clinical year? A retrospective analysis of routinely collected objective structured clinical examination scores among the first two matriculating classes of a reformed curriculum in one Polish medical school.

OBJECTIVE: As a result of a curriculum reform launched in 2012 at our institution, preclinical training was shortened to 2 years instead of the traditional 3 years, creating additional incentives to optimise teaching methods. In accordance with the new curriculum, a semester-long preclinical module of clinical skills (CS) laboratory training takes place in the second year of study, while an introductory clinical course (ie, brief introductory clerkships) is scheduled for the Fall semester of the third year. Objective structured clinical examinations (OSCEs) are carried out at the conclusion of both the preclinical module and the introductory clinical course. Our aim was to compare the scores at physical examination stations between the first and second matriculating classes of a newly reformed curriculum on preclinical second-year OSCEs and early clinical third-year OSCEs. DESIGN: Analysis of routinely collected data. SETTING: One Polish medical school. PARTICIPANTS: Complete OSCE records for 462 second-year students and 445 third-year students. OUTCOME MEASURES: OSCE scores by matriculation year. RESULTS: In comparison to the first class of the newly reformed curriculum, significantly higher (ie, better) OSCE scores were observed for those students who matriculated in 2013, a year after implementing the reformed curriculum. This finding was consistent for both second-year and third-year cohorts. Additionally, the magnitude of the improvement in median third-year OSCE scores was proportional to the corresponding advancement in preceding second-year preclinical OSCE scores for each of two different sets of physical examination tasks. In contrast, no significant difference was noted between the academic years in the ability to interpret laboratory data or ECG - tasks which had not been included in the second-year preclinical training. CONCLUSION: Our results suggest the importance of preclinical training in a CS laboratory to improve students' competence in physical examination at the completion of introductory clinical clerkships during the first clinical year.