Home noninvasive ventilatory support for patients with chronic obstructive pulmonary disease:patient selection and perspectives

Long-term or home mechanical noninvasive ventilation (Home-NIV) has become a well-established form of therapy over the last few decades for chronic hypercapnic COPD patients in European countries. However, meta-analyses and clinical guidelines do not recommend Home-NIV for COPD patients on a routine basis. In particular, there is ongoing debate about Home-NIV in chronic hypercapnic COPD regarding the overall effects, the most favorable treatment strategy, the selection of eligible patients, and the time point at which it is prescribed. The current review focuses on specific aspects of patient selection and discusses the various scientific as well as clinical-guided perspectives on Home-NIV in patients suffering from chronic hypercapnic COPD. In addition, special attention will be given to the topic of ventilator settings and interfaces

Change of Hemoglobin Levels in the Early Post-cardiac Arrest Phase Is Associated With Outcome

Background: The post-cardiac arrest (CA) phase is characterized by high fluid requirements, endothelial activation and increased vascular permeability. Erythrocytes are large cells and may not leave circulation despite massive capillary leak. We hypothesized that dynamic changes in hemoglobin concentrations may reflect the degree of vascular permeability and may be associated with neurologic function after CA.Methods: We included patients ≥18 years, who suffered a non-traumatic CA between 2013 and 2018 from the prospective Vienna Clinical Cardiac Arrest Registry. Patients without return of spontaneous circulation (ROSC), with extracorporeal life support, with any form of bleeding, undergoing surgery, receiving transfusions, without targeted temperature management or with incomplete datasets for multivariable analysis were excluded. The primary outcome was neurologic function at day 30 assessed by the Cerebral Performance Category scale. Differences of hemoglobin concentrations at admission and 12 h after ROSC were calculated and associations with neurologic function were investigated by uni- and multivariable logistic regression.Results: Two hundred and seventy-five patients were eligible for analysis of which 143 (52%) had poor neurologic function. For every g/dl increase in hemoglobin from admission to 12 h the odds of poor neurologic function increased by 26% (crude OR 1.26, 1.07–1.49, p = 0.006). The effect remained unchanged after adjustment for fluid balance and traditional prognostication markers (adjusted OR 1.27, 1.05–1.54, p = 0.014).Conclusion: Increasing hemoglobin levels in spite of a positive fluid balance may serve as a surrogate parameter of vascular permeability and are associated with poor neurologic function in the early post-cardiac arrest period

Towards a new tuberculosis drug: pyridomycin - nature's isoniazid

Tuberculosis, a global threat to public health, is becoming untreatable due to widespread drug resistance to frontline drugs such as the InhA-inhibitor isoniazid. Historically, by inhibiting highly vulnerable targets, natural products have been an important source of antibiotics including potent anti-tuberculosis agents. Here, we describe pyridomycin, a compound produced by Dactylosporangium fulvum with specific cidal activity against mycobacteria. By selecting pyridomycin-resistant mutants of Mycobacterium tuberculosis, whole-genome sequencing and genetic validation, we identified the NADH-dependent enoyl(Acyl-Carrier-Protein) reductase InhA as the principal target and demonstrate that pyridomycin inhibits mycolic acid synthesis in M. tuberculosis. Furthermore, biochemical and structural studies show that pyridomycin inhibits InhA directly as a competitive inhibitor of the NADH-binding site, thereby identifying a new, druggable pocket in InhA. Importantly, the most frequently encountered isoniazid-resistant clinical isolates remain fully susceptible to pyridomycin, thus opening new avenues for drug development

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Covalent attachment of proteins to peptidoglycan.

Bacterial surface proteins are key players in host-symbiont or host-pathogen interactions. How these proteins are targeted and displayed at the cell surface are challenging issues of both fundamental and clinical relevance. While surface proteins of Gram-negative bacteria are assembled in the outer membrane, Gram-positive bacteria predominantly utilize their thick cell wall as a platform to anchor their surface proteins. This surface display involves both covalent and noncovalent interactions with either the peptidoglycan or secondary wall polymers such as teichoic acid or lipoteichoic acid. This review focuses on the role of enzymes that covalently link surface proteins to the peptidoglycan, the well-known sortases in Gram-positive bacteria, and the recently characterized l,d-transpeptidases in Gram-negative bacteria

The Enterococcus hirae Mur-2 enzyme displays N-acetylglucosaminidase activity.

International audienceEnterococcus hirae produces two autolytic enzymes named Mur-1 and Mur-2, both previously described as N-acetylmuramidases. We used tandem mass spectrometry to show that Mur-2 in fact displays N-acetylglucosaminidase activity. This result reveals that Mur-2 and its counterparts studied to date, which are members of glycosyl hydrolase family 73 from the CAZy (Carbohydrate-Active enZyme) database, display the same catalytic activity