Tranilast increases vasodilator response to acetylcholine in rat mesenteric resistance arteries through increased EDHF participation

Background and Purpose: Tranilast, in addition to its capacity to inhibit mast cell degranulation, has other biological effects, including inhibition of reactive oxygen species, cytokines, leukotrienes and prostaglandin release. In the current study, we analyzed whether tranilast could alter endothelial function in rat mesenteric resistance arteries (MRA). Experimental Approach: Acetylcholine-induced relaxation was analyzed in MRA (untreated and 1-hour tranilast treatment) from 6 month-old Wistar rats. To assess the possible participation of endothelial nitric oxide or prostanoids, acetylcholineinduced relaxation was analyzed in the presence of L-NAME or indomethacin. The participation of endothelium-derived hyperpolarizing factor (EDHF) in acetylcholine-induced response was analyzed by preincubation with TRAM-34 plus apamin or by precontraction with a high K+ solution. Nitric oxide (NO) and superoxide anion levels were measured, as well as vasomotor responses to NO donor DEA-NO and to large conductance calcium-activated potassium channel opener NS1619. Key Results: Acetylcholine-induced relaxation was greater in tranilast-incubated MRA. Acetylcholine-induced vasodilation was decreased by L-NAME in a similar manner in both experimental groups. Indomethacin did not modify vasodilation. Preincubation with a high K+ solution or TRAM-34 plus apamin reduced the vasodilation to ACh more markedly in tranilastincubated segments. NO and superoxide anion production, and vasodilator responses to DEA-NO or NS1619 remained unmodified in the presence of tranilast. Conclusions and Implications: Tranilast increased the endothelium-dependent relaxation to acetylcholine in rat MRA. This effect is independent of the nitric oxide and cyclooxygenase pathways but involves EDHF, and is mediated by an increased role of small conductance calcium-activated K+ channelsThis study was supported by Ministerio de Ciencia e Innovación (SAF 2009-10374), Ministerio de Economía y Competitividad (SAF 2012-38530), and Fundación Mapfre. F.E. Xavier is recipient of research fellowship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brazil

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Respiratory Syncytial Virus Preterm (32-36 Completed Weeks Gestation) Risk Estimation Measure for RSV Hospitalization in Ireland : A Prospective Study

BACKGROUND: In several countries RSV prophylaxis is offered to late preterm infants who are at escalated risk of respiratory syncytial virus hospitalization (RSVH). However, targeted prophylaxis should be informed by country specific data. This study, which uniquely includes 36 weeks gestational age (GA) infants, aims to establish the risk factors for RSVH in 32-36 weeks GA infants in Ireland. METHODS: A 13 hospital prospective observational study of laboratory confirmed RSVH in non-prophylaxed 32-36 weeks GA infants was conducted from July 2011- February 2014. Baseline and first year clinical data were analyzed using IBM SPSSV22. Significant (P<0.05) variables were entered into multiple logistic regression to determine independent risk factors for RSVH. RESULTS: Sixty-three percent of eligible infants (1,825/2,877) were recruited. The RSVH rate was 3.6 % (65/1807 analyzed infant records).There was no RSV attributable mortality. Twelve infants required intensive care. Of fifteen variables correlating to RSVH, five independent risk factors were identified: older siblings (OR 3.8; 95% CI 1.97, 7.41), being Caucasian (OR 2.3; 95% CI; 1.04, 5.29), neonatal respiratory morbidity (OR 2.2; 95% CI; 1.28, 3.94); birth 15 July-Dec15th (OR 2.1; 95% CI; 1.09, 3.92) and family history of asthma (OR 1.9; 95% CI; 1.01, 3.39). Birth 36 weeks to 36+6 days mitigated RSVH risk (RR 0.58; 95% CI; 0.34, 0.99), however risk factors were similar to the 32-35 weeks GA cohort. CONCLUSIONS: Neonatal respiratory morbidity or being Caucasian were population specific independent risk factors for RSVH in 32-36 weeks GA in Ireland whereas the other identified independent risk factors mirrored those established in previous studies

Respiratory Syncytial Virus Preterm (32-36 Completed Weeks Gestation) Risk Estimation Measure for RSV Hospitalization in Ireland : A Prospective Study

BACKGROUND: In several countries RSV prophylaxis is offered to late preterm infants who are at escalated risk of respiratory syncytial virus hospitalization (RSVH). However, targeted prophylaxis should be informed by country specific data. This study, which uniquely includes 36 weeks gestational age (GA) infants, aims to establish the risk factors for RSVH in 32-36 weeks GA infants in Ireland. METHODS: A 13 hospital prospective observational study of laboratory confirmed RSVH in non-prophylaxed 32-36 weeks GA infants was conducted from July 2011- February 2014. Baseline and first year clinical data were analyzed using IBM SPSSV22. Significant (P<0.05) variables were entered into multiple logistic regression to determine independent risk factors for RSVH. RESULTS: Sixty-three percent of eligible infants (1,825/2,877) were recruited. The RSVH rate was 3.6 % (65/1807 analyzed infant records).There was no RSV attributable mortality. Twelve infants required intensive care. Of fifteen variables correlating to RSVH, five independent risk factors were identified: older siblings (OR 3.8; 95% CI 1.97, 7.41), being Caucasian (OR 2.3; 95% CI; 1.04, 5.29), neonatal respiratory morbidity (OR 2.2; 95% CI; 1.28, 3.94); birth 15 July-Dec15th (OR 2.1; 95% CI; 1.09, 3.92) and family history of asthma (OR 1.9; 95% CI; 1.01, 3.39). Birth 36 weeks to 36+6 days mitigated RSVH risk (RR 0.58; 95% CI; 0.34, 0.99), however risk factors were similar to the 32-35 weeks GA cohort. CONCLUSIONS: Neonatal respiratory morbidity or being Caucasian were population specific independent risk factors for RSVH in 32-36 weeks GA in Ireland whereas the other identified independent risk factors mirrored those established in previous studies

Two Zinc Uptake Systems Contribute to the Full Virulence of Listeria monocytogenes during Growth In Vitro and In Vivo

We report here the identification and characterization of two zinc uptake systems, ZurAM and ZinABC, in the intracellular pathogen Listeria monocytogenes. Transcription of both operons was zinc responsive and regulated by the zinc-sensing repressor Zur. Deletion of either zurAM or zinA had no detectable effect on growth in defined media, but a double zurAM zinA mutant was unable to grow in the absence of zinc supplementation. Deletion of zinA had no detectable effect on intracellular growth in HeLa epithelial cells. In contrast, growth of the zurAM mutant was significantly impaired in these cells, indicating the importance of the ZurAM system during intracellular growth. Notably, the deletion of both zinA and zurAM severely attenuated intracellular growth, with the double mutant being defective in actin-based motility and unable to spread from cell to cell. Deletion of either zurAM or zinA had a significant effect on virulence in an oral mouse model, indicating that both zinc uptake systems are important in vivo and establishing the importance of zinc acquisition during infection by L. monocytogenes. The presence of two zinc uptake systems may offer a mechanism by which L. monocytogenes can respond to zinc deficiency within a variety of environments and during different stages of infection, with each system making distinct contributions under different stress conditions