However, absolute cAMP levels measured by ELISA were not predictive of cAMP priming effects. Importantly, inhibition of de novo cAMP synthesis decreased the number of lung endothelial cells with activated caspase-1 during infection. Collectively, our data suggest lung endothelial cells rely on cAMP signaling to prime caspase-1 activation during P. aeruginosa infection.BACKGROUND D-dimer is elevated in a variety of conditions. The purpose of this study was to assess the positive predictive value of D-dimer to rule in patients with confirmed pulmonary embolism, deep vein thrombosis, acute aortic dissection or thrombosis of the upper extremity in comparison to patients with elevated D-dimer for other reasons. METHODS AND RESULTS We studied 1334 patients presenting to the emergency department with pulmonary embolism (n=193), deep vein thrombosis (n=73), acute aortic dissection (n=22), thrombosis of the upper extremity (n=8) and 1038 controls. The positive predictive value was increased with higher D-dimer concentrations improving the ability to identify diseases with high thrombus burden. Patients with venous thromboembolism, acute aortic dissection and thrombosis of the upper extremity showed a maximum positive predictive value of 85.2% at a D-dimer level of 7.8 mg/L (95% confidence interval (CI) 78.1 to 90.4). The maximum positive predictive value was lower in cancer patient/acute aortic dissection/thrombosis of the upper extremity from controls was significantly higher in cancer versus non-cancer patients (area under the curve 0.905 in cancer patients, 95% CI 0.89 to 0.92, vs. area under the curve 0.857 in non-cancer patients, 95% CI 0.84 to 0.88; P=0.0349). CONCLUSION D-dimers are useful not only to rule out but also to rule in venous thromboembolism and acute aortic dissection with an at least moderate discriminatory ability, both in patients with and without cancer.PDGF-A is a key contributor to lung development in mice. Its expression is needed for secondary septation of the alveoli and deletion of the gene leads to abnormally enlarged alveolar air spaces in mice. In humans, the same phenotype is the hallmark of bronchopulmonary dysplasia (BPD), a disease that affects premature babies and may have long lasting consequences in adulthood. So far, the knowledge regarding adult effects of developmental arrest in the lung is limited. This is attributable to few follow-up studies of BPD survivors and lack of good experimental models that could help predict the outcomes of this early age disease for the adult individual. In this study, we used the constitutive lung-specific Pdgfa deletion mouse model to analyze the consequences of developmental lung defects in adult mice. We assessed lung morphology, physiology, cellular content, ECM composition and proteomics data in mature mice, that perinatally exhibited lungs with a BPD-like morphology. Histological and physiological analyses both revealed that enlarged alveolar air spaces remained until adulthood, resulting in higher lung compliance and higher respiratory volume in knockout mice. Still, no or only small differences were seen in cellular, ECM and protein content when comparing knockout and control mice. Taken together, our results indicate that Pdgfa deletion-induced lung developmental arrest has consequences for the adult lung at the morphological and functional level. In addition, these mice can reach adulthood with a BPD-like phenotype, which makes them a robust model to further investigate the pathophysiological progression of the disease and test putative regenerative therapies.The prevalence of asthma symptoms in Canary Islanders, a southwestern European population from Spain, is almost three times higher than the country average. Because the genetic risks identified so far explain less than 5% of asthma heritability, here we aimed to discover new asthma loci by completing the first admixture mapping study in the Canary Islands leveraging their distinctive genetic makeup, where significant Northwest African influences co-exist in the European genetic diversity landscape. A two-stage study was conducted in 1,491 unrelated individuals self-declaring having a Canary Islands origin for the four grandparents. Local ancestry estimates were obtained for the shared positions with reference data from putative ancestral populations from Europe, North Africa and sub-Saharan Africa. Selleckchem Tacrolimus Case-control deviations in local ancestry were tested for each ancestry separately using logistic regressions adjusting for principal components, followed by fine mapping analyses based on imputed genotypes and of analyses of the likely deleterious exonic variants. The admixture mapping analysis of asthma detected that local North African ancestry in a locus spanning 365 kb of chromosome 16q23.3 associated with asthma risk at study-wide significance (lowest p=1.12x10-4; OR=2.05; 95%CI=1.41-3.00). Fine mapping studies identified a variant associated with asthma and results were replicated in independent samples (rs3852738, OR=1.34; 95%CI=1.13-1.59, p=7.58x10-4). Whole-exome sequencing data from a subset of individuals revealed an enrichment of likely deleterious variants among asthma cases in 16q23.3, particularly in the PLCG2 gene (p=3.67x10-4). By completing the first mapping study of asthma in admixed populations from Europe, our results revealed a new plausible asthma locus.OBJECTIVES To identify whether combination therapy with mucolytics and proton pump inhibitors (PPIs) leads to faster and more effective symptomatic relief in patients with laryngopharyngeal reflux (LPR). METHODS Patients diagnosed as LPR with a reflux symptom index (RSI) ≥ 13 and a reflux finding score (RFS) ≥ 7 were enrolled in this prospective study. Patients were randomly allocated to control (PPI only) or experimental (PPI + mucolytics) groups and changes in RSI and RFS values were assessed at 1- and 3-month follow-up. RESULTS One hundred sixteen patients were randomly allocated into either the control group (n = 59) or the experimental group (n = 57). The RSI and RFS scores significantly decreased in both groups (all P less then .001) after 1 month of treatment; however, there was no significant difference in RSI change between groups (P = .223). After 3 months of treatment, there remained no significant difference in RSI change between groups (P = .592). CONCLUSIONS Combination therapy with mucolytics and PPI compared to PPI alone did not lead to faster or more effective symptomatic relief in LPR patients.Selleckchem Tacrolimus
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