Pneumonia is an infection of the lower respiratory tract caused by microbial pathogens. Two such pathogens, Streptococcus pneumoniae and Staphylococcus aureus, are the most common causes of community-acquired and hospital-acquired pneumonia respectively. Each expresses strains highly resistant to penicillin and other antibiotics, and a significant number of people succumb to infection by these pathogens every year. Urinary metabolite changes in a C57Bl/6 mouse model with lung infection from either S. pneumoniae or S. aureus were characterized using multivariate targeted profiling data obtained from (1)H NMR spectra. Marked changes in the urinary metabolite profile occurred within 24 h after infection with either pathogen. Specifically, significant decreases in TCA cycle intermediates, coupled with increases in fucose, creatine, and taurine were observed in the urine of S. pneumoniae-treated mice. Infection with S. aureus resulted in the decrease of a number of urinary metabolites including 1-methylnicotinamide, 3-methyl-2-oxovalerate, 2-oxoisocaproate, N-isovaleroylglycine and others. Disturbances in gut-derived microbial metabolites were also observed. Analysis of metabolic trajectory data indicated that, as the mice recovered from infection, their urinary metabolic profile became similar to that of the preinfected state. These results underline the potential of metabolomics as a tool for diagnosis, health monitoring, and drug development, and show its usefulness for understanding microbial-host interactions.

BackgroundPulmonary fibrotic diseases induce significant morbidity and mortality, for which there are limited therapeutic options available. Rac2, a ras-related guanosine triphosphatase expressed mainly in hematopoietic cells, is a crucial molecule regulating a diversity of mast cell, macrophage, and neutrophil functions. All these cell types have been implicated in the development of pulmonary fibrosis in a variety of animal models. For the studies described here we hypothesized that Rac2 deficiency protects mice from bleomycin-induced pulmonary fibrosis.MethodsTo determine the role of Rac2 in pulmonary fibrosis we used a bleomycin-induced mouse model. Anesthetized C57BL/6 wild type and rac2 -/- mice were instilled intratracheally with bleomycin sulphate (1.25 U/Kg) or saline as control. Bronchoalveolar lavage (BAL) samples were collected at days 3 and 7 of treatment and analyzed for matrix metalloproteinases (MMPs). On day 21 after bleomycin treatment, we measured airway resistance and elastance in tracheotomized animals. Lung sections were stained for histological analysis, while homogenates were analyzed for hydroxyproline and total collagen content.ResultsBLM-treated rac2 -/- mice had reduced MMP-9 levels in the BAL on day 3 and reduced neutrophilia and TNF and CCL3/MIP-1α levels in the BAL on day 7 compared to BLM-treated WT mice. We also showed that rac2 -/- mice had significantly lower mortality (30%) than WT mice (70%) at day 21 of bleomycin treatment. Lung function was diminished in bleomycin-treated WT mice, while it was unaffected in bleomycin-treated rac2 -/- mice. Histological analysis of inflammation and fibrosis as well as collagen and hydroxyproline content in the lungs did not show significant differences between BLM-treated rac2 -/- and WT and mice that survived to day 21.ConclusionRac2 plays an important role in bleomycin-induced lung injury. It is an important signaling molecule leading to BLM-induced mortality and it also mediates the physiological changes seen in the airways after BLM-induced injury.

Résumé Objectives: We aimed to evaluate the effects of cannabis on workplace safety outcomes and road traffic collisions (using operation of a motor vehicle as a proxy for other safety-sensitive tasks) via a systematic literature review and meta-analysis. Methods: We searched MEDLINE and the reference lists of relevant articles. We extracted data on cannabis testing (requiring testing in a biological matrix for inclusion), characteristics of the participant groups, and measures of effect. Our main analysis included all eligible studies, a sensitivity analysis considered results from peer-reviewed publications only. Results: Of the 864 deduplicated hits identified by our search, 11 studies investigating road traffic collisions met our eligibility criteria and were included; there were no eligible studies on other workplace safety outcomes. We found that the presence of cannabis resulted in an increased risk estimate for road traffic collisions, with an odds ratio of 2.49 (95% confidence interval 1.68–3.71, P < 0.00001, n = 49,870). When considering peer-reviewed publications only, the odds ratio for road traffic collisions with cannabis was 2.84 (95% confidence interval 1.71–4.71, P < 0.0001, n = 38,947). Conclusions: Based on the risk increase for road traffic collisions seen in our analysis, the use of cannabis is deemed inadvisable for persons performing safety-sensitive work. Until definitive evidence on the duration of effect becomes available, we recommend restricting safety-sensitive duties for at least 24 hours after using cannabis, or for longer if there is concern about ongoing impairment. Objectifs: Nous avions pour objectif d’évaluer les effets du cannabis sur les résultats de sécurité sur les lieus de travail et sur les accidents de la route (utilisation d’un véhicule automobile comme substitut pour d’autres tâches liées à la sécurité) via une revue systématique de la littérature et une méta-analyse. Méthodes: Nous avons effectué une recherche dans MEDLINE et les listes de référence des articles pertinents. Nous avons recueilli des données sur les tests de cannabis (nécessitant des tests dans une matrice biologique pour inclusion), les caractéristiques des groupes de participants et l’évaluation de l’effet. Notre analyse principale incluait toutes les études éligibles, une analyse de discernement prenant en compte uniquement les résultats de publications revues par des pairs. Résultats: Sur les 864 réponses dédoublées identifiées par notre recherche, 11 études portant sur des collisions de la route satisfaisaient nos critères d’éligibilité et ont été incluses; il n’y a pas eu d’études admissibles sur d’autres résultats en matière de sécurité au travail. Nous avons constaté que la présence de cannabis augmentait l’estimation du risque de collision avec un ratio de probabilité (odds ratio OR) de 2,49 (intervalle de confiance à 95% (IC) de 1,68 à 3,71, p < 0,00001, n = 49870). En considérant uniquement les publications revues par les pairs, le OR pour les collisions incluant le cannabis sur la route était de 2,84 (IC 95%: 1,71 à 4,71, p < 0,0001, n = 38947). Conclusions: Sur la base de l’augmentation du risque de collision sur la route constaté dans notre analyse, l’usage du cannabis est jugé déconseillé aux personnes exécutant des travaux critiques pour la sécurité. En attendant que des preuves définitives de la durée de l’effet deviennent disponibles, nous recommandons de limiter les tâches liées à la sécurité pendant au moins 24 heures après avoir consommé du cannabis, ou plus longtemps s’il existe une préoccupation au sujet de l’incapacité.

BackgroundNeutrophils are abundant leukocytes that play a primary role in defence against pathogens. Neutrophils enter sites of infection where they eliminate pathogens via phagocytosis and the release of antimicrobial mediators via degranulation. Rho GTPases, particularly Rac2, play a key role in neutrophil degranulation. The purpose of this study was to identify Rac2-dependent changes in protein abundance in stimulated neutrophils.MethodsWe performed a proteomic analysis on secretagogue-stimulated bone marrow neutrophils that were isolated from wild-type and Rac2-/- mice. Protein abundance was analyzed by 2-dimensional SDS-PAGE of fluorescently labelled samples which allowed the detection ~3500 proteins.ResultsWe identified 22 proteins that showed significant changes in abundance after secretagogue-stimulation of wild-type neutrophils, which did not occur in neutrophils isolated from Rac2-/- mice. As expected, the abundance of several granule proteins was reduced in wild-type cells; this did not occur in Rac2-/- neutrophils which confirms the requirement for Rac2 in degranulation. We also found changes in abundance of many actin remodelling proteins including coronin-1A, β-actin and the F-actin capping protein, (CapZ-β). Coronin-1A showed elevated levels of several isoforms after stimulation of neutrophils from wild-type, but not from Rac2-/- mice. These isoforms were immunoreactive with anti-phospho-threonine antibodies, suggesting that neutrophil stimulation triggers a Rac2-dependent kinase cascade that results in the phosphorylation of coronin-1A.ConclusionThe control of Rac2-mediated degranulation in neutrophils likely functions through actin remodelling via activation of several actin-binding proteins. We found coronin-1A to be a novel downstream effector protein of this pathway that is threonine phosphorylated in response to secretagogue stimulation.

ARTICLE INFO ______________________________________________________________ ______________________ Main findings:We describe the use of a novel endoscopic approach in the management of unremitting gross hematuria following post-percutaneous nephrolithotomy (PCNL) in a 65-years-old male. This approach proved successful and cost-effective in managing haemorrhage post-PCNL when renal angiography failed to localize the source of bleeding.Case hypothesis: The recommended treatment modality for renal calculi ≥ 2cm is PCNL. It is essential that clinicians are aware of the various complications that can arise from PCNL, including arteriovenous fistula, which is typically managed with renal angio--embolization. The development of a renal arteriopelvic fistula (APF) is an extremely rare complication, and accounts of haemorrhage from renal APF and its treatment have not been well-described in the literature. We successfully hypothesized that the ureteroscopic localization, fulguration, and closure with a fibrin sealant at the site of the arterial bleed results in optimal treatment for this clinical presentation. We report this case in detail. Promising Future Implications: The successful and cost-effective endoscopic approach described here for treatment of post-PCNL renal APF and unremitting gross hematuria ought to be considered as an adjunct to renal angiography and embolization when the source of bleeding cannot be accurately identified using traditional imaging modalities.