Evidences of exopolysaccharide production by Helicobacter pylori submitted to hydrodynamic stress

Helicobacter pylori is a widespread Gram-negative bacterium that infects the stomach of humans leading to the onset of several gastric disorders, such as gastritis, gastric ulcers, and cancers. The transmission of H. pylori remains unclear but two different pathways have been suggested: faecal-oral and oraloral. It has been reported that H. pylori has the ability to incorporate in biofilms formed on water-exposed surfaces thus providing a route of infection. On the other hand, a polysaccharide-containing biofilm has been observed at the air-liquid interface when H. pylori is grown in a glass fermenter1. Because exopolysaccharides (EPS) play a determinant role in bacterial adhesion by conferring protection against adverse conditions such as starvation and environmental aggressions, EPS production would be expected to be higher if the bacterium is exposed to water. In this work the capability of H. pylori to produce EPS when exposed to water and under hydrodynamic stress has been evaluated. H. pylori was inoculated in autoclaved distilled water and allowed to stand under gentle stirring at room temperature. The significant and continuous increase in the sugar content 192 hours after inoculation suggests the production of exopolysaccharides. This evidence is reinforced by epiflourescence microscopical observation of the bacteria stained with DAPI (4,6-diamidino-2-phenylindole) that revealed the presence of bacterial aggregates 318 hours after inoculation

First-in-Human Phase I Study to Evaluate the Brain-Penetrant PI3K/mTOR Inhibitor GDC-0084 in Patients with Progressive or Recurrent High-Grade Glioma.

PurposeGDC-0084 is an oral, brain-penetrant small-molecule inhibitor of PI3K and mTOR. A first-in-human, phase I study was conducted in patients with recurrent high-grade glioma.Patients and methodsGDC-0084 was administered orally, once daily, to evaluate safety, pharmacokinetics (PK), and activity. Fluorodeoxyglucose-PET (FDG-PET) was performed to measure metabolic responses.ResultsForty-seven heavily pretreated patients enrolled in eight cohorts (2-65 mg). Dose-limiting toxicities included 1 case of grade 2 bradycardia and grade 3 myocardial ischemia (15 mg), grade 3 stomatitis (45 mg), and 2 cases of grade 3 mucosal inflammation (65 mg); the MTD was 45 mg/day. GDC-0084 demonstrated linear and dose-proportional PK, with a half-life (∼19 hours) supportive of once-daily dosing. At 45 mg/day, steady-state concentrations exceeded preclinical target concentrations producing antitumor activity in xenograft models. FDG-PET in 7 of 27 patients (26%) showed metabolic partial response. At doses ≥45 mg/day, a trend toward decreased median standardized uptake value in normal brain was observed, suggesting central nervous system penetration of drug. In two resection specimens, GDC-0084 was detected at similar levels in tumor and brain tissue, with a brain tissue/tumor-to-plasma ratio of >1 and >0.5 for total and free drug, respectively. Best overall response was stable disease in 19 patients (40%) and progressive disease in 26 patients (55%); 2 patients (4%) were nonevaluable.ConclusionsGDC-0084 demonstrated classic PI3K/mTOR-inhibitor related toxicities. FDG-PET and concentration data from brain tumor tissue suggest that GDC-0084 crossed the blood-brain barrier

Identification of cell-surface mannans in a virulent Helicobacter pylori strain

With the intent of contributing to a carbohydrate-based vaccine against the gastroduodenal pathogen, Helicobacter pylori, we report here the structure of cell-surface mannans obtained from a virulent strain. Unlike other wild-type strains, this strain was found to express in good quantities this polysaccharide in vitro. Structural analysis revealed a branched mannan formed by a backbone of α-(1→6)-linked mannopyranosyl residues with approximately 80% branching at the O-2 position. The branches were composed of O-2-linked Man residues in both α- and β-configurations: (image) In addition, this strain also expressed cell-surface emblematic H. pylori lipopolysaccharides (LPS) containing partially fucosylated polyLacNAc O-chains. Affinity assays with polymyxin-B and concanavalin A revealed no association between the mannan and the LPS. The described mannans may be implicated in the mediation of host–microbial interactions and immunological modulation.This work was supported by Fundacao para a Ciencia e Tecnologia (FCT) through project Pylori E&LPS POCI/QUI/56393/2004, PhD grant SFRH/BD/19929/2004, by the Natural Sciences and Engineering Research Council of Canada (NSERC), and by the European Network of Research Infrastructures within the 6th Framework Programme of the EC (Contract # RII3-026145, EU-NMR). The authors further thank Dr. Adrien Favier (RALF-NMR facility, Grenoble - France) for conducting NMR experiments

Characterization of Systemic Disease Development and Paw Inflammation in a Susceptible Mouse Model of Mayaro Virus Infection and Validation Using X-ray Synchrotron Microtomography

Mayaro virus (MAYV) is an emerging arthropod-borne virus endemic in Latin America and the causative agent of arthritogenic febrile disease. Mayaro fever is poorly understood; thus, we established an in vivo model of infection in susceptible type-I interferon receptor-deficient mice (IFNAR−/−) to characterize the disease. MAYV inoculations in the hind paws of IFNAR−/− mice result in visible paw inflammation, evolve into a disseminated infection and involve the activation of immune responses and inflammation. The histological analysis of inflamed paws indicated edema at the dermis and between muscle fibers and ligaments. Paw edema affected multiple tissues and was associated with MAYV replication, the local production of CXCL1 and the recruitment of granulocytes and mononuclear leukocytes to muscle. We developed a semi-automated X-ray microtomography method to visualize both soft tissue and bone, allowing for the quantification of MAYV-induced paw edema in 3D with a voxel size of 69 µm3. The results confirmed early edema onset and spreading through multiple tissues in inoculated paws. In conclusion, we detailed features of MAYV-induced systemic disease and the manifestation of paw edema in a mouse model extensively used to study infection with alphaviruses. The participation of lymphocytes and neutrophils and expression of CXCL1 are key features in both systemic and local manifestations of MAYV disease

Impact of Trauma System Structure on Injury Outcomes : A Systematic Review and Meta-Analysis

The effectiveness of trauma systems in decreasing injury mortality and morbidity has been well demonstrated. However, little is known about which components contribute to their effectiveness. We aimed to systematically review the evidence of the impact of trauma system components on clinically important injury outcomes. We searched MEDLINE, EMBASE, Cochrane CENTRAL, and BIOSIS/Web of Knowledge, gray literature and trauma association Web sites to identify studies evaluating the association between at least one trauma system component and injury outcome. We calculated pooled effect estimates using inverse-variance random-effects models. We evaluated quality of evidence using GRADE criteria. We screened 15,974 records, retaining 41 studies for qualitative synthesis and 19 for meta-analysis. Two recommended trauma system components were associated with reduced odds of mortality: inclusive design (odds ratio [OR] = 0.72 [0.65-0.80]) and helicopter transport (OR = 0.70 [0.55-0.88]). Pre-Hospital Advanced Trauma Life Support was associated with a significant reduction in hospital days (mean difference [MD] = 5.7 [4.4-7.0]) but a nonsignificant reduction in mortality (OR = 0.78 [0.44-1.39]). Population density of surgeons was associated with a nonsignificant decrease in mortality (MD = 0.58 [-0.22 to 1.39]). Trauma system maturity was associated with a significant reduction in mortality (OR = 0.76 [0.68-0.85]). Quality of evidence was low or very low for mortality and healthcare utilization. This review offers low-quality evidence for the effectiveness of an inclusive design and trauma system maturity and very-low-quality evidence for helicopter transport in reducing injury mortality. Further research should evaluate other recommended components of trauma systems and non-fatal outcomes and explore the impact of system component interactions.Peer reviewe

Impact of Trauma System Structure on Injury Outcomes : A Systematic Review and Meta-Analysis

The effectiveness of trauma systems in decreasing injury mortality and morbidity has been well demonstrated. However, little is known about which components contribute to their effectiveness. We aimed to systematically review the evidence of the impact of trauma system components on clinically important injury outcomes. We searched MEDLINE, EMBASE, Cochrane CENTRAL, and BIOSIS/Web of Knowledge, gray literature and trauma association Web sites to identify studies evaluating the association between at least one trauma system component and injury outcome. We calculated pooled effect estimates using inverse-variance random-effects models. We evaluated quality of evidence using GRADE criteria. We screened 15,974 records, retaining 41 studies for qualitative synthesis and 19 for meta-analysis. Two recommended trauma system components were associated with reduced odds of mortality: inclusive design (odds ratio [OR] = 0.72 [0.65-0.80]) and helicopter transport (OR = 0.70 [0.55-0.88]). Pre-Hospital Advanced Trauma Life Support was associated with a significant reduction in hospital days (mean difference [MD] = 5.7 [4.4-7.0]) but a nonsignificant reduction in mortality (OR = 0.78 [0.44-1.39]). Population density of surgeons was associated with a nonsignificant decrease in mortality (MD = 0.58 [-0.22 to 1.39]). Trauma system maturity was associated with a significant reduction in mortality (OR = 0.76 [0.68-0.85]). Quality of evidence was low or very low for mortality and healthcare utilization. This review offers low-quality evidence for the effectiveness of an inclusive design and trauma system maturity and very-low-quality evidence for helicopter transport in reducing injury mortality. Further research should evaluate other recommended components of trauma systems and non-fatal outcomes and explore the impact of system component interactions.Peer reviewe

Evaluation of Bacteria and Fungi DNA Abundance in Human Tissues

Whereas targeted and shotgun sequencing approaches are both powerful in allowing the study of tissue-associated microbiota, the human: microorganism abundance ratios in tissues of interest will ultimately determine the most suitable sequencing approach. In addition, it is possible that the knowledge of the relative abundance of bacteria and fungi during a treatment course or in pathological conditions can be relevant in many medical conditions. Here, we present a qPCR-targeted approach to determine the absolute and relative amounts of bacteria and fungi and demonstrate their relative DNA abundance in nine different human tissue types for a total of 87 samples. In these tissues, fungi genomes are more abundant in stool and skin samples but have much lower levels in other tissues. Bacteria genomes prevail in stool, skin, oral swabs, saliva, and gastric fluids. These findings were confirmed by shotgun sequencing for stool and gastric fluids. This approach may contribute to a more comprehensive view of the human microbiota in targeted studies for assessing the abundance levels of microorganisms during disease treatment/progression and to indicate the most informative methods for studying microbial composition (shotgun versus targeted sequencing) for various samples types

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13

Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV