Lack of Association between Measles Virus Vaccine and Autism with Enteropathy: A Case-Control Study

Background: The presence of measles virus (MV) RNA in bowel tissue from children with autism spectrum disorders (ASD) and gastrointestinal (GI) disturbances was reported in 1998. Subsequent investigations found no associations between MV exposure and ASD but did not test for the presence of MV RNA in bowel or focus on children with ASD and GI disturbances. Failure to replicate the original study design may contribute to continued public concern with respect to the safety of the measles, mumps, and rubella (MMR) vaccine. Methodology/Principal Findings: The objective of this case-control study was to determine whether children with GI disturbances and autism are more likely than children with GI disturbances alone to have MV RNA and/or inflammation in bowel tissues and if autism and/or GI episode onset relate temporally to receipt of MMR. The sample was an age-matched group of US children undergoing clinically-indicated ileocolonoscopy. Ileal and cecal tissues from 25 children with autism and GI disturbances and 13 children with GI disturbances alone (controls) were evaluated by real-time reverse transcription (RT)-PCR for presence of MV RNA in three laboratories blinded to diagnosis, including one wherein the original findings suggesting a link between MV and ASD were reported. The temporal order of onset of GI episodes and autism relative to timing of MMR administration was examined. We found no differences between case and control groups in the presence of MV RNA in ileum and cecum. Results were consistent across the three laboratory sites. GI symptom and autism onset were unrelated to MMR timing. Eighty-eight percent of ASD cases had behavioral regression. Conclusions/Significance: This study provides strong evidence against association of autism with persistent MV RNA in the GI tract or MMR exposure. Autism with GI disturbances is associated with elevated rates of regression in language or other skills and may represent an endophenotype distinct from other ASD

The use of cystatin C to inhibit epithelial–mesenchymal transition and morphological transformation stimulated by transforming growth factor-β

INTRODUCTION: Transforming growth factor-β (TGF-β) is a potent suppressor of mammary epithelial cell (MEC) proliferation and is thus an inhibitor of mammary tumor formation. Malignant MECs typically evolve resistance to TGF-β-mediated growth arrest, enhancing their proliferation, invasion, and metastasis when stimulated by TGF-β. Recent findings suggest that therapeutics designed to antagonize TGF-β signaling may alleviate breast cancer progression, thereby improving the prognosis and treatment of breast cancer patients. We identified the cysteine protease inhibitor cystatin C (CystC) as a novel TGF-β type II receptor antagonist that inhibits TGF-β binding and signaling in normal and cancer cells. We hypothesized that the oncogenic activities of TGF-β, particularly its stimulation of mammary epithelial–mesenchymal transition (EMT), can be prevented by CystC. METHOD: Retroviral infection was used to constitutively express CystC or a CystC mutant impaired in its ability to inhibit cathepsin protease activity (namely Δ14CystC) in murine NMuMG MECs and in normal rat kidney (NRK) fibroblasts. The effect of recombinant CystC administration or CystC expression on TGF-β stimulation of NMuMG cell EMT in vitro was determined with immunofluorescence to monitor rearrangements of actin cytoskeletal architecture and E-cadherin expression. Soft-agar growth assays were performed to determine the effectiveness of CystC in preventing TGF-β stimulation of morphological transformation and anchorage-independent growth in NRK fibroblasts. Matrigel invasion assays were performed to determine the ability of CystC to inhibit NMuMG and NRK motility stimulated by TGF-β. RESULTS: CystC and Δ14CystC both inhibited NMuMG cell EMT and invasion stimulated by TGF-β by preventing actin cytoskeletal rearrangements and E-cadherin downregulation. Moreover, both CystC molecules completely antagonized TGF-β-mediated morphological transformation and anchorage-independent growth of NRK cells, and inhibited their invasion through synthetic basement membranes. Both CystC and Δ14CystC also inhibited TGF-β signaling in two tumorigenic human breast cancer cell lines. CONCLUSION: Our findings show that TGF-β stimulation of initiating metastatic events, including decreased cell polarization, reduced cell–cell contact, and elevated cell invasion and migration, are prevented by CystC treatment. Our findings also suggest that the future development of CystC or its peptide mimetics hold the potential to improve the therapeutic response of human breast cancers regulated by TGF-β

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Intranasal delivery of transforming growth factor-beta1 in mice after stroke reduces infarct volume and increases neurogenesis in the subventricular zone

<p>Abstract</p> <p>Background</p> <p>The effect of neurotrophic factors in enhancing stroke-induced neurogenesis in the adult subventricular zone (SVZ) is limited by their poor blood-brain barrier (BBB) permeability.</p> <p>Intranasal administration is a noninvasive and valid method for delivery of neuropeptides into the brain, to bypass the BBB. We investigated the effect of treatment with intranasal transforming growth factor-β1 (TGF-β1) on neurogenesis in the adult mouse SVZ following focal ischemia. The modified Neurological Severity Scores (NSS) test was used to evaluate neurological function, and infarct volumes were determined from hematoxylin-stained sections. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) labeling was performed at 7 days after middle cerebral artery occlusion (MCAO). Immunohistochemistry was used to detect bromodeoxyuridine (BrdU) and neuron- or glia-specific markers for identifying neurogenesis in the SVZ at 7, 14, 21, 28 days after MCAO.</p> <p>Results</p> <p>Intranasal treatment of TGF-β1 shows significant improvement in neurological function and reduction of infarct volume compared with control animals. TGF-β1 treated mice had significantly less TUNEL-positive cells in the ipsilateral striatum than that in control groups. The number of BrdU-incorporated cells in the SVZ and striatum was significantly increased in the TGF-β1 treated group compared with control animals at each time point. In addition, numbers of BrdU- labeled cells coexpressed with the migrating neuroblast marker doublecortin (DCX) and the mature neuronal marker neuronal nuclei (NeuN) were significantly increased after intranasal delivery of TGF-β1, while only a few BrdU labeled cells co-stained with glial fibrillary acidic protein (GFAP).</p> <p>Conclusion</p> <p>Intranasal administration of TGF-β1 reduces infarct volume, improves functional recovery and enhances neurogenesis in mice after stroke. Intranasal TGF-β1 may have therapeutic potential for cerebrovascular disorders.</p

Longitudinal study of adolescent tobacco use and tobacco control policies in India

Abstract Background This project will use a multilevel longitudinal cohort study design to assess whether changes in Community Tobacco Environmental (CTE) factors, measured as community compliance with tobacco control policies and community density of tobacco vendors and tobacco advertisements, are associated with adolescent tobacco use in urban India. India’s tobacco control policies regulate secondhand smoke exposure, access to tobacco products and exposure to tobacco marketing. Research data about the association between community level compliance with tobacco control policies and youth tobacco use are largely unavailable, and are needed to inform policy enforcement, implementation and development. Methods The geographic scope will include Mumbai and Kolkata, India. The study protocol calls for an annual comprehensive longitudinal population-based tobacco use risk and protective factors survey in a cohort of 1820 adolescents ages 12–14 years (and their parent) from baseline (Wave 1) to 36-month follow-up (Wave 4). Geographic Information Systems data collection will be used to map tobacco vendors, tobacco advertisements, availability of e-cigarettes, COTPA defined public places, and compliance with tobacco sale, point-of-sale and smoke-free laws. Finally, we will estimate the longitudinal associations between CTE factors and adolescent tobacco use, and assess whether the associations are moderated by family level factors, and mediated by individual level factors. Discussion India experiences a high burden of disease and mortality from tobacco use. To address this burden, significant long-term prevention and control activities need to include the joint impact of policy, community and family factors on adolescent tobacco use onset. The findings from this study can be used to guide the development and implementation of future tobacco control policy designed to minimize adolescent tobacco use.https://deepblue.lib.umich.edu/bitstream/2027.42/144539/1/12889_2018_Article_5727.pd

Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease

Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes ($\textit{ITGA4 }$ and $\textit{ITGB8}$) and at previously implicated loci ($\textit{ITGAL }$and $\textit{ICAM1}$). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, $\textit{PLCG2}$, and a negative regulator of inflammation, $\textit{SLAMF8}$. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.This work was co-funded by the Wellcome Trust [098051] and the Medical Research Council, UK [MR/J00314X/1]. Case collections were supported by Crohn’s and Colitis UK. KMdL, LM, CAL, YL, DR, JG-A, NJP, CAA and JCB are supported by the Wellcome Trust [098051; 093885/Z/10/Z; 094491/Z/10/Z]. KMdL is supported by a Woolf Fisher Trust scholarship. CAL is a clinical lecturer funded by the NIHR. We thank Anna Stanton for co-ordinating the Guy’s and St Thomas’ patient recruitment. We acknowledge support from the Department of Health via the NIHR comprehensive Biomedical Research Centre awards to Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London and to Addenbrooke’s Hospital, Cambridge in partnership with the University of Cambridge. This research was also supported by the NIHR Newcastle Biomedical Research Centre. The UK Household Longitudinal Study is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

Alignment of the CMS silicon tracker during commissioning with cosmic rays

This is the Pre-print version of the Article. The official published version of the Paper can be accessed from the link below - Copyright @ 2010 IOPThe CMS silicon tracker, consisting of 1440 silicon pixel and 15 148 silicon strip detector modules, has been aligned using more than three million cosmic ray charged particles, with additional information from optical surveys. The positions of the modules were determined with respect to cosmic ray trajectories to an average precision of 3–4 microns RMS in the barrel and 3–14 microns RMS in the endcap in the most sensitive coordinate. The results have been validated by several studies, including laser beam cross-checks, track fit self-consistency, track residuals in overlapping module regions, and track parameter resolution, and are compared with predictions obtained from simulation. Correlated systematic effects have been investigated. The track parameter resolutions obtained with this alignment are close to the design performance.This work is supported by FMSR (Austria); FNRS and FWO (Belgium); CNPq, CAPES, FAPERJ, and FAPESP (Brazil); MES (Bulgaria); CERN; CAS, MoST, and NSFC (China); COLCIENCIAS (Colombia); MSES (Croatia); RPF (Cyprus); Academy of Sciences and NICPB (Estonia); Academy of Finland, ME, and HIP (Finland); CEA and CNRS/IN2P3 (France); BMBF, DFG, and HGF (Germany); GSRT (Greece); OTKA and NKTH (Hungary); DAE and DST (India); IPM (Iran); SFI (Ireland); INFN (Italy); NRF (Korea); LAS (Lithuania); CINVESTAV, CONACYT, SEP, and UASLP-FAI (Mexico); PAEC (Pakistan); SCSR (Poland); FCT (Portugal); JINR (Armenia, Belarus, Georgia, Ukraine, Uzbekistan); MST and MAE (Russia); MSTDS (Serbia); MICINN and CPAN (Spain); Swiss Funding Agencies (Switzerland); NSC (Taipei); TUBITAK and TAEK (Turkey); STFC (United Kingdom); DOE and NSF (USA)