System-based proteomic and metabonomic analysis of the Df(16)A+/- mouse identifies potential miR-185 targets and molecular pathway alterations

Deletions on chromosome 22q11.2 are a strong genetic risk factor for development of schizophrenia and cognitive dysfunction. We employed shotgun liquid chromatography-mass spectrometry (LC-MS) proteomic and metabonomic profiling approaches on prefrontal cortex (PFC) and hippocampal (HPC) tissue from Df(16)A +/- mice, a model of the 22q11.2 deletion syndrome. Proteomic results were compared with previous transcriptomic profiling studies of the same brain regions. The aim was to investigate how the combined effect of the 22q11.2 deletion and the corresponding miRNA dysregulation affects the cell biology at the systems level. The proteomic brain profiling analysis revealed PFC and HPC changes in various molecular pathways associated with chromatin remodelling and RNA transcription, indicative of an epigenetic component of the 22q11.2DS. Further, alterations in glycolysis/gluconeogenesis, mitochondrial function and lipid biosynthesis were identified. Metabonomic profiling substantiated the proteomic findings by identifying changes in 22q11.2 deletion syndrome (22q11.2DS)-related pathways, such as changes in ceramide phosphoethanolamines, sphingomyelin, carnitines, tyrosine derivates and panthothenic acid. The proteomic findings were confirmed using selected reaction monitoring mass spectrometry, validating decreased levels of several proteins encoded on 22q11.2, increased levels of the computationally predicted putative miR-185 targets UDP-N-acetylglucosamine-peptide N-acetylglucosaminyltransferase 110 kDa subunit (OGT1) and kinesin heavy chain isoform 5A and alterations in the non-miR-185 targets serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform, neurofilament light chain and vesicular glutamate transporter 1. Furthermore, alterations in the proteins associated with mammalian target of rapamycin signalling were detected in the PFC and with glutamatergic signalling in the hippocampus. Based on the proteomic and metabonomic findings, we were able to develop a schematic model summarizing the most prominent molecular network findings in the Df(16)A +/- mouse. Interestingly, the implicated pathways can be linked to one of the most consistent and strongest proteomic candidates, (OGT1), which is a predicted miR-185 target. Our results provide novel insights into system-biological mechanisms associated with the 22q11DS, which may be linked to cognitive dysfunction and an increased risk to develop schizophrenia. Further investigation of these pathways could help to identify novel drug targets for the treatment of schizophrenia

Neuroanatomical phenotypes in a mouse model of the 22q11.2 microdeletion

Recurrent deletions at the 22q11.2 locus have been established as a strong genetic risk factor for the development of schizophrenia and cognitive dysfunction. Individuals with 22q11.2 deletions have a range of well-defined volumetric abnormalities in a number of critical brain structures. A mouse model of the 22q11.2 deletion (Df(16)A+/-) has previously been utilized to characterize disease-associated abnormalities on synaptic, cellular, neurocircuitry, and behavioral levels. We performed a high-resolution MRI analysis of mutant mice compared with wild-type littermates. Our analysis revealed a striking similarity in the specific volumetric changes of Df(16)A+/-mice compared with human 22q11.2 deletion carriers, including in cortico-cerebellar, cortico-striatal and cortico-limbic circuits. In addition, higher resolution magnetic resonance imaging compared with neuroimaging in human subjects allowed the detection of previously unknown subtle local differences. The cerebellar findings in Df(16)A+/-mice are particularly instructive as they are localized to specific areas within both the deep cerebellar nuclei and the cerebellar cortex. Our study indicates that the Df(16)A+/-mouse model recapitulates most of the hallmark neuroanatomical changes observed in 22q11.2 deletion carriers. Our findings will help guide the design and interpretation of additional complementary studies and thereby advance our understanding of the abnormal brain development underlying the emergence of 22q11.2 deletion-associated psychiatric and cognitive symptoms.Molecular Psychiatry advance online publication, 3 September 2013; doi:10.1038/mp.2013.112

Antibiotic treatment of infections caused by carbapenem-resistant Gram-negative bacilli: an international ESCMID cross-sectional survey among infectious diseases specialists practicing in large hospitals

Objectives: To explore contemporary antibiotic management of infections caused by carbapenem-resistant Gram-negative bacteria in hospitals. Methods: Cross-sectional, internet-based questionnaire survey. We contacted representatives of all hospitals with more than 800 acute-care hospital beds in France, Greece, Israel, Italy, Kosovo, Slovenia, Spain and selected hospitals in the USA. We asked respondents to describe the most common actual practice at their hospital regarding management of carbapenem-resistant Enterobacteriaceae, Acinetobacter baumannii and Pseudomonas aeruginosa through close-ended questions. Results: Between January and June 2017, 115 of 141 eligible hospitals participated (overall response rate 81.6%, country-specific rates 66.7%–100%). Most were tertiary-care (99/114, 86.8%), university-affiliated (110/115, 89.1%) hospitals and most representatives were infectious disease specialists (99/115, 86.1%). Combination therapy was prescribed in 114/115 (99.1%) hospitals at least occasionally. Respondents were more likely to consider combination therapy when treating bacteraemia, pneumonia and central nervous system infections and for Enterobacteriaceae, P. aeruginosa and A. baumannii similarly. Combination of a polymyxin with a carbapenem was used in most cases, whereas combinations of a polymyxin with tigecycline, an aminoglycoside, fosfomycin or rifampicin were also common. Monotherapy was used for treatment of complicated urinary tract infections, usually with an aminoglycoside or a polymyxin. The intended goal of combination therapy was to improve the effectiveness of the treatment and to prevent development of resistance. In general, respondents shared the misconception that combination therapy is supported by strong scientific evidence. Conclusions: Combination therapy was the preferred treatment strategy for infections caused by carbapenem-resistant Gram-negative bacteria among hospital representatives, even though high-quality evidence for carbapenem-based combination therapy is lacking. © 2018 European Society of Clinical Microbiology and Infectious Disease

HIV testing history and access to treatment among migrants living with HIV in Europe

Introduction: Migrants are overrepresented in the European HIV epidemic. We aimed to understand the barriers and facilitators to HIV testing and current treatment and healthcare needs of migrants living with HIV in Europe. Methods: A cross-sectional study was conducted in 57 HIV clinics in nine countries (Belgium, Germany, Greece, Italy, The Netherlands, Portugal, Spain, Switzerland and United Kingdom), July 2013 to July 2015. HIV-positive patients were eligible for inclusion if they were as follows: 18 years or older; foreign-born residents and diagnosed within five years of recruitment. Questionnaires were completed electronically in one of 15 languages and linked to clinical records. Primary outcomes were access to primary care and previous negative HIV test. Data were analysed using random effects logistic regression. Outcomes of interest are presented for women, heterosexual men and gay/bisexual men. Results: A total of 2093 respondents (658 women, 446 heterosexual men and 989 gay/bisexual men) were included. The prevalence of a previous negative HIV test was 46.7%, 43.4% and 82.0% for women, heterosexual and gay/bisexual men respectively. In multivariable analysis previous testing was positively associated with: receipt of post-migration antenatal care among women, permanent residency among heterosexual men and identifying as gay rather than bisexual among gay/bisexual men. Access to primary care was found to be high (>83%) in all groups and was strongly associated with country of residence. Late diagnosis was common for women and heterosexual men (60.8% and 67.1%, respectively) despite utilization of health services prior to diagnosis. Across all groups almost three-quarters of people on antiretrovirals had an HIV viral load <50 copies/mL. Conclusions: Migrants access healthcare in Europe and while many migrants had previously tested for HIV, that they went on to test positive at a later date suggests that opportunities for HIV prevention are being missed. Expansion of testing beyond sexual health and antenatal settings is still required and testing opportunities should be linked with combination prevention measures such as access to PrEP and treatment as prevention. © 2018 The Authors. Journal of the International AIDS Society published by John Wiley & sons Ltd on behalf of the International AIDS Society

High levels of postmigration HIV acquisition within nine European countries

Objective: We aimed to estimate the proportion of postmigration HIV acquisition among HIV-positive migrants in Europe. Design: To reach HIV-positive migrants, we designed a cross-sectional study performed in HIV clinics. Methods: The study was conducted from July 2013 to July 2015 in 57 clinics (nine European countries), targeting individuals over 18 years diagnosed in the preceding 5 years and born abroad. Electronic questionnaires supplemented with clinical data were completed in any of 15 languages. Postmigration HIV acquisition was estimated through Bayesian approaches combining extensive information on migration and patients' characteristics. CD4+ cell counts and HIV-RNA trajectories from seroconversion were estimated by bivariate linear mixed models fitted to natural history data. Postmigration acquisition risk factors were investigated with weighted logistic regression. Results: Of 2009 participants, 46% were MSM and a third originated from sub-Saharan Africa and Latin America & Caribbean, respectively. Median time in host countries was 8 years. Postmigration HIV acquisition was 63% (95% confidence interval: 57-67%); 72% among MSM, 58 and 51% in heterosexual men and women, respectively. Postmigration HIV acquisition was 71% for Latin America and Caribbean migrants and 45% for people from sub-Saharan Africa. Factors associated with postmigration HIV acquisition among heterosexual women and MSM were age at migration, length of stay in host country and HIV diagnosis year and among heterosexual men, length of stay in host country and HIV diagnosis year. Conclusion: A substantial proportion of HIV-positive migrants living in Europe acquired HIV postmigration. This has important implications for European public health policies. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved