NADPH oxidase activity is associated with cardiac osteopontin and pro-collagen type I expression in uremia.

International audienceCardiovascular disease is a frequent complication inducing mortality in chronic kidney disease (CKD) patients, which can be determined by both traditional risk factors and non-traditional risk factors such as malnutrition and oxidative stress. This study aimed to investigate the role of oxidative stress in uremia-induced cardiopathy in an experimental CKD model. CKD was induced in Sprague-Dawley rats by a 4-week diet supplemented in adenine, calcium and phosphorous and depleted in proteins. CKD was associated with a 3-fold increase in superoxide anion production from the NADPH oxidase in the left ventricle, but the maximal activity of mitochondrial respiratory chain complexes was not different. Although manganese mitochondrial SOD activity decreased, total SOD activity was not affected and catalase or GPx activities were increased, strengthening the major role of NADPH oxidase in superoxide anion output. Superoxide anion output was associated with enhanced expression of osteopontin (×7.7) and accumulation of pro-collagen type I (×3.7). To conclude, the increased activity of NADPH oxidase during CKD is associated with protein modifications which could activate a pathway leading to cardiac remodelling

Clostridium perfringens Epsilon Toxin Targets Granule Cells in the Mouse Cerebellum and Stimulates Glutamate Release

Epsilon toxin (ET) produced by C. perfringens types B and D is a highly potent pore-forming toxin. ET-intoxicated animals express severe neurological disorders that are thought to result from the formation of vasogenic brain edemas and indirect neuronal excitotoxicity. The cerebellum is a predilection site for ET damage. ET has been proposed to bind to glial cells such as astrocytes and oligodendrocytes. However, the possibility that ET binds and attacks the neurons remains an open question. Using specific anti-ET mouse polyclonal antibodies and mouse brain slices preincubated with ET, we found that several brain structures were labeled, the cerebellum being a prominent one. In cerebellar slices, we analyzed the co-staining of ET with specific cell markers, and found that ET binds to the cell body of granule cells, oligodendrocytes, but not astrocytes or nerve endings. Identification of granule cells as neuronal ET targets was confirmed by the observation that ET induced intracellular Ca2+ rises and glutamate release in primary cultures of granule cells. In cultured cerebellar slices, whole cell patch-clamp recordings of synaptic currents in Purkinje cells revealed that ET greatly stimulates both spontaneous excitatory and inhibitory activities. However, pharmacological dissection of these effects indicated that they were only a result of an increased granule cell firing activity and did not involve a direct action of the toxin on glutamatergic nerve terminals or inhibitory interneurons. Patch-clamp recordings of granule cell somata showed that ET causes a decrease in neuronal membrane resistance associated with pore-opening and depolarization of the neuronal membrane, which subsequently lead to the firing of the neuronal network and stimulation of glutamate release. This work demonstrates that a subset of neurons can be directly targeted by ET, suggesting that part of ET-induced neuronal damage observed in neuronal tissue is due to a direct effect of ET on neurons

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

Transpressional tectonics and Carboniferous magmatism in the Limousin, Massif Central, France: Structural and ⁴⁰Ar/³⁹Ar investigations

New structural, microstructural, and 40Ar/39 Ar data from the NW Massif Central (France) provide additional constraints on the timing and tectonic setting of late Variscan granite magmatism. Previous studies had emphasized the role of late orogenic extension in the emplacement of granite plutons in the Limousin region. In contrast, the new data set is consistent with syntectonic emplacement of magma in a dextral simple shear active from 350 to 300 Ma in a transpressional regime. As an alternative hypothesis to late orogenic extension, we propose that magmas migrated into tensional bridges between active P shears associated with a lithospheric shear zone comparable to a pop-up structure. The Galician region, in the western end of the Ibero-Armorican tectonic arc, exhibits major left-lateral ductile shear zones which can be interpreted as conjugate structures to the Limousin and Armorican shear zones. Copyright 2007 by the American Geophysical Union

Physiological maps and chemical-induced disease ontologies: tools to support NAMs development for next-generation risk assessment

editorial reviewedPhysiological maps (PM) can be defined as a graphical representation of cellular and molecular processes associated to specific organ functions (Vinken et al. 2021). Within the ONTOX project, we designed a total of 6 PMs describing physiological processes in the liver, the kidney and the brain. These PMs are then used as a tool to assess relevant mechanistic coverage and linkage between a specific organ function and a toxicological endpoint. Based on the Disease Maps project (Mazein et al. 2018) pipeline, we developed the first version of 6 PMs describing the following physiological processes: bile secretion & lipid metabolism (liver), vitamin D metabolism & urine composition (kidney), neural tube closure (update of the work of Heusinkveld et al. 2021) & brain development (brain). Our workflow included: (i) data collection from expert curated literature (ii) identification of the relevant biological mechanisms, (iii) screening of online databases (e.g. Wikipathways, Reactome, and KEGG) for previously described pathways, (iv) manual curation and integration of the data into a PM using CellDesigner, and (v) visualization on the MINERVA platform (Hoksza et al. 2019). These qualitative PMs represent an important tool for exploring curated literature, analyzing networks and benchmarking the development of new adverse outcome pathways (AOPs). These PMs provide the basis for developing quantitative disease ontologies, integrating different layers of pathological and toxicological information, chemical information (drug-induced pathways) and kinetic data. The resulting chemical-induced disease ontologies will provide a multi-layered platform for integration and visualization of such information. The ontologies will contribute to improving understanding of organ/disease related pathways in response to chemicals, visualize omics datasets, develop quantitative methods for computational disease modeling and for predicting toxicity, set up an in vitro & in silico test battery to detect a specific type of toxicity, and develop new animal-free approaches for next generation risk assessment

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Traitement des atteintes cardiovasculaires et rénales au-delà de la baisse de pression artérielle chez le rat (interaction entre système rénine-angiotensine-aldostérone, apport en sodium et stress oxydant)

MONTPELLIER-BU Médecine UPM (341722108) / SudocPARIS-BIUP (751062107) / SudocMONTPELLIER-BU Médecine (341722104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Quand la tension fait perdre l attention (découverte et prise en charge d un nouveau facteur de risque dans les affections vasculaires cérébrales)

MONTPELLIER-BU Pharmacie (341722105) / SudocSudocFranceF

Modulations des atteintes cardiovasculaires et rénales dans l'insulino-résistance

L'insulino-résistance est une caractéristique majeure du syndrome métabolique dont l'incidence ne cesse d'augmenter dans les pays industrialisés parallèlement à l'épidémie d'obésité. La résistance à l'insuline s'accompagne de diverses atteintes au niveau cardiaque, vasculaire et rénal. L'objectif principal était dans un modèle d'insulino-résistance induite par un excès de fructose chez le rat d'évaluer l'influence de la modulation en sodium (en excès ou en restriction) sur les changements métaboliques cardio-rénaux. D'une part, l'influence d'une restriction sodée concomitante à un régime riche en fructose a été évaluée. Nous avons montré que la restriction sodée prévenait les dommages cardio-rénaux. Ces effets bénéfiques ont été associés à une diminution de l'inflammation rénale et du stress oxydant. De plus, une prévention des modifications du tissu adipeux induites par le régime riche en fructose a été également observée. D'autre part l'impact d'une insulino-résistance en présence d'une consommation excessive et précoce (sevrage) en sodium a été évalué. Quand l'insulino-résistance (régime fructose) est initiée secondairement à un régime hypersodé, l'hypertrophie cardiaque associée au régime sodé est diminuée après l'ajout d'une insulino-résistance. Ce résultat paradoxal pourrait représenter une mal-adaptation du muscle cardiaque que confirme l'altération de la fonction systolique. En conclusion ce travail démontre une fois de plus l'impact de la nutrition dans la modulation des atteintes des organes cibles. L'importance d'adopter une nutrition raisonnée par contrôle de l'ingestion de sodium peut permettre de réduire les atteintes des organes cibles observées dans l'insulino-résistance.Insulin resistance is a major feature of the metabolic syndrome whose incidence is increasing in industrialized countries, in parallel with the obesity epidemic. Insulin resistance is associated with various cardiac, vascular and renal damages. The main objective was to evaluate the influence of sodium modulation (excess or restriction) on cardio-renal changes in a model of insulin resistance induced by fructose in rats. On one hand, the influence of salt restriction concomitant with a high fructose diet was evaluated. We have shown that sodium restriction prevents cardio-renal damages. These beneficial effects were associated with a reduction in renal inflammation and oxidative stress. In addition, a prevention of adipose tissue changes induced by fructose-rich diet was also obeserved. On the other hand impact of insulin resistance in presence of an early (weaning) sodium and excessive consumption of sodium was evaluated. When insulin resistance (fructose diet) was initiated secondary to high salt diet, cardiac hypertrophy associated with sodium diet decreased after the addition of insulin resistance. This paradoxal result could represent a maladaptation of cardiac muscle confirmed the impaired systolic function. In conclusion this work further demonstrates the impact of nutrition in the modulation of target organ damage. Reducing sodium intake may provide an easy way to reduce target organ damage observed in insulino resistance.MONTPELLIER-BU Médecine UPM (341722108) / SudocSudocFranceF