Activated protein C increases sensitivity to vasoconstriction in rabbit Escherichia coli endotoxin-induced shock

INTRODUCTION: The aim of this study was to investigate the effects of activated protein C (aPC) on vascular function, endothelial injury, and haemostasis in a rabbit endotoxin-induced shock model. METHOD: This study included 22 male New Zealand rabbits weighing 2.5 to 3 kg each. In vitro vascular reactivity, endothelium CD31-PECAM1 immunohistochemistry, plasma coagulation factors and monocyte tissue factor (TF) expression were performed 5 days (D5) after onset of endotoxic shock (initiated by 0.5 mg/kg intravenous bolus of Escherichia coli lipopolysaccharide (LPS)) with or without treatment with aPC injected as an intravenous 2 mg/kg bolus 1 hour after LPS (LPS+aPC group and LPS group, respectively). RESULTS: LPS decreased the sensitivity to phenylephrine (PE) in aortic rings without endothelium (E-) when compared to E- rings from the control group (p < 0.05). This was abolished by N(G)-nitro-L-arginine methyl ester and not observed in E- rings from aPC-treated rabbits. Although aPC failed to decrease monocyte TF expression in endotoxinic animals at D5, aPC treatment restored the endothelium-dependent sensitivity in response to PE (2.0 ± 0.2 μM in rings with endothelium (E+) versus 1.0 ± 0.2 μM in E- rings (p < 0.05) in the LPS+aPC group versus 2.4 ± 0.3 μM in E+ rings versus 2.2 ± 0.2 μM in E- rings (p value not significant), in the LPS group). Endotoxin-induced de-endothelialisation was reduced by aPC at D5 (28.5 ± 2.3% in the LPS+aPC group versus 40.4 ± 2.4% in the LPS group, p < 0.05). CONCLUSION: These data indicate that aPC increased the sensitivity to a vasoconstrictor agent (PE) associated with restoration of endothelial modulation, and protected against endothelial histological injury in endotoxin-induced shock. It failed to inhibit TF expression at D5 after LPS injection

Laboratoire d’analyse secondaire et des méthodes appliquées à la sociologie – Institut du longitudinal

Michel Forsé, directeur de recherche au CNRS avec Yaël Brinbaum, Alain Degenne, Irène Fournier, Marie-Odile Lebeaux, Florence Maillochon, Marion Selz, Louis-André Vallet, chercheurs ou ingénieurs du CNRS au LASMAS-IdL Méthodes quantitatives en sociologie Conduit sous les auspices du LASMAS-IdL et partie prenante du DEA « Sociologie », cet enseignement répond à une demande grandissante de formation en méthodologie quantitative pour les sciences sociales. Il a pour objet de permettre à ceux qui..

A cross-sectional study to assess job strain of emergency healthcare workers by Karasek questionnaire: The SEEK study

BackgroundEmergency healthcare workers (eHCWs) are particularly at risk of stress, but data using the gold standard questionnaire of Karasek are scarce. We assessed the level of stress of eHCWs and aimed to compare it with the general population.MethodsThis is a cross-sectional nationwide study in French Emergency Departments (EDs), using the job-content questionnaire of Karasek, compared with the 25,000 answers in the French general population (controls from the SUMER study). The descriptions of job demand, job control, and social support were described as well as the prevalence of job strain and isostrain. Putative factors were searched using mixed-method analysis.ResultsA total of 166 eHCWs (37.9 ± 10.5 years old, 42% men) from five French EDs were included: 53 emergency physicians and 104 emergency paramedics, compared to 25,000 workers with other occupations. Job demand was highest for physicians (28.3 ± 3.3) and paramedics (25.9 ± 3.8), compared to controls (36.0 ± 7.2; p &lt; 0.001). Job control was the lowest for physicians (61.2 ± 5.8) and paramedics (59.1 ± 6.8), compared to controls (70.4 ± 11.7; p &lt; 0.001). Mean social support did not differ between groups (23.6 ± 3.4 for physicians, 22.6 ± 2.9 for paramedics, and 23.7 ± 3.6 for controls). The prevalence of job strain was massively higher for physicians (95.8%) and paramedics (84.8%), compared to controls (23.9%; p &lt; 0.001), as well as for isostrain (45.1% for physicians, 56.8% for paramedics, and 14.3% for controls, p &lt; 0.001). We did not find any significant impact of sociodemographic characteristics on job control, job demand, or social support.ConclusionEmergency healthcare workers have a dramatic rate of job strain, necessitating urgent promotion of policy to take care of them

Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA

Background: Gitelman syndrome is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. Gitelman syndrome is caused by biallelic pathogenic variants in SLC12A3, encoding the Na+-Cl− cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of CLCNKB, HNF1B, FXYD2, or KCNJ10 may result in the same renal phenotype of Gitelman syndrome, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a Gitelman syndrome phenotype, the genotype is unknown. Methods: We identified mitochondrial DNA (mtDNA) variants in three families with Gitelman-like electrolyte abnormalities, then investigated 156 families for variants in MT-TI and MT-TF, which encode the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. Mitochondrial dysfunction was induced in NCC-expressing HEK293 cells to assess the effect on thiazide-sensitive 22Na+ transport. Results: Genetic investigations revealed four mtDNA variants in 13 families: m.591C>T (n=7), m.616T>C (n=1), m.643A>G (n=1) (all in MT-TF), and m.4291T>C (n=4, in MT-TI). Variants were near homoplasmic in affected individuals. All variants were classified as pathogenic, except for m.643A>G, which was classified as a variant of uncertain significance. Importantly, affected members of six families with an MT-TF variant additionally suffered from progressive chronic kidney disease. Dysfunction of oxidative phosphorylation complex IV and reduced maximal mitochondrial respiratory capacity were found in patient fibroblasts. In vitro pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated sodium uptake. Conclusion: Pathogenic mtDNA variants in MT-TF and MT-TI can cause a Gitelman-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained Gitelman syndrome-like tubulopathies

A global database of water vapor isotopes measured with high temporal resolution infrared laser spectroscopy

The isotopic composition of water vapour provides integrated perspectives on the hydrological histories of air masses and has been widely used for tracing physical processes in hydrological and climatic studies. Over the last two decades, the infrared laser spectroscopy technique has been used to measure the isotopic composition of water vapour near the Earth's surface. Here, we have assembled a global database of high temporal resolution stable water vapour isotope ratios (delta O-18 and delta D) observed using this measurement technique. As of March 2018, the database includes data collected at 35 sites in 15 Koppen climate zones from the years 2004 to 2017. The key variables in each dataset are hourly values of delta O-18 and delta D in atmospheric water vapour. To support interpretation of the isotopologue data, synchronized time series of standard meteorological variables from in situ observations and ERA5 reanalyses are also provided. This database is intended to serve as a centralized platform allowing researchers to share their vapour isotope datasets, thus facilitating investigations that transcend disciplinary and geographic boundaries

Étude diagnostique d’un protocole de dessin d’items évaluant la mémoire sémantique chez des patients suspectés de présenter une maladie neurodégénérative

Semantic Memory (SM) consists in overall knowledges that allows us to understand our environment. Semantic Memory Disorders are mostly encounterd in neurodegenerative diseases, mostly in Frontotemporal Lobar Dementia (FTLD) such as the semantic variant of primary progressive aphasia (PPAvs), the comportemental-semantic variant of Frontotemporal Lobar Dementia (FTLDcs) but also in Alzheimer’s Disease (AD). Most of semantic memory tests rely on verbal modality. Thus, semantic memory evaluation can interfere with language skills. The item drawing task has been developed in Rouen to evaluate semantic memory in non-verbal production mode. The main objective of this study was to establish a cut-off value, distinguishing patients with TS from those without, after having set up a rating guide allowing it to be reproducible. A cut-off value of 43/49 (sensitivity rate of 100% and Negative Predictive Value of 100%), enables to detect every patient with semantic memory deficits (True Positive). Concerning interrater reliability, intraclass coefficient reaches 98,9%. Further studies could include more participants in order to improve the test characteristics.La mémoire sémantique (MS) est définie comme l’ensemble des connaissances du monde qui nous entoure et nous permet de mettre du sens sur notre environnement. Les troubles sémantiques (TS) sont majoritairement retrouvés dans le cadre de certaines typologies de dégénérescence lobaire fronto-temporale (DLFT), comme l’aphasie progressive primaire variant sémantique (APPvs), la dégénérescence lobaire fronto temporale variant sémantique-comportemental (DLFTsc) mais également dans le cadre de la maladie d’Alzheimer (MA). Actuellement, les tests proposent principalement une évaluation en modalité de production verbale. L’altération du langage oral chez certains patients peut biaiser l’interprétation de ces tests. Le test de dessin d’items de mémoire a été développé à Rouen pour évaluer la mémoire sémantique en modalité de production non verbale. L’objectif de cette étude était d’établir une valeur seuil, permettant de dépister les patients atteints d’un TS, après avoir mis en place un guide de cotation pour qu’elle puisse être reproductible. La valeur seuil de 43/49 avec un taux de sensibilité à 100% et une Valeur Prédictive Négative (VPN) à 100%, lui permet donc de repérer tous les Vrais Positifs (VP). Concernant la reproductibilité inter-cotateurs, le coefficient intra-classe est de 98,9%. La poursuite de cette étude diagnostique permettra d’augmenter le nombre de participants tout en confirmant les seuils de sévérité des TS

Altérations de l'état acide base et maladie rénale chronique (mécanismes et conséquences)

L acidose métabolique est une complication fréquente de la maladie rénale chronique (MRC). Les mécanismes physiopathologiques sous-jacents ainsi que l impact potentiel sur l évolution de la fonction rénale restent incertains. Le premier objectif de ce travail était de décrire les modifications de l homéostasie acide-base et d identifier les facteurs associés dans la cohorte NéphroTest composée de patients ayant une MRC de tout stade et toute cause. Nous montrons que l acidose métabolique est d origine tubulaire, par défaut d excrétion urinaire d ammonium. La diminution de l ammoniurie survient précocement, avant la survenue d une acidémie. L ammoniurie à jeun dépend fortement de la valeur du débit de filtration glomérulaire, mais aussi de la kaliémie, du pH urinaire et du traitement. L ammoniurie des 24h est de plus influencée par les apports alimentaires. La deuxième partie du travail porte sur les conséquences des modifications de l état acide-base. Une ammoniurie basse est associée à un risque plus élevé de progression de la MRC, alors qu il n y a pas de sur-risque associé à la bicarbonatémie ou l acidémie. Le risque de progression est plus fortement associé à l ammoniurie à jeun qu à l ammoniurie des 24h. Ces données suggèrent que c est l état du bilan acide qui est délétère pour le rein et non la concentration plasmatique de bicarbonate. En conclusion, les patients ayant une MRC développent précocement une acidose métabolique d origine tubulaire. Celle-ci est délétère pour le rein, avant même que l acidose ne soit patente, suggérant une nécessité de dépistage et de prise en charge plus précoce que ce qui est actuellement préconisé.Metabolic acidosis occurs frequently during the course of chronic kidney disease (CKD). However, the underlying pathophysiologic mechanisms are still unclear. Moreover, whether metabolic acidosis is an independent factor of CKD progression remains uncertain. Our first goal was to describe the changes in acid-base status and to describe the factors associated to these changes in patients with CKD. We analyzed the data of the NéphroTest study cohort that enrolled patients with all-stages and all-causes CKD. Metabolic acidosis is associated with a defect in urinary ammonia excretion leading to a renal tubular acidosis. This defect occurs at an early stage of CKD, before the onset of overt metabolic acidosis. Fasting urinary ammonia excretion is highly dependent on glomerular filtration rate but also on plasma potassium concentration, urinary pH and treatment. Twenty-four hours ammonia excretion is also influenced by diet. Secondly, we tested whether changes in acid-base status were associated with renal outcomes. A lower urinary ammonia excretion was associated with a faster rate of decline in glomerular filtration rate while plasma bicarbonate concentration or overt acidosis were not. The association was stronger with fasting than with 24-hours ammonia excretion. These results suggest that the inability to excrete the daily acid load is deleterious regarding renal outcomes and that alkali-based therapy should be used earlier than currently advised.PARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF