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Administration, Oral, Biomarkers analysis, Biopsy, Chenodeoxycholic Acid administration dosage, Chenodeoxycholic Acid therapeutic use, Double-Blind Method, Female, Humans, Liver Function Tests, Male, Middle Aged, Chenodeoxycholic Acid analogs derivatives, and Non-alcoholic Fatty Liver Disease drug therapy

Background: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH.
Methods: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6.
Findings: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group).
Interpretation: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes.
Funding: Intercept Pharmaceuticals.
(Copyright © 2019 Elsevier Ltd. All rights reserved.)

Marine biology, limnology, Biologie marine, limnologie, Ecology, Ecologie, Environment, Environnement, Oceanography, Océanographie, Sciences biologiques et medicales, Biological and medical sciences, Sciences biologiques fondamentales et appliquees. Psychologie, Fundamental and applied biological sciences. Psychology, Ecologie animale, vegetale et microbienne, Animal, plant and microbial ecology, Ecologie animale et végétale, Animal and plant ecology, Synécologie, Synecology, Ecosystèmes saumâtres, Brackish water ecosystems, Milieu saumâtre, Brackish water environment, Medio salobre, Estuaire, Estuaries, Estuario, Etude comparative, Comparative study, Estudio comparativo, Extracellulaire, Extracellular, Extracelular, Glucide, Carbohydrate, Glúcido, Phytobenthos, Fitobentos, Répartition spatiale, Spatial distribution, Distribución espacial, Vasière, Mud flats, Fondo fangoso, Zone intertidale, Intertidal zone, Zona intertidal, Ems-Dollard estuary, Extracellular carbohydrate, Grain size distribution, Humber estuary, Marennes-Oléron Bay, Microphytobenthos, Monosaccharide distribution, and Tidal flats

In this study, the spatial distribution of two operationally defined extracellular carbohydrate fractions (water- and EDTA-extractable carbohydrates) were examined in three intertidal mudflats in Western Europe (Dollard, the Netherlands; Marennes, France; Humber, UK). The three mudflats were sampled along cross-shore transects and sediment cores were sliced to a depth of 5 cm. In these mudflats diatoms were the dominant component of the microphytobenthos. Carbohydrate content showed little variation with depth but varied along transects within each mudflat. Carbohydrate contents were also significantly different between mudflats and the carbohydrate contents of the stations within a mudflat grouped together resulting in separate clusters. This was also observed when the Marennes mudflat was investigated on a temporal scale. These results suggest that processes that act on the scale of whole mudflats determine the variations in extracellular carbohydrate contents In the surface 0.5 cm of the sediment, water-extractable carbohydrates showed a correlation with both chlorophyll a content and median grain size while EDTA-extractable carbohydrates were only correlated with median grain size. Incubation experiments also showed the importance of microphytobenthos as a source of extracellular carbohydrate especially when subjected to the light. Analyses of the monosaccharide distribution of the carbohydrate fractions revealed that the carbohydrate composition was largely similar between the areas investigated. Structurally. the carbohydrates found in these sediments seem to represent a biorefractory part of the freshly produced carbohydrates that remained after rapid degradation of the mare labile component.

General chemistry, physical chemistry, Chimie générale, chimie physique, Metallurgy, welding, Métallurgie, soudage, Sciences exactes et technologie, Exact sciences and technology, Physique, Physics, Etat condense: structure, proprietes mecaniques et thermiques, Condensed matter: structure, mechanical and thermal properties, Surfaces et interfaces; couches minces et trichites (structure et propriétés non électroniques), Surfaces and interfaces; thin films and whiskers (structure and nonelectronic properties), Structure et morphologie de couches minces, Thin film structure and morphology, Structure et morphologie; épaisseur, Structure and morphology; thickness, Diffraction RX, XRD, Dépôt physique phase vapeur, Physical vapor deposition, Etude expérimentale, Experimental study, Frottement, Friction, Magnétron, Magnetrons, Microscopie électronique balayage, Scanning electron microscopy, Microstructure, Molybdène sulfure, Molybdenum sulfides, Propriété mécanique, Mechanical properties, Pulvérisation irradiation, Sputtering, Revêtement, Coatings, Tribologie, Tribology, Usure, and Wear

MoSx coatings were prepared with an unbalanced DC magnetron-sputtering system by varying the DC power mode, target type and liquid nitrogen trap. The composition and surface morphology were examined by energy dispersive X-ray and scanning electron microscopy; structural characterization was determined by X-ray diffraction. The friction and wear properties were evaluated with a fretting tester in dry (< 10% relative humidity) and humid (50% and 90% relative humidity) air. MoSx coatings deposited by simple DC power tended to form rougher surfaces, and had a higher edge orientation of crystallites with worse tribological performance than those by bipolar pulsed DC power. MoSx coatings made by a cold pressed target had a lower deposition rate, and were inclined to form (002) basal orientations parallel to the surface especially at higher argon pressures. The contents of oxygen and carbon in the MoSx coating with the use of liquid nitrogen trap were greatly reduced, but MoSx coatings had lower coefficients of friction and shorter wear life at higher relative humidity. The role of these deposition variables in the formation process is discussed.

General chemistry, physical chemistry, Chimie générale, chimie physique, Metallurgy, welding, Métallurgie, soudage, Sciences exactes et technologie, Exact sciences and technology, Physique, Physics, Etat condense: structure, proprietes mecaniques et thermiques, Condensed matter: structure, mechanical and thermal properties, Surfaces et interfaces; couches minces et trichites (structure et propriétés non électroniques), Surfaces and interfaces; thin films and whiskers (structure and nonelectronic properties), Propriétés physiques non électroniques de couches minces, Physical properties of thin films, nonelectronic, Propriétés mécaniques et acoustiques, Mechanical and acoustical properties, Coefficient frottement, Friction factor, Dépôt physique phase vapeur, Physical vapor deposition, Essai usure, Wear testing, Etude expérimentale, Experimental study, Magnétron, Magnetrons, Microstructure, Molybdène sulfure, Molybdenum sulfides, Propriété mécanique, Mechanical properties, Propriété surface, Surface properties, Revêtement, Coatings, SEM, Tribologie, Tribology, Usure petit débattement, Fretting wear, Desgate pequinio desplazamiento, Usure, and Wear

MoSx coatings were prepared by bipolar pulse DC (balanced and unbalanced) magnetron-sputtering systems. Deposition parameters, cathode current density, argon pressure, bias voltage and magnetron sputtering conditions, were varied in order to obtain low friction and wear-resistant coatings. Composition and surface morphology were determined by energy dispersive X-rays and scanning electron microscopy, while the structure was investigated by X-ray diffraction. The friction and wear properties were investigated by fretting tests in ambient air of < 10% and 50% relative humidity. On proper selection of the argon pressure and the cathode current density, MoSx coatings characterised by a strong (002) basal plane orientation parallel to the substrate were obtained in a reproducible way. Such coatings deposited under optimised conditions exhibit very good lubricity and high wear-resistance, even in ambient air with a relative humidity of 50%. Conversely, when deposition parameters such as higher argon pressure and larger cathode current density result in the deposition of a MoSx coatings with a needle-like structure and preferential (100) and (110) plane orientations, a lower wear resistance is achieved especially in air of 50% relative humidity. Ion bombardment, achieved by applying a negative voltage bias or unbalanced sputtering conditions, improves the friction and wear performance. Conversely, a positive bias voltage deteriorates the tribological performance of the coatings. Experimental data on the friction and sliding wear resistance for MoSx coatings indicate that the best tribological properties are obtained with low sulfur and featureless MoSx coatings.

Marine biology, limnology, Biologie marine, limnologie, Ecology, Ecologie, Environment, Environnement, Oceanography, Océanographie, Sciences exactes et technologie, Exact sciences and technology, Terre, ocean, espace, Earth, ocean, space, Sciences de la terre, Earth sciences, Formations superficielles, Surficial geology, Quaternaire marin et continental, Marine and continental quaternary, Europe, Europa, Océan Atlantique, Atlantic Ocean, Océano Atlántico, Procaryote, prokaryotes, Bactérie, bacteria, Carbone organique, organic carbon, Carbono orgánico, Effet biogène, biogenic effects, Effet tampon, buffer effects, Efecto tampón, Fer, iron, Hierro, Milieu littoral, coastal environment, Medio litoral, Oxydation, oxidation, Oxidación, Porosité, porosity, Porosidad, Réduction chimique, chemical reduction, Reducción química, Sulfate, sulfates, Sulfato, Sulfure, sulfides, Sulfuro, Sédiment marin, marine sediments, Sedimento marino, Variation verticale, and vertical variations

The Bassin d'Arcachon (south-west France) was chosen as a model ecosystem to study the chemical and microbiological buffering towards free sulphide. Data were collected on the vertical distribution of oxygen, sulphur and iron compounds and the vertical distribution of colourless sulphur bacteria and sulphide-producing bacteria. In addition, data on the chemical and biological buffering capacity towards free sulphide were collected in sediment slurries from defined depth layers using a biological sulphide and oxygen monitor (BOSM) equipped with electrodes for oxygen, sulphide, redox and pH. The data showed that a substantial population of aerobic sulphide-oxidizing bacteria was present, yet buffering towards free sulphide could mainly be attributed to chemical processes: in particular, reactions with iron were of importance. Interestingly, the potential microbiological rate of sulphide oxidation was orders of magnitude higher than the rate of sulphate reduction reported for this ecosystem. The ecological implications of these observations for the Bassin d'Arcachon are that the powerful biological buffering capacity towards the free sulphide present will become effective after the chemical buffering capacity has been depleted. Under such conditions the colourless sulphur bacteria will no longer face the competition with iron, and thus may be expected to proliferate. The crucial factor then becomes the availability of oxygen.

Electronics, Electronique, Sciences exactes et technologie, Exact sciences and technology, Sciences appliquees, Applied sciences, Electronique, Electronics, Electronique des semiconducteurs. Microélectronique. Optoélectronique. Dispositifs à l'état solide, Semiconductor electronics. Microelectronics. Optoelectronics. Solid state devices, Circuits intégrés, Integrated circuits, Conception. Technologies. Analyse fonctionnement. Essais, Design. Technologies. Operation analysis. Testing, Aluminium, Aluminio, Circuit intégré, Integrated circuit, Circuito integrado, Electrodiffusion, Electrodifusión, Encapsulation, Encapsulación, Etude expérimentale, Experimental study, Estudio experimental, Fiabilité, Reliability, Fiabilidad, Interconnexion, Interconnection, Interconección, Métallisation, Metallizing, Metalización, Or, Gold, Oro, Phénomène transport, Transport process, and Fenómeno transporte

Energy, Énergie, Metallurgy, welding, Métallurgie, soudage, Sciences exactes et technologie, Exact sciences and technology, Sciences appliquees, Applied sciences, Energie, Energy, Energie. Utilisation thermique des combustibles, Energy. Thermal use of fuels, Installations de production et de conversion d'énergie: énergie électrique, énergie thermique., Installations for energy generation and conversion: thermal and electrical energy., Centrales nucléaires à fission, Fission nuclear power plants, America, South America, Amérique du Sud, Amérique, America del sur, Analyse, Analysis, Arbre événement, Brésil, Brazil, Brasil, Centrale nucléaire, Nuclear power plant, Planta nuclear, Evaluation probabiliste, Programme ordinateur, Computer program, Risque, Risk, Riesgo, Sécurité, Safety, and Securidad

Description de la méthodologie utilisée dans le programme d'ordinateur d'analyse d'arbres d'événements pour des évaluations probabilistes de risques. Description détaillée de la structure du programme et de ses entrées et sorties. Discussion de quelques limitations de la version actuelle du programme.

Animals, Antioxidants metabolism, Apoptosis drug effects, Body Weight drug effects, Carbon Tetrachloride antagonists inhibitors, Carcinogens toxicity, Cell Division drug effects, Diet, Diethylnitrosamine toxicity, Iron administration dosage, Iron metabolism, Kupffer Cells drug effects, Kupffer Cells pathology, Liver metabolism, Liver pathology, Liver Neoplasms, Experimental chemically induced, Liver Neoplasms, Experimental pathology, Male, Necrosis, Organ Size drug effects, Rats, Rats, Wistar, Ubiquinone metabolism, Vitamin E metabolism, Carbon Tetrachloride toxicity, Iron pharmacology, Liver drug effects, and Liver Neoplasms, Experimental prevention control

Background/aims: The aim of this study was to investigate if feeding with carbonyl iron would facilitate the development of preneoplastic lesions initiated by diethylnitrosamine (DEN) and promoted by CCl4-induced liver cirrhosis.
Methods: Male Wistar rats were fed a diet with 1.25%-2.5% carbonyl iron for 23 weeks and received intragastric injections of CCl4 (1.0 or 2.0 ml/kg per week) for 13 weeks, followed by one i.p. injection of DEN (200 mg/kg), after which CCl4 was administered for 8 additional weeks. Animals were killed 48 h after the first CCl4 injection to evaluate liver necrosis, 8 weeks later to evaluate fibrosis, and 9 weeks after DEN to determine formation of glutathione S-transferase 7,7 (GST-7,7) positive foci.
Results: Treatment with iron counteracted the increased serum alanine aminotransferase levels and liver necrosis following CCl4 administration. Hepatic levels of reduced Q9 and alpha-tocopherol were elevated in rats treated with CCl4 and decreased in rats treated with iron compared to the controls. Fibrogenesis was not altered by iron treatment. Nine weeks after DEN initiation, the number and volume density of GST-7,7-positive foci in rats treated with CCl4 were significantly increased as compared with controls, but co-treatment with iron inhibited this increase. Apoptotic index was increased in iron-loaded livers, and labelling index (the fraction of S-phase hepatocytes) was decreased by co-treatment with iron in livers exposed to CCl4.
Conclusion: Carbonyl iron depleted hepatic levels of antioxidants, it decreased CCl4-induced necrosis and cell proliferation, it enhanced apoptosis and did not facilitate fibrogenesis. These effects together may explain the suppression of CCl4-induced promotion after DEN initiation exerted by carbonyl iron in the present study.

Antibodies, Monoclonal immunology, Antibody Affinity immunology, Carrier Proteins genetics, Gene Expression, Humans, Immunoglobulin Variable Region immunology, Immunoglobulin Variable Region isolation purification, Immunoglobulin kappa-Chains genetics, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins immunology, Recombinant Fusion Proteins isolation purification, Substrate Specificity genetics, Substrate Specificity immunology, Antibodies, Monoclonal genetics, Antibody Affinity genetics, Gene Library, Immunoglobulin Variable Region genetics, Peptides immunology, and Plant Proteins immunology

The application of recombinant antibodies in plant biology research is limited because plant researchers have minimal access to high-quality phage display libraries. Therefore, we constructed a library of 1.3 x 10(10) clones displaying human single-chain variable fragments (scFvs) that is available to the academic community. The scFvs selected from the library against a diverse set of plant proteins showed moderate to high antigen-binding affinity together with high specificity. Moreover, to optimize an scFv as immunodetection agent, two expression systems that allow efficient production and purification of bivalent scFv-Fc and scFv-CkappaZIP fusion proteins were integrated. We are convinced that this antibody platform will further stimulate applications of recombinant antibodies such as the diagnostic detection or immunomodulation of specific antigens in plants.

Animals, Bacterial Typing Techniques, Carrier State microbiology, Cluster Analysis, Escherichia coli isolation purification, Genotype, Humans, Molecular Epidemiology, Molecular Typing, Multilocus Sequence Typing, Netherlands, Plasmids analysis, Polymerase Chain Reaction, Zoonoses microbiology, Carrier State veterinary, Escherichia coli enzymology, Escherichia coli genetics, Escherichia coli Infections microbiology, Meat microbiology, Poultry microbiology, and beta-Lactamases genetics

Intestinal carriage of extended-spectrum beta-lactamase (ESBL) -producing bacteria in food-producing animals and contamination of retail meat may contribute to increased incidences of infections with ESBL-producing bacteria in humans. Therefore, distribution of ESBL genes, plasmids and strain genotypes in Escherichia coli obtained from poultry and retail chicken meat in the Netherlands was determined and defined as 'poultry-associated' (PA). Subsequently, the proportion of E. coli isolates with PA ESBL genes, plasmids and strains was quantified in a representative sample of clinical isolates. The E. coli were derived from 98 retail chicken meat samples, a prevalence survey among poultry, and 516 human clinical samples from 31 laboratories collected during a 3-month period in 2009. Isolates were analysed using an ESBL-specific microarray, sequencing of ESBL genes, PCR-based replicon typing of plasmids, plasmid multi-locus sequence typing (pMLST) and strain genotyping (MLST). Six ESBL genes were defined as PA (bla(CTX-M-1) , bla(CTX-M-2) , bla(SHV-2) , bla(SHV-12) , bla(TEM-20) , bla(TEM-52) ): 35% of the human isolates contained PA ESBL genes and 19% contained PA ESBL genes located on IncI1 plasmids that were genetically indistinguishable from those obtained from poultry (meat). Of these ESBL genes, 86% were bla(CTX-M-1) and bla(TEM-52) genes, which were also the predominant genes in poultry (78%) and retail chicken meat (75%). Of the retail meat samples, 94% contained ESBL-producing isolates of which 39% belonged to E. coli genotypes also present in human samples. These findings are suggestive for transmission of ESBL genes, plasmids and E. coli isolates from poultry to humans, most likely through the food chain.
(2011 The Authors. Clinical Microbiology and Infection; 2011 European Society of Clinical Microbiology and Infectious Diseases.)