Safety, tolerability, and efficacy of maralixibat in adults with primary sclerosing cholangitis: Open-label pilot study

BACKGROUND: Primary sclerosing cholangitis (PSC) is frequently associated with pruritus, which significantly impairs quality of life. Maralixibat is a selective ileal bile acid transporter (IBAT) inhibitor that lowers circulating bile acid (BA) levels and reduces pruritus in cholestatic liver diseases. This is the first proof-of-concept study of IBAT inhibition in PSC. METHODS: This open-label study evaluated the safety and tolerability of maralixibat ≤10 mg/d for 14 weeks in adults with PSC. Measures of pruritus, biomarkers of BA synthesis, cholestasis, and liver function were also assessed. RESULTS: Of 27 enrolled participants, 85.2% completed treatment. Gastrointestinal treatment-emergent adverse events (TEAEs) occurred in 81.5%, with diarrhea in 51.9%. TEAEs were mostly mild or moderate (63.0%); 1 serious TEAE (cholangitis) was considered treatment related. Mean serum BA (sBA) levels decreased by 16.7% (-14.84 µmol/L; 95% CI, -27.25 to -2.43; p = 0.0043) by week 14/early termination (ET). In participants with baseline sBA levels above normal (n = 18), mean sBA decreased by 40.0% (-22.3 µmol/L, 95% CI, -40.38 to -4.3; p = 0.004) by week 14/ET. Liver enzyme elevations were not significant; however, increases of unknown clinical significance in conjugated bilirubin levels were observed. ItchRO weekly sum scores decreased from baseline to week 14/ET by 8.4% (p = 0.0495), by 12.6% (p = 0.0275) in 18 participants with pruritus at baseline, and by 70% (p = 0.0078) in 8 participants with ItchRO daily average score ≥3 at baseline. CONCLUSIONS: Maralixibat was associated with reduced sBA levels in adults with PSC. In participants with more severe baseline pruritus, pruritus improved significantly from baseline. TEAEs were mostly gastrointestinal related. These results support further investigation of IBAT inhibitors for adults with PSC-associated pruritus. ClinicalTrials.gov: NCT02061540

CoastColour Round Robin datasets: A data base to evaluate the performance of algorithms for the retrieval of water quality parameters in coastal waters

The use of in situ measurements is essential in the validation and evaluation of the algorithms that provide coastal water quality data products from ocean colour satellite remote sensing. Over the past decade, various types of ocean colour algorithms have been developed to deal with the optical complexity of coastal waters. Yet there is a lack of a comprehensive intercomparison due to the availability of quality checked in situ databases. The CoastColour Round Robin (CCRR) project, funded by the European Space Agency (ESA), was designed to bring together three reference data sets using these to test algorithms and to assess their accuracy for retrieving water quality parameters. This paper provides a detailed description of these reference data sets, which include the Medium Resolution Imaging Spectrometer (MERIS) level 2 match-ups, in situ reflectance measurements, and synthetic data generated by a radiative transfer model (HydroLight). These data sets, representing mainly coastal waters, are available from doi:10.1594/PANGAEA.841950. The data sets mainly consist of 6484 marine reflectance (either multispectral or hyperspectral) associated with various geometrical (sensor viewing and solar angles) and sky conditions and water constituents: total suspended matter (TSM) and chlorophyll a (CHL) concentrations, and the absorption of coloured dissolved organic matter (CDOM). Inherent optical properties are also provided in the simulated data sets (5000 simulations) and from 3054 match-up locations. The distributions of reflectance at selected MERIS bands and band ratios, CHL and TSM as a function of reflectance, from the three data sets are compared. Match-up and in situ sites where deviations occur are identified. The distributions of the three reflectance data sets are also compared to the simulated and in situ reflectances used previously by the International Ocean Colour Coordinating Group (IOCCG, 2006) for algorithm testing, showing a clear extension of the CCRR data which covers more turbid waters.JRC.H.1-Water Resource

Replication and shedding kinetics of infectious hematopoietic necrosis virus in juvenile rainbow trout

Viral replication and shedding are key components of transmission and fitness, the kinetics of which are heavily dependent on virus, host, and environmental factors. To date, no studies have quantified the shedding kinetics of infectious hematopoietic necrosis virus (IHNV) in rainbow trout (Oncorhynchus mykiss), or how they are associated with replication, making it difficult to ascertain the transmission dynamics of this pathogen of high agricultural and conservation importance. Here, the replication and shedding kinetics of two M genogroup IHNV genotypes were examined in their naturally co-evolved rainbow trout host. Within host virus replication began rapidly, approaching maximum values by day 3 post-infection, after which viral load was maintained or gradually dropped through day 7. Host innate immune response measured as stimulation of Mx-1 gene expression generally followed within host viral loads. Shedding also began very quickly and peaked within 2 days, defining a generally uniform early peak period of shedding from 1 to 4 days after exposure to virus. This was followed by a post-peak period where shedding declined, such that the majority of fish were no longer shedding by day 12 post-infection. Despite similar kinetics, the average shedding rate over the course of infection was significantly lower in mixed compared to single genotype infections, suggesting a competition effect, however, this did not significantly impact the total amount of virus shed. The data also indicated that the duration of shedding, rather than peak amount of virus shed, was correlated with fish mortality. Generally, the majority of virus produced during infection appeared to be shed into the environment rather than maintained in the host, although there was more retention of within host virus during the post-peak period. Viral virulence was correlated with shedding, such that the more virulent of the two genotypes shed more total virus. This fundamental understanding of IHNV shedding kinetics and variation at the individual fish level could assist with management decisions about how to respond to disease outbreaks when they occur. (C) 2016 Elsevier B.V. All rights reserved

CoastColour Round Robin data sets: A database to evaluate the performance of algorithms for the retrieval of water quality parameters in coastal waters

The use of in situ measurements is essential in the validation and evaluation of the algorithms that provide coastal water quality data products from ocean colour satellite remote sensing. Over the past decade, various types of ocean colour algorithms have been developed to deal with the optical complexity of coastal waters. Yet there is a lack of a comprehensive intercomparison due to the availability of quality checked in situ databases. The CoastColour Round Robin (CCRR) project, funded by the European Space Agency (ESA), was designed to bring together three reference data sets using these to test algorithms and to assess their accuracy for retrieving water quality parameters. This paper provides a detailed description of these reference data sets, which include the Medium Resolution Imaging Spectrometer (MERIS) level 2 match-ups, in situ reflectance measurements, and synthetic data generated by a radiative transfer model (HydroLight). These data sets, representing mainly coastal waters, are available from doi:10.1594/PANGAEA.841950. The data sets mainly consist of 6484 marine reflectance (either multispectral or hyperspectral) associated with various geometrical (sensor viewing and solar angles) and sky conditions and water constituents: total suspended matter (TSM) and chlorophyll a (CHL) concentrations, and the absorption of coloured dissolved organic matter (CDOM). Inherent optical properties are also provided in the simulated data sets (5000 simulations) and from 3054 match-up locations. The distributions of reflectance at selected MERIS bands and band ratios, CHL and TSM as a function of reflectance, from the three data sets are compared. Match-up and in situ sites where deviations occur are identified. The distributions of the three reflectance data sets are also compared to the simulated and in situ reflectances used previously by the International Ocean Colour Coordinating Group (IOCCG, 2006) for algorithm testing, showing a clear extension of the CCRR data which covers more turbid waters

La Crise du Vin Français ? L’Effet des Évolutions Sociaux et Culturelles sur l’Adaptabilité de l’Économie du Vin Français = French Wine in Crisis? The Effect of Culture and Social Changes on the French Wine Economy

On lit souvent dans les journaux français qu’il y a une crise du vin. Le terme « une crise du vin » doit d’abord être plus spécifié pour vraiment comprendre l’état actuel de l’économie du vin. Ces articles font références aux plusieurs d’indications économiques et sociales que le vin français souffre d’une demande qui baisse et qui baissera de plus en plus. En citant des statistiques et des chiffres, il paraît qu’il y a un problème dramatique. Depuis les années cinquante, lorsque la consommation du vin a atteint son niveau le plus haut, la consommation nationale, et mondiale, est fortement en baisse actuellement. Pendant les années soixante, chaque français consommait en moyen 140 litres par an. Aujourd’hui, la consommation moyenne n’est que 57 litres par an par personne, même si on prend en compte la croissance de la population française. Il n’y a aussi aucune indication d’un relèvement dans l’avenir car les boissons non alcooliques et la bière deviennent de plus en plus populaire en même temps que les pays occidentaux commencent à imposer une réglementation plus stricte sur la consommation de l’alcool. Cette baisse dans l’Europe force les pays producteurs à chercher des nouveaux clients, qu’ils trouvent surtout dans l’Australie, les Etats-Unis, et le Japon, pour donner quelques exemples. Malheureusement, c’est précisément dans ces pays, avec l’exception du Japon, où on voit une nouvelle croissance dans la production du vin. La concurrence de ces pays peut expliquer la baisse des exportations des vins français depuis 2000. Même si cette baisse est petite, elle sert à un avertissement pour l’avenir . Ce qui est claire est que la consommation évolue. L’image que le vin français a créée contribue significativement à son rôle dans la société et dans la culture aujourd’hui. Mais, cette l’image, face aux évolutions sociales, culturelles, et économiques, coince le vin français et elle va aussi contribuer, involontairement, à une consolidation dans l’économie du vin. Cela se voit déjà aux niveaux de la production, de la distribution, et de la vente. Souvent, quand on parle de la consolidation, on pense à une économie motivée uniquement par la vente, qui fait tout ce qui est nécessaire de vendre son produite pour moins cher que ses concurrents. Aujourd’hui, cela implique l’adoption des adaptations qui sont souvent des techniques et méthodes modernes. Mais, la préservation de l’histoire et de la tradition est fortement liée à l’identité française car cette histoire dans lequel le vin joue un rôle important est la racine de l’identité française. Cependant, au niveau économique, la préservation de l’histoire, des industries et des économies uniquement françaises, implique souvent un empêchement du commerce. L’économie de vin, et même celle de la France, sont en train de lutter entre ses poursuites économiques et son désir de préserver ses qualités et ses valeurs historiques. Les viticulteurs répondent à ce problème avec une stratégie qui veut préserver leur diversité et leur qualité de leurs vins, face à la consolidation dans l’économie moderne. Cependant, la mise en application de cette stratégie coïncide (par hasard ?) avec une baisse de consommation qui continue aujourd’hui. Seulement maintenant voit-on un mouvement d’évoluer l’image du vin français. Mais, c’est une évolution qui semble plutôt réactionnaire. Si les viticulteurs veulent garder leurs traditions et éviter le destin de la paysannerie français, il faut qu’ils fassent une compromise entre la diversité de la tradition viticole française et le besoin d’une nouvelle image. Cependant, leurs liens forts à leur image et valeurs historiques rendent cette transition difficile

Host DNA Repair Proteins in Response to Pseudomonas aeruginosa in Lung Epithelial Cells and in Mice ▿

Although DNA repair proteins in bacteria are critical for pathogens' genome stability and for subverting the host defense, the role of host DNA repair proteins in response to bacterial infection is poorly defined. Here, we demonstrate, for the first time, that infection with the Gram-negative bacterium Pseudomonas aeruginosa significantly altered the expression and enzymatic activity of 8-oxoguanine DNA glycosylase (OGG1) in lung epithelial cells. Downregulation of OGG1 by a small interfering RNA strategy resulted in severe DNA damage and cell death. In addition, acetylation of OGG1 is required for host responses to bacterial genotoxicity, as mutations of OGG1 acetylation sites increased Cockayne syndrome group B (CSB) protein expression. These results also indicate that CSB may be involved in DNA repair activity during infection. Furthermore, OGG1 knockout mice exhibited increased lung injury after infection with P. aeruginosa, as demonstrated by higher myeloperoxidase activity and lipid peroxidation. Together, our studies indicate that P. aeruginosa infection induces significant DNA damage in host cells and that DNA repair proteins play a critical role in the host response to P. aeruginosa infection, serving as promising targets for the treatment of this condition and perhaps more broadly Gram-negative bacterial infections