Early liver transplantation for severe alcohol-related hepatitis not responding to medical treatment: a prospective controlled study

peer reviewedBackground: Early liver transplantation for severe alcohol-related hepatitis is an emerging treatment option. We aimed to assess the risk of alcohol relapse 2 years after early liver transplantation for alcohol-related hepatitis compared with liver transplantation for alcohol-related cirrhosis after at least 6 months of abstinence. Methods: We conducted a multicentre, non-randomised, non-inferiority, controlled study in 19 French and Belgian hospitals. All participants were aged 18 years or older. There were three groups of patients recruited prospectively: patients with severe alcohol-related hepatitis who did not respond to medical treatment and were eligible for early liver transplantation according to a new selection scoring system based on social and addiction items that can be quantified in points (early transplantation group); patients with alcohol-related cirrhosis listed for liver transplantation after at least 6 months of abstinence (standard transplantation group); patients with severe alcohol-related hepatitis not responding to medical treatment not eligible for early liver transplantation according to the selection score (not eligible for early transplantation group), this group did not enter any further liver transplantation processes. We also defined a historical control group of patients with severe alcohol-related hepatitis unresponsive to medical therapy and non-transplanted. The primary outcome was the non-inferiority of 2-year rate of alcohol relapse after transplantation in the early transplantation group compared with the standard transplantation group using the alcohol timeline follow back (TLFB) method and a prespecified non-inferiority margin of 10%. Secondary outcomes were the pattern of alcohol relapse, 2-year survival rate post-transplant in the early transplantation group compared with the standard transplantation group, and 2-year overall survival in the early transplantation group compared with patients in the not eligible for early transplantation group and historical controls. This trial is registered with ClinicalTrials.gov, NCT01756794. Findings: Between Dec 5, 2012, and June 30, 2016, we included 149 patients with severe alcohol-related hepatitis: 102 in the early transplantation group and 47 in the not eligible for early transplantation group. 129 patients were included in the standard transplantation group. 68 patients in the early transplantation group and 93 patients in the standard transplantation group received a liver transplant. 23 (34%) patients relapsed in the early transplantation group, and 23 (25%) patients relapsed in the standard transplantation group; therefore, the non-inferiority of early transplantation versus standard transplantation was not demonstrated (absolute difference 9·1% [95% CI –∞ to 21·1]; p=0·45). The 2-year rate of high alcohol intake was greater in the early transplantation group than the standard transplantation group (absolute difference 16·7% [95% CI 5·8–27·6]) The time spent drinking alcohol was not different between the two groups (standardised difference 0·24 [95% CI −0·07 to 0·55]), but the time spent drinking a large quantity of alcohol was higher in the early transplantation group than the standard transplantation group (standardised difference 0·50 [95% CI 0·17–0·82]). 2-year post-transplant survival was similar between the early transplantation group and the standard transplantation group (hazard ratio [HR] 0·87 [95% CI 0·33–2·26]); 2-year overall survival was higher in the early transplantation group than the not eligible for early transplantation group and historical controls (HR 0·27 [95% CI 0·16–0·47] and 0·21 [0·13–0·32]). Interpretation: We cannot conclude non-inferiority in terms of rate of alcohol relapse post-transplant between early liver transplantation and standard transplantation. High alcohol intake is more frequent after early liver transplantation. This prospective controlled study confirms the important survival benefit related to early liver transplantation for severe alcohol-related hepatitis; and this study provides objective data on survival and alcohol relapse to tailor the management of patients with severe alcohol-related hepatitis. Funding: The present study has been granted by the French Ministry of Health—Programme Hospitalier de Recherche Clinique 2010

L’immigration féminine au Canada durant les années 1920 : la mise en place d’une politique fondée sur le « genre »

Les différentes vagues d’immigration qui ponctuent l’histoire canadienne ont toujours comporté un nombre important de femmes venues s’engager comme domestiques. Après la Première Guerre mondiale, la pénurie de ce type de main-d’oeuvre n’ayant cessé de croître depuis le xixe siècle, le gouvernement canadien crée, à l’intérieur du ministère de l’Immigration et de la Colonisation, une division spéciale afin de recruter des femmes d’origine britannique qui acceptent de venir s’établir au Canada comme domestiques. Cette nouvelle structure administrative, composée d’un personnel presque exclusivement féminin, a comme mandat de sélectionner les candidates, puis de les prendre en charge en les surveillant et en les protégeant. Dans cet article, l’auteure démontre que le gouvernement canadien, dans les années 1920, a mis en place une politique fondée sur le « genre » qui lui a permis d’exercer un contrôle sur les domestiques immigrantes et de favoriser, par l’entremise de cette politique restrictive d’immigration qui dirige les femmes immigrantes non accompagnées essentiellement vers la domesticité, le maintien des femmes dans leur rôle traditionnel de ménagères.The different waves of immigration marking the history of Canada have always included a significant number of women landing in Canada to be hired as domestic workers. In response to a steadily increasing shortage of this type of worker since the 19th Century, the Government of Canada after the First World War created a special division within the Department of Immigration and Colonization to recruit women of British origin who would agree to settle in Canada as domestic workers. The mandate of this new administration, almost exclusively composed of women, was to select candidates and assume responsibility for watching over them. In this article, the author will show that in the 1920s the Canadian government put into effect a policy founded on “gender” permitting it to exercise control over immigrant domestics and to favour immigration practices which, through the built-in bias of a restrictive immigration policy, directed unaccompanied females towards employment, essentially as household labourers, and this for the purpose of maintaining women in their traditional role as housewives

Nf1 RasGAP inhibition of LIMK2 mediates a new cross-talk between Ras and Rho pathways.

BACKGROUND: Ras GTPases mediate numerous biological processes through their ability to cycle between an inactive GDP-bound form and an active GTP-bound form. Guanine nucleotide exchange factors (GEFs) favor the formation of the active Ras-GTP, whereas GTPase activating proteins (GAPs) promote the formation of inactive Ras-GDP. Numerous studies have established complex signaling cross-talks between Ras GTPases and other members of the superfamily of small GTPases. GEFs were thought to play a major role in these cross-talks. However, recently GAPs were also shown to play crucial roles in these processes. Among RasGAPs, Nf1 is of special interest. Nf1 is responsible for the genetic disease Neurofibromatosis type I, and recent data strongly suggest that this RasGAP connects different signaling pathways. METHODOLOGY/PRINCIPAL FINDINGS: In order to know if the RasGAP Nf1 might play a role in connecting Ras GTPases to other small GTPase pathways, we systematically looked for new partners of Nf1, by performing a yeast two-hybrid screening on its SecPH domain. LIMK2, a major kinase of the Rho/ROCK/LIMK2/cofilin pathway, was identified in this screening. We confirmed this interaction by co-immunoprecipitation experiments, and further characterized it. We also demonstrated its specificity: the close related homolog of LIMK2, LIMK1, does not interact with the SecPH domain of Nf1. We then showed that SecPH partially inhibits the kinase activity of LIMK2 on cofilin. Our results furthermore suggest a precise mechanism for this inhibition: in fact, SecPH would specifically prevent LIMK2 activation by ROCK, its upstream regulator. CONCLUSIONS/SIGNIFICANCE: Although previous data had already connected Nf1 to actin cytoskeleton dynamics, our study provides for the first time possible detailed molecular requirements of this involvement. Nf1/LIMK2 interaction and inhibition allows to directly connect neurofibromatosis type I to actin cytoskeleton remodeling, and provides evidence that the RasGAP Nf1 mediates a new cross-talk between Ras and Rho signaling pathways within the superfamily of small GTPases

Influence of environment and host plant genotype on the structure and diversity of the Brassica napus seed microbiota

International audienceSeeds are involved in the transmission of microorganisms from one plant generation to the next and consequently act as reservoirs for the plant microbiota. The driving processes influencing seed microbiota assemblage have not been yet deciphered because of confounding factors related to environmental location, agricultural practices and host genotype selection. Nine genotypes were chosen among a large panel of genetically diverse Brassica napus accessions. The taxonomic structure of the seed microbiota was monitored by amplification and subsequent high-throughput sequencing of gyrB and ITS1 markers for two successive years on seed lots collected from self-pollinated plants. Seed germination capacities were compared between all seed lots. Although harvesting year was the main driver of seed microbiota composition, the host genotype also significantly altered the structure of seed microbial assemblages. The core microbiota of B. napus included nine fungal taxa shared between all the genotypes and years, while no bacterial taxa were conserved across all genotypes and years. The harvesting year had the major effect on seed germination but with some differences between genotypes. The study demonstrated the relative contribution of host- and environmental-filtering on the assemblage of the seed microbiota. It suggested some influence of these assemblages on seed germination

LINGO-1, a protein involved in various neurodevelopmental processes, interacts with neurofibromin (Nf1), the protein responsible for neurofibromatosis type I: molecular studies and functional implications

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Direct Comparison of Bayesian and Fermi Deconvolution Approaches for Myocardial Blood Flow Quantification: In silico and Clinical Validations

International audienceCardiac magnetic resonance myocardial perfusion imaging can detect coronary artery disease and is an alternative to single-photon emission computed tomography or positron emission tomography. However, the complex, non-linear MR signal and the lack of robust quantification of myocardial blood flow have hindered its widespread clinical application thus far. Recently, a new Bayesian approach was developed for brain imaging and evaluation of perfusion indexes ( Kudo et al., 2014 ). In addition to providing accurate perfusion measurements, this probabilistic approach appears more robust than previous approaches, particularly due to its insensitivity to bolus arrival delays. We assessed the performance of this approach against a well-known and commonly deployed model-independent method based on the Fermi function for cardiac magnetic resonance myocardial perfusion imaging. The methods were first evaluated for accuracy and precision using a digital phantom to test them against the ground truth; next, they were applied in a group of coronary artery disease patients. The Bayesian method can be considered an appropriate model-independent method with which to estimate myocardial blood flow and delays. The digital phantom comprised a set of synthetic time-concentration curve combinations generated with a 2-compartment exchange model and a realistic combination of perfusion indexes, arterial input dynamics, noise and delays collected from the clinical dataset. The myocardial blood flow values estimated with the two methods showed an excellent correlation coefficient ( r 2 > 0.9) under all noise and delay conditions. The Bayesian approach showed excellent robustness to bolus arrival delays, with a similar performance to Fermi modeling when delays were considered. Delays were better estimated with the Bayesian approach than with Fermi modeling. An in vivo analysis of coronary artery disease patients revealed that the Bayesian approach had an excellent ability to distinguish between abnormal and normal myocardium. The Bayesian approach was able to discriminate not only flows but also delays with increased sensitivity by offering a clearly enlarged range of distribution for the physiologic parameters