Early life stress in mice is a suitable model for Irritable Bowel Syndrome but does not predispose to colitis nor increase susceptibility to enteric infections.

Neonatal period is characterized by an immature intestinal barrier. Scattered evidence suggests that early life stressful events induce long lasting alterations of intestinal homeostasis mimicking Irritable Bowel Syndrome (IBS). Those observations highlighting defect of intestinal barrier by early life stress questioned its potential role as a risk factor for gastrointestinal disorders such as colitis and infections. In this study, we aimed to analyze if maternal separation (MS) in mice mimicks IBS main features. We next addressed whether MS could trigger or exacerbate colitis in genetically predisposed mice and/or enhance susceptibility to gastrointestinal infections in wild type mice. MS induced main features of IBS in adult wild type male mice i.e. intestinal hyperpermeability, visceral hypersensitivity, microbiota dysbiosis, bile acid malabsorption and low grade inflammation in intestine associated with a defect of Paneth cells and the ILC3 population. This breach in mucosal barrier functions in adults was associated with a systemic IgG response against commensal E. coli and increased IFNγ secretion by splenocytes. However, in IL10-/- mice, MS did not trigger nor worsen colitis. Furthermore, wild type mice submitted to MS did not show increase susceptibility to gastrointestinal infections (S. Typhimurium, L. monocytogenes or T. gondii) compared to controls. Altogether, our results identify MS in mice as a good experimental model for IBS mimicking all the main features. In addition, early life stress, even though it has long lasting consequences on intestinal homeostasis, does not constitute a facilitating factor to colitis in predisposed individuals nor to gastrointestinal infections in wild type mice.

The relationship between liver stiffness measurement and outcome in patients with chronic hepatitis C and cirrhosis: a retrospective longitudinal hospital study.

BACKGROUND: There is a relationship between liver stiffness measurement (LSM) and outcome of HCV patients. AIM: To evaluate the performance of LSM to predict outcome of HCV patients at risk of liver-related complication. METHODS: We established a retrospective longitudinal cohort of 341 HCV patients with unequivocal cirrhosis. All underwent LSM and were followed from September 2006 to July 2015. Outcome measure was a composite end-point of end-stage liver disease (ESLD) and/or hepatocellular carcinoma (HCC). Cox models and areas under receiver operating characteristic (AUROC) curves were used to evaluate independent risk factors of outcome. RESULTS: Overall, LSM was below the 12.5 kPa threshold in 129 (37.8%) patients, including three-fourth and one-third of patients with or without a sustained virological response respectively. Liver disease progressed in 136 (39.9%) patients after a median observational period of 23.5 months. Older age, male gender, alcohol use disorders, metabolic syndrome and LSM were independent risk factors of liver disease progression. Age, alcohol use disorders and LSM were independently associated with ESLD. Age, gender and metabolic syndrome, but not LSM, were associated with HCC. The AUROC curves for disease progression, ESLD and HCC were 0.67, 0.70 and 0.58 respectively. Patients with a liver stiffness >12.5 kPa were at the highest risk of liver disease progression; below 12.5 kPa, liver stiffness was not discriminant. CONCLUSION: Liver stiffness measurement is not a surrogate of disease progression of HCV patients with cirrhosis. HCV patients with cirrhosis should undergo the recommended follow-up, regardless of liver stiffness measurement.

Baseline sensitivity of T cells to alpha-IFN correlates with sustained virological response to IFN-based triple therapy in HCV infection.

Chronic infection with HCV is a public health problem with approximately 170 million people infected worldwide. Interferon alpha (IFNα) sensitivity in liver and IL28B genotype has been identified as important determinants of HCV clearance in the setting of pegylated interferon/ribavirin treatment. Herein, we explored IFNα sensitivity in PBMC from 21 healthy donors and 21 HCV-infected patients treated with pegylated interferon/ribavirin and HCV nonstructural protein-3 inhibitors (i.e. telaprevir/boceprevir). We explored phospho-STAT1 level as read-out for IFN signalling pathway activation in PBMC, T cells and monocytes and correlated results with virological response. We found that PBMC from healthy donors are desensitized to IFNα after priming and challenged with IFNα, with a subsequent decrease of phospho-STAT1 and interferon-stimulated genes. Furthermore, we show that CD3+ T cells, but not monocytes, become desensitized after 4 weeks of treatment, with a significant decrease of phospho-STAT1 after ex vivo IFNα stimulation. Finally, we identified baseline phospho-STAT1 level in CD3+ T cells as a potential biomarker of sustained virological response, regardless of the IL28B genotype. In the upcoming costly era of IFN-sparing regimen, baseline IFNα sensitivity could act as biomarker to define cost-effectiveness strategies of treatment by identifying patients who will or will not respond to IFN-based treatments.

Rapid progression of antiviral treatments of chronic hepatitis C virus infection.

The treatment of hepatitis C virus (HCV) infection with pegylated interferon alfa and ribavirin leads to a sustained virologic response in around 50% of patients with HCV genotype 1, 65% with HCV genotype 4, 75% with HCV genotype 3 and around 80% with HCV genotype 2. A better understanding of the HCV life-cycle recently resulted in the development of several potential direct-acting antiviral drugs (DAAs) targeting viral proteins (NS3/4A protease inhibitors, NS5B nucleos(t)idic and non nucleos(t)idic polymerase inhibitors, NS5A replication complex inhibitors). A lot of data have been reported with the combinations of pegylated interferon-alfa/ribavirin and the first generation oral DAAs, Telaprevir and Boceprevir. These regimens have demonstrated a high level of antiviral efficacy and an acceptable safety profile in treatment-naïve patients and in prior non-responders to pegylated interferon-alfa/ribavirin. After this first major step, the combination of the second generation DAAs with pegylated interferon-alfa/ribavirin will impact antiviral potency and tolerance and will reduce the duration of therapies and the pill burden. The next step will be the oral combination of new DAAs which is likely to become the standard of care for chronic HCV after 2015. Most studies are conducted in small numbers of "easy-to-treat" patients with short post-treatment period for concluding to a sustained virologic response: extension of both the numbers of treated patients and post-treatment follow-up, inclusion of more difficult-to-treat patients (experienced genotype 3-infected or genotype 1-infected patients who failed to first generation protease inhibitors, cirrhotic, HIV co-infected patients, allograft recipients or candidates to transplantation) will probably reduce the overall rate of cure.

Fundamental principles of data assimilation underlying the Verdandi library: applications to biophysical model personalization within euHeart.

We present the fundamental principles of data assimilation underlying the Verdandi library, and how they are articulated with the modular architecture of the library. This translates--in particular--into the definition of standardized interfaces through which the data assimilation library interoperates with the model simulation software and the so-called observation manager. We also survey various examples of data assimilation applied to the personalization of biophysical models, in particular, for cardiac modeling applications within the euHeart European project. This illustrates the power of data assimilation concepts in such novel applications, with tremendous potential in clinical diagnosis assistance.

T-cell responses to hepatitis B splice-generated protein of hepatitis B virus and inflammatory cytokines/chemokines in chronic hepatitis B patients. ANRS study: HB EP 02 HBSP-FIBRO.

A new hepatitis B virus (HBV) protein, hepatitis B splice-generated protein (HBSP), has been detected in liver biopsy specimens from patients with chronic active hepatitis. The aim of this study was to characterize the phenotype and functions of peripheral HBSP-specific T cells and to determine whether these T-cell responses may be implicated in liver damage or viral control. Two groups of patients were studied: HBV-infected patients with chronic active hepatitis and HBV-infected patients who were inactive carriers of hepatitis B surface antigen. HBSP-specific T-cell responses were analysed ex vivo and after in vitro stimulation of peripheral blood mononuclear cells. Soluble cytokines and chemokines were analysed in sera and in cell culture supernatants. Few HBSP- or capsid-specific T-cell responses were detected in patients with chronic active hepatitis whereas frequency of HBV-specific T cells was significantly higher in inactive carrier patients. HBSP activated CD8+ and CD4+ T cells that recognized multiple epitopes and secreted inflammatory cytokines. The IL-12 level was significantly lower in sera from asymptomatic carrier patients compared to patients with chronic active hepatitis. IL-12 and IP-10 levels in the sera were significantly and independently correlated with both alanine amino transferase and HBV DNA levels. Our results show that the HBSP protein activates cellular immune responses in HBV-infected patients but has probably no prominent role in liver damage. The pattern of cytokines and chemokines in sera was linked to HBV viral load and was consistent with the level of inflammation during chronic hepatitis.

[Treatment initiation in psychotic and manic episodes: French attitudes collected by Focus Group]. / L'initiation thérapeutique dans les épisodes psychotiques et maniaques : recueil des attitudes françaises par Focus Group.

An accurate treatment of first episodes in schizophrenia and bipolar disorders has a significant impact on compliance and prognosis. However, existing therapeutic guidelines may be poorly respected and may concern only typical clinical situations. Medical attitudes in clinical practice have been collected and structured on the basis of small interactive meetings (Focus Group [FG]), and a synthesis of practical attitudes has been compared with updated guidelines. The FG method applied to treatment initiation in schizophrenia and bipolar disorder is seen as complementary to evidence-based guidelines. It reveals that, in a reflexive manner, clinical attitudes are often more diverse and frequently consider first treatments after global evaluation, taking more into account external factors such as clinicians' experience, patient's history and willingness, clinical setting, and environment. A symptomatic approach is sometimes preferred, and a better alliance is always considered as a main objective. The FG method could be a supplementary support to continuous medical education.

Discrimination of agonist and antagonist forms of CXCL10 in biological samples.

The ready access to commercially available multiplex assays and the importance of inflammation in disease pathogenesis has resulted in an abundance of studies aimed at identifying surrogate biomarkers for different clinically important questions. Establishing a link between a biomarker and disease pathogenesis, however, is quite complex, and in some instances this complexity is compounded by post-translational modifications and the use of immunoassays that do not always discriminate between the different forms of the same protein. Herein, we provide a detailed description of an assay system that has been established to discriminate the agonist form of CXCL10 from the NH(2) -terminal truncated form of the molecule generated by dipeptidylpeptidase IV (DPP4) cleavage. We demonstrate the utility of this assay system for monitoring agonist and antagonist forms of CXCL10 in culture supernatant, patient plasma and urine samples. Given the important role of CXCL10 in chronic inflammatory diseases and its suggested role as a predictive marker in managing patients with chronic hepatitis C, asthma, atopic dermatitis, transplantation, tuberculosis, kidney injury, cancer and other diseases, we believe that our method will be of general interest to the research and medical community.

[Management, needs and expectations of patients suffering from bipolar I disorders (The ECHO study - France)]. / Prises en charge, besoins et attentes de patients souffrant de troubles bipolaires I (Étude ECHO - France).

AIM: The ECHO study is the first French study directly asking patients with bipolar I disorders on the history and experiences of their disease, their perceptions of care, their sociofamilial relationships, and their expectations regarding what should be done by healthcare professionals and their environment. METHOD: Three hundred euthymic patients suffering from bipolar disorder I were interviewed using a semi-standardized evaluation through telephone interviews. These patients were selected according to the quota method of nationally representative INSEE 99 to be representative of the French population. RESULTS: Ninety-nine percent of patients consulted at least once for psychological signs before the correct diagnosis was established. The average age at the time of diagnosis was of 30.1 years (± 11.3). The average time between first consultation for psychological symptoms and diagnosis is about 5 years. In 92% of cases, the psychiatrist is the health professional that made the diagnosis; 74% of patients were also followed by a general practitioner. One hundred percent of participants had been hospitalized for manic episodes (criterion for inclusion in the study) and 86% were also hospitalized for depressive symptoms. The experience of hospitalization is positive (feeling of security for 84% of the sample, feelings of being helped for 81% of the sample), although these experiences are also associated with the perception of confinement (52% of the sample). At the time of the interview, 97% of these patients were followed by one or more health professionals. Only 34% of these patients were taking a mood stabilizer (lithium, anticonvulsant or atypical antipsychotic with indications in France for bipolar disorder), while 44% were taking an antidepressant and 38% were taking anxiolytics; 84% of patients had experienced side effects related to their current treatment. Acceptance of the disease is difficult and only 56% of patients personally feel they suffer from bipolar disorders. Patients believe that their mental health problems have a significant impact on their lives, including impact on their self-esteem and happiness. Relationships with family, friends but also sexual relations are affected. Even in the euthymic phase, 44% of patients have difficulties in their daily tasks. Three quarters of patients said they had already experienced rejection or discrimination related to their disease. Finally, patients gave a score of 6.4 out of 10 to assess the impact of the disorder on their quality of life. Patients request more dialogue with health professionals and a more personalized treatment, taking into account side effects. They also want more information on the treatment. They would also like to be supported, together with their families, and advised on how to cope with the disease.

Supplementation with a new therapeutic oxygen carrier reduces chronic fibrosis and organ dysfunction in kidney static preservation.

Static preservation is currently the most widely used organ preservation strategy; however, decreased donor organ quality is impacting outcome negatively. M101 is an O2 carrier with high-oxygen affinity and the capacity to function at low temperatures. We tested the benefits of M101 both in vitro, on cold preserved LLC-PK1, as well as in vivo, in a large white pig kidney autotransplantation model. In vitro, M101 supplementation reduced cold storage-induced cell death. In vivo, early follow-up demonstrated superiority of M101-supplemented solutions, lowering the peak of serum creatinine and increasing the speed of function recovery. On the longer term, supplementation with M101 reduced kidney inflammation levels and maintained structural integrity, particularly with University of Wisconsin (UW). At the end of the 3-month follow-up, M101 supplementation proved beneficial in terms of survival and function, as well as slowing the advance of interstitial fibrosis. We show that addition of M101 to classic organ preservation protocols with UW and Histidine-Tryptophane-Ketoglutarate, the two most widely used solutions worldwide in kidney preservation, provides significant benefits to grafts, both on early function recovery and outcome. Simple supplementation of the solution with M101 is easily translatable to the clinic and shows promises in terms of outcome.

The accuracy of the FIB-4 index for the diagnosis of mild fibrosis in chronic hepatitis B.

BACKGROUND: The Fib-4 index is a simple and inexpensive biomarker to delineate liver fibrosis in chronic hepatitis C. AIM: To assess the accuracy of the FIB-4 index in chronic hepatitis B. METHODS: We compared the FIB-4 index with 138 synchronous liver biopsies and with 372 synchronous FibroTest performed either in France or in an endemic area (Mayotte, an overseas collectivity of France). RESULTS: The FIB-4 index allowed the correct identification of patients with nil-to-moderate fibrosis with an area under the receiving operating characteristic curve of 0.81 (P < 0.001), increasing as a function of the length of the liver biopsy (up to 0.94 for liver biopsies >or=20 mm). A cut-off value

Improved symptom control, functioning and satisfaction in French patients treated with long-acting injectable risperidone.

OBJECTIVE: To investigate the efficacy and tolerability of direct initiation of long-acting injectable risperidone (LAIR) in adults with schizophrenia or other psychotic disorders requiring a change of treatment. METHODS: Patients clinically stable for one month or more on their previous medication received 25 mg of LAIR (increased to 37.5 or 50 mg, if necessary) every 14 days for six months. RESULTS: Of 202 patients (70% male, mean age 38 years), the majority (86%) had DSM-IV schizophrenia (mainly paranoid). Previous treatments were atypical antipsychotics (65%), depot (34%) and oral (9%) conventional neuroleptics. Mean total positive and negative syndrome scale (PANSS) score was significantly reduced from baseline to treatment endpoint (79.4 versus 68.3, P<0.001), as were all subscale and symptom factor scores. The clinical global impression-disease severity (CGI-S), general assessment of functioning (GAF), health-related quality of life (SF-36) and patient satisfaction with treatment were also improved significantly. At endpoint, 31% rated the treatment as 'very good' compared with 8% at baseline. The total extrapyramidal symptoms rating scale (ESRS) and Parkinsonism subscale scores were reduced significantly (P<0.001) from baseline at one month and further improved until treatment endpoint. CONCLUSION: LAIR significantly improved disease symptoms, patient functioning, movement disorders, health-related quality of life and treatment satisfaction. It therefore provides a useful option for the management of patients with psychotic disorders.

Changes in aortic blood flow induced by passive leg raising predict fluid responsiveness in critically ill patients.

INTRODUCTION: Esophageal Doppler provides a continuous and non-invasive estimate of descending aortic blood flow (ABF) and corrected left ventricular ejection time (LVETc). Considering passive leg raising (PLR) as a reversible volume expansion (VE), we compared the relative abilities of PLR-induced ABF variations, LVETc and respiratory pulsed pressure variations (DeltaPP) to predict fluid responsiveness. METHODS: We studied 22 critically ill patients in acute circulatory failure in the supine position, during PLR, back to the supine position and after two consecutive VEs of 250 ml of saline. Responders were defined by an increase in ABF induced by 500 ml VE of more than 15%. RESULTS: Ten patients were responders and 12 were non-responders. In responders, the increase in ABF induced by PLR was similar to that induced by a 250 ml VE (16% versus 20%; p = 0.15). A PLR-induced increase in ABF of more than 8% predicted fluid responsiveness with a sensitivity of 90% and a specificity of 83%. Corresponding positive and negative predictive values (PPV and NPV, respectively) were 82% and 91%, respectively. A DeltaPP threshold value of 12% predicted fluid responsiveness with a sensitivity of 70% and a specificity of 92%. Corresponding PPV and NPV were 87% and 78%, respectively. A LVETc of 245 ms or less predicted fluid responsiveness with a sensitivity of 70%, and a specificity of 67%. Corresponding PPV and NPV were 60% and 66%, respectively. CONCLUSION: The PLR-induced increase in ABF and a DeltaPP of more than 12% offer similar predictive values in predicting fluid responsiveness. An isolated basal LVETc value is not a reliable criterion for predicting response to fluid loading.

Association of idiopathic hepatic sinusoidal dilatation with the immunological features of the antiphospholipid syndrome.

BACKGROUND: Isolated sinusoidal dilatation is an uncommon hepatic lesion and the cause is largely unknown. OBJECTIVE: To investigate whether prothrombotic disorders or perisinusoidal cell changes could be involved in pure idiopathic hepatic sinusoidal dilatation (HSD). METHODS: Evaluation for associated conditions, prothrombotic disorders, and studies of hepatic perisinusoidal cell activation in consecutive patients, seen between 1993 and 2002, with isolated sinusoidal dilatation unrelated to outflow block, sinusoidal infiltration, or hepatic granulomas. RESULTS: Among 11 patients, associated conditions were prothrombotic disorders (n = 5) and oral contraceptive use (n = 3). Prothrombotic disorders were polycythemia vera (n = 1) and anticardiolipin antibodies combined with lupus anticoagulant (n = 4). No genetic thrombophilia factor was found. Of four patients with lupus anticoagulant, three had antinuclear factors and high serum levels of anticardiolipin antibodies at repeated testing. There was no evidence of intrahepatic or extrahepatic thrombosis in any of the patients. Sinusoidal dilatation was marked in six of 11 patients (54%), including two patients with antiphospholipid antibodies. Activated perisinusoidal cells were only found around markedly dilated sinusoids. CONCLUSION: Idiopathic pure HSD is frequently associated with the immunological features of the antiphospholipid syndrome. Therefore, finding pure HSD in a liver biopsy specimen should prompt the search for antiphospholipid antibodies.

Impact of a commercial peat moss operation on water quality and biota in a small tributary of the Richibucto River, Kent County, New Brunswick, Canada.

The St-Charles Plain (Kent County, New Brunswick, Canada) commercial peat moss operation has been ongoing since 1983. To process the peat, a dry extraction method is used that requires extensive drainage of the peat bog. The water is directed toward sedimentation ponds, where it drains into a small brook, which feeds into a river affected by tidal salt water. Water discharge from the bog contains large amounts of peat particles that deposit in the surrounding watershed. As a result, the pH of the freshwater sites that receive the drainage water from the commercial operation, is fairly acidic (pH 3.9-4.7). Water samples from or near the peat moss operation have a higher concentration of total phosphorous and total organic carbon. The peat particles contain relatively high levels of total mercury, as reflected by analysis of peat sediments. However, the water samples contained low levels of dissolved mercury. Indigenous samples of biota-namely, sand shrimps (Crangon septemspinosa) and mummichogs (Fundulus heteroclitus)-did not contain mercury levels higher in the impacted sites than in the reference sites. Introduced blue mussels (Mytilus edulis) did not accumulate significant amounts of mercury during a 62-day exposure in the study area. Overall, the data suggest that although relatively large amounts of mercury-containing peat particles are discharged into the ecosystem, bioaccumulation of mercury in the biota does not occur.