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International audience; Introduction - Sustained high alcohol intake is necessary but not sufficient to produce alcohol-related cirrhosis. Identification of risk factors, apart from lifetime alcohol exposure, would assist in discovery of mechanisms and prediction of risk. Methods - We conducted a multicenter case-control study (GenomALC) comparing 1,293 cases (with alcohol-related cirrhosis, 75.6% male) and 754 controls (with equivalent alcohol exposure but no evidence of liver disease, 73.6% male). Information confirming or excluding cirrhosis, and on alcohol intake and other potential risk factors, was obtained from clinical records and by interview. Case-control differences in risk factors discovered in the GenomALC participants were validated using similar data from 407 cases and 6,573 controls from UK Biobank. Results - The GenomALC case and control groups reported similar lifetime alcohol intake (1,374 vs 1,412 kg). Cases had a higher prevalence of diabetes (20.5% (262/1,288) vs 6.5% (48/734), P = 2.27 × 10) and higher premorbid body mass index (26.37 ± 0.16 kg/m) than controls (24.44 ± 0.18 kg/m, P = 5.77 × 10). Controls were significantly more likely to have been wine drinkers, coffee drinkers, smokers, and cannabis users than cases. Cases reported a higher proportion of parents who died of liver disease than controls (odds ratio 2.25 95% confidence interval 1.55-3.26). Data from UK Biobank confirmed these findings for diabetes, body mass index, proportion of alcohol as wine, and coffee consumption. Discussion - If these relationships are causal, measures such as weight loss, intensive treatment of diabetes or prediabetic states, and coffee consumption should reduce the risk of alcohol-related cirrhosis.

International audience; BACKGROUND and AIMS: Only a minority of excess alcohol drinkers develop cirrhosis. We developed and evaluated risk stratification scores to identify those at highest risk. METHODS: Three cohorts (GenomALC-1: n=1690, GenomALC-2: n=3037, UK Biobank: relevant n=6898) with a history of heavy alcohol consumption (≥80 g/day (men), ≥50 g/day (women), for ≥10 years) were included. Cases were participants with alcohol-related cirrhosis. Controls had a history of similar alcohol consumption but no evidence of liver disease. Risk scores were computed from up to eight genetic loci identified previously as associated with alcohol-related cirrhosis and three clinical risk factors. Score performance for the stratification of alcohol-related cirrhosis risk was assessed and compared across the alcohol-related liver disease spectrum, including hepatocellular carcinoma (HCC). RESULTS: A combination of three single nucleotide polymorphisms (SNPs) (PNPLA3:rs738409, SUGP1-TM6SF2:rs10401969, HSD17B13:rs6834314) and diabetes status best discriminated for cirrhosis risk. The odds ratio (OR) and 95% confidence intervals (CI) for the extreme score quintiles (Q1-Q5) of the 3-SNP score, based on independent allelic effect size estimates, were 5.99 (4.18;8.60) (GenomALC-1); 2.81 (2.03;3.89) (GenomALC-2); and 3.10 (2.32;4.14) (UK Biobank). Patients with diabetes and high-risk score, compared to those without diabetes and a low-risk score, had ORs increased to 14.7 (7.69;28.1) (GenomALC-1) and 17.1 (11.3;25.7) (UK Biobank). Patients with cirrhosis and HCC had significantly higher mean risk scores than patients with cirrhosis alone (0.76±0.06 versus 0.61±0.02, p=0.007). Score performance was not significantly enhanced by information on additional genetic risk variants, body mass index or coffee consumption. CONCLUSIONS: A risk score based on three genetic risk variants and diabetes status can provide meaningful risk stratification for cirrhosis in excess drinkers, allowing earlier prevention planning including intensive intervention. LAY SUMMARY: Excessive chronic drinking leads to liver cirrhosis in some people, but so far there is no way to identify those at high risk of developing this debilitating disease. Our study has developed a genetic risk score (GRS) test that can identify patients at high risk and shows that the risk of cirrhosis is increased >10-fold with just two risk factors - diabetes and high GRS. Risk assessment using this test has potential for early and personalised management of this disease in high-risk patients.

International audience; Background and aims - Only a minority of heavy drinkers progress to alcohol-associated cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC. Approach and results - We analyzed data from 1,128 subjects of European ancestry with ALC and 614 heavy-drinking subjects without known liver disease from Australia, the United States, the United Kingdom, and three countries in Europe. A genome-wide association study (GWAS) was performed, adjusting for principal components and clinical covariates (alcohol use, age, sex, body mass index, and diabetes). We validated our GWAS findings using UK Biobank. We then performed a meta-analysis combining data from our study, the UK Biobank, and a previously published GWAS. Our GWAS found genome-wide significant risk association of rs738409 in patatin-like phospholipase domain containing 3 (PNPLA3) (odds ratio [OR] = 2.19 [G allele], P = 4.93 × 10 ) and rs4607179 near HSD17B13 (OR = 0.57 [C allele], P = 1.09 × 10 ) with ALC. Conditional analysis accounting for the PNPLA3 and HSD17B13 loci identified a protective association at rs374702773 in Fas-associated factor family member 2 (FAF2) (OR = 0.61 [del(T) allele], P = 2.56 × 10 ) for ALC. This association was replicated in the UK Biobank using conditional analysis (OR = 0.79, P = 0.001). Meta-analysis (without conditioning) confirmed genome-wide significance for the identified FAF2 locus as well as PNPLA3 and HSD17B13. Two other previously known loci (SERPINA1 and SUGP1/TM6SF2) were also genome-wide significant in the meta-analysis. GeneOntology pathway analysis identified lipid droplets as the target for several identified genes. In conclusion, our GWAS identified a locus at FAF2 associated with reduced risk of ALC among heavy drinkers. Like the PNPLA3 and HSD17B13 gene products, the FAF2 product has been localized to fat droplets in hepatocytes. Conclusions - Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC.

International audience; Researchers have claimed that craving and Attentional Bias (AB) towards alcohol-related cues can be explained by a common incentive-salience mechanism. However, the exact relationship between AB and craving is a matter of debate. The aim of this study was to show that metacognitions moderate the effect of AB on craving. A sample of 38 alcohol abusers undergoing post-withdrawal treating in a hospital setting completed the visual Dot Probe Detection Task (DPDT), while both pre- and post-task measures of craving were recorded. Our results confirmed significant effects of both exposure to pictures of alcohol, and metacognitions, on craving; in particular, the interaction Metacognition * DPDT was significant. Although we initially confirmed a significant main effect of AB on craving, it became non-significant when adjusted for inter-subject variance, and metacognitions. The effect of the interaction AB * Metacognition on craving was not significant. Our findings support the hypothesis that craving and AB share variance, but the relationship appears to be spurious, and caused by confounding factors. We discuss these results with reference to the metacognitive model of addiction.

International audience; Addiction transfer from alcohol to sugar has been demonstrated in the alcohol postdependent state model in rats. To assess whether changes in sugar intake and craving can occur during alcohol withdrawal in humans we conducted a prospective, observational study in a university hospital addictions treatment center. Recruited patients had severe alcohol use disorder, were hospitalized for 7 days in the short-stay unit for alcohol withdrawal and then for 6 weeks in the rehabilitation unit. During the hospital stay, they had no access to alcohol but had full access to sweet products and beverages in a shop and vending machines located inside the hospital. Alcohol craving was assessed using a visual analogue scale on days 1, 15 and 45. Sugar craving, sweet products stored by patients in their rooms and weight were assessed on the same days. Thirty-five patients were included. Sugar craving increased in 14 patients during the hospital stay while no change was observed in the remaining 21. Significant increases in both the amounts of sweet products stored in the patients' rooms (p

Les Interventions Non Medicamenteuses (INM) sont devenues des solutions incontournables pour ameliorer la qualite de vie et la sante. Elles presentent dans certains cas un impact positif sur la duree de vie et des benefices sociaux et economiques. Leur usage augmente sans cesse. Une plateforme universitaire collaborative basee a Montpellier, la Plateforme CEPS, reflechit aux manieres de les evaluer. Cet article presente plus en detail ses activites.

International audience; Background and aims: Completely substituting e-cigarettes (EC) for combustible tobacco cigarettes reduces exposure to toxicants and carcinogens. However, a large proportion of EC users (dual users) continue to smoke conventional cigarettes. This study aimed to compare estimated nicotine intake and e-cigarette use characteristics between exclusive EC users and dual users.Design: Web-based anonymous cross-sectional survey.Setting: France.Participants: A total of 3189 adults, current users of electronic cigarettes (EC). Data collection between 4 October 2014 and 11 November 2014.Measurements: Primary outcome: estimated nicotine intake per day (mg) from participants' reports.Secondary outcomes: duration, frequency of EC use and nicotine content of e-liquids used/day. Dual use was defined as using at least one cigarette per day while also using EC.Findings: A total of 2836 respondents reported exclusive EC use and 353 reported being dual users. Backward stepwise logistic regression showed that dual users had higher estimated combined daily nicotine intake from e-liquids and cigarettes [estimate: 2.14, standard error (SE) = 0.26, adjusted odds ratio (aOR) = 8.48, 95% confidence interval (CI) = 5.11-14.09, P < 0.001], but lower daily nicotine intake from EC (estimate: -2.14, SE = 0.26, aOR = 0.12, CI = 0.07-0.196, P < 0.001) and reported fewer months of EC use (estimate: -0.31, SE = 0.14, aOR = 0.73, CI = 0.56-0.95, P = 0.022) compared with exclusive EC users.Conclusion: Dual e-cigarette users in France may have higher nicotine intake overall than exclusive e-cigarette users, but they may take in less nicotine from their e-cigarettes.

International audience; Background: The objective was to explore the role of patient sex in cognitive recovery and to identify predictive factors for non-recovery in alcohol use disorder (AUD). Methods: All patients with AUD admitted to a residential addictions treatment center were systematically assessed at admission and after 6 weeks of abstinence in a controlled environment. The inclusion criteria were that patients were admitted for AUD with baseline alcohol-related cognitive impairment (baseline total Montreal Cognitive Assessment (MoCA) score \textless 26) and reassessed at 6 weeks (n = 395). A logistic regression model was built to determine the influence of sex on recovery status (MoCA \textless or >= 26) taking into account the interaction effect of sex with alcohol consumption on cognitive function. Results: The mean age was 50.10 years (SD = 9.79), and 27.41% were women. At baseline, the mean MoCA scores were 21.36 (SD = 3.04). Participants who did not achieve recovery (59.3% of women vs 53.8% of men) had lower total MoCA scores at baseline. The 2 factors that was significantly and independently associated with non-recovery and with a non-zero coefficient was being a woman and initial MoCA score (respective adjusted odds ratios (AOR) = 1.5 and 0.96, p-values \textless 0.05). Conclusions: These results could influence the time required in a controlled environment to maintain abstinence and the duration of in-care for women.

Author(s): Whitfield, John B; Rahman, Khairunnessa; Haber, Paul S; Day, Christopher P; Masson, Steven; Daly, Ann K; Cordell, Heather J; Mueller, Sebastian; Seitz, Helmut K; Liangpunsakul, Suthat; Westerhold, Chi; Liang, Tiebing; Lumeng, Lawrence; Foroud, Tatiana; Nalpas, Bertrand; Mathurin, Philippe; Stickel, Felix; Soyka, Michael; Botwin, Gregory J; Morgan, Timothy R; Seth, Devanshi; GenomALC Consortium | Abstract: BackgroundThe risk of alcohol-related liver cirrhosis increases with increasing alcohol consumption, but many people with very high intake escape from liver disease. We postulate that susceptibility to alcoholic cirrhosis has a complex genetic component and propose that this can be dissected through a large and sufficiently powered genomewide association study (GWAS).MethodsThe GenomALC Consortium comprises researchers from Australia, France, Germany, Switzerland, United Kingdom, and United States, with a joint aim of exploring the genetic and genomic basis of alcoholic cirrhosis. For this National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism funded study, we are recruiting high-risk drinkers who are either cases (with alcoholic cirrhosis) or controls (drinking comparable amounts over similar time, but free of significant liver disease). Extensive phenotypic data are obtained using semistructured interviews and patient records, and blood samples are collected.ResultsWe have successfully recruited 859 participants including 538 matched case-control samples as of September 2014, using study-specific inclusion-exclusion criteria and data collection protocols. Of these, 580 are cases (442 men and 138 women) and 279 are controls (205 men and 74 women). Duration of excessive drinking was slightly greater in cases than controls and was significantly less in women than men. Cases had significantly lower lifetime alcohol intake than controls. Both cases and controls had a high prevalence of reported parental alcohol problems, but cases were significantly more likely to report that a father with alcohol problems had died from liver disease (odds ratio 2.53, 95% confidence interval 1.31 to 4.87, pn=n0.0055).ConclusionsRecruitment of participants for a GWAS of alcoholic cirrhosis has proved feasible across countries with multiple sites. Affected patients often consume less alcohol than unaffected ones, emphasizing the existence of individual vulnerability factors. Cases are more likely to report liver disease in a father with alcohol problems than controls, consistent with a potential genetic component to the risk of alcoholic cirrhosis.

We report a new strategy based on scientific education for sensitizing teenagers to the addiction-related harms. This strategy is diverted from a program called “Apprentis Chercheurs”. Pairs of young adolescents are welcome in research laboratories working on addiction all along the school year. They are fully integrated in the research team and directly participate to the experiments under the supervision of a senior researcher. At the end of the school year, they orally communicate their results to other students of their schools, their teachers, their parents and the research team in a peer-to-peer approach during a scientific conference organized within every participant research center.

Aim : Optimal management of hepatitis C virus (HCV) infection is controversial in heavy drinkers. We compared the management of HCV infection of heavy drinkers with that of patients without a history of alcohol abuse. Methods : In a retrospective case–control study, 69 HCV-infected heavy drinkers [daily alcohol consumption at referral above 60 g/day, hereafter ‘alcohol group’] were compared with matched HCV-infected patients with low alcohol consumption (

This study aims to evaluate the effectiveness of a web-based intervention to reduce alcohol consumption among hazardous drinkers. A two-group parallel randomized controlled trial was conducted among adults identified as hazardous drinkers according to the Alcohol Use Disorders Identification Test. The intervention delivers personalized normative feedback and some general information about alcohol. Participants can review their motivations and fears regarding reducing their alcohol intake, set individual goals and monitor their progress via a consumption diary and other tools. Within the control group, participants were provided with the same diary but could not access other services from the program. The primary outcome measure was the absolute difference in weekly alcohol intake (WAI) between baseline and 6-week follow-up. Secondary outcome measures included: relative difference in WAI; difference in excessive drinking and significant WAI reduction (decrease of 10% or more in WAI). One thousand one hundred and forty-seven people participated in the trial and 339 subjects completed it. Relative to the control group, participants in the intervention group reported a significantly greater mean absolute reduction in WAI (-3.3 versus -1.2, P = 0.03). Secondary outcomes also presented significant effects. This trial provides preliminary support to the effectiveness of this program in helping hazardous drinkers reduce their drinking, provided it is completely and regularly used.

Background. Cognitive dysfunction is a common feature in alcohol use disorders. Its persistence following alcohol detoxification may impair quality of life and increase the risk of relapse. We analyzed cognitive impairment changes using the Montreal Cognitive Assessment (MoCA) score in a large sample of alcohol-dependent inpatients hospitalized for at least 4 weeks. Method. This was an observational longitudinal survey. Inclusion criteria were alcohol dependence (DSM-IV) and alcohol abstinence for at least one week. The MoCA test was administered on admission and at discharge. Results. 236 patients were included. The mean MoCA score significantly increased from 22.1±3.7 on admission to 25.11±3.12 at discharge. The corresponding effect-size of improvement was high, 1.1 [95% CI 1.0–1.2]. The degree of improvement was inversely correlated with the baseline MoCA score. The rate of high and normal, that is, >26, MoCA values increased from 15.8% on admission to 53.8% at discharge. MoCA score improvement was not correlated with the total length of abstinence prior to admission. Conclusion. The MoCA score seems to be a useful tool for measuring changes in cognitive performance in alcohol-dependent patients. A significant improvement in cognitive function was observed whatever the degree of impairment on admission and even after a long abstinence period.

Article disponible en ligne à l'adresse : http://www.scirp.org/journal/psych; International audience; We performed a community research program in order to analyze the evolution of interpersonal values following alcohol withdrawal in alcoholics attending to a self-help group. The Gordon ques-tionnaire on interpersonal values was administered every 3 months during one year to 145 indi-viduals having recently stopped drinking. At baseline, scores of 5 interpersonal categories (de-pendence, conformism, consideration, independence, kindness) were in the medium interval of usual values while that of command category was low, specifically in men. Values of conformism and independence increased according to time while those of dependence and consideration de-creased but the differences were significant only in those who remained abstinent all along the observation period. In those who relapsed, there were no modifications; however, sharing these values might have allowed these subjects to be less isolated. We will describe in details the nature of these evolutions.

Background. Defective hepatitis B virus (HBV) particles, generated from singly spliced HBV RNA, have been detected in chronic carriers of HBV. The present study was designed to quantify the expression of defective HBV (dHBV) and wild-type HBV (wtHBV) genomes in the serum of patients with HBV infection and its relation to the severity of liver disease. Methods. HBV and dHBV loads were determined by quantitative polymerase chain reaction in the serum of 89 untreatedHBV-infectedpatients(31coinfectedwithhumanimmunodeficiencyvirus[HIV]type1)withliverdisease of different stages. The ratio of dHBV DNA to total (wtHBV plus dHBV) HBV DNA (dHBV/HBV ratio) was used to express data independently of the level of viral replication. Results. DespiteaglobalcorrelationbetweendHBVandwtHBVload,thedHBV/HBVratiorangedfrom0.001% to 69%. The variation in dHBV/HBV ratio was independent of HIV coinfection, HBV genotype, and precore mutations. The mean dHBV/HBV ratio was higher in patients with severe liver necrosis and fibrosis. Conclusions. OurdataindicatethatanelevateddHBV/HBVratioisassociatedwithlivernecroinflammationand fibrosis disease, suggesting a regulation of dHBV expression according to the severity of the liver disease. The dHBV/ HBV ratio may help to better define liver disease stage during HBV infection. Persistent human hepatitis B virus (HBV) infection is a major public health problem. The major complications of chronic HBV infection are the development of liver cirrhosis and hepatocellular carcinoma (HCC) [1‐3]. Evidence indicating a direct involvement of HBV in this process is now available [3]; indeed, recent data have demonstrated that serum HBV DNA levels are strong predictorsoftheriskofHCC,independentofhepatitisB e antigen (HBeAg) expression, serum alanine amino

Background: Liver biopsy indication for the evaluation of alcoholic liver disease is controversial. Our aim was to investigate the influence of the biopsy on the patients’ motivation for abstinence. Methods: We retrospectively analysed, in a population of 324 patients hospitalized for alcohol withdrawal, the impact of liver biopsy on the following clinical outcomes: rapid loss to follow-up (immediately after hospital discharge), early relapse ( 12 months). The biopsy was performed in 136 patients who had liver enzymes perturbations. Hepatic lesions were graded as mild (isolated steatosis and/or non-bridging fibrosis), moderate (bridging fibrosis and/or moderate alcoholic hepatitis) or severe (cirrhosis and/or marked alcoholic hepatitis) in 66 (48%), 41 (30%) and 29 (21%) cases, respectively. Results: In univariate analysis, patients who had a liver biopsy were less likely to be rapidly lost to follow-up (12% versus 27%, P = 0.003) but had a lower rate of long-term abstinence (20% versus 34%, P = 0.025). In multivariate analysis, age was the only factor significantly associated with clinical outcome: older patients had higher rate of long-term abstinence (OR = 1.041; P = 0.010). Among patients who had a biopsy, those with severe hepatic lesions had a lower rate of rapid relapse than those with moderate or mild lesions (32% versus 68% and 56%, P = 0.018) but the rate of long-term abstinence was similar in the three groups. Conclusion: This observational study does not support the notion that liver biopsy has a significant influence on the maintenance of alcohol abstinence in patients with alcoholic liver disease.

To optimize the management of patients with chronic hepatitis C virus (HCV) infection, noninvasive tests to determine the degree of hepatic fibrosis have been developed. The aims of this study were (1) to validate a simple, inexpensive, noninvasive test called FIB-4, which combines standard biochemical values (platelets, ALT, AST) and age, in a series of 847 liver biopsies performed in HCV-monoinfected patients; and (2) to compare the results of 780 FIB-4 and FibroTests performed the same day in a series of 592 HCV-infected patients. The FIB-4 index enabled the correct identification of patients with severe fibrosis (F3-F4) and cirrhosis with an area under the receiver operating characteristic curve of 0.85 (95% CI 0.82-0.89) and 0.91 (95% CI 0.86-0.93), respectively. An FIB-4 index1.45 had a negative predictive value of 94.7% to exclude severe fibrosis with a sensitivity of 74.3%. An FIB-4 index higher than 3.25 had a positive predictive value to confirm the existence of a significant fibrosis (F3-F4) of 82.1% with a specificity of 98.2%. Using these ranges, 72.8% of the 847 liver biopsies were correctly classified. The FIB-4 index was strongly correlated to the FibroTest results for a score1.45 or3.25 (kappa = 0.561, P0.01). A FIB-4 value1.45 or3.25 (64.6% of the cases) was concordant with FibroTest results in 92.1% and 76%, respectively.For values outside 1.45-3.25, the FIB-4 index is a simple, accurate, and inexpensive method for assessing liver fibrosis and proved to be concordant with FibroTest results.

Objective No efficient medical treatment is available for severe acute hepatitis (SAH) except N-acetylcysteine for acetaminophen-induced acute liver failure. The human C-type lectin Reg3α, referred to as ALF-5755, improved survival in an animal model of acute liver failure and was well tolerated in a phase 1 trial in humans. We performed a phase 2a trial of ALF5755 in non-acetaminophen induced SAH. Design double-blind, randomized, placebo-controlled study. The primary end-point was the improvement in the coagulation protein synthesis assessed by the change of Prothrombin (PR) during the 72 hours following treatment initiation calculated as PRH0 minus PRH72 divided by 72 (PR slope H0H72). Intention to treat (ITT) and per-protocol (PP) analysis of the entire group and the Hepatitis B virus (HBV)/AIH (auto-immune hepatitis) sub-group were done separately. Results 57 patients were included. Twenty-eight received ALF-5755, 29 the placebo. Etiologies were: Hepatitis A (n = 10), HBV (n = 13), AIH (n = 9), drug-induced (n = 8), other (n = 17). On the whole group, nor the PR slope H0H72 (0.18±0.31 vs 0.25±0.32), nor the transplant-free survival rate at day 21 (75 vs 86%) differed between groups. Conversely, in the HBV-AIH subgroup, in which ALF was more severe, PR slope H0-H72 was higher in the ALF-5755 arm, the difference being significant in PP analysis (0.048±0.066 vs -0.040±0.099, p = 0.04); the median length of hospitalization was lower in the ALF-5755 group (8 vs 14 days, p = 0.02). Conclusion ALF-5755 was not efficient in a ITT analysis performed on the whole sample; however it led to a significant, although moderate, clinical benefit in a PP analysis of the sub-group of patients with HBV or AIH related SAH. As HBV is the major cause of SAH in Asia and Africa and AIH a growing cause, this study emphasizes the need to pursuit the evaluation of this novel medical treatment of SAH. Trial Registration ClinicalTrials.gov NCT01318525

AIMS: Although the prevalence of alcohol problems amongst detainees is suspected to be high, often only more flagrant problems are detected, restricting the possibilities for intervention in alcohol misuse and reducing opportunities for preventive efforts. This study examined the re-test reliability of AUDIT (the Alcohol Use Disorder Identification Test) in screening prisoners METHODS: AUDIT was administered for the first time on the day of entry to prison and again about 15 days later. The results were analysed according to two AUDIT thresholds: a score of 8 or higher and 12 or higher. RESULTS: Of 75 consecutive entrants tested, 47 male prisoners completed the study. At the first administration, 19.1% of these 47 men met criteria for a probable alcohol problem but this percentage rose to 59.6% on the second occasion (P = 0.0001). The proportion of subjects with a score 12 or higher (probably dependent) was 10.6% the first time versus 42.6% the second time (P = 0.0001). In the 19 who scored positive at the second administration only, changes in answers to the 10 items were coherent with a total score growing from 3.0 to 18.1 (P = 0.0001). No prisoner had a lower AUDIT score on the second administration. As alcohol problems are not routinely considered during the medical and biological examination at entry, no confirmation of the AUDIT results could be obtained, although those obtained at the second administration fitted well with the prevalence rates in previous reports. CONCLUSIONS: AUDIT, for the purpose of giving a prevalence estimate or to enter appropriate prisoners into more detailed assessment or interventions, should not be conducted immediately at entry, but some weeks later.

Article en libre accès : http://file.scirp.org/Html/5-6901050_44430.htm; International audience; Many studies have examined the risk factors for relapse in alcohol-dependent patients within the first year of treatment, and have generally focused on two personality dimensions: emotional instability and difficulty in establishing relationships. In this study, we examine if these weaknesses remain in prolonged alcohol abstinence. To do so, we administer the NEO PI-R to two groups of subjects. Group 1, Inactive Drinkers (ID), consists of 51 patients with at least two years of abstinence (average length of abstinence for this group is 6.2 years); Group 2, Recently Detoxified Drinkers (RDD), comprises 93 patients who have recently ceased consuming alcohol. Based on NEO PI-R scores, our results evidence that inactive drinkers experience significant reduction in emotional instability and improvement in relationships to others. We further observe that, with long-term abstinence, these personality dimensions normalize, ceasing to be risk factors for relapse. Additionally, we find that this long-term amelioration of traits altered by alcohol amounts to an improved behavioral adaptation to life events rather than an actual change in personality.

The purpose of this study was to compare interferon-alfa alone (12-month course with high initial doses) with a combination of interferon-alfa and ribavirin in patients infected with genotype 1b. Three hundred and seven patients were randomized into 3 groups to receive 6 mega units (MU) of interferon-alfa-2b subcutaneously 3 times weekly for 6 months followed by 3 MU for 6 months (n = 95, group A); 10 MU for 3 months followed by 6 MU for 3 months, followed by 3 MU for 6 months (n = 83, group B); or the group-A schedule in combination with ribavirin (n = 129, group C) for 4 (n = 46), 6 (n = 44), or 12 months (n = 39). Negative polymerase chain reaction (PCR) was more frequent in group C than in groups A or B after 3 months of treatment (P< .006), at the end of treatment (P= .017), and at the end of follow-up (32.8%, 16.9%, and 14.1%, respectively, P< .003). A complete response (negative PCR and normal alanine transaminase) was higher in group C than in the other groups and when comparing 12- to 4- and 6-month combination therapy at the end of treatment (P = .05) and of follow-up (45.2% vs. 25.4%, respectively, P = .05). The greater efficacy of the combination was related to the higher rate of primary virological response and also to a decrease in the percentage of breakthrough and of relapse. In 1b-infected patients, the combination of high doses of interferon-alfa (6 MU) and ribavirin for 12 months appears to be the best therapy, with a high rate of sustained response.

Background: Since the identification of the hepatitis C virus (HCV) in 1989, hepatitis C infection has been recognized as an infection of public health importance. However, the magnitude of the problem is not well estimated at the European level. In order to assess the burden of HCV infection and to analyse the prevention and management policies of this illness at the European level, we performed a survey of European Union (EU) member state health authorities. Methods: For this purpose, we collected all currently running policies regarding the surveillance, prevention and medical care of HCV infection in EU states through a questionnaire sent to the public health authorities of each member state. Results: Based on the data reported by the different member-states, we estimated that 2.4–5.0 million subjects are HCV seropositive in the EU. If we assume, in accordance with the literature, that approximately 70% of those seropositive for HCV have a viral multiplication, 1.7–3.5 million subjects are potentially infectious and most of them may need to be treated. However, the level of assessment of HCV burden is very variable from one state to another and needs to be improved. For HCV prevention and management, the current national policies and practices are very heterogeneous. The surveillance systems for HCV developed in the EU countries need to be Improved and harmonized before the establishment of a European surveillance network. Conclusions: Based on these findings, there is need to promote, coordinate, support and fund European collaborations for this major public health problem.

Several epidemiological studies suggest that chronic alcoholics are at risk of viral infections. Clinical and basic research has demonstrated that alcohol not only worsens the natural history of chronic viral hepatitis, but also seems to interact with the viral replication cycle leading to an unusual serum virological profile and/or modification in the serum concentration of viral particles. Infections with hepatitis B and C viruses are a major risk for the development of hepatocellular carcinoma in excessive drinkers who should be protected against these viruses.

The prognosis for patients with primary liver cancer (PLC) often depends on tumor recurrence and the development of extrahepatic metastases, particularly after liver transplantation. We have developed a sensitive test to detect both spontaneous circulation of tumor cells and the spread of liver cells due to chemoembolization and alcoholization. Reverse-transcription polymerase chain reaction was used to search for cells expressing alpha-fetoprotein (AFP) messenger RNA in the peripheral blood of 84 patients with PLC and 102 controls (55 patients with chronic hepatitis and/or cirrhosis, 10 patients with benign liver tumors or liver metastases from intestinal cancers, and 37 healthy individuals). By spiking the blood of healthy volunteers with HepG2 cells, we assessed the sensitivity limit: one HepG2 cell mixed with 10 7 leukocytes. All 102 controls tested negative. In contrast, 28 patients (33.3%) with PLC tested positive. Positivity for the test was significantly associated with portal thrombosis, tumor size, intravascular tumor emboli, serum AFP level, and extrahepatic metastases. Patients were followed up for a mean period of 39 +/- 51 weeks: the probability of developing extrahepatic metastases was significantly higher in positive than in negative patients. Eighteen negative patients with PLC were tested before, 1 hour after, and 24 hours after locoregional therapy: 9 tested positive either 1 or 24 hours after alcoholization or chemoembolization. In conclusion, we have developed a highly specific and sensitive test to detect circulating tumor cells in patients with PLC. This test is likely to be clinically useful in evaluating the risk of developing extrahepatic metastases and the possibility of iatrogenic spreading of liver-derived, possibly tumorous, cells. (Hepatology 1997 Oct;26(4):998-1005)

Recent studies performed in Japan have suggested that hepatitis C virus (HCV) genome heterogeneity might be taken as a predictive virological parameter of response to interferon alfa (IFN-alpha) treatment. However, there is presently no information on the impact of this virological parameter in patients from Western countries infected by different HCV genotypes. We have investigated this issue by using amplification of HCV E2 hypervariable region 1, followed by single-strand conformation polymorphism assay (PCR-SSCP). We have studied 95 French patients infected with various genotypes and treated with IFN-alpha-2b. We analyzed the impact of the following parameters by univariate and multivariate analyses: HCV heterogeneity, HCV genotype, viral load, and liver histology in response to therapy. Age40 years (P.01), viral load35 x 10(5) Eq/mL (P.01), genotype 1 (P.01), and a number of SSCP bands3 (P.001) were significantly associated with nonresponse or relapse; cirrhosis was associated with nonresponse. In multivariate analysis, three variables were independently associated with the absence of long-term response: SSCP bands3, genotype 1, and viral load35 x 10(5) with odds ratios of 19, 7.5, and 11.8, respectively. Our data establish the major importance of HCV genome heterogeneity in patients infected with both HCV types associated with low (genotype 1b) or high (genotype 3a) response to IFN-alpha.

Background: Behavioral addiction is an emerging concept based on the resemblance between symptoms or feelings provided by drugs and those obtained with various behaviors such as gambling, etc. Following an observational study of a tango dancer exhibiting criteria of dependence on this dance, we performed a survey to assess whether this case was unique or frequently encountered in the tango dancing community. Methods: We designed an online survey based on both the DSM-IV and Goodman's criteria of dependence; we added questions relative to the positive and negative effects of tango dancing and a self-evaluation of the degree of addiction to tango. The questionnaire was sent via Internet to all the tango dancers subscribing to “ToutTango”, an electronic monthly journal. The prevalence of dependence was analyzed using DSM-IV, Goodman's criteria and self-rating scores separately. Results: 1,129 tango dancers answered the questionnaire. Dependence rates were 45.1, 6.9 and 35.9%, respectively, according to the DSM-IV, Goodman's criteria and self-rating scores. Physical symptoms of withdrawal were reported by 20% of the entire sample and one-third described a strong craving for dancing. Positive effects were high both in dependent and non-dependent groups and were markedly greater than negative effects. Long practice of tango dancing did not modify the dependence rate or reduce the level of positive effects. Conclusions: Tango dancing could lead to dependence as currently defined. However, this dependence is associated with marked and sustained positive effects whilst the negative are few. Identifying the precise substratum of this dependence needs further investigation.

BACKGROUND AIMS: Polymorphisms in IL28B were shown to affect clearance of hepatitis C virus (HCV) infection in genome wide association (GWA) studies. Only a fraction of patients with chronic HCV infection develop liver fibrosis a process that might also be affected by genetic factors. We performed a 2 stage GWA study of liver fibrosis progression related to HCV infection. METHODS: We studied well characterized HCV infected patients of European descent who underwent liver biopsies before treatment. We defined various liver fibrosis phenotypes on the basis of METAVIR scores with and without taking the duration of HCV infection into account. Our GWA analyses were conducted on a filtered primary cohort of 1161 patients using 780650 single nucleotide polymorphisms (SNPs). We genotyped 96 SNPs with P values

Background In France outpatient centres for the care of alcoholics are healthcare establishments providing medical, psychological and social support. Although they meet the practical needs of these patients, their degree of use in each of these domains and the respective mobilisation of different skills by the care team are not well understood. Our aim was therefore to determine in detail the management involved as a function of the severity of alcohol dependence. For this purpose, all the procedures involved were compiled in a thesaurus describing its type (psychological, medical, social, reception), its scheduled or unscheduled nature, its method (face-to-face, telephone, letter) and its duration. The severity of dependence was evaluated using the Addiction Severity Index (ASI). Results 45 patients were included and followed-up during 291 ± 114 days. The mean initial ASI scores (± SD) were: medical (M) = 0.39 ± 0.3, working-income (ER) = 0.5 ± 0.3, alcohol (A) = 0.51 ± 0.2, illicit drugs (D) = 0.07 ± 0.08, legal (L) = 0.06 ± 0.13, familial and social environment (FS) = 0.34 ± 0.26, psychological (P) = 0.39 ± 0.22. The total number of procedures was 1341 (29.8 per patient) corresponding to 754.4 hours (16.7 per patient). The intensity of management peaked during the first month of treatment, and then declined rapidly; the maximum incidence of abstinence was observed during the 3rd month of management. Interviews with patients, group therapy and staff meetings represented 68.7%, 9.9% and 13.9% of all procedures, respectively. In patients with severe dependence, as compared to moderate, management was twice as intense in the psychological and social domains, but not in the medical domain. The ASI questionnaire was completed a second time by 24 patients, after an average of 3.2 months. The improvement was significant in the M, A, D and P domains only. Conclusion This study provided an overview of the methods employed in managing a sample of patients consulting an alcoholism centre in line with standards for medical, psychological and social establishments. The predominance of the social and psychological domains over the medical domain was clearly established. Relapses were common after the third month of treatment, but a remobilisation of teams made it possible to contain them. These results provide a framework for discussions on the organisation of healthcare systems and highly suggest that staff need to maintain a constant level of care throughout the treatment process.

Background and aim: The importance of the hepatocyte ploidisation pattern to the control of cell proliferation and differentiation has been well established. However, there are no data that have characterised hepatocyte ploidy at various stages of chronic liver inflammation and fibrosis in vivo. Methods: We therefore investigated hepatocyte ploidy/binuclearity patterns in 57 patients with chronic hepatitis, using a recently developed methodology which allows simultaneous hepatocyte ploidy and binuclearity analyses on the same liver section. Results: The percentage of mononuclear diploid hepatocytes was significantly reduced in patients with high hepatitis activity and marked fibrosis (low activity: 75.1 (18.8)% v high activity: 61.8 (21.6)%, p = 0.0111, and low fibrosis: 77.3 (13.8)% v high fibrosis: 57.4 (23.3)%, p = 0.0002). Accordingly, the percentage of mononuclear polyploid hepatocytes increased in patients with high hepatitis activity and marked fibrosis (low activity: 11.9 (15.5)% v high activity: 22.2 (20.1)%, p = 0.0166, and low fibrosis: 9.4 (10.7)% v high fibrosis: 26.4 (21.6)%, p = 0.0001). In addition, the fraction of binuclear hepatocytes was significantly higher in patients with hepatitis B virus (HBV) than in those with hepatitis C virus (HCV) infections (HBV: 18.2 (7.6)% v HCV: 12.0 (4.8)%; p = 0.0020). Under multivariate analysis, HBV infection was an independent factor accounting for the larger binuclear hepatocyte fraction (p = 0.0294). Conclusion: Our results revealed an increase in the polyploid hepatocyte fraction which correlates with the severity of chronic hepatitis; moreover, we demonstrated that HBV and HCV related chronic hepatitis exhibited distinctive hepatocyte ploidy patterns, thus allowing the suggestion that these two viral infections may modulate liver ploidy through different mechanisms.

The clinical impact of circulating tumor cell (CTC) detection is controversial, mainly due to drawbacks of molecular approaches applied to this field. We sought to determine if the specific identification and counting of circulating tumor cells by cytomorphologic analysis has clinical usefulness. Peripheral blood (6 mL), treated using isolation by size of epithelial tumor cells, was obtained from 44 patients with primary liver cancer (PLC) and without metastases, 30 patients with chronic active hepatitis, 39 with liver cirrhosis, and 38 healthy individuals, and followed up for a mean period of 1 year. We searched for beta-catenin mutations in 60 single microdissected CTCs. One patient with liver cancer developed extrahepatic metastases during follow-up. CTCs and microemboli were found in 23 of the 44 patients with liver cancer and in none of the patients with chronic active hepatitis, patients with cirrhosis, or healthy subjects. Their presence was significantly associated with tumor diffusion (P =.0001) and portal tumor thrombosis (P =.006). Both the presence (P =.01) and number (P =.02) of CTCs and microemboli were significantly associated with a shorter survival. Beta-catenin mutations were found in 3 of 60 CTCs, arguing against their impact on the initial step of tumor cell invasion. In conclusion, the highly sensitive and specific detection of CTCs and microemboli may have clinical implications for cancer staging and outcome prediction. We also show the feasibility of molecular studies of individual circulating tumor cells, aimed at identifying gene mutations involved in tumor invasion.

AIMS: Although the prevalence of alcohol problems amongst detainees is suspected to be high, often only more flagrant problems are detected, restricting the possibilities for intervention in alcohol misuse and reducing opportunities for preventive efforts. This study examined the re-test reliability of AUDIT (the Alcohol Use Disorder Identification Test) in screening prisoners METHODS: AUDIT was administered for the first time on the day of entry to prison and again about 15 days later. The results were analysed according to two AUDIT thresholds: a score of 8 or higher and 12 or higher. RESULTS: Of 75 consecutive entrants tested, 47 male prisoners completed the study. At the first administration, 19.1% of these 47 men met criteria for a probable alcohol problem but this percentage rose to 59.6% on the second occasion (P = 0.0001). The proportion of subjects with a score 12 or higher (probably dependent) was 10.6% the first time versus 42.6% the second time (P = 0.0001). In the 19 who scored positive at the second administration only, changes in answers to the 10 items were coherent with a total score growing from 3.0 to 18.1 (P = 0.0001). No prisoner had a lower AUDIT score on the second administration. As alcohol problems are not routinely considered during the medical and biological examination at entry, no confirmation of the AUDIT results could be obtained, although those obtained at the second administration fitted well with the prevalence rates in previous reports. CONCLUSIONS: AUDIT, for the purpose of giving a prevalence estimate or to enter appropriate prisoners into more detailed assessment or interventions, should not be conducted immediately at entry, but some weeks later.

BACKGROUND To evaluate the impact of kidney transplantation on histopathological progression of hepatitis C virus (HCV)-related liver disease. METHODS In a retrospective study, 28 HCV-positive renal transplant patients, who underwent two sequential liver biopsies with a mean of 7.1+/-4.0 years, were compared with 28 matched immunocompetent controls. RESULTS According to the Metavir score, the initial and final activity scores (from 0 to 3) increased from 0.2+/-0.4 to 1.4+/-1.1 (P

Vaccine therapy is now used in various infectious diseases. The hepatitis B virus (HBV) leads to chronic infection in around 5% of patients with a high risk of chronic active hepatitis which may result in cirrhosis and hepatocellular carcinoma. The partial efficacy of antiviral therapies (40% of sustained inhibition of HBV replication), their cost, their possible side effects and the immune-mediated pathology of HBV infection explain the need of new immune therapies in treating HBV infection. Experimental and clinical evidences suggest the usefulness of vaccine therapy in HBV chronic infection. In a pilot and opened study, forty-six consecutive chronic HBsAg carriers with chronic hepatitis and detectable serum HBV DNA were given 3 standard injections of the GenHevac B vaccine at one month interval. Six months after the first injection, 12 patients (26.1%) had undetectable HBV DNA while 8 others showed significant decrease (more than 50%) in HBV DNA titers. Six of these 12 responders received a standard course of alpha-Interferon (5 MU thrice weekly subcutaneously for 4 months) and all six had still undetectable HBV replication at the end of follow-up. Among the 34 non responders to vaccine, 20 were given alpha-interferon and 2 the monophosphate derivate of Vidarabine: 12 of these 22 patients stopped HBV replication and in all 12, vaccine therapy had induced a significant decrease of HBV replication before the antiviral treatment with a decrease of mean serum HBV DNA from 392 pg/ml before to 217 pg/ml after vaccine therapy. In an ongoing controlled study, using the same vaccine schedule, serum HBV DNA disappeared more frequently after 6 months, in patients who were given a preS2/S vaccine (7/35) than in patients who received a S vaccine (1/21) or no vaccine (1/32). In responders to vaccine, an induction of specific proliferative responses was observed and this may contribute to the potential efficacy of anti-HBV vaccine therapy. No side-effect or vaccine-induced escape-mutants occurred during the follow-up. In summary, serum HBV DNA disappeared in 28 of the 46 patients (60.9%) who were given vaccine therapy, with (64.2%) or without (55.6%) Interferon. These results are not different at 6 months and at the end of follow-up from those of 43 HBsAg chronic carriers who were given only an antiviral treatment. Active immune therapy against HBV appears efficient and less expensive than antiviral therapies in stopping HBV replication. Such results need to be confirmed by the completed results of our controlled, randomized trial which is now conducted in our unit.

BACKGROUND & AIMS: Mutations in hepatitis C virus (HCV) nonstructural protein 5A (NS5A) may correlate with response to interferon in Japanese patients with chronic hepatitis C. The aim of this study was to examine whether these findings could be expanded to European patients infected with genotypes associated to low (1b) or high (3a) response rates. METHODS: Pretreatment serum samples of 66 patients with chronic HCV infection, 48 infected with genotype 1b and 18 with 3a, were analyzed. RESULTS: Among patients infected with genotype 3a, 1 of 7 long-term responders and none of 11 nonresponders showed NS5A amino acid mutations. Among patients infected with genotype 1b, all 7 long-term responders, but also 27 of 41 nonresponders, showed NS5A mutations. There was no correlation between number of mutations and response to therapy. In 10 patients, sequences obtained before and after treatment were compared and failed to show any change. Serum HCV RNA levels did not differ between patients with and without mutations in NS5A sequence. CONCLUSIONS: No significant correlation was found in patients infected with genotypes 1b or 3a between NS5A sequence and response to interferon alfa. NS5A mutations do not correlate with viral load. Changes in this region were not found during interferon alfa treatment. (Gastroenterology 1997 Aug;113(2):567-72)

We investigated the MspI restriction site of the human collagen type I A2 (COL1A2) gene in alcoholic subjects with and without liver disease, using the nested polymerase chain reaction to analyse trace cellular DNA in plasma samples. This procedure is rapid, it requires only 200 microliters plasma, and the results correlate perfectly with those of Southern blotting. Alcoholic subjects with acute alcoholic hepatitis had a significantly lower frequency of the minor allele than healthy controls or alcoholics with minimal liver abnormalities, i.e. steatosis. Our results reinforce the hypothesis of a genetic predisposition of certain alcoholics to liver damage.

To determine factors associated with fibrosis progression in hepatitis C virus (HCV)-infected patients without significant initial pathological lesions.Seventy six untreated HCV-infected patients with initially normal liver as defined by a Knodell scoreor = 3, with 2 liver biopsies and detectable HCV-RNA were included. Markers of fibrosis progression were assessed.Median duration of infection and time between paired biopsies was 13 (95% CI: 1-28) and 4 (95% CI: 2-16) years respectively. Alanine-transaminase (ALT) activity was normal in 43.4% of cases. 50% demonstrated progression of the necro-inflammation and 34% of fibrosis after a median time evolution of 4 years (95% CI: 2-16). The median difference in the necro-inflammation and fibrosis score between biopsies was low, 1.5 and 0.0 respectively. Univariate analysis showed there was no difference between fibrosis activity or evolution according to genotype or viral load. A higher fibrosis progression (P = 0.03) was observed in patients with body mass index (BMI)25. Fibrosis progression correlated with the time interval between biopsies (P = 0.01). A significant progression of activity (1.7 vs 0.4, P0.05) or fibrosis (0.9 vs 0.0, P0.01) was observed in patients with elevated ALT. There was a significant correlation between activity progression and fibrosis progression (P = 0.003). Multivariate analysis demonstrated that fibrosis progression was associated with elevated ALT, BMI25 and the time interval between 2 biopsies.There is no fibrosis progression in 66% of patients without significant initial histopathological lesion. Fibrosis progression is associated with elevated ALT and BMI25.

The precise nature and origin(s) of the abnormalities in lipoprotein and apolipoprotein profile associated with severe hepatic dysfunction and the presence of spur cells remain poorly defined. To shed light on this question, we have analyzed the plasma lipoprotein and apolipoprotein profiles in five patients with alcoholic cirrhosis and spur cells, and compared them with those of a group with similar hepatocellular dysfunction, but lacking spur cells, and with that of a control group. Lipoproteins were subfractionated by density gradient ultracentrifugation and their physicochemical properties were determined; apolipoprotein A-I, A-II, and B contents in plasma and the respective subfractions were quantitated by radial immunodiffusion, while the complement of low molecular weight apolipoproteins in each subfraction was analyzed by isoelectric focusing and electrophoresis in alkaline-urea polyacrylamide gels. Spur cell plasma was distinguished by reduced levels of apoA-II and elevated ratios of apoA-I/apoA-II (approximately 13:1 as compared to 3.3-3.9:1 in the other two groups), and by reduced concentrations of HDL3. Gradient fractionation showed the apoA-II content of HDL3 to be dramatically and significantly diminished in spur cell plasma; in addition, apoA-II content was reduced relative to apoA-I in this subclass (4.7:1 as compared to 1:1 in cirrhotics lacking spur cells and 1.9:1 in controls). Spur cell HDL2 was similarly deficient in apoA-II, with elevated ratios of apoA-I:apoA-II (9.8:1 in comparison with 1.9-2.5:1 in the two other groups). Nonetheless, high HDL2 concentrations were seen in both series of cirrhotic patients, irrespective of red cell morphology. Spur cell HDL2 thus appears to consist primarily of particles possessing only apoA-I, with a minor population containing both apoA-I and apoA-II. The free cholesterol content of all lipoprotein subfractions from spur cell plasma was increased, as indeed was the molar ratio of free cholesterol to phospholipid, in comparison with that of corresponding fractions from alcoholic cirrhotics lacking spur cells and of control subjects. LDL levels were reduced in spur cell plasma, thereby distinguishing this group from the cirrhotics without spur cells who displayed elevated LDL levels. Markedly reduced plasma levels of apoA-II, HDL3, and LDL appear characteristic of alcoholic cirrhotics presenting with spur cells. Our findings suggest that apoA-II may be essential to the normal function and metabolism of HDL, one aspect of which may be the transport of free cholesterol and thereby the direct or indirect maintenance of red cell morphology.

— Aims: While it was thought that all alcoholic beverages share a similar liver toxicity when drunk at a high level, recent epidemiological surveys have suggested that wine drinking might decrease the risk of alcoholic cirrhosis in heavy drinkers. Therefore, we performed a study aiming to analyse the type and the intake levels of alcoholic beverages in heavy drinkers according to the severity of the liver disease. Methods: This is a case–control study enrolling 42 cirrhotic and 60 non-cirrhotic patients. Liver status was assessed using clinical, biological, histological and ultrasonographic procedures. Alcohol consumption was recorded using the Lifetime Drinking History method. Results: We did not find any significant differences in total alcohol consumption between cases and controls and, moreover, in our series, the relative percentage of pure alcohol drunk in wine was significantly higher in cirrhotic, than in non-cirrhotic, patients. Conclusions: Our results confirm that the absence of a link between the type of alcoholic beverage and the occurrence of cirrhosis is still valid.