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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.

To determine whether the presence of prostate-derived cells in the peripheral blood circulation is a marker of prostate cancer and to define the clinical impact of the test.We tested the peripheral blood of 99 patients with prostate adenocarcinoma (PAC), 79 of them undergoing radical prostatectomy, and 92 controls (31 healthy volunteers, 50 patients with adenoma and 11 with prostatitis) using a highly controlled procedure including reverse-transcriptase polymerase chain reaction (RT-PCR) targeted to prostate-specific antigen (PSA) mRNA. Patients were followed for 26 +/- 12 (range: 4 to 49) months. Forty tumor tissues were analyzed by immunohistochemistry for expression of p53 and E-cadherin antigens.Thirty three (33%) patients with PAC and 2 (2%) controls scored positive (p0.0001) for the test. Detection of circulating prostatic cells was associated with development of metastases (p0. 001), with relapse (p0.001) and with a serum PSA level at diagnosis higher than 15 ng./ml. (p = 0.009). The rate of development of metastases according to time was significantly higher in patients who scored positive for the test (p0.04). In a multivariate analysis, only the RT-PCR test was an independent risk factor associated with relapse (RR: 6.7). Finally, E-cadherin expression was significantly lower in the tumor tissues of positive patients as compared with those who scored negative for the test (p0.01).This RT-PCR procedure, performed at diagnosis and with appropriate controls, is a clinically useful assay in evaluating the risk of tumor recurrence after radical prostatectomy in patients with PAC.

In 1996, the French Réseau National de Santé Publique was funded by the Direction General V of the EU to perform a European survey on the epidemiology, the surveillance, the prevention and the management of hepatitis C virus (HCV) infection in the EU member states. This study included two approaches: one consisting of a survey of public health authorities on all the implemented policies dealing with epidemiological status, surveillance and prevention of HCV infection; and the second, in which a large series of hepatologists were interviewed on their own practices with regard to hepatitis C.

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.

The aim of this study was to evaluate the impact of the host immune status and of virological and environmental parameters on the development of cirrhosis during chronic hepatitis C virus infection.Liver histology (cirrhosis or not, Knodell score) was evaluated according to age, sex, route and age of contamination, alcohol consumption and immune status in a large series of 553 HBsAg-negative patients (whose duration of hepatitis C virus infection could be precisely evaluated) divided into three groups: group 1 consisted of 462 immunocompetent subjects (46.1% intravenous drug users, 53.9% transfused), infected for a mean of 12.5+/-6.7 years, including 16.6% of alcohol abusers (80 g/day); groups 2a and 2b consisted of 91 immunocompromised patients, 52 human immunodeficiency virus-coinfected patients corresponding to group 2a and 39 kidney recipients undergoing immunosuppressive therapy for group 2b, having been infected by hepatitis C virus for a mean of 12.6+/-5.3 and 11.5+/-5.3 years, respectively.Group 1: cirrhosis was present in 11.0% of group 1 patients and in 23.6% of immunocompetent patients with a duration of hepatitis C virus infection of 20 years or more. Forty-three percent of patients with cirrhosis and with hepatitis C virus infection for more than 20 years were alcohol abusers. The time taken to develop cirrhosis was 14+/-7 years in patients infected before the age of 40 years as compared to 8+/-5 years in those infected after 40 years (p0.001). Groups 2a and 2b: cirrhosis was present in 19.8% of immunocompromised patients, a significantly higher rate than in immunocompetent patients (p0.01). Alcohol abuse did not increase the risk of cirrhosis in this group. All patients but one were infected by hepatitis C virus before the age of 40 and the calculated time elapsed until the occurrence of cirrhosis was 12.4+/-5.5 years. In groups 1, 2a and 2b, there was no relation between histological severity, hepatitis C virus genotype and viral load. Four variables were independently associated with the occurrence of cirrhosis in the multivariate analysis: age over 40 at time of contamination (RR=9.3 in age range 40 to 59 and 91.2 inor =60 years); long duration (or =20 years) of hepatitis C virus infection (RR=15.4); alcohol consumption over 80 g/d (RR=2.9); and human immunodeficiency virus-coinfection (RR=2.6).Our study on a large series of well-characterized patients provides an accurate evaluation of the risk of cirrhosis in parenterally-contaminated immunocompetent hepatitis C virus-infected patients, with an overall figure of 11%. It also demonstrates the impact of the host immune status on the risk of severe histological lesions during chronic hepatitis C virus infection. It finally establishes the importance of age at the time of viral infection in the occurrence of cirrhosis, as well as the importance of alcohol consumption. Thus, at least following parenteral infection, both host-related and environmental cofactors play a major role in the severity of the liver lesions associated with hepatitis C virus infection.

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.

Aims: To compare the efficacy of carbohydrate-deficient transferrin and gamma-glutamyltransferase for the diagnosis of excessive alcohol intake in patients admitted in a liver unit. Methods: The 346 patients were divided into three groups of alcoholics: 57 patients (31 men, 26 women) with a normal liver, 77 patients (51 men, 26 women) with non-cirrhotic alcoholic liver disease, and 61 patients (43 men, 18 women) with alcoholic cirrhosis; and three groups of non-alcoholics: 35 abstainers (21 men, 14 women), and 58 healthy blood donors (26 men, 32 women), and 58 patients (32 men, 26 women) who had a non-alcoholic liver disease. Carbohydrate-deficient transferrin and gamma-glutamyltransferase were measured at admission using commercially available kits. Results: Carbohydrate-deficient transferrin was more sensitive than gamma-glutamyltransferase in patients without alcoholic liver disease, in both men (85 vs 54%) and women (64 vs 36%). Carbohydrate-deficient transferrin sensitivity decreased slightly but not sigficantly according to the severity of the liver disease in men and women. The sensitivity of gamma-glutamyltransferase which was low in men and women without alcoholic liver disease, improved in groups with moderate or severe alcoholic liver disease: not less than 80% in men and up to 100% in women. The specificity of carbohydrate-deficient transferrin in patients with non-alcoholic liver disease was consistently higher than that of gamma-glutamyltransferase (80% vs 60%). Conclusions: In liver units, carbohydrate-deficient transferrin can help to identify excessive drinkers without liver disease with a higher efficacy than that of gamma-glutamyltransferase; carbohydrate-deficient transferrin can also be used to distinguish between alcoholics with moderate liver disease and patients with non-alcoholic liver diseases.

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 Alcohol has particularly toxic effects on the central and peripheral nervous systems. Optic neuropathy (ON) is one of these neurological complications. Its diagnosis has not been codified, and its prevalence is poorly known. The aim of this pilot study was to assess the prevalence of ON and identify risk factors in a cohort of patients hospitalized for alcohol withdrawal. Methods This was a single-center prospective study. A complete standardized eye examination was performed during the patient's alcohol withdrawal; The data collected included: sociodemographic status; the number of withdrawals; the type and amount of alcohol drunk, tobacco, and illicit drug consumption; and ophthalmological results. Results One hundred patients were included prospectively from January 2010 to June 2011 (67 men and 33 women) with a mean age of 47 ± 12 and 46 ± 10 years, respectively. The average alcohol consumption was higher for men than women: 207 ± 122 vs. 146 ± 92 g/d, p = 0.013. The most frequent definition of ON in the literature is a decrease in visual acuity associated with impaired color vision. Thirteen percent of men and 3% of women met these criteria. But monocular ON was observed in 22% of men and 18% women, and partial damage was demonstrated in 27% of men and 7% of women. Conclusions ON is a relatively rare complication of chronic alcohol consumption, but the high prevalence of incomplete forms should prompt screening and early treatment.

Alcoholic liver disease (ALD) causes more than 5000 deaths per year in France. Most of those deaths could be prevented by an early diagnosis, which would give the patients the opportunity to modify their alcohol consumption while liver lesions are still reversible. Hepatic histology is the main parameter that predicts morbidity and mortality in patients with ALD. Non-invasive methods such as biomarker tests (e.g. FibroTest(®) or FibroMetre A(®)) or hepatic elastography (FibroScan(®)) may allow diagnosing alcohol-induced liver lesion without systematic biopsy. Despite promising preliminary results, those methods are not validated yet in ALD. A validation of non-invasive methods for ALD could allow a large screening of the severe forms of this pathology.

There is a high frequency of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections among individuals with alcoholic liver disease (ALD) and alcohol-associated hepatocellular carcinoma (HCC), suggesting that these viruses are implicated in the pathogenesis of these diseases. Alcohol may act synergistically by promoting the development and progression of liver disease. The interactions of alcohol with infected hepatocytes and with antiviral immunity may result in altered patterns of virus gene expression and replication, making diagnosis difficult in some cases of ALD and HCC. The potential association of ALD and alcoholic HCC with serologically negative virus variants raises major difficulties in the epidemiologic assessment of cause and effect, providing major challenges for the future.

Among the reported interactions between ethanol and hepatitis B virus (HBV), studies of transgenic mice have suggested an effect of ethanol on the secretion of viral envelope proteins.We further investigated these interactions in vitro by determining HBs antigen levels and performing northern blots of viral mRNA in human cell culture (HepG2 HBV positive cells) exposed for 3 to 12 days to various concentrations of ethanol.In cultures exposed to 200 mM ethanol, HBs antigen concentrations increased in the medium (p0.05) after 3 days as Pre-S1 and Pre-S2 protein concentrations. This increase was not specific, as albumin and ferritin increased in the same proportions. Ethanol also increased the HBs antigen concentration in the cells (p0.05), whereas levels of viral mRNA encoding surface proteins were unaffected.These findings show that short-term ethanol exposure in vitro can induce HBs antigen overexpression via a post-transcriptional mechanism.

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

To assess the possible influence of age, gender, cigarette smoking, menstrual cycle and oral contraceptives on red blood cell (RBC) deformability, cell transit parameters for one-hundred-ninety-four healthy adult subjects (seventy-nine males and one-hundred-fiveteen females) have been measured by filtration with the Cell Transit Analyser (CTA). The CTA provides the distribution of cell transit times of 5000 red blood cells, the mean transit time of the RBC population and different percentiles such as p50, p75, p90 and p95. First, correlations between and mean cell volume (MCV) were calculated for the entire population. Secondly, the influence of sex, age, cigarette smoking, menstrual cycle and oral contraceptives on the RBC mean transit time was evaluated. For RBC with 80 fl and MCV was found (r = 0.41; P < 0.001). No effect of age, cigarette smoking and oral contraceptives was found. Nevertheless, influence of sex and menstrual cycle were demonstrated. A significant increase of the CTA parameters measured in the female population with respect to the male population and during menstruation, preovulation and post-ovulation periods was observed. During ovulation, the CTA parameters are comparable to the same parameters in males.

The role of HBV and HCV in the course of primary liver cancer in patients who are negative for HBsAg has been debated. Using a combination of serological and polymerase chain reaction assays, we investigated the association between HCV and HBV infections and primary liver cancer in 24 HBsAg-negative patients living in France. The presence of HCV RNA and HBV DNA sequences was tested for in serum and in tumorous and nontumorous liver samples. Twelve patients had anti-HCV, and 11 patients had anti-HBs and/or anti-HBc. HCV RNA sequences were found in the serum samples of all anti-HCV–positive patients and none of the patients who were negative. Patients with HCV viremia had HCV RNA genomic sequences and presumed replicative intermediates in both tumorous and nontumorous specimens. Sequence analysis of a hypervariable region in the E2/NS1 gene of HCV showed significant variations between the viral molecules isolated from the nontumorous, tumorous and serum samples. This eliminated the hypothesis of the contamination of the tumor by nontumorous cells and serum particles and assessed that liver tumor cells did contain HCV RNA genomes. Eleven of 22 patients tested had HBV DNA in the serum; 5 patients were anti-HBc positive and anti-HBs positive. Patients with HBV viremia had HBV DNA sequences in both tumorous and nontumorous liver specimens. Selective loss of part of the HBV genome in the tumorous tissue of two of these patients suggested HBV DNA persistence in clonally expanded malignant cells. Only 4 of the 22 patients were negative for both viruses. Our results show that HBsAg-negative hepatocellular cancer in France is associated with chronic HBV or HCV infection and, in some cases, both; these findings are consistent with an etiological role for HBV and HCV in HCC that develops in cirrhotic patients living in areas of low prevalence. (HEPATOLOGY 1993;17:20–29.)

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National audience; Il a été récemment démontré que l’élastographie par pression de radiation (Supersonic Shear Imaging - SSI) est capable de quantifier les propriétés viscoélastiques du foie chez l’homme. Cette technique développée à l’institut Langevin a démontré sa bonne reproductibilité, répétabilité et son indépendance vis à vis de la respiration du sujet. La technique SSI est basée sur l’utilisation in vivo de la pression de radiation ultrasonore, qui permet d'induire une onde de cisaillement profondément dans les tissus. La propagation de cette onde est alors imagée grâce à un échographe ultrarapide (5000 images/secondes). L’estimation de la vitesse de l’onde en fonction de la fréquence donne alors accès aux paramètres viscoélastiques des tissus. Cette étude a permis de construire de solides bases pour élaborer un protocole clinique de qualité. Dans le travail qui suit, la technique SSI, adaptée à une sonde courbe (C42 – 2.5 MHz), est utilisée pour cartographier entre les côtes les propriétés viscoélastiques de 142 patients atteints de maladies hépatiques chroniques (VHC, VHB, cirrhose connue). Sur ces mêmes patients un examen Fibroscan (élastographie transitoire monodimensionelle) ainsi qu’une prise de sang sont réalisés. Cette dernière permettant de déterminer le niveau de fibrose des patients et leur score METAVIR (Fib4, FORN’s, APRI). Les paramètres viscoélastiques du foie sont déterminés sur une large bande fréquentielle et cartographiés sur une surface de 120x75 mm². Cette étude montre que la technique SSI permet de discriminer de manière quantitative et avec une bonne différentiation les niveaux de fibrose des patients (p-index ~=.10-16 ). La technique permet de s'affranchir des problèmes d'hétérogénéités affectant les techniques d'élastographie 1D. Cette étude suggère ainsi que la technique SSI pourrait devenir un examen de routine complémentaire précis et fiable pour la détermination du niveau de fibrose hépatique et permettrait de diagnostiquer plus rapidement les pathologies hépatiques chroniques.

Two types of factors can theoretically modulate alcohol metabolism toward increased acetaldehyde production. These factors are the following: (a) individual, genetically determined isoenzymes with distinct catalytic properties, and (b) modifications of enzyme activity induced by alcohol itself or liver damage. To investigate the respective roles of these factors in white individuals, we studied the alcohol dehydrogenase phenotype, together with liver alcohol dehydrogenase and aldehyde dehydrogenase activities, in 161 patients. Patients with alcoholic cirrhosis (n = 31) were compared with three types of controls: patients with nonalcoholic cirrhosis (n = 25) and excessive (n = 62) and moderate drinkers (n = 43) without liver disease. No association between alcohol dehydrogenase-3 phenotype and alcoholic cirrhosis was found. The prevalence of atypical alcohol dehydrogenase in the four groups was less than 1%. Patients with cirrhosis, regardless of its cause, had significantly lower alcohol dehydrogenase activity than the patients without cirrhosis (p less than 0.05 and p less than 0.01 vs. excessive and moderate drinkers, respectively). Among the noncirrhotic patients, alcohol dehydrogenase activity was significantly lower in the excessive drinkers than in the moderate drinkers (p less than 0.001). Aldehyde dehydrogenase activity was not different between cirrhosis-free excessive and moderate drinkers; in contrast, compared with these two groups, it was significantly lower in the two cirrhosis groups (p less than 0.01). These results suggest that no phenotypic pattern of alcohol dehydrogenase-3 associated with alcoholic cirrhosis in white patients exists, that liver alcohol dehydrogenase activity falls as a consequence of both alcohol abuse and cirrhosis and that liver aldehyde dehydrogenase activity is unaffected by alcohol abuse and only falls after the onset of cirrhosis.

Hepatitis B virus (HBV) infections with an unusual serological profile, viz. positivity of HBV-DNA in the absence of hepatitis B surface antigen (HBsAg), have been described in alcoholics. This atypical pattern could be due to a low circulating level of viral particles rendering HBsAg undetectable with commercial kits, whereas HBV-DNA remains positive using the highly sensitive hybridization technique. We hypothesize that the well-known alcohol-induced impairment of protein secretion could also concern HBsAg particles and leads to a decrease in serum levels of the HBs antigen. To verify this hypothesis, we used HBsAg-positive transgenic mice as an animal model. Twelve HBsAg+ mice were separated into two groups; one group ( n = 6) was submitted to increasing alcoholisation over an 18-week period, while the other ( n = 6) was water fed. Seven HBsAg- littermates acted as controls: three received the alcohol regimen and the remaining four water. Chronic excessive alcoholisation lead to a significant decrease in serum HBsAg concentrations, while there was no obvious change in liver S mRNA. Ultrastructural studies showed a significant decrease in the number of microtubules in the livers of alcohol-fed mice. Finally, immunohistochemical studies performed at the end of the experiment showed a greater accumulation of HBsAg in the livers of HBsAg+ alcohol-fed (mainly located in the centrilobular area) than in the HBsAg+ water-fed mice. Our results (i) validate our initial hypothesis that chronic alcohol abuse leads to a decrease in serum HBsAg concentrations. This could explain, in part at least, the serological dissociations which were observed, (ii) Confirm the utility of screening serum HBV-DNA in alcoholics, (iii) Demonstrate that transgenic HBsAg+ mice offer a valid model for the study of the interactions between HBV and alcohol.

To evaluate the factors determining the severity of chronic hepatitis B virus infection and the interactions of human immunodeficiency virus and hepatitis delta virus infections, we retrospectively analyzed 260 patients, 146 of whom were followed for a mean of 31.4 ± 1.8 mo. Human immunodeficiency virus, hepatitis B virus, and hepatitis delta virus status and aminotransferase activities, histological activity index, alcohol consumption and the prevalence of cirrhosis were investigated. The patients included 54 homosexuals, 19 parenteral drug abusers and 187 subjects with other or unidentified risk factors for exposure to hepatitis B virus. Thirty-five patients (13%) were positive for antibody to human immunodeficiency virus; 27 were homosexual and 8 were drug abusers. The mean aminotransferase activities, histological activity index and the prevalence of cirrhosis were similar in the human immunodeficiency virus–positive and human immunodeficiency virus–negative subgroups. Actuarial survival was significantly lower in the human immunodeficiency virus–positive group than in the human immunodeficiency virus–negative subjects (p = 0.004); the cause of death was clearly related to liver failure in four of the five human immunodeficiency virus–positive patients and two of the six human immunodeficiency virus–negative subjects who died. To evaluate the factors determining the severity of liver disease, we compared homogeneous subgroups of subjects. Among the homosexual patients, the prevalence of HBeAg and hepatitis B virus DNA, aminotransferase activities and the histological activity index did not differ according to human immunodeficiency virus antibody status. By contrast, human immunodeficiency virus–positive drug abusers had a higher histological activity index than their human immunodeficiency virus–negative counterparts (14.3 vs. 11.1; p = 0.02), despite a similar prevalence of hepatitis delta virus (around 70%) and similar alcohol consumption. In a stepwise logistic regression analysis, risk factor for exposure to hepatitis B virus was the most reliable variable for predicting the histological activity index (p = 0.0002). Age (p < 0.0001), excessive alcohol consumption (p = 0.0002) and risk factor for exposure to hepatitis B virus (p = 0.01) were independently predictive of cirrhosis. The group of drug abusers showed both the highest histological activity index and the highest rate of cirrhosis. In contrast to previous studies, these results show the potential severity of chronic hepatitis B virus–related liver disease in human immunodeficiency virus–positive subjects. Indeed, they suggest that human immunodeficiency virus infection does not attenuate and may even worsen hepatitis B virus–related chronic liver damage. They also show the importance of the type of risk factor for exposure to hepatitis B virus in the outcome of chronic hepatitis B virus infection (Hepatology 1992;15:578–583).

We determined serum hepatitis C status using a RIBA2 kit and a sensitive PCR procedure in 62 chronic alcoholics, 36 of whom had anti-HCV antibodies (Ab) detectable in an ELISA1 assay. Anti-HCV antibodies were detected in 22 patients using RIBA2. HCV RNA was detected by means of PCR in 18 patients who were RIBA2 positive and in none who were RIBA2 negative. Liver biopsies, available for 12 HCV RNA-positive patients, revealed histological features of purely alcohol-related lesions in seven and mixed alcohol-viral lesions in five. These results indicate that HCV replication is maintained in most alcoholics who score positive for anti-HCV Ab in the RIBA2 test, and that HCV viremia can be associated with histological features typical of alcoholic liver disease.

In liver and serum, AST activity is dependent on two isoenzymes, which are mitochondrial and cytosolic in nature. In an attempt to explain the well-known increase of serum mitochondrial AST-to-total AST ratio in chronic alcoholism (which is due to a specific increase of the mitochondrial isoenzyme), we analyzed: (a) liver and serum AST, ALT and glutamate dehydrogenase activities in 23 active drinkers with minimal liver changes, 11 alcoholic patients with cirrhosis who had stopped drinking, 18 nonalcoholic patients with viral chronic hepatitis and 11 subjects with normal livers; and (b) the expression of messenger RNAs for AST isoenzymes in the corresponding liver samples. Enzymatic activities were decreased in the liver irrespective of the origin of the liver disease. In patients with viral chronic hepatitis (or in those with alcoholic cirrhosis when abstinent), variations in liver proteins and messenger RNAs paralleled significant decreases in mitochondrial AST, ALT and glutamate dehydrogenase and a nonsignificant decrease of cytosolic AST. In alcoholic patients with minimal liver changes, the significant decrease of hepatic cytosolic AST, ALT and glutamate dehydrogenase activities contrasted with a close-to-normal liver mitochondrial AST activity; the increased amounts of mitochondrial AST messenger RNA give evidence for a pretranslational mechanism of regulation, indicating a possible increase in the total production of mitochondrial AST in the liver. The decrease of hepatic cytosolic AST activity was statistically significant only in alcoholic patients without cirrhosis who had a normal cytosolic AST mRNA level, thus suggesting a contributory role of translational or posttranslational regulation. In conclusion, regulation of AST isozymes during liver disease is complex, including differential, pretranslational and translational or posttranslational mechanisms. (HEPATOLOGY 1991;14:620–625.)

The effects of alcohol withdrawal on total and segmental transit time were evaluated in 20 chronic alcoholic subjects. After withdrawal, colorectal transit time significantly increased from 24.9 +/- 3.6 to 33.3 +/- 4.5 hours mean +/- SE (P less than 0.01). This was the result of an exclusive increase in rectosigmoid transit time from 2.8 +/- 0.7 to 9.8 +/- 2.1 hours (P less than 0.001). No variations were found in right or left colon transit time. Distal colonic motility is thus a crucial factor in the genesis of diarrhea in chronic alcoholic subjects.

Red blood cell (RBC) deformability in chronic alcoholism has been studied, using the Cell Transit Analyzer (CTA) which provides transit times of 5000 individual RBC passing via cylindrical micropores of 5.0 pm in diameter and 15 pm in length. Blood from chronic alcoholic patients without cirrhosis was studied before and after 8 days alcohol withdrawal. The results indicate: 1) the mean transit time of the RBC population from alcoholic patients is greater than those of the control population, 2) these changes affect the entire cell population and not only a sub-population, 3) alcohol withdrawal for 8 days improved the deformability of the most rigid cells of alcoholic patients (i.e., a slight but significant decrease of the highest percentile values of the transit time distribution).

We conducted a retrospective study in 229 patients to determine the prevalence of hepatitis C virus (HCV) according to the type of liver disease and also the serum hepatitis B virus (HBV) status. There were 55 cases of hepatocellular carcinoma (HCC), 78 cases of alcoholic cirrhosis (AC) and 96 cases of non-cirrhotic alcohol liver disease (NCA). Half the AC and NCA groups were constituted of patients with or without serum HBV markers. The prevalence of anti-HCV antibodies in HCC (58.2%) was significantly higher than in the other groups (AC, 35.9%; NCA, 17.7%). Combining the two AC and NCA groups gave a 25.8% anti-HCV prevalence in the alcoholics. Altogether anti-HCV antibodies were more frequently present in HBV-positive than in HBV-negative patients (42.2 vs. 26.1%, p less than 0.01), although the difference was not significant when the HCC group was separately analysed. The S/N ratio of anti-HCV-positive samples varied according to the type of the disease (tumorous vs. non-tumorous) and to the serum HBV status. Indeed, 65.6% of HCC had a S/N greater than 4 compared to only 32.2 and 23.5% in AC and NCA, respectively (p less than 0.01). On the other hand more than half of the AC and NCA had a S/N less than 2, indicating possible artefacts in certain cases. The 15 HBsAg and anti-HCV-positive patients had a significantly lower mean S/N than patients displaying only antibodies against HBV, even in the HCC group.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of hepatitis B virus (HBV) in the course of patients with primary liver cancer who are negative for hepatitis B surface antigen has been debated. We used the polymerase chain reaction to evaluate 28 such patients for the presence of DNA and RNA sequences of the virus; 22 of these patients had associated cirrhosis. The patients were from areas with different prevalences of HBV infection (South Africa, Italy, France, and Japan).Antibodies to the surface and core antigens of HBV were detected in 10 of the 23 patients tested. HBV DNA sequences were detected in 17 of the 28 patients, including 8 of the 10 with HBV antibodies and 6 of 13 without HBV serologic markers. HBV RNA molecules were found in four of five tumors tested.Our investigation indicates that transcriptionally active HBV genomes are present in various geographic areas among patients with liver cancer who are negative for hepatitis B surface antigen. This observation is consistent with an etiologic role for the virus in the development of these tumors.

Background Carbohydrate-deficient transferrin (CDT), the sum of a- and disialotransferrin, is considered the most efficient routine biological marker of alcohol abuse. In recent years, methods based on capillary zone electrophoresis (CZE) have been developed using specialized monocapillary systems. These are characterized by a high analytical detection level, counterbalanced by a poor productivity. We evaluated a new CZE method for CDT measurement on the Sebia Capillarys®, an eight-capillary system developed for routine serum capillary electrophoresis. Methods Precision and possible biases due to abnormal (low or high) transferrin levels or lipemic samples were assessed. Exactitude and precision were tested by comparison with a HPLC procedure acknowledged to be the most reliable to date. The validity of the manufacturer's cut-off was checked by measuring CDT in a population comprising abstaining patients, moderate alcohol consumers and alcohol abusers. Lastly, the method was compared to the routine %CDT TIA and N Latex CDT methods. Results The imprecision was 18.5% at the minimum detection level and decreased to 6.1% for high CDT values. No significant shift in the CDT results was observed in relation to abnormally low or high serum transferrin, or in lipemic samples. A high level of concordance was observed with the HPLC method used as reference. The results were strongly correlated with both other routine methods ( r > 0.90). The diagnostic values were comparable to the literature data, even if differences in the studied populations make difficult a direct comparison of the results. Our data suggested that the cut-off could be raised from 1.3% to 1.4% to reduce the number of false positive values without loss of diagnostic efficiency. Conclusions This Capillarys® method from Sebia showed good precision as compared to those published using other CZE methods. Capillarys® method correlated well with HPLC and two routine methods. However, we noticed significant bias at low CDT concentrations. Therefore, with the advantage of high throughput and full automation, these results indicate that the new method is a consistent alternative to the other methods proposed for routine CDT measurement.

Summary The aim of this study was to assess the reversibility of cirrhosis after therapy in a large series of patients with cirrhosis from various etiologies. We performed a retrospective study of 113 patients with biopsy-proven cirrhosis who underwent specific therapy and follow-up biopsies. Two pathologists performed blinded analyses of indirect biochemical and morphological signs of cirrhosis. Fourteen (12.4%) of the 113 cirrhotic patients had biopsy-proven disappearance of cirrhosis, defined as a decrease of 2 or greater in their METAVIR fibrosis score: 8 were related to hepatitis C virus, 3 to hepatitis B virus, and 3 to autoimmune cirrhosis. Necro-inflammatory activity decreased from 2.4 ± 0.65 to 0.85 ± 0.9 ( P = .004), and fibrosis from 4 to 1.7 ± 0.61 ( P = .001). Prothrombin time (n = 1), platelet count (n = 2), serum albumin level (n = 2), and ultrasound abnormalities (n = 6) normalized in patients who had initial abnormalities. Hyaluronic acid and procollagen type III serum level decreased in all. In the 11 patients with regression of viral cirrhosis, 2 were nonresponders and 9 were responders, including 2 relapsers. The 3 patients with regressive autoimmune cirrhosis were complete responders to immunosupressive therapy. Using repeated liver biopsies, clinicobiochemical, radiologic, and endoscopic tests, we provide evidence for potential reversibility of cirrhosis after long-lasting suppression of the necro-inflammatory activity of liver disease.

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. This study analyzes the biochemical, serological, and virological efficacy and the safety of adefovir dipivoxil in patients with renal disturbances. Methods. Twelve patients with lamivudine-resistant hepatitis B virus (HBV) chronic infection were treated for a median time of 15 (3–19) months. The daily dosage was 10 mg initially and then adjusted according to renal function. Results. Median (range) ALT values remained stable: 55 (13–117) and 37 (17–266) UI/L. After the 12th month, the median decline in serum HBV DNA was from 8.76 (6.3–9.7) to 2.97 (1.15–5.65) log10 Eq/ml (median decline of –5.5 log10). No virologic breakthrough was observed. One of the six HBeAg-positive patients lost HBe Ag but without HBe seroconversion; none had HBs Ag loss. There were no significant clinical and biochemical adverse effects. In the 11 nonhemodialysed patients, the creatinine clearance significantly improved from 70 (30–100) to 88 (38–125) ml/mn (P=0.01) and the mean serum creatinine levels increased only slightly from 114 (91–839) to 130 (81–561) μmol/ml (NS). Serum phosphorus remained stable. The urinary level of protein decreased from 0.16 (0.08–8.63) to 0.12 (0.01–0.74) g/day (NS). Conclusions. Adefovir dipivoxil is safe for the treatment of chronic hepatitis B in patients with varying degrees of renal dysfunction and lamivudine-resistant HBV and results in biochemical and virological efficacy similar to that reported in the general population.

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.

BACKGROUND The deterioration of chronic hepatitis C is frequent in kidney recipients and results in a decrease in survival of patients and allografts. Interferon is contraindicated because of the risk of rejection and its low efficacy. The aim of this study was to analyze the biologic, virologic, and histopathologic efficacy of ribavirin alone in kidney allograft recipients with hepatitis C. METHODS Thirteen kidney recipients (eight men and five women, 46+/-11 years of age) with severe Metavir score of fibrosis (eight F3 and five F4) were treated with ribavirin alone during 22.4+/-13.9 months. Liver biopsy was performed before and during therapy, with a mean interval time of 5.7+/-9.3 years. RESULTS The transaminase level decreased significantly (128+/-77 vs. 53+/-28, P=0.001) without significant change of serum quantitative hepatitis C virus load. The comparison of pretreatment and on-treatment biopsy specimens showed a significant decrease in the activity Metavir score (1.23+/-1.01 vs. 2.46+/-0.78, P=0.05) and a nonsignificant trend for a decrease in the fibrosis score. Ribavirin tolerance was fair, and only one patient required erythropoietin therapy. CONCLUSIONS Ribavirin alone in kidney allograft recipients results in biologic and histologic improvement without a virologic response and is reasonably well tolerated.

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.

We analysed liver histology findings in a large cohort of patients with chronic hepatitis C and in roughly half of them their response to interferon-alpha-based on iron parameters and HFE status. Histological activity and virological response to antiviral therapy (n = 146) were analysed in 273 immunocompetent and nonalcoholic patients with chronic hepatitis C, in terms of serum iron load, intrahepatic iron load (n = 110) and HFE mutations. Patients who were heterozygous for the C282Y and H63D mutations exhibited higher iron serum parameters than subjects without these mutations. The intrahepatic iron load was higher in H63D patients only. No association was observed between HFE mutations and histological activity. Increased iron parameters were associated with liver disease severity by univariate analysis only. Genotype 1 and ferritinaemia were associated with a poor response to antiviral therapy, whereas the H63D mutation emerged as a positive predictive factor for end of treatment and sustained antiviral response. Therefore, in chronic hepatitis C patients serum and intrahepatic iron levels were weakly correlated with histological activity, while HFE mutations were not. As for the response to interferon-alpha, elevated ferritinaemia constituted a negative predictive factor whereas the H63D mutation was a positive one. The H63D mutation might form part of an immunogenetic profile influencing the response to interferon therapy.

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/Aims: Debate continues on whether serum and intrahepatic HCV viral loads are correlated and if HCV viral load correlates with the severity of liver disease. These difficulties may at least in part be linked to liver cell heterogeneity, when total liver extracts from HCV-infected individuals are tested for HCV RNA quantification. We have therefore investigated the feasibility of quantifying HCV replication using a laser-based microdissection technique. Methods: We compared the results with those obtained for serum HCV RNA quantification and immunochemistry in the case of HCV antigen detection in the liver. Twenty-one HCV-positive patients with chronic active hepatitis ( n =10) or cirrhosis ( n =11) were analyzed. Results: A positive correlation ( P =0.0019) was observed between HCV RNA quantifications in sera and microdissected cells. Immunohistochemistry demonstrated that HCV antigen hepatocytes were randomly distributed within liver lobules. Their percentage varied in different patients (0–40%), but did not correlate with the HCV viral load. Conclusions: We have designed a sensitive methodology to evaluate the intrahepatic HCV viral load by combining a standardized RNA quantification method with microdissected hepatocytes from frozen liver needle biopsies. Our results directly demonstrate a positive correlation between serum and intrahepatic viral loads, which therefore provides a reliable reflection of intrahepatic HCV replication.

Information on the position of private practitioners faced with the problem of alcoholism mainly concerns the role of the general practitioner in the follow-up of these patients and there is little information from private specialists, hence the need for new dataAll the general practitioners and specialists in the Languedoc-Roussillon area were interviewed through a mailed questionnaire regarding their opinion on alcohol consumption and public health; their definition of the risks; moderate consumption and health; how they approached the question of drinking during consultations and their involvement in training and prevention.Six hundred sixty-five practitioners (12.4% of those interviewed) returned the questionnaire. The profile of those who replied was identical to that of the whole population surveyed. The medical corps is clearly aware of the need to fight against alcohol abuse, but this is associated with a relative ignorance of the basics of alcoholism, a non-systematic approach of the question of drinking during consultations, little involvement in its management, limited use of the specialised structures and limited training on the question. The specialists are less involved than the general practitioners, but appear more at ease when approaching the question of drinking with their patients and resort more frequently to specialised structures than the general practitioners. Continued medical training on alcoholism only concerned a minority of practitioners and its practical impact was low.With regard to alcoholism, the practitioners fulfill their role in providing medical care, within the limits of available therapeutic resources, but their role with regard to the reduction of the risks, i.e., primary or early prevention is more or less disregarded.

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

tibility variation that can be noninvasively measured by frequency shift using susceptibility MRI. Methods: Ten subjectswere studied: six chronicMA-dependent subjects (age =44.5±3.5 years, MA use duration=17.4±3.4 years, daily used=1.0±1.2 grams) and four non-drug user controls (age =47.0±2.8 years). MRI data were acquired on a Siemens 3T TimTrio scanner using a Gradient-echo sequence (TE/TR=30/3500ms, resolution=0.4mm×0.4mm×2.0mm). The acquired phase data were unwrapped, and the phase contribution from non-brain structure such as air-tissue interface was removed. For group comparison, phase images from individual subjects were registered to a MNI 1mm brain template for analyses in the same brain regions. Results: The frequency shift in the globus pallidus of MA users (1.52±0.16Hz) were higher than those in the controls (1.18±0.18Hz), p=0.03. However, the values in the putamen and caudate were not significantly different between the two groups. Age-dependent increase in frequency shift was found in MA users only (r=0.35, p=0.017), but the slope was not different from the controls. Conclusions: Chronic MA users had higher frequency shift that likely reflect higher levels of iron concentration in the globus pallidus. These findings are consistent with those observed in the MA-treated young vervet monkeys, and suggest that MA use may lead to accelerated aging especially to the dopaminergic system. Ongoing studies will evaluate group differences in age-dependent changes in brain iron levels. Financial support: NIH K24-DA6142, R24-DA027318, and K02DA020569.

Background/Aims : This controlled study aimed to evaluate the efficacy and potential side effects of hepatitis B virus (HBV) vaccination as active immunotherapy in HBV-related chronic hepatitis. Methods : The 118 included patients were ‘naive' subjects who had never received any previous anti-HBV therapy, showed detectable serum HBV DNA and had biopsy-proven chronic hepatitis. In a 12-month follow-up they were given either five intramuscular injections of 20 μ g of a preS2/S (GenHevac B ® , Pasteur-Merieux) (n=46) or an S vaccine (Recombivax ® Merck & Co.) (n=34) or no treatment as a control (n=37). The efficacy of vaccination was evaluated by testing for serum HBV DNA negativation using a standard liquid hybridization assay. Results : Three months after the first three vaccine injections, the percentage of serum HBV DNA negativation was higher in the vaccine groups (16.3%) than in the control group (2.7%) (P=0.033, by the χ 2 Pearson test) and was more frequently observed in patients who had pretreatment viremia > 200 pg/ml (none in the control group vs. 16.7% in the vaccinated groups) ( P =0.025). After 12 months follow-up and five vaccine injections, there was no difference in the rate of serum HBV DNA negativation between vaccinated and unvaccinated subjects but HBV vaccines significantly decreased the HBV viral load between the sixth and twelfth months ( P =0.04) in contrast with the control group. The rate of HBe/anti-HBe seroconversion after 6 months of follow-up occurred only in eight (13.3%) vaccinated patients and in one (3.6%) of the controls. Disappearance of serum HBsAg was not observed in any of the patients. Conclusions : This controlled study offers direct evidence that the HBV vaccine may decrease HBV replication in chronic hepatitis B patients. It also emphasizes the need for reinforced immunization strategies as well as combination therapies.