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1.  Long term histological improvement and clearance of intrahepatic hepatitis C virus RNA following sustained response to interferon-ribavirin combination therapy in liver transplanted patients with hepatitis C virus recurrence 
Gut  2003;52(2):283-287.
Background and objective: A proportion of liver transplanted patients with recurrent chronic hepatitis have a sustained virological response to combination therapy with interferon plus ribavirin. However, the long term benefit of antiviral therapy with regard to hepatitis C virus (HCV) RNA clearance remains unknown in patients with HCV recurrence. This study examined the long term biochemical, virological, and histological outcome in transplanted patients with recurrent chronic hepatitis who had a sustained virological response to antiviral therapy.
Patients and methods: Fifty four patients with recurrent hepatitis C were treated with antiviral therapy involving induction by combination therapy (interferon (IFN) plus ribavirin) for six months and maintenance ribavirin therapy for 12 months. Fourteen patients who had recurrent chronic hepatitis and sustained virological response to antiviral therapy were followed for three years after the end of antiviral therapy. Serum alanine aminotransferases were assessed every three months during the observation period. Serum hepatitis C RNA detected by polymerase chain reaction was evaluated every six months during follow up, and protocol biopsy procedures were performed routinely every year. Semiquantitative histopathological assessment of allograft hepatitis was performed using the Knodell score and HCV was also detected by polymerase chain reaction on frozen graft tissue samples.
Results: At the end of antiviral therapy, the sustained response rate was 26%. A complete response (normal serum alanine aminotransferase level and undetectable serum HCV RNA) was achieved in 13/14 (93%) patients three years after the end of treatment. A comparison of liver histology findings before and after a mean of three years after antiviral therapy showed a clear improvement in 12/14 (86%) patients. In 5/14 (36%) patients, the last biopsy showed normal or near normal histological findings. After three years of follow up, the total Knodell score was 3.2 (range 1–8) versus 8.3 (range 5–12) before treatment (p=0.001). Graft HCV RNA was detectable before treatment in all 14 patients and was undetectable at the end of follow up in 13/14 (93%) patients tested.
Conclusion: In patients with biochemical and virological responses induced by ribavirin and interferon, a complete response was sustained in 93% for at least three years after cessation of therapy. This long term response was associated with absence of detectable intrahepatic hepatitis C RNA and marked histological improvement.
PMCID: PMC1774965  PMID: 12524414
2.  Effect of a Combination of Clevudine and Emtricitabine with Adenovirus-Mediated Delivery of Gamma Interferon in the Woodchuck Model of Hepatitis B Virus Infection 
Our aim was to evaluate the antiviral effect of a combination of two nucleoside reverse transcriptase inhibitors, emtricitabine (FTC) and clevudine (L-FMAU), with the addition of an adenovirus-driven delivery of recombinant gamma interferon (IFN-γ) in the woodchuck model of hepatitis B virus infection. Six woodchuck hepatitis virus (WHV)-infected woodchucks received L-FMAU (10 mg/kg) plus FTC (30 mg/kg) intraperitoneally for 8 weeks; six other animals received in addition an intravenous injection of a recombinant adenovirus vector expressing woodchuck IFN-γ (Ad-IFN) at weeks 4 and 8. In the control group, two animals received Ad-IFN alone, two received adenovirus vector expressing the green fluorescent protein reporter gene, and one remained untreated. In less than 2 weeks, all woodchucks that received L-FMAU plus FTC showed a rapid and marked inhibition of viral replication, with a 4-log10 drop in serum WHV DNA. In two animals, viremia remained suppressed for several months after the end of treatment. Similarly, a dramatic decrease in intrahepatic replicative intermediates of viral DNA was observed in the L-FMAU/FTC-treated groups. The additional administration of Ad-IFN led to increased inflammation in the liver but did not enhance the antiviral effect of the L-FMAU/FTC combination. In conclusion, therapies combining L-FMAU and FTC in WHV-infected woodchucks resulted in a potent and sustained antihepadnaviral effect both in the liver and in the blood circulation. However, no extra benefit of adding IFN-γ gene transduction to the L-FMAU/FTC combination could be detected.
PMCID: PMC434178  PMID: 15215126
3.  Recurrence of hepatocellular carcinoma as a mixed hepatoblastoma after liver transplantation 
Gut  1999;45(4):622-625.
BACKGROUND—Hepatoblastoma is an exceptional cause of primary malignant liver tumour in the adult.
PATIENT—The case is reported of an adult patient transplanted for alcoholic cirrhosis complicated by multifocal hepatocellular carcinoma in whom a recurrence in the form of a mixed hepatoblastoma invading the whole transplanted liver developed three months after liver transplantation.
METHODS—Complete clinical, histopathological, and immunohistochemical data were reviewed.
RESULTS—The recurrent tumour invaded the whole liver. The major component was a mixed hepatoblastoma, with an epithelial component expressing cytokeratin and a mesenchymal component expressing vimentin. The tumour also contained a minor hepatocarcinomatous component expressing α fetoprotein. The rapid growth of the tumour prevented any attempt at treatment. Although direct evidence is lacking, the most likely hypothesis to explain the observations is a marked phenotypic change in the initial malignant population at recurrence.
CONCLUSION—This case supports a possible filiation between hepatocellular carcinoma and hepatoblastoma in adults.

Keywords: hepatoblastoma; hepatocellular carcinoma; liver; transplantation
PMCID: PMC1727669  PMID: 10486376
4.  Familial occurrence of nodular regenerative hyperplasia of the liver: a report on three families 
Gut  1999;45(2):289-294.
BACKGROUND/AIMS—Nodular regenerative hyperplasia of the liver is a histological lesion usually associated with systemic diseases, haematological malignancies, or drugs. Its prognosis depends on portal hypertension, which usually is well tolerated and requires medical management only.
PATIENTS—Three unrelated families, in which two sibling adult male patients presented with nodular regenerative hyperplasia of the liver, were studied.
METHODS—Complete clinical charts and liver biopsy specimens were available for all patients. In addition, explanted livers were available for examination for the two transplanted patients.
RESULTS—There was no evidence of any of the various clinical situations known to be associated with nodular regenerative hyperplasia of the liver. Portal hypertension was severe, requiring surgical treatment in two cases. Renal lesions were present in three patients. In two patients, progressive evolution to liver atrophy and hepatic failure, associated with renal failure, led to combined liver and renal transplantation.
CONCLUSIONS—This report describes the existence of familial cases of nodular regenerative hyperplasia of the liver, occurring without underlying or associated systemic disease, characterised by a poor clinical course and often associated with progressive renal failure.

Keywords: nodular regenerative hyperplasia; liver; transplantation; familial
PMCID: PMC1727622  PMID: 10403744
5.  Antiviral Activity of β-l-2′,3′-Dideoxy-2′,3′-Didehydro-5-Fluorocytidine in Woodchucks Chronically Infected with Woodchuck Hepatitis Virus 
The l-nucleoside analog β-l-2′,3′-dideoxy-2′,3′-didehydro-5-fluorocytidine (β-l-Fd4C) was first shown to exhibit potent activity against hepatitis B virus (HBV) in tissue culture and then to significantly inhibit viral spread during acute infection in the duck HBV model (F. Le Guerhier et al., Antimicrob. Agents Chemother. 44:111–122, 2000). We have therefore examined its antiviral activity in a mammalian model of chronic HBV infection, the woodchuck chronically infected with woodchuck hepatitis virus (WHV). Side-by-side comparison of β-l-Fd4C and lamivudine administered intraperitoneally during short-term and long-term protocols demonstrated a more profound inhibition of viremia in β-l-Fd4C-treated groups. Moreover, β-l-Fd4C induced a marked inhibition of intrahepatic viral DNA synthesis compared with that induced by lamivudine. Nevertheless, covalently closed circular (CCC) DNA persistence explained the lack of clearance of infected hepatocytes expressing viral antigens and the relapse of WHV replication after drug withdrawal. Liver histology showed a decrease in the inflammatory activity of chronic hepatitis in woodchucks receiving β-l-Fd4C. An electron microscopy study showed the absence of ultrastructural changes of hepatic mitochondria, biliary canaliculi, and bile ducts. However, a loss of weight was observed in all animals, whatever the treatment, as was a transient skin pigmentation in all woodchucks during β-l-Fd4C treatment. There was no evidence that lamivudine or β-l-Fd4C could prevent the development of hepatocellular carcinoma with the protocols used. These results indicate that β-l-Fd4C exhibits a more potent antiviral effect than lamivudine in the WHV model but was not able to eradicate CCC DNA and infected cells from the liver at the dosage and with the protocol used.
PMCID: PMC90426  PMID: 11257017
6.  Monitoring levels of human cytomegalovirus DNA in blood after liver transplantation. 
Journal of Clinical Microbiology  1995;33(2):389-394.
We evaluated a semiquantitative PCR assay prospectively in 40 liver transplant recipients as an aid in making a prompt diagnosis of cytomegalovirus (CMV) infection. For 2 months after transplantation, clinical specimens from patients were tested weekly by PCR, virus isolation from peripheral blood and urine, and CMV serology. The incidence of active CMV infection was 70%. The levels of CMV DNA determined by hybridization of PCR samples and densitometric scanning of blots were assigned a score of 1 to 4 by comparison with four external standards amplified in parallel and corresponding to a range of 80 to 80,000 genomes. The first detection of CMV in blood by PCR occurred at a mean of 15 days, and high-level PCR scores of 3 or 4 were obtained 21 days after transplantation, whereas viremia occurred 33 days after transplantation. Significantly higher levels of CMV DNA were seen in patients with CMV disease (P < 0.05) than in asymptomatic patients. The prevalence of symptomatic CMV infection was 30%. The positive predictive value of PCR was 48%, while the negative predictive value was 100%. After treatment, the clearance of CMV DNA was always observed and the disappearance of symptoms occurred concomitantly with undetectable PCR signals.
PMCID: PMC227954  PMID: 7714198
7.  Azathioprine induced liver disease: nodular regenerative hyperplasia of the liver and perivenous fibrosis in a patient treated for multiple sclerosis. 
Gut  1991;32(6):715-717.
Azathioprine hepatotoxicity has been described mainly in renal transplant recipients. Most reported cases are related to lesions of the venous system of the liver: peliosis hepatis, veno-occlusive disease of the liver, perisinusoidal fibrosis, and nodular regenerative hyperplasia of the liver. The most common clinical manifestation of these hepatic vascular lesions is portal hypertension. We present a case of nodular regenerative hyperplasia and perivenous fibrosis in a patient receiving azathioprine for multiple sclerosis. Histological abnormalities were similar to those described in renal transplant patients, and azathioprine was the only potential hepatotoxic agent present.
PMCID: PMC1378897  PMID: 2060883
8.  Membrane insertion of uracil permease, a polytopic yeast plasma membrane protein. 
Molecular and Cellular Biology  1991;11(2):1114-1124.
Uracil permease is a multispanning protein of the Saccharomyces cerevisiae plasma membrane which is encoded by the FUR4 gene and produced in limited amounts. It has a long N-terminal hydrophilic segment, which is followed by 10 to 12 putative transmembrane segments, and a hydrophilic C terminus. The protein carries seven potential N-linked glycosylation sites, three of which are in its N-terminal segment. Overexpression of this permease and specific antibodies were used to show that uracil permease undergoes neither N-linked glycosylation nor proteolytic processing. Uracil permease N-terminal segments of increasing lengths were fused to a reporter glycoprotein, acid phosphatase. The in vitro and in vivo fates of the resulting hybrid proteins were analyzed to identify the first signal anchor sequence of the permease and demonstrate the cytosolic orientation of its N-terminal hydrophilic sequence. In vivo insertion of the hybrid protein bearing the first signal anchor sequence of uracil permease into the endoplasmic reticulum membrane was severely blocked in sec61 and sec62 translocation mutants.
PMCID: PMC359790  PMID: 1846664
9.  Cloning and transcriptional control of a eucaryotic permease gene. 
Molecular and Cellular Biology  1982;2(8):977-984.
The uracil permease gene of the yeast Saccharomyces cerevisiae was cloned on a hybrid plasmid which replicates autonomously in both yeast and Escherichia coli. Cloning was carried out by complementation in yeast. The smallest DNA fragment found to complement the uracil permease deficiency in recipient yeast cells measured approximately 2.3 kilobases. In strains transformed by the plasmid with the uracil permease gene inserted, initial rates of uracil uptake increased up to 25 times more than the rates found in the wild type. Using DNA probes carrying several regions of the cloned gene, I showed that a strain carrying the dhul-I mutation, which is not linked to the permease structural gene and is responsible for enhanced uptake velocity of uracil, had enhanced transcription of the permease gene. By using DNA probes recloned in phage M13 mp7, the direction of transcription of the permease gene relative to the restriction map was deduced. A half-life of 2 min was found for the permease mRNA in labeling kinetics experiments.
PMCID: PMC369885  PMID: 6290876
10.  Characterization of cytosine permeation in Saccharomyces cerevisiae. 
Journal of Bacteriology  1975;122(2):629-641.
Cytosine permeation in Saccharomyces cerevisiae has been studied. Cytosine uptake is mediated by a permease which is also responsible for purines transport. The Km for the transport of various substrates of this permease have been determined. By means of appropriate selective techniques, mutants with altered Km and mutants lacking the permease have been selected. Cytosine transport is active and is inhibited by 2,4-dinitrophenol, an uncoupler of oxidative phosphorylation, and by N-ethylmaleimide, a reagent of--SH group. Internal labeled cytosine is chased by addition of unlabeled cytosine in the medium. These results support the hypothesis of a carrier-mediated transport, with reduced internal affinity, allowing the release and accumulation of cytosine in the inner compartment. The efflux of cytosine from cytosine permease-less cells has also been studied and shows first order kinetics. A diffusion coefficient of 5.7 per 10- minus 8 cm per S- minus 1 has been evaluated for this efflux.
PMCID: PMC246101  PMID: 47858

Results 1-10 (10)