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Biomedical subjects

R Zemel

Publications and source records attributed to R Zemel.

At least 19 recordsLinked to original sources
PubMed2001

The addition of mycophenolate mofetil for suppressing hepatitis B virus replication in liver recipients who developed lamivudine resistance--no beneficial effect.

BACKGROUND: Mycophenolate mofetil is used as an immunosuppressive agent in liver transplant recipients. Its active compound, mycophenolic acid, also inhibits the replication of Epstein-Barr virus and human immunodeficiency virus. Based on a study indicating the effectiveness of mycophenolate mofetil on hepatitis B virus (HBV) replication in infected human hepatocyte cells in culture, we examined the efficacy of mycophenolate mofetil in suppressing HBV replication in lamivudine-resistant liver allograft recipients with recurrent HBV infection. METHOD: The study population included four liver allograft recipients (three males, one female), median age 51 years (range 41-57 years), with recurrent HBV infection who proved to be resistant to lamivudine. All received standard maintenance immunosuppression therapy. Median pretreatment serum alanine aminotransferase level was 75 mu/L (range 39-182 mu/L) and HBV DNA level (quantitative dot blot), 70 pg/ml (range: 10-5,000 pg/ml). Mycophenolate mofetil, 1.0 g p.o. twice daily, was administered for 8 weeks, concomitant with a reduction in the maintenance corticosteroid and cyclosporine doses. RESULTS: After mycophenolate mofetil was administered, the serum alanine aminotransferase level increased in two patients, did not change in one, and decreased in one. Serum HBV DNA levels increased in three patients and decreased (nonsignficantly) in only one patient. Two patients complained of abdominal pain and nausea. CONCLUSIONS: Mycophenolate mofetil at the dosage used is not effective in suppressing HBV replication after liver transplantation.

Adult↗
PubMed2001

Cell transformation induced by hepatitis C virus NS3 serine protease.

Persistent infection with hepatitis C virus (HCV) may lead to hepatocellular carcinoma (HCC). It has been suggested that HCV-encoded proteins are directly involved in the tumorigenic process. The HCV nonstructural protein NS3 has been identified as a virus-encoded serine protease. To study whether HCV NS3 has oncogenic activity, nontumorigenic rat fibroblast (RF) cells were stably transfected with an expression vector containing cDNA for the NS3 serine protease (nucleotides 3356-4080). The NS3 serine protease activity was determined in the transfected cells. The transfected cells grew rapidly and proliferated serum independently, lost contact inhibition, grew anchorage independently in soft agar and induced significant tumour formation in nude mice. Cells transfected with an expression vector containing a mutated NS3 serine protease (serine 139 to alanine at the catalytic site) showed no transforming abilities; their growth was dependent on serum and they did not grow anchorage independently in soft agar. Moreover, cells transfected with the NS3 serine protease and treated with the chymotrypsin inhibitors TPCK and PMSF (a serine protease inhibitor) lost their transforming feature. These results suggest that the NS3 serine protease of HCV is involved in cell transformation and that the ability to transform requires an active enzyme.

Animals↗
PubMed2000

Fulminant non--A-G viral hepatitis leading to liver transplantation.

BACKGROUND: All hepatotropic viruses are known to cause fulminant hepatic failure (FHF). However, in 30% to 40% of patients with FHF, the precise cause remains unknown. We aimed to better define this subgroup. METHODS: We evaluated the clinical course and outcome of 7 patients admitted during a 22-month period with fulminant viral hepatitis leading to liver transplantation; none had serologic or molecular evidence of hepatitis A, B, C, D, E, or G viral infection, thus the term non-A-G viral hepatitis. All known etiologies of FHF were excluded. RESULTS: All patients had prodromal symptoms suggestive of viral causes. Mean age was 30 years. The interval between onset of jaundice and appearance of encephalopathy was 23 days (range, 4-50 days). Five patients had grade III/IV encephalopathy. Serum alanine aminotransferase levels showed a single peak of activity. The duration between first symptoms and liver transplantation was 28 days (range, 12-71 days). Results of histological study of the explanted liver showed submassive (4 patients) or massive (3 patients) hepatocyte necrosis. In all patients, results of polymerase chain reaction analysis did not detect hepatitis B virus DNA, hepatitis C virus RNA, or hepatitis G virus RNA in the explanted liver. After transplantation, 2 patients showed (6 months later) increased liver enzyme levels of undetermined cause, and results of a liver biopsy showed mild lobular hepatitis; 1 patient had lymphoproliferative disorder (Epstein-Barr virus-originated); and 1 patient, aplastic anemia, which is known to be associated with seronegative viral hepatitis. The latter patient died, whereas the other 6 patients are alive (survival rate, 86%). CONCLUSIONS: Our patients with non-A-G viral hepatitis had a severe acute onset with progressive FHF requiring liver transplantation. There is some suggestion of recurrent viral disease after transplantation implicating other unknown viruses in the etiology.

Adolescent↗
PubMed2000

Mutations at vicinity of catalytic sites of hepatitis C virus NS3 serine protease gene isolated from hepatocellular carcinoma tissue.

The mechanism of hepatitis C virus (HCV) -induced hepatotocellular carcinoma (HCC) is still unknown, but in vitro studies clearly suggest that HCV proteins exert a direct effect on liver carcinogenesis. HCV NS3 serine protease is known to play a key role in the life cycle of the virus and may interact with the host cellular regulatory proteins. The aim of the present study was to conduct a genetic analysis of the HCV NS3 gene coding for the serine protease isolated from serum, tumor, and nontumor tissue of HCC patients. RNA was extracted and HCV cDNA was amplified by nested reverse transcriptase-polymerase chain reaction (RT-PCR). Sequence comparison yielded unique changes at the vicinity of the catalytic sites of the NS3 clones isolated only from HCC tissue. These changes included the insertion of a "large" and charged amino acid, substitution of a polar with a hydrophobic amino acid, and substitution of a charged with a polar amino acid. Those changes affect the electrostatic charge around the active site, and thus the activity and substrate specificity of the serine protease. This is the first study to define significant amino acid changes at the catalytic domain of the NS3 serine protease gene isolated from HCC tissue.

Amino Acid Sequence↗
PubMed2000

Information processing with population codes.

Information is encoded in the brain by populations or clusters of cells, rather than by single cells. This encoding strategy is known as population coding. Here we review the standard use of population codes for encoding and decoding information, and consider how population codes can be used to support neural computations such as noise removal and nonlinear mapping. More radical ideas about how population codes may directly represent information about stimulus uncertainty are also discussed.

Animals↗
PubMed2000

Streptozotocin and alloxan-based selection improves toxin resistance of insulin-producing RINm cells.

The aim of our study was to develop a method for selection of subpopulations of insulin producing RINm cells with higher resistance to beta cell toxins. Cells, resistant to streptozotocin (RINmS) and alloxan (RINmA), were obtained by repeated exposure of parental RINm cells to these two toxins, while the defense capacity was estimated by the MTT colorimetric method, and [3H]-thymidine incorporation assay. We found that RINmS and RINmA displayed higher resistance to both streptozotocin (STZ) and alloxan (AL) when compared to the parental RINm cells. In contrast, no differences in sensitivity to hydrogen peroxide were found between toxin selected and parental cells. Partial protection from the toxic effect of STZ and AL was obtained only in the parental RINm cells after preincubation of cells with the unmetabolizable 3-O-methyl-glucose. The possibility that GLUT-2 is involved in cell sensitivity to toxins was confirmed by Western blot analysis, which showed higher expression of GLUT-2 in parental RINm compared to RINmS and RINmA cells. In addition to the higher cell defense property evidenced in the selected cells, we also found higher insulin content and insulin secretion in both RINmS and RINmA cells when compared to the parental RINm cells. In conclusion, STZ and AL treatment can be used for selection of cell sub-populations with higher cell defense properties and hormone production. The different GLUT-2 expression in parental and resistant cells suggest involvement of GLUT-2 in mechanisms of cell response to different toxins.

3-O-Methylglucose↗
PubMed1999

Association of lamivudine resistance in recurrent hepatitis B after liver transplantation with advanced hepatic fibrosis.

BACKGROUND: Orthotopic liver transplantation (OLT) in patients with hepatitis B virus (HBV) infection is known to be associated with a high recurrence rate and poor prognosis. Lamivudine, a nucleoside analogue, is a potent inhibitor of HBV replication, but it is associated with a 14-39% rate of resistance. METHODS: We report on four patients who underwent OLT for HBV infection. In all cases, the HBV infection recurred in the grafted liver and was treated with lamivudine (100 mg daily) on a compassionate-use basis. The patients were monitored closely for serum liver enzymes, hepatitis B surface antigen and HBV DNA (by hybridization). Liver biopsy was performed before and after lamivudine therapy. HBV DNA was amplified from serum for each patient and sequenced through a conserved polymerase domain, the tyrosine-methionine-aspartate-aspartate (YMDD) locus. RESULTS: All four patients exhibited lamivudine resistance 9-20 months after initiation of the drug. In all patients with a clinically mild disease, liver histology findings (12-24 months after lamivudine therapy) showed progressive fibrosis as compared to biopsies performed before lamivudine therapy, with a significant increase (> or =2 points) in the Knodell score in three patients. Moreover, two patients exhibited worsening of the necroinflammatory process. A mutation at the YMDD motif of the HBV polymerase gene was detected in all cases. CONCLUSIONS: Lamivudine resistance frequently occurs in patients with recurrent HBV infection after OLT and is associated with advanced hepatic fibrosis and necroinflammatory process. A combination of antiviral therapies may be necessary.

Adult↗
PubMed1999

Nitric oxide metabolites in decompensated liver cirrhosis.

High levels of nitric oxide are thought to be the cause of some of the complications associated with decompensated end-stage liver disease. To assess nitric oxide metabolism in cirrhotic patients, we measured the levels of nitric oxide metabolites (nitrosohemoglobin, methemoglobin, nitrate, and nitrite) in normal subjects, in patients with decompensated cirrhosis, in patients with renal failure (model for impaired NO metabolites excretion), and in patients with mononitrates-treated anginal syndrome (model for exogenous nitric oxide). When compared to controls, patients with decompensated cirrhosis exhibited elevated levels of nitrate only. A significant increase of nitrate was also noted in patients receiving exogenous nitrates, whereas patients with impaired excretion had significantly elevated levels of both nitrite and nitrate. In conclusion, nitric oxide metabolism in patients with decompensated cirrhosis is similar to that of patients receiving nitric oxide from an exogenous source. Renal impairment, whether alone or associated with cirrhosis, causes a change in nitric oxide metabolism. These findings may have clinical implications for nitrates treatment in patients with decompensated cirrhosis.

Adult↗
PubMed1999

Efficacy of lamivudine in patients with hepatitis B virus precore mutant infection before and after liver transplantation.

OBJECTIVE: Hepatitis B virus (HBV) precore mutant infection is associated with a more severe liver disease and a poorer response to interferon. We evaluated the efficacy and tolerance of lamivudine to induce complete and sustained suppression of viral replication in seven patients infected with HBV precore mutant (HBeAg-/HBeAb+/HBV DNA+) (in three patients mutation at codon 1896 was detected by direct sequencing). METHODS: Of the seven patients, five had decompensated HBV cirrhosis in a replicative phase and were liver transplant candidates (Group A) and two patients underwent orthotopic liver transplantation (OLT) for HBV liver cirrhosis and developed recurrent HBV infection in the grafted liver (Group B). Lamivudine 100 mg daily was administered orally for a period of 6-75 wk. RESULTS: After 6-8 wk lamivudine therapy was well tolerated and successfully suppressed HBV replication to an undetectable serum level of HBV DNA by polymerase chain reaction in six patients. In Group A, two patients underwent successful OLT with no evidence of HBV reinfection 2-14 months later. Lamivudine was continued after OLT with no episodes of rejection. Three patients died before a suitable liver could be found (one remained serum HBV DNA+ after 6 wk of lamivudine therapy). In Group B, 9-14 months after lamivudine therapy both patients developed lamivudine resistance (increased liver enzymes, reappearance of serum HBsAg and HBV DNA [by hybridization]). In both patients liver histology had progressed and in both, mutation at codon 552 of the HBV polymerase gene was detected. CONCLUSIONS: Lamivudine is well tolerated in patients with decompensated liver cirrhosis due to HBV precore mutant infection who are liver transplant candidates. In four patients (80%) potent suppression of viral replication was detected, allowing OLT to be performed. However, post-OLT, a resistant mutant developed under lamivudine therapy. Combination therapy with other antiviral agents should be evaluated to discourage the emergence of lamivudine-resistant mutants.

Antiviral Agents↗
PubMed1998

Treatment of colorectal liver metastases by cryotherapy.

One hundred fifty-eight procedures were performed on 136 patients with unresectable hepatic metastases using hepatic cryotherapy to ablate the tumors. The median age was 62 years. Patients included 90 males and 46 females. Fifty-eight patients had synchronous metastases, 55 had bilobar lesions, and 90 had precryo chemotherapy. Median preoperative carcinoembryonic antigen (CEA) level was 14.4 ng/dl. The numbers of lesions treated, frozen, and resected were two and one. Median survival of all patients was 30 months. Survival for 39 patients was 37 months. Patients with a CEA level > 100 ng/dl had a statistically worse survival rate than those with a level < 100 ng/dl (P < .001). Twenty patients underwent recryotherapy with median survival of 34 months. Recurrent disease developed in 78% of patients--82% of the patients developed liver recurrence. Complication rates were comparable to liver resection. Operative mortality was 3.7%. Hepatic cryotherapy is effective and safe in treating colorectal hepatic metastases under ultrasound guidance.

Adult↗
PubMed1998

Viremia, genetic heterogeneity, and immunity to hepatitis G/GB-C virus in multiply transfused patients with thalassemia.

BACKGROUND: Thalassemia patients are at high risk for posttransfusion hepatitis. Hepatitis G virus (HGV) has been suspected of being responsible for acute and chronic hepatitis. STUDY DESIGN AND METHODS: The prevalence of HGV infection, its possible association to liver disease, the genetic heterogeneity among the various HGV isolates, and immunity to HGV were studied in 36 thalassemia patients with reverse transcriptase-polymerase chain reaction assay and sequence analysis. RESULTS: HGV RNA was detected in seven patients (19.4%), only two of whom had evidence of hepatitis C virus infection as well. Sequence analysis of the NS3 gene from isolates of the five patients infected with HGV alone revealed 84.7 to 90.9 percent homology at the nucleotide level. Prolonged HGV viremia was not associated with significant liver enzyme elevation. All five patients were chronically infected with the same viral strain. E2 antibodies were detected in 57 percent of the HGV-nonviremic patients and in only 1 of 7 viremic patients. CONCLUSION: HGV is associated with persistent viremia but not with significant biochemical evidence of liver damage. There is some genetic heterogeneity among HGV isolates from thalassemia patients in Israel.

Amino Acid Sequence↗
PubMed1997

Infectious complications of hepatic cryosurgery.

Hepatic cryosurgery is a novel procedure for patients with metastatic liver disease. To date, no reviews of the infectious complications of this procedure have been published. One hundred and fifty patients underwent 158 hepatic cryosurgical procedures at Allegheny General Hospital (Pittsburgh) from November 1987 through July 1995. Gastrointestinal malignancies accounted for 93% of the underlying diagnoses. The following 12 infections were directly related to the cryosurgical procedure: hepatic abscess (six), intraperitoneal abscess (three), ascending cholangitis (two), and an intrahepatic device (Infusaid; Strato/Infusoid, Norwood, MA) infection (one). Enterococcus was the most commonly isolated organism. Seven of the 12 infections were polymicrobial. The patients who developed infections had longer hospital stays (26 days vs. 13 days) and had more days of fever (6.5 days vs. 2.3 days). than those who did not develop infections. If perioperative manipulation of the biliary tree is avoided, the infection rate in patients who undergo hepatic cryosurgery may be decreased even further. Overall, cryoablation of the liver is not related to an increased risk of infection.

Age Factors↗
PubMed1995

Hepatic cryosurgery in treating colorectal metastases.

BACKGROUND: The purpose of this study was to determine the effectiveness of cryosurgery as an adjunct to resection in treating patients with hepatic metastases from colorectal adenocarcinoma. METHODS: Forty-seven patients with documented metastases limited to the liver from colorectal adenocarcinoma were treated with cryosurgery with or without resection from November 1987 to February 1992 and were followed until February 1994. Intraoperative ultrasound was used to map the lesions and place the cryoprobes. Each lesion was frozen to -196 degrees centigrade for 15 minutes, thawed for 10 minutes, and frozen again for 15 minutes. Follow-up computed tomographic scans were obtained before hospital discharge and 6 months and 1 year after cryosurgery. Carcinoembryonic antigen levels were obtained monthly. RESULTS: Thirty-one males and 16 females, with a median age of 63 years, were treated. The median hospital stay was 10 days, and follow-up ranged from 24 to 57 months, with a median follow-up of 26 months. The actual survival at 24 months was 62%. Eleven percent of these patients had no evidence of disease at a median follow-up of 30 months. Complications included myoglobinuria, coagulopathy, pleural effusions, and bile duct injuries. Two patients (4%) died because of multisystem organ failure with irreversible coagulopathies. CONCLUSIONS: Cryosurgical ablation increases the number of patients with liver metastases who potentially can become disease free. However, the effect on overall survival will require a longer follow-up period.

Adult↗
PubMed1995

Hepatic cryosurgery in the treatment of unresectable metastases.

The treatment of unresectable hepatic metastases has generally been limited to systemic or intra-arterial chemotherapy. Cryosurgery has the advantage of potentially ablating such unresectable tumours. From November 1987 to August 1994, 140 patients underwent 155 procedures using hepatic cryosurgery with and without resection for documented metastatic disease. Intra-operative ultrasound was used for monitoring the freezing zone. The tumours were frozen using liquid nitrogen cooled to -196 degrees C for 15 min. The median number of lesions treated was three. Median hospital stay was 10 days. The operative mortality was 4%. Complications included coagulopathy, hypothermia, myoglobinuria, pleural effusions, ATN and infection. The median survival for all patients was 22 months. Of those patients followed for more than 2 years, the median survival was 25 months. Of the 65 patients that are still alive, the median follow-up is 27 months.

Adolescent↗
PubMed1994

Crystal structure of a catalytic antibody Fab with esterase-like activity.

BACKGROUND: Antibodies with catalytic properties can be prepared by eliciting an antibody response against 'transition state analog' haptens. The specificity, rate and number of reaction cycles observed with these antibodies more closely resemble the properties of enzymes than any of the many other known enzyme-mimicking systems. RESULTS: We have determined to 3 A resolution the first X-ray structure of a catalytic antibody Fab. This antibody catalyzes the hydrolysis of a p-nitrophenyl ester. In conjunction with binding studies in solution, this structure of the uncomplexed site suggests a model for transition state fixation where two tyrosines mimic the oxyanion binding hole of serine proteases. A comparison with the structures of known Fabs specific for low molecular weight haptens reveals that this catalytic antibody has an unusually long groove at its combining site. CONCLUSION: Since transition state analogs contain elements of the desired product, product inhibition is a severe problem in antibody catalysis. The observation of a long groove at the combining site may relate to the ability of this catalytic antibody to achieve multiple cycles of reaction.

Antibodies, Monoclonal↗