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Biomedical subjects

M Rabinovitz

Publications and source records attributed to M Rabinovitz.

At least 19 recordsLinked to original sources
PubMed1996

Candida albicans osteomyelitis in a liver transplant recipient: a case report and review of the literature.

A 51-year-old man developed fever and back pain 2 months after orthotopic liver transplantation for end-stage liver disease secondary to chronic hepatitis C infection. CT scan demonstrated destructive lesions in T12 suggestive of osteomyelitis. Aspiration biopsy of the vertebra revealed granulomatous inflammation and yeast forms; culture yielded Candida albicans. The patient improved with intravenous amphotericin B and 5-fluorocytosine and did not require surgical intervention. Candida osteomyelitis is a rare condition and to our knowledge it has not been reported before in liver transplant recipients. Awareness of this potential complication may shorten the delay in making the definitive diagnosis, which in turn may increase the likelihood of a response without sequela.

Candidiasis↗
PubMed1996

alpha-Interferon retreatment of patients with chronic hepatitis C.

To evaluate the effect of a second cycle of alpha-IFN treatment on patients who have not responded to a first cycle or responded and relapsed, 37 patients, 25 men and 12 women, mean age 41 yr, were retreated with alpha-interferon (IFN). Seven patients responded to the first cycle of treatment, and 30 did not. Five patients who had not responded to the second cycle received a third one. All patients received twice the dose of the first cycle unless they experienced side effects during the first cycle. Thus, nine patients received 9 mU/w, nine received 15 mU/w, and 19 received 30 mU/w for 6 months. Complete response was defined as nondetectable hepatic hepatitis C virus (HCV)-RNA at the end of therapy; sustained response was defined as normal ALT levels with negative serum HCV-RNA at > 6 months after cessation of therapy. Of the 30 nonresponders to the first cycle, eight responded to the second, but only four (13%) had a sustained response. Six of the seven responders to the first cycle responded to the second cycle, but only three had a sustained response (3/7, 43%) (p = NS). Although 33 and 21% (p = NS) of those who were treated with 15 mU/w and 30 mU/w, respectively, showed a sustained response, none of those treated with 9 mU/w had a sustained response (p = NS). Although age or sex of the patients studied had no effect on the response rate, liver histology was an important factor because only noncirrhotics showed a long term response (47 vs 0%; p < 0.02). There was no difference in response rate between patients with chronic active hepatitis and chronic persistent hepatitis. In conclusion, noncirrhotic patients who have not responded or responded and relapsed to a 6-month course of alpha-INF (3-5 mU three times per week) should try a second course at a dose of 15 mU/w. Retreatment may induce complete and long lasting response in 13% of the initial nonresponders and 43% of the initial responders. A second course of alpha-IFN in nonresponding cirrhotics appears ineffective in clearing the virus at the doses used.

Adult↗
PubMed1995

Primary biliary cirrhosis diagnosed during pregnancy. Does it have a different outcome?

Pregnancy in women with primary biliary cirrhosis (PBC) is uncommon, and once it occurs it usually does not worsen the liver disease. First manifestation of PBC during pregnancy in women with no known liver disease at the time of conception is very rare, and the natural history of this disease in such cases is yet unknown. Herein we describe a woman who had been diagnosed with PBC during the third trimester of pregnancy and, while she gave birth to a normal healthy child, her disease rapidly deteriorated and she has been listed for liver transplantation. It appears that PBC that is first noted during pregnancy might have a different course than that of PBC diagnosed before pregnancy.

Adult↗
PubMed1995

Inhibition of human immunodeficiency virus type 1 integrase by a hydrophobic cation: the phenanthroline-cuprous complex.

The human immunodeficiency virus type 1 integrase (HIV-1 integrase) is required for integration of a double-stranded DNA copy of the viral RNA genome into a host chromosome and for HIV replication. We have examined the effects of 2:1 1,10-phenanthroline-cuprous complexes on purified HIV-1 integrase. Although the uncomplexed phenanthrolines are not active below 100 microM, four of the cuprous complexes (neocuproine, 4-phenyl neocuproine, 2,3,4,7,8,9-hexamethyl phenanthroline, and 2,3,4,7,8-pentamethyl phenanthroline) have a 50% inhibitory concentration (IC50) for integration ranging between 1 and 10 microM. Disintegration is also inhibited by these phenanthroline-cuprous complexes at slightly higher concentrations (between 10 and 40 microM). Dialysis experiments showed that the inhibition is reversible and kinetic analyses revealed that the mode of inhibition by these cuprous complexes appears to be noncompetitive with respect to the substrate DNA. Consistent with these findings, binding assays demonstrate that, although these complexes can inhibit binding to DNA at high concentrations, they do not inhibit binding of integrase to the DNA substrate at their IC50 values. Because these complexes do not bind to B-DNA below 50 microM, inhibition via binding to a specific region on the enzyme was examined. Using deletion mutants of integrase, it was determined that neither the amino-terminal (zinc finger) nor the carboxy-terminal (DNA-binding) integrase domain is required for inhibition by the phenanthroline-cuprous complexes. Therefore, inhibition via binding to the enzyme catalytic core or to the interface between the enzyme and a noncanonical DNA structure generated during the enzymatic reaction is the probable mechanism. These results suggest the utility of neocuproine-cuprous complexes in developing inhibitors of HIV-1 integrase as well as probes for drug-binding sites and enzymatic reaction mechanism.

Base Sequence↗
PubMed1995

Biliary tract calculi in primary sclerosing cholangitis.

UNLABELLED: By conventional criteria the diagnosis of primary sclerosing cholangitis (PSC) is excluded if biliary tract calculi are present. OBJECTIVE: To compare patients with sclerosing cholangitis with and without calculi. METHODS: Retrospective review between 8/91 and 9/93 identified 63 patients with sclerosing cholangitis alone (Group A) and 22 patients with sclerosing cholangitis and biliary tract calculi (Group B). The mean follow-up was 13.6 months. Clinical features reviewed were age, sex, associated inflammatory disease (IBD), and clinical presentation. Cholangiographic features compared were site and extent of disease. Endoscopic stone extraction was reviewed for success and complications. RESULTS: Both groups had the following features in common: 1) mean age (45.9 vs 46.3 yr), 2) prevalence of IBD (68.3 vs 72.7%), 3) extent of bile duct strictures (intrahepatic: 28.5% vs 27.2%; extrahepatic: 12.7% vs 13.6%; both: 58.7% vs 54.5%). There were proportionately more women in Group B (45.5% vs 33.3%). Symptomatic presentation (pain, pruritus, jaundice, and cholangitis) was seen more often in Group B: 86.4% compared with Group A: 39.7% (specifically cholangitis was seen in 22.7% vs 4.7%). Among Group B, calculi developed subsequent (mean 40.2 months) after the diagnosis of sclerosing cholangitis in 77.3% of patients. The distribution of calculi was cholelithiasis: 7 (31.8%); choledocholithiasis: 9 (40.9%); and both: 6 (27.2%). Of the patients with choledocholithiasis alone, 78% had undergone previous cholecystectomy. Endoscopic stone extraction was successful in 13 (86.6%) of the patients with choledocholithiasis. Complications included mild pancreatitis in one patient and bleeding from sphincterotomy site in another patient which responded to sclerotherapy. In follow-up, only one patient had recurrent calculi and underwent successful stone extraction. CONCLUSION: We suggest that biliary tract calculi are a part of the spectrum of otherwise typical PSC and therefore their presence should not necessarily exclude the diagnosis.

Adult↗
PubMed1995

The phosphofructokinase-uncharged tRNA interaction in metabolic and cell cycle control: an interpretive review.

When the tRNA of mammalian cells is incompletely charged due to amino acid deficiency or by analogs which cannot be activated, many metabolic events become limited. This rapid demise of cell function appears to be because of the inhibition of phosphofructokinase (PFK) by uncharged tRNA (FEBS Lett. 302: 113 (1992)). Charged tRNA has been shown to be "sequestered within the protein synthetic machinery", (Negrutskii, B.S. and Deutscher, M.P., Proc. Natl. Acad. Sci. USA 89 3601 (1992) and would therefore be removed from an inhibitory role. Besides the direct demonstration that tRNA inhibits PFK in an assay regarded as indicative of its control mechanism, several reports in the literature support this model. These include 1) The rapid onset of inhibition of glycolysis and glucose uptake by intact cells upon amino acid deficiency and the similar lesion at the 43S ribosomal subunit on glucose or amino acid deprivation. 2) The recognition that unusually high concentrations of cAMP required to stimulate protein synthesis in energy depleted or gel filtered lysates correlates with its action on PFK as an analog of the positive effector, adenosine-5'-monophosphate. 3)The often repeated observation that the product of PFK activity, fructose-1,6-diphosphate, is a stimulant of protein synthesis (see Jackson, R.J., et al. Eur. J. Biochem. 131: 289-313 (1983)). This diphosphate has been shown to be the proximate effector binding to eIF-2B, the guanine nucleotide exchange factor (Singh, L.P. Arror, A.R. and Wahba, A.J., FASEB J. 8 279 (1994)) which by releasing GDP bound to the inactive GDP:eIF-2 complex, permits the factor to initiate a new peptide chain. The above information supports the view that the block at the G1 restriction point in the cell cycle of normal cells brought about by amino acid deprivation is a result of inhibition of protein synthesis through the phosphofructokinase-uncharged tRNA mechanism. This is consistent with observations in the literature that tumor and transformed cells, which are more resistant to this block (Pardee, A.B., Proc. Natl. Acad. Sci. U.S.A. 71:1286-1291 (1974)) have a higher phosphofructokinase activity or higher levels of fructose-1,6-diphosphate.

Amino Acids↗
PubMed1994

Postinfantile giant cell hepatitis associated with anti-M2 mitochondrial antibodies.

Whereas giant cell hepatitis (GCH) is a common diagnosis made in neonates, it is rare in the adult population. The diagnosis of GCH is based on the presence of giant cell transformation of hepatocytes. It is commonly associated with either viral hepatitis or autoimmune disorders. A patient with GCH who had anti-M2 mitochondrial antibodies is described. This combination, which has not been previously reported, underscores the association of GCH with autoimmune disorders and stresses the importance of corticosteroids as an empirical initial therapy.

Acute Disease↗
PubMed1993

Prophylactic versus emergency sclerotherapy of large esophageal varices prior to liver transplantation.

From January 1985 through July 1987, adult patients accepted for liver transplantation with large esophageal varices were enrolled in a study evaluating the use of prophylactic vs emergency sclerotherapy. Six hundred forty-eight subjects received prophylactic sclerotherapy, and 172 received emergent sclerotherapy. Esophageal stricture formation was increased 12.9-fold (P < 0.001), esophageal perforation 6.4-fold (P < 0.005), and postsclerotherapy bleeding esophageal ulcers 3.7-fold (P < 0.001) in those receiving emergency sclerotherapy as opposed to prophylactic sclerotherapy. These differences were even greater if the number of sclerotherapy sessions rather than the number of patients was used as the denominator for the comparisons. In total, 19.6% of emergency sclerotherapy cases were associated with an untoward outcome of sclerotherapy; only 1.9% of cases receiving prophylactic sclerotherapy experienced an untoward outcome (P < 0.001). These data demonstrate that emergency sclerotherapy is associated with a greater prevalence of complications and support earlier studies that show that sclerotherapy prevents variceal bleeding over the short term. The data also suggest that when applied to patients with large varices awaiting orthotopic liver transplantation, it enhances the chance of a patient surviving to be transplanted by preventing a variceal bleed and the spiral of liver failure and death that frequently follows an episode of acute variceal bleeding.

Adult↗
PubMed1992

The pleiotypic response to amino acid deprivation is the result of interactions between components of the glycolysis and protein synthesis pathways.

Several diverse metabolic events become compromised when mammalian cells are made deficient in essential amino acids or when charging of their tRNA is blocked by amino acid analogs. This rapid general demise of cell function can be due to inhibition of phosphofructokinase (PFK) by uncharged tRNA. It has now been demonstrated that when tRNA is added to PFK in an assay dependent upon the reassociation of inactive, dissociated enzyme subunits, nanomolar concentrations cause complete inhibition. The model for control suggests that charged tRNA becomes associated with EF-1, which is specific for aminoacyl-tRNAs and is present in sufficiently high concentrations in cells to sequester that charged forms from an inhibitory role. Support for this model include: (1) the rapid onset of inhibition of glycolysis and glucose uptake upon amino acid deficiency; (2) the unique role of the product of PFK activity, fructose-1,6-diphosphate, in reactions of peptide chain initiation, particularly its role as a co-factor for purified eIF-2B, the GDP/GTP exchange factor; (3) the correlations of this interaction with the cellular and molecular lesions of insulin insufficiency; (4) the recognition that the anomalous role of high concentrations of cAMP as a stimulant of peptide chain initiation in energy depleted or gel-filtered cell lysates correlates with its stimulatory action on PFK as an analog for the positive effector, adenosine-5'-monophosphate; and (5) the role of fructose-1,6-diphosphate in the formation of glyceraldehyde-3-phosphate, a substrate for synthesis of ribose-5-phosphate via the non-oxidative portion of the pentose phosphate pathway, which, as a precursor of phosphoribosylpyrophosphate, is essential for nucleic acid synthesis.

Amino Acids↗
PubMed1992

Lack of increase in heterozygous alpha 1-antitrypsin deficiency phenotypes among patients with hepatocellular and bile duct carcinoma.

Homozygous alpha 1-antitrypsin deficiency (PiZZ phenotype) is known to be associated with increased risk of cirrhosis and primary liver cancer. Although a relationship between heterozygous alpha 1-antitrypsin deficiency and chronic liver disease was suggested recently, it is still a matter of controversy whether such patients are at increased risk of liver cancer. The goal of this study was to determine the prevalence of heterozygous alpha 1-antitrypsin deficiency of different phenotypes among patients with primary hepatobiliary cancers. We studied 82 patients with primary hepatobiliary cancer; 59 had hepatocellular carcinoma and 23 had bile duct carcinoma. alpha 1-Antitrypsin quantitation and phenotyping were performed in each patient using standard methods. The distribution of the various Pi phenotypes was compared with that found in a normal population and reported elsewhere. Odds-ratio and chi 2 tests were used to measure the relative risk and the significance of association, respectively, between primary hepatobiliary cancers and heterozygous alpha 1-antitrypsin deficiency. Four patients in each of the cancer groups were heterozygous. Among the hepatocellular carcinoma patients, three had the PiMS phenotype and one had the PiMZ phenotype. Of these four heterozygous patients, only two had cirrhosis; one had cryptogenic cirrhosis and the other had hepatitis B virus-related cirrhosis. One noncirrhotic patient with a PiMZ phenotype had a fibrolamellar carcinoma. Of the four patients with bile duct carcinoma, three had the PiMS phenotype and one had the PiMZ phenotype. Of the four heterozygous patients, two had primary sclerosing cholangitis without associated inflammatory bowel disease and one patient had had previous biliary operations.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma, Bile Duct↗
PubMed1992

Association between heterozygous alpha 1-antitrypsin deficiency and genetic hemochromatosis.

Primary hemochromatosis is a genetically determined autosomal recessive disorder characterized by the excessive accumulation of body iron, most of which is deposited in the parenchymal cells of various organs. alpha 1-Antitrypsin deficiency is characterized among others by defective secretion of alpha 1-antitrypsin from liver cells. Whereas the risk of cirrhosis is increased in homozygous patients (PI ZZ) and possible in heterozygous patients (non-PI MM) as well, a greater risk for hepatocellular carcinoma has been suggested only in homozygous patients. Because these two metabolic disorders are relatively common, it has been difficult to determine whether they are associated with each other. In this study, we tried to determine the relationship between these two disorders using the case material seen at the University of Pittsburgh during a 7-yr period. We studied 15 patients with genetic hemochromatosis. alpha 1-Antitrypsin quantitation and phenotyping were performed in each case using standard methods. The distribution of the various Pi phenotypes was compared with that found in a normal population and reported elsewhere. Odds ratio and chi 2 tests were used to measure the relative risk and significance of association, respectively. Eleven patients (73%) were found to be PI M and four (27%) were identified as being heterozygotes: three (20%) were PI MZ, and one (7%) was PI MS. The prevalence of the PI MS phenotype was similar to that in the general population (7% vs. 6.4%; NS). The PI MZ phenotype, however, was statistically more common in patients with hemochromatosis than in the general population (20% vs. 2.2%; p less than 0.004).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Simultaneous occurrence of primary sclerosing cholangitis and autoimmune chronic active hepatitis in a patient with ulcerative colitis.

The simultaneous occurrence of PSC and autoimmune CAH in a patient with ulcerative colitis is described. Although each disease is a well documented complication of UC, their combination has never been reported. The diagnosis of PSC was based on typical findings on ERCP and liver biopsy and that of CAH was based on typical findings on liver biopsy supported by HLA typings and a remarkable response to a combination of glucocorticoids and azathioprine. The difficulties in establishing the diagnosis and the management of such patients are discussed.

Adult↗
PubMed1992

Vitamin D and osteocalcin levels in liver transplant recipients. Is osteocalcin a reliable marker of bone turnover in such cases?

Patients with advanced liver disease are at increased risk for the development of hepatic osteodystrophy in the form of either osteomalacia or osteoporosis. The pathogenesis of these two bone diseases is multifactorial and includes, among other factors, alterations in vitamin D metabolism, malnutrition and hypogonadism. Little is known regarding vitamin D metabolism and the osteoblastic activity in liver transplant recipients. In order to clarify these issues, vitamin D metabolites and osteocalcin levels were measured prior to and 30 days following liver transplantation in 30 cirrhotic patients of various etiologies. While the mean plasma concentrations of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D of the entire group of 30 patients were significantly greater prior to orthotopic liver transplantation (OLTx) as compared to those after OLTx (11.5 +/- 8.6 vs. 7.4 +/- 5.8 ng/ml, p = 0.0066 and 41.0 +/- 34.6 vs. 20.4 +/- 11.0 pg/ml, p = 0.0003, respectively), no significant changes in osteocalcin concentrations pre- or post-transplantation could be demonstrated (5.2 +/- 3.0 vs. 6.4 +/- 4.1 ng/ml, p = 0.51). Furthermore, no correlation between the plasma concentration of osteocalcin and either vitamin D metabolite, the prothrombin time or cyclosporine levels was found. The reasons for the normal levels of osteocalcin prior to OLTx can be explained by the fact that in vitamin-K-deficient states osteocalcin is predominantly decarboxylated and, therefore, a smaller proportion is bound to bone and/or the synthesis of osteocalcin is partially modulated by 1,25-dihydroxyvitamin D, the level of which has been found to be normal.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Bacteriuria in patients with cirrhosis.

The prevalence and bacteriology of bacteriuria was studied in 140 patients with cirrhosis of the liver, referred to the University of Pittsburgh Medical Center for evaluation for liver transplantation (72 males and 68 females; mean age 46 years). Urine samples were obtained for cultures within 24 h after admission. Significant bacteriuria (SB) (> 10(5) bacteria/ml) was present in 25 patients (18%), the most common being E. coli (36%) and coagulase-negative staphylococcus (20%). SB was more common in females than in males (32 vs. 4%, p < 0.001), and was seen in every category of cirrhosis. The occurrence of bacteriuria did not correlate with the severity of the underlying liver disease or with the age of the patient. Based upon these results, it can be concluded that: (1) bacteriuria is common in patients with advanced liver disease and occurs in approximately 20% of the cases; (2) it is more common in females than in males; and (3) its prevalence in patients with primary biliary cirrhosis is similar to that in other types of chronic advanced liver disease.

Adult↗
PubMed1992

Hepatotoxicity of nonsteroidal anti-inflammatory drugs.

The steady increase in nonsteroidal anti-inflammatory drug (NSAID) use over the past decade has been associated with an increased awareness of the gastrointestinal complications of these agents. As a result, several reviews on this topic have been published. Associated with the increased recognition of the untoward gastrointestinal consequences of NSAID use has been an increasing awareness of the untoward hepatic consequences of NSAID use. Nonetheless, many physicians either remain unaware of the hepatotoxic potential of NSAIDs or are unsure which agents are either safer or associated with a greater risk for hepatotoxicity. The following is an overview of the hepatotoxicity of NSAIDs that identifies both the type and severity of such reactions, where sufficient data exist to allow such judgements to be made.

Anti-Inflammatory Agents, Non-Steroidal↗