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Biomedical subjects

A I Sharara

Publications and source records attributed to A I Sharara.

At least 19 recordsLinked to original sources
PubMed1999

Liver disease in pregnancy.

Acute viral hepatitis is the most common cause of jaundice in pregnancy. The course of acute hepatitis is unaffected by pregnancy, except in patients with hepatitis E and disseminated herpes simplex infections, in which maternal and fetal mortality rates are significantly increased. Chronic hepatitis B or C infections may be transmitted to neonates; however, hepatitis B virus transmission is effectively prevented with perinatal hepatitis B vaccination and prophylaxis with hepatitis B immune globulin. Cholelithiasis occurs in 6 percent of pregnancies; complications can safely be treated with surgery. Women with chronic liver disease or cirrhosis exhibit a higher risk of fetal loss during pregnancy. Preeclampsia is associated with HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome, acute fatty liver of pregnancy, and hepatic infarction and rupture. These rare diseases result in increased maternal and fetal mortality. Treatment involves prompt delivery, whereupon the liver disease quickly reverses. Therapy with penicillamine, trientine, prednisone or azathioprine can be safely continued during pregnancy.

Cholelithiasis↗
PubMed1997

Interferon (IFN)-alpha activation of human blood mononuclear cells in vitro and in vivo for nitric oxide synthase (NOS) type 2 mRNA and protein expression: possible relationship of induced NOS2 to the anti-hepatitis C effects of IFN-alpha in vivo.

Although researchers have noted high level activation of rodent mononuclear phagocytes for nitric oxide (NO) synthase type 2 (S2) expression and NO production with a variety of agents such as interferon (IFN) gamma and endotoxin, it has been difficult to demonstrate activation of human mononuclear phagocytes. The purpose of this study was to determine if IFN-alpha serves as an activator in vitro and in vivo in humans. Treatment of normal monocytes or mononuclear cells in vitro with IFN-alpha caused a dose-dependent increase in monocyte NOS2 activity and NO production, and increased expression of NOS2 protein and mRNA expression. To determine if in vivo administration of IFN-alpha also modulated NOS2, we studied blood cells from patients with hepatitis C before and after IFN-alpha therapy. Untreated patients with chronic hepatitis C virus infection had levels of NOS activity and NOS2 antigen in freshly isolated mononuclear cells similar to those of healthy subjects, and they expressed minimal or no NOS2 mRNA. However, IFN-alpha treatment of patients with hepatitis C infection was associated with a significant elevation in mononuclear cell NOS activity, NOS2 antigen content, and NOS2 mRNA content. IFN-alpha-treated patients had significant decreases in levels of serum alanine aminotransferase and plasma hepatitis C mRNA. The degree of IFN-alpha-enhanced mononuclear cell NOS2 antigen content correlated significantly with the degree of reduction in serum alanine aminotransferase levels. Thus, IFN-alpha treatment of cells in vitro or administration of IFN-alpha to hepatitis C patients in vivo increases expression of mononuclear cell NOS2 mRNA expression, NOS activity, NOS2 antigen expression, and NO production. Since NO has been reported to have antiviral activity for a variety of viruses, we speculate that induced NO production may be related to the antiviral action(s) of IFN-alpha in hepatitis C infection.

Adult↗
PubMed1997

Hepatitis C in pregnancy.

OBJECTIVE: To review the epidemiology and clinical course of hepatitis C virus (HCV) infection, to examine current data on the vertical transmission of HCV to neonates, and to develop recommendations for intrapartum and postpartum follow-up of neonates born to HCV-infected mothers. DATA SOURCES: The English-language medical literature from 1988 to 1996 was reviewed through MEDLINE. METHODS OF STUDY SELECTION: Case series evaluating vertical transmission of HCV infection in neonates, determined by HCV RNA testing, after delivery and breast-feeding were reviewed and summarized. TABULATION, INTEGRATION, AND RESULTS: Vertical transmission of HCV infection was examined with respect to maternal human immunodeficiency virus (HIV) status (as heterosexual transmission of HCV is enhanced in HIV-positive patients) and chronicity of HCV infection. Vertical transmission of HCV from HIV-negative mothers with chronic hepatitis C ranged from 0 to 18%. The risk of HCV vertical transmission from HIV-negative mothers with acute hepatitis C may be higher than that from mothers with chronic HCV infection. Vertical transmission of HCV was proportional to maternal HCV RNA levels; no transmission was noted in women without HCV RNA, whereas the greatest transmission was noted in women with HCV RNA greater than 1 million copies/mL. Vertical transmission of HCV from HIV-positive mothers with chronic hepatitis C ranged from 6 to 36%. In colostrum, HCV RNA was found to be present in low titers. No studies have documented transmission of HCV infection to infants via breast-feeding. CONCLUSION: Vertical transmission of HCV complicates up to 18% of pregnancies in HCV-positive, HIV-negative women and 6-36% in HCV-positive, HIV-positive women. The highest rates of vertical transmission of HCV were noted in women with high HCV RNA or concurrent HIV infection. Breast-feeding has not been associated with vertical transmission of HCV infection.

Breast Feeding↗
PubMed1997

Chronic hepatitis C.

BACKGROUND: Infection with the hepatitis C virus (HCV) is a leading cause of chronic liver disease worldwide. Epidemiologic and natural history studies have helped to define the clinical impact of HCV infection, and molecular diagnostic assays have established clinical endpoints against which therapeutic regimens are currently tested. The absence of definitive therapy has generated controversy regarding indications and optimal candidacy for currently approved treatment. This paper reviews the epidemiology, natural history, clinical manifestations, diagnostic modalities, and current treatment of chronic HCV infection. METHODS: Search of the MEDLINE database for English-language articles and abstracts on chronic HCV infection yielded data from more than 500 original papers, reviews, and abstracts. RESULTS AND CONCLUSIONS: Hepatitis C virus is transmitted primarily through contaminated blood and less effectively by human body secretions, but a large proportion of patients have no clearly identifiable parenteral risk factors for viral acquisition. Infection with HCV results in subclinical chronic hepatitis in the majority of patients and may progress, usually over decades, to cirrhosis and hepatocellular carcinoma. Extrahepatic manifestations of HCV infection include porphyria cutanea tarda, mixed essential cryoglobulinemia, and membranoproliferative glomerulonephritis. Diagnostic modalities are accurate in estimating viral load and genotype and may be helpful in predicting and assessing response to treatment. Current therapy is limited to interferon alfa and is effective at viral eradication in only a small number of patients. The adjuvant use of drugs, such as ribavirin, in combination with interferon may hold promise at enhancing viral eradication. Understanding the mechanisms behind viral persistence and immune escape of HCV will be essential in developing effective future therapeutic and preventive strategies.

Antiviral Agents↗
PubMed1997

Regulation of biliary secretion through apical purinergic receptors in cultured rat cholangiocytes.

To evaluate whether ATP in bile serves as a signaling factor regulating ductular secretion, voltage-clamp studies were performed using a novel normal rat cholangiocyte (NRC) model. In the presence of amiloride (100 microM) to block Na+ channels, exposure of the apical membrane to ATP significantly increased the short-circuit current (Isc) from 18.2 +/- 5.9 to 52.8 +/- 12.7 microA (n = 18). The response to ATP is mediated by basolateral-to-apical Cl- transport because it is inhibited by 1) the Cl- channel blockers 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (1 mM), diphenylanthranilic acid (1.5 mM), or 5-nitro-2-(3-phenylpropylamino)benzoic acid (50 or 100 microM) in the apical chamber, 2) the K+ channel blocker Ba2+ (5 mM), or 3) the Na(+)-K(+)-2Cl- cotransport inhibitor bumetanide (200 microM) in the basolateral chamber. Other nucleotides stimulated an increase in Isc with a rank order potency of UTP = ATP = adenosine 5'-O-(3)-thiotriphosphate, consistent with P2u purinergic receptors. ADP, AMP, 2-methylthioadenosine 5'-triphosphate, and adenosine had no effect. A cDNA encoding a rat P2u receptor (rP2uR) was isolated from a liver cDNA library, and functional expression of the corresponding mRNA in Xenopus laevis oocytes resulted in the appearance of ATP-stimulated currents with a similar pharmacological profile. Northern analysis identified hybridizing mRNA transcripts in NRC as well as other cell types in rat liver. These findings indicate that exposure of polarized cholangiocytes to ATP results in luminal Cl- secretion through activation of P2u receptors in the apical membrane. Release of ATP into bile may serve as an autocrine or paracrine signal regulating cholangiocyte secretory function.

Adenosine Triphosphate↗
PubMed1996

Hepatitis C.

OBJECTIVES: To review the virology, epidemiology, pathogenesis, natural history, clinical manifestations, and current treatment of hepatitis C virus (HCV) infection. DATA SOURCES: The MEDLINE database (1966 to 1996) was searched for English-language articles and abstracts on HCV and non-A, non-B hepatitis. Papers cited in relevant primary articles were also reviewed. STUDY SELECTION: More than 500 original and review articles were evaluated, and the most relevant were selected. DATA EXTRACTION: Data were extracted and reviewed by all authors. DATA SYNTHESIS: In most patients, HCV infection results in chronic hepatitis. The disease is insidious and subclinical but may progress over decades into end-stage liver disease and hepatocellular carcinoma, which makes HCV cirrhosis a leading indication for orthotopic liver transplantation. Current diagnostic methods are highly sensitive and specific, and quantitative assessment of viral load may help to predict and monitor response to treatment. The only available therapeutic option is interferon, and this agent is effective in only a small subset of patients. CONCLUSIONS: Infection with HCV is a significant public health problem that has important clinical and financial consequences. The tailoring of specific therapy according to viral load or genotype, better patient selection, and use of combination drug regimens may improve the chance of viral clearance and sustained biochemical and histologic response. Further understanding of the basic virology of HCV and the exact mechanisms of viral persistence and tissue injury is needed to help define future therapeutic and preventive strategies.

Carcinoma, Hepatocellular↗
PubMed1996

Cytomegalovirus infection following liver transplantation: review of the literature.

Cytomegalovirus (CMV) remains a major cause of problems following solid organ transplantation, accounting for a significant increase in morbidity and affiliated costs. Infection with CMV following orthotopic liver transplantation (OLT) is commonly seen as a result of marked cell-mediated immunosuppression and is an independent risk factor for opportunistic and fungal infections. The role of CMV infection in acute cellular or chronic rejection remains unclear. Recent advances in diagnostic modalities, particularly the use of the antigenemia assay and the polymerase chain reaction, have provided ways to quantitate viral load during infection or disease, as well as providing a useful marker of response to therapy. Ganciclovir remains the best antiviral agent for the treatment of CMV disease, but the use of combination therapy with other antivirals or CMV immunoglobulin may improve outcome for patients with severe disease. The ideal prophylactic therapy for patients undergoing OLT remains to be identified, as tested regimens have shown variable efficacy when analyzed with regard to defined risk groups. The use of risk group-specific prophylaxis may prove to be most successful, however, in terms of efficacy and cost savings. Future advances in basic CMV virology and transplant immunology will be essential in defining rational approaches to control and prevention of CMV infection and disease following liver transplantation.

Animals↗
PubMed1996

Evidence that ursodeoxycholic acid prevents steroid-resistant rejection in adult liver transplantation.

Steroid-resistant rejection continues to be a serious problem in liver transplantation. Since ursodeoxycholic acid (UDCA) is beneficial in several cholestatic disorders and possesses in vitro immunomodulatory and immunosuppressive effects, we have tested in a pilot study the effects of adjuvant UDCA in the prevention of steroid-resistant rejection. Fifty consecutive liver transplant patients were treated with a standard cyclosporine immunosuppressive regimen. Treatment with UDCA (10 mg/kg/d) was initiated in each patient who developed biopsy-proven rejection or biochemical evidence of cholestasis. Clinical and laboratory features were monitored for evidence of rejection. Data were analyzed after at least a 10-month follow-up period was available in each patient. Seven patients died during the study period, all within 4 wk of surgery. No evidence of rejection was documented in these patients. Twenty three of the 43 survivors 53% (23/43) developed an episode of rejection, and UDCA was initiated in each of them. Only one patient had a second episode of rejection, which responded to intravenous methylprednisolone therapy; no patient required antilymphocyte therapy. There was no evidence of toxicity for UDCA. These data suggest that UDCA can be given safely following OLT and may contribute to prevention of steroid-resistant rejection in liver transplant recipients.

Adolescent↗
PubMed1995

Sphingolipid-gated Ca2+ release from intracellular stores of endothelial cells is mediated by a novel Ca(2+)-permeable channel.

Sphingolipid-gated Ca2+ signaling is mediated through Ca(2+)-permeable channels. In this report, we characterize the properties of the channel in a human endothelial cell line (EA.hy926). Ca2+ release from intracellular stores is not antagonized by nifedipine, omega conotoxin G-VIa, or heparin. To further characterize the molecular properties of the channel, we developed a novel assay to directly measure efflux of Ca2+ from intracellular stores of permeabilized Xenopus oocytes. Following size fractionation by sucrose gradient, poly(A)+ RNA from EA.hy926 cells is microinjected into oocytes of Xenopus laevis. We find that the mRNA encoding Ca2+ release activity is approximately 1.5-2.0 kilobases in length. The sphingolipid-gated Ca(2+)-permeable channel is thus likely to be a novel Ca(2+)-permeable channel distinct from other characterized intracellular Ca2+ channels such as the ryanodyne receptor and the inositol 1,4,5-trisphosphate receptor. The method described here provides a new approach to further characterizing this channel and other intracellular Ca2+ channels.

Animals↗
PubMed1995

Phenylalanine-stimulated secretion of cholecystokinin is calcium dependent.

The secretion of cholecystokinin was examined in STC-1 cells, an intestinal cholecystokinin (CCK)-secreting cell line. Exposure to the amino acid L-phenylalanine increased release of CCK by 135%, 180%, and 251% of control levels after 15-min treatments with 5, 20, and 50 mM phenylalanine, respectively. L-Phenylalanine-induced secretion of CCK was inhibited by the calcium channel blocker diltiazem (10 microM). L-Phenylalanine (20 mM) also significantly increased cytosolic calcium levels in fura 2-acetoxymethyl ester (fura 2-AM)-loaded cells, and this increase was diltiazem sensitive. D-Phenylalanine, over the dose range of 5-50 mM, produced nonsignificant increases in CCK release. Treatment of STC-1 cells with 300 ng/ml of pertussis toxin for either 4 or 24 h did not significantly affect either basal release of CCK or L-phenylalanine-stimulated secretion. Patch-clamp recordings from cell-attached membrane patches showed a stimulation in calcium channel activity after L-phenylalanine. These results indicate that, in STC-1 cells, L-phenylalanine stimulates release of cholecystokinin via a calcium-dependent process.

Animals↗
PubMed1994

Paroxysmal cold hemoglobinuria associated with non-Hodgkin's lymphoma.

This report describes a patient with severe unexplained recurrent hemolytic anemia and congestive heart failure. Donath-Landsteiner antibodies, suggestive of paroxysmal cold hemoglobinuria (PCH), were detected. On postmortem examination, a diagnosis of non-Hodgkin's lymphoma, primarily involving the heart, was made. This previously undescribed association expands on the clinical and serologic spectrum of non-Hodgkin's lymphoma and PCH. Unexplained hemolytic anemia in the elderly should raise the suspicion of an underlying lymphoproliferative disorder.

Aged↗