Development of ganciclovir resistance during treatment of primary cytomegalovirus infection after liver transplantation.
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Adolescent↗
Biomedical subjects
S L Orloff
Publications and source records attributed to S L Orloff.
HIV antigens and T-cell receptor variable beta chain families.
The authors investigated whether the human immunodeficiency virus (HIV) has restrictive effects on the variable region of the beta chain (V beta) of the T-cell antigen receptor (TCR), by in vitro cultivation of non-HIV-infected peripheral blood lymphocytes with one of six HIV antigens or heat-inactivated whole virus (HIV-HI). Resting and blastic CD4+ and CD8- cells were assessed with 3-colour cytofluorometry and monoclonal antibodies to various V beta families/subfamilies. The V beta families affected include V beta's 13.1/.3, 8, and 21 with gp 120; V beta 21 with gp 160 and RT; V beta 8 with p25; V beta's 8 and 21 with Rev; and V beta's 3 and 21 with HIV-2 Vpx. V beta family-specific effects with HIV-HI did not differ significantly from those found with IL-2 stimulation. Findings differed between CD4+ and CD8+ cells. For CD4+ lymphocytes, significant V beta-specific decreases were found, not the expansions found with superantigens or mitogens. CD8+ lymphocytes showed slight but significant expansions. The effects on V beta's 8, 13, and 21 are consistent with previous studies of HIV-infected persons. However, it is difficult to accept that antigens encoded by different HIV genetic regions cause proportionate diminutions of similar V beta families. The authors suggest that these effects may be secondary to changes in cytokine profiles rather than direct interactions with TCR V beta's.
Adult↗
Experimental, clinical, and metabolic results of side-to-side portacaval shunt for intractable cirrhotic ascites.
BACKGROUND: Intractable ascites, refractory to medical therapy, occurs in approximately 10 percent of patients with ascites from cirrhosis and is almost always fatal. Sinusoidal hypertension resulting from hepatic venous outflow obstruction plays a primary role in the pathogenesis of cirrhotic ascites and provides the rationale for decompression of the liver by side-to-side portacaval shunt in treatment of intractable ascites. This report presents the experimental basis for the use of side-to-side shunt and long-term results of a prospective study in 34 selected patients with intractable cirrhotic ascites. STUDY DESIGN: In the experimental studies, hepatic venous outflow obstruction and massive ascites were produced in dogs by ligation of the hepatic veins, and the effect of portacaval shunts on ascites, thoracic duct lymph flow, and aldosterone secretion were measured. In the clinical study, 34 carefully selected patients with cirrhosis (91 percent alcoholic) and truly intractable ascites (failure of medical therapy for 5 to 24 months) underwent side-to-side portacaval shunt. The effects on ascites, survival, metabolic abnormalities, and quality of life were studied prospectively during follow-up that was longer than 5 years in all but two patients. Quantitative Child's risk classes in percent of patients were A in 0, B in 68, and C in 32. RESULTS: In the experimental studies, side-to-side portacaval shunt permanently relieved severe ascites, reduced the 13-fold increase in thoracic duct lymph flow rate to almost normal, and abolished the aldosterone hypersecretory response to minimal hepatic venous outflow obstruction. End-to-side portacaval shunt was much less effective. In the clinical study, side-to-side portacaval shunt reduced mean portal vein-inferior vena cava pressure gradient from 282 mm saline to 4 mm and permanently relieved all patients of ascites without subsequent requirement of diuretic therapy. Two patients who died of hepatoma, and one who died of heart failure developed terminal ascites. Thirty-day mortality rate was 6 percent, and long-term survival rates at 5, 10, and 15 years were 75 percent, 74 percent, and 73 percent. In metabolic studies, side-to-side shunt produced marked diuresis and natriuresis and abolished hypersecretion of aldosterone. Quality of life was generally improved as a result of a low incidence of recurrent portal-systemic encephalopathy (6 percent), abstinence from alcohol in 91 percent, improvement in liver function in 81 percent, and improvement in Child's risk class. The portacaval anastomosis remained permanently patent in every patient. CONCLUSIONS: Side-to-side portacaval shunt is very effective treatment of intractable ascites from cirrhosis. Our results are attributable to careful selection of patients, an organized system of care, and a program of rigorous, lifelong follow-up that emphasizes abstinence from alcohol and dietary protein restriction.
Adult↗
Determinants of perinatal HIV-1 transmission.
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Female↗
Mechanisms of human immunodeficiency virus Type 1 (HIV-1) neutralization: irreversible inactivation of infectivity by anti-HIV-1 antibody.
An assay for the neutralization of human immunodeficiency virus type 1 (HIV-1) is described in which the reduction in infectious titer of HIV-1 after preincubation at 37 degrees C with antibody-positive serum is the measure of neutralization. The assay format and its controls allow several experimental manipulations that, taken together, indicate an effect of antibody on HIV-1 infectivity that occurs before or independently of HIV-1 attachment. The direct inactivation of HIV-1 infectivity by antibody is irreversible and temperature dependent, requires a bivalent antibody directed against accessible envelope determinants, and does not require a heat-labile or (Ca2+)- or (Mg2+)-dependent cofactor. The mechanism of inactivation cannot be explained by agglutination of virus, nor is it associated with disruption or dissociation of envelope protein from virions. Rather, the antibody is likely to perturb some metastable property of the envelope that is required for entry. Laboratory-adapted HIV-1 isolates were more sensitive to the inactivating effects of sera than were primary patient isolates. The latter were particularly resistant to inactivation by contemporary autologous sera, a feature not explained by blocking antibodies. Additional studies showed a weak relationship between disease course and serum inactivation of the reference LAI laboratory strain of HIV-1. Heteroduplex analysis and autologous inactivation assays of sequential specimens from individual patients indicate that over time, the viral quasispecies that emerge and dominate are resistant to the inactivating effects of earlier sera.
Animals↗
Advances in the management of patients with Zollinger-Ellison syndrome.
A detailed description of recent advances in the management of patients with Zollinger-Ellison syndrome (ZES) is presented. The clinical presentation is reviewed, and newer diagnostic tools, both preoperative and intraoperative, are discussed. An update on surgical management is presented, including indications for abdominal exploration, intraoperative localization techniques, surgical excision, and the approach to patients with metastases or in whom no tumor is found. New strategies in the medical management of ZES also are reviewed. An update on patient survival is presented, and a review of the management of patients with multiple endocrine neoplasia type 1 and ZES is discussed.
Abdomen↗
Increase in sensitivity to soluble CD4 by primary HIV type 1 isolates after passage through C8166 cells: association with sequence differences in the first constant (C1) region of glycoprotein 120.
Primary isolates of human immunodeficiency virus type 1 (HIV-1) were obtained by coculture of peripheral blood lymphocytes (PBLs) from HIV-1-infected people with PBLs from uninfected donors. These viral stocks tend to be resistant to neutralization/inactivation by soluble CD4 (sCD4). When these stocks were passed through the T cell line C8166, virus stocks emerged that were sensitive to sCD4. Pre- and post-C8166 stocks maintained their sCD4-resistant and -sensitive phenotypes, respectively, with further passage in PBLs. Pre- and post-C8166 stocks were biologically cloned by two cycles of limiting dilution. The majority (14 of 17) of pre-C8166 clones were sCD4 resistant, and, conversely, the majority of post-C8166 clones (11 of 12) were sensitive to sCD4. Nucleotide and predicted amino acid sequence analysis in the env (gp120) region revealed a limited number of differences between the clones. The only differences that sorted with biological phenotype were in the first constant (C1) region of gp120. Adaptation to growth in C8166 cells and conversion from the sCD4-resistant to the sCD4-sensitive phenotype represent the emergence to prominence of viral species in the pre-C8166 stock that have a replication advantage in C8166 coincident with increased sensitivity to sCD4.
Amino Acid Sequence↗
Long-term outcome in kidney transplant patients with hepatitis C (HCV) infection.
To assess the prevalence and long-term impact of HCV on kidney transplant recipients, we assayed 716 pre-transplant sera using a first-generation ELISA. The anti-HCV positive sera were confirmed by a 6-antigen radioimmunoassay (RIA). Patients were followed up for 5 years. Graft survival, function, evidence of chemical hepatitis (AST > 2x normal), patient mortality and cause of death were evaluated. The prevalence of anti-HCV antibody was 10.3%. In the 638 patients who were followed up for 5 years, there were no differences in graft function, graft survival, overall mortality, or death from sepsis or liver disease. Peak AST levels were significantly higher in anti-HCV positive patients compared to anti-HCV negative patients. At 5 years, the AST levels remained significantly higher in the anti-HCV positive group, however, this was only 6 U/1 > normal. Liver biopsies performed 3 to 7 years post-transplant in 80% of anti-HCV positive patients with chemical hepatitis showed 12% CAH, 50% mild hepatitis and 38% normal histology. Six (9.7%) patients seroconverted from anti-HCV positive to anti-HCV negative 2 to 5 years post-transplant. The presence of anti-HCV does not appear to alter long-term patient or graft survival, and histologic evidence of severe chronic liver disease was rare in anti-HCV positive patients with chemical hepatitis. From these results, the presence of anti-HCV antibody should not preclude kidney transplantation.
Adolescent↗
Treatment of bleeding from portal hypertensive gastropathy by portacaval shunt.
Portal hypertensive gastropathy is a vascular disorder of the gastric mucosa distinguished by ectasia of the mucosal capillaries and submucosal veins without inflammation. During 1988 to 1993, 12 patients with biopsy-proven cirrhosis (10 alcoholic, 2 posthepatitic) were evaluated and treated prospectively by portacaval shunt for active bleeding from severe portal hypertensive gastropathy. Eleven patients had been hospitalized for bleeding three to nine times previously, and one was bleeding uncontrollably for the first time. Requirement for blood transfusions ranged from 11 to 39 units cumulatively, of which 8 to 30 units were required specifically to replace blood lost from portal hypertensive gastropathy. Admission findings were ascites in 9 patients, jaundice in 8, severe muscle wasting in 10, hyperdynamic state in 9. Child's risk class was C in 7, B in 4, A in 1. Ten of the 12 patients had previously received repetitive endoscopic sclerotherapy for esophageal varices, which has been reported to precipitate portal hypertensive gastropathy. Eight patients had failed propranolol therapy for bleeding. Portacaval shunt was performed emergently in 11 patients and electively in 1, and permanently stopped bleeding in all by reducing the mean portal vein-inferior vena cava pressure gradient from 251 to 16 mm saline. There were no operative deaths, and two unrelated late deaths after 13 and 24 months. During 1 to 6.75 years of follow-up, all shunts remained patent by ultrasonography, the gastric mucosa reverted to normal on serial endoscopy, and there was no gastrointestinal bleeding. Recurrent portal-systemic encephalopathy developed in only 8% of patients. Quality of life was generally good.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic beta-Antagonists↗
Three decades of experience with emergency portacaval shunt for acutely bleeding esophageal varices in 400 unselected patients with cirrhosis of the liver.
BACKGROUND: Emergency treatment of acute bleeding is of singular and paramount importance in the therapy of portal hypertension and esophagogastric varices. Accordingly, for more than three decades we have conducted prospective studies of emergency therapy, and particularly of emergency portacaval shunt (EPCS). STUDY DESIGN: Emergency portacaval shunt was performed upon 400 patients with cirrhosis of the liver and acutely bleeding esophagogastric varices according to three principles: operation within eight hours of initial contact; unselected patients, meaning that no patient with variceal bleeding caused by hepatic disease was excluded from EPCS, and prospective study, meaning that a well-defined protocol was consistently used and data were collected on-line. Patients were divided into an early group of 180 treated from 1963 to 1978 and a recent group of 220 treated from 1978 to July, 1990, with similar characteristics, but strikingly different outcome. Follow-up rates at one, five, and ten years were 100, 98, and 97 percent, respectively; 96 percent of patients underwent EPCS five or more years ago. Proof of acute variceal bleeding and of cirrhosis of the liver (alcoholic in 95 percent) was obtained in every patient. Child's risk classes determined quantitatively were A in 11 percent of the patients, B in 65 percent, and C in 24 percent. All patients had a direct portacaval shunt, side-to-side in 85 percent, which reduced the mean portal vein to inferior vena cava pressure gradient from 271 to 21 mm saline solution. RESULTS: All but four patients (99 percent) had immediate and permanent control of variceal bleeding. Thrombosis of the shunt occurred in only two patients (0.5 percent). Survival rates at 30 days, five years, ten years, and 15 years in the early group were 58, 40, 30, and 30 percent, respectively, while in the recent group they were 85, 78, 71, and 57 percent, respectively (p < 0.0001). Other striking gains in the recent group were abstention from alcohol, improvement in liver function and improvement in Child's class, all in 70 percent of patients. Recurrent portal-systemic encephalopathy occurred in 9 percent of the early group and 8 percent of the recent group. CONCLUSIONS: Emergency portacaval shunt substantially improved survival and quality of life of patients with cirrhosis of the liver and bleeding varices. Our results are attributable to rapid and simplified diagnosis, prompt operation, an organized system of care, and rigorous, lifelong follow-up evaluation that emphasized abstinence from alcohol and dietary protein control. Transplantation of the liver is infrequently required in patients whose bleeding is permanently controlled.
Adult↗
A role for calcitonin gene-related peptide in protection against gastric ulceration.
OBJECTIVE: The goal of this investigation was to determine the role of calcitonin gene-related peptide (CGRP) in gastric mucosal resistance to ulceration. SUMMARY BACKGROUND DATA: CGRP is a 37-amino acid peptide found in the peripheral ends of afferent gastric neurons. CGRP is known to inhibit acid secretion, stimulate mucosal blood flow, and stimulate release of somatostatin. METHODS: The release of CGRP in response to intragastric and intra-arterial administration of capsaicin in the isolated, vascularly perfused rat stomach was measured by radioimmunoassay. The molecular forms of CGRP released were analyzed by gel filtration chromatography. The effect of intravenous CGRP or intragastric capsaicin on gastric ulceration induced by 100 mmol/L HCl and indomethacin was studied in intact and endogenous CGRP-depleted rats. RESULTS: Intra-arterial capsaicin (concentration range, 10(-7) to 10(-5) mol/L) stimulated a prompt and sustained release of immunoreactive CGRP, of which 84% coeluted with rat 1-37 CGRP I by gel filtration. Intragastric capsaicin (range, 10(-5) to 10(-4) mol/L) failed to release CGRP into the vascular perfusate. In intact rats, intragastric capsaicin (10(-6) mol/L) or intravenous CGRP I (10 micrograms/kg/hr) reduced the number and area of mucosal lesions caused by HCl and indomethacin compared with the findings in control rats. Rats depleted of endogenous CGRP were more susceptible to gastric ulceration than were normal rats. Intragastric capsaicin failed to protect the mucosa of CGRP-depleted rats, whereas exogenous intravenous CGRP was effective. CONCLUSIONS: These data support the hypothesis that CGRP released from gastric enteric neurons mediates gastric mucosal resistance to ulceration by noxious agents.
Animals↗
Induction of tolerance to small bowel allotransplants by mixed allogeneic chimerism.
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Animals↗
The site of antiviral action of 3-nitrosobenzamide on the infectivity process of human immunodeficiency virus in human lymphocytes.
The C-nitroso compound 3-nitrosobenzamide, which has been shown to remove zinc from the retroviral-type zinc finger of p7NC nucleocapsid proteins, inhibits acute infection of human immunodeficiency virus type 1 in cultured human lymphocytes. The attachment of the virus to lymphocytes and the activities of critical viral enzymes, such as reverse transcriptase, protease, and integrase, are not affected by 3-nitrosobenzamide. However, the process of reverse transcription to form proviral DNA is effectively abolished by the drug, identifying the mode of action of 3-nitrosobenzamide as interrupting the role of p7NC in accurate proviral DNA synthesis during the infectious phase of the virus life cycle.
Antiviral Agents↗
Inactivation of HIV-infected H9 cells in whole blood preparations by lysing/fixing reagents used in flow cytometry.
Reagents that lyse red blood cells and fix white blood cells were tested for their ability to inactivate cell-associated human immunodeficiency virus (HIV). Whole blood was spiked with cells from an HIV-positive cell line (H9), lysed, and fixed. The cell preparations were then cocultured with T cell blasts in serial ten-fold dilutions to rescue infectious virus and measure viral titer. All commercial lysing and fixing reagents tested inactivated cell-associated HIV by 3-5 logs, while ammonium chloride had little effect. Although an additional incubation with 1% formaldehyde for 30 min did not increase the effectiveness of the commercial lysing/fixing reagents, it did inactivate cell-associated HIV in blood treated with ammonium chloride.
Cell Death↗
Two mechanisms of soluble CD4 (sCD4)-mediated inhibition of human immunodeficiency virus type 1 (HIV-1) infectivity and their relation to primary HIV-1 isolates with reduced sensitivity to sCD4.
Two assays for measuring inhibition of human immunodeficiency virus type 1 (HIV-1) infection by soluble CD4 (sCD4) are described. Experiments in which sCD4, HIV-1, and cell concentrations and sequence of combination, noninfectious/infectious particle ratio, and temperature were varied produced results that support the conclusion that sCD4 inhibits HIV-1 infection by two mechanisms: reversible blockage of receptor binding and irreversible inactivation of infectivity. Fresh isolates obtained from HIV-1-infected persons were tested in both assays and found to be more resistant to both mechanisms of sCD4-mediated inhibition than multiply passaged laboratory strains. Binding studies revealed similar affinities for sCD4 in detergent lysates of sensitive and resistant strains at both 4 and 37 degrees C. The avidity of intact virions for sCD4 was lower at 4 than at 37 degrees C, and in the presence of excess sCD4, less sCD4 was bound at 4 than at 37 degrees C. The avidity differences were similar for fresh isolates and laboratory strains. However, fresh isolates were more resistant to sCD4-induced shedding of envelope glycoprotein gp120 from intact virions than was the laboratory strain. Relative resistance to sCD4 by certain isolates does not represent a lower intrinsic affinity of their envelope for sCD4 or a lower capacity for sCD4 binding. Rather, an event that occurs after binding may account for the differences. This postbinding event or feature may be determined by regions of the envelope outside the CD4 binding site.
Antibodies, Viral↗
Inactivation of human immunodeficiency virus type I in human milk: effects of intrinsic factors in human milk and of pasteurization.
Human milk was inoculated with human immunodeficiency virus type I (HIV-1) or with HIV-1-infected cells in volumes and containers typically used in human milk banks. The inoculated milk was pasteurized at 62.5 degrees C for 30 minutes in a water bath, i.e., conditions currently in use or proposed for human milk pasteurization. The process of HIV-1 inoculation and pasteurization effectively inactivated the infectivity of both cell-free HIV-1 and HIV-1-infected cells. No virus was recovered after the process, even after repeated subculturing in attempts to rescue the virus. Pasteurization reduced the infectious titer of cell-free HIV-1 and HIV-1-infected cells by more than 5 logs and 6 logs respectively. Human milk contains one or more components that inactive HIV-1 but that are not toxic for the cells used to replicate virus. These components have not been identified, but physical and solubility properties are consistent with characteristics of lipids.
Disinfection↗
Intestinal acid inhibits gastric acid secretion by neural and hormonal mechanisms in rats.
To determine the relative contributions of neural reflexes and intestinal hormones to the inhibition of gastric acid secretion by intestinal acidification, rats with an extrinsically denervated, transplanted segment of jejunum, and those with an innervated segment of jejunum, were studied. Postoperatively, meal-stimulated gastric acid secretion was measured. When the acid secretory response to intragastric liver extract reached a plateau, graded concentrations of hydrochloric acid or saline were instilled into the jejunal segments. Gastric acid secretion was inhibited by intrajejunal acid (pH 2.5) by 79% in the innervated rats and by 64% in the transplanted group. Thus at a pH of 2.5 there was a 15% greater maximum inhibition of plateau acid response in the innervated rats than in the transplanted rats, presumably because of the extrinsic neural contribution. To examine the hormonal mediators, the effects of a somatostatin monoclonal antibody and a CCK-A receptor antagonist (L 364718) on acid-induced inhibition of gastric acid secretion were studied in transplanted rats. Treatment with a somatostatin monoclonal antibody or with L 364718 reduced the acid-induced (pH 2.5) inhibition of gastric acid secretion by 93 and 27%, respectively. Jejunal acidification inhibits gastric acid secretion in the rat by both neural and hormonal mechanisms. The hormonal mechanism is mediated by somatostatin and CCK.
Acids↗
Penetration of CD4 T cells by HIV-1. The CD4 receptor does not internalize with HIV, and CD4-related signal transduction events are not required for entry.
Receptor binding of HIV to the CD4 molecule is required for efficient infection of T cells, but the post-binding steps that result in penetration of HIV are not well understood. CD4 is induced to internalize upon T cell activation, and mAb to CD4 modify signal transduction and T cell activation as does HIV in some systems. It is not known whether HIV binding triggers CD4 endocytosis or whether signal transduction events are required for penetration. Selected inhibitors of signal transduction were evaluated for their effects on penetration using two assays that are dependent on penetration. After short term exposure to inhibitor and HIV, cells were analyzed for reverse-transcribed HIV DNA (DNA amplification assay), or productive infection is monitored (infectivity assay). Viral penetration was tested in the presence of H7 (protein kinase C inhibition), EGTA (extracellular Ca2+ chelation), cyclosporine A (inhibition of Ca2+/calmodulin-dependent activation), or pertussis toxin (inhibition of G protein function). All agents were used at concentrations that were inhibitory for their respective signal transduction pathways. None of the inhibitors affected viral penetration. We tracked the CD4 molecule with fluorescent probes that do not interfere with HIV binding in a system where CD4 T cells were saturated with HIV and the penetration event was relatively synchronized. Under conditions where detection of CD4 was more sensitive than the detection of HIV, HIV internalization was readily detected but CD4 internalization was not.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗