Pseudotypes in HIV-infected mice.
Explore the source record for details and available documents.
Biomedical subjects
Publications and source records attributed to L Rabin.
Explore the source record for details and available documents.
The SCID-hu mouse, engrafted with human hematolymphoid organs, is permissive for infection with the human immunodeficiency virus (HIV). This mouse model was used to test compounds for antiviral efficacy. Two weeks after infection with HIV, 100 percent (40/40) of SCID-hu mice were positive for HIV by the polymerase chain reaction. When first treated with 3'-azido-3'-deoxythymidine (AZT), none (0/17) were HIV-positive by this assay. However, AZT-treated SCID-hu mice did have a few infected cells; after AZT treatment was stopped, viral spread was detected by polymerase chain reaction in such mice. Thus, the SCID-hu mouse provides a means to directly compare new antiviral compounds with AZT and to further improve antiviral efficacy.
We describe three patients with cholesteryl ester storage disease. Diagnosis was confirmed by demonstrating a deficiency in lysosomal acid cholesteryl hydrolase activity in cultured skin fibroblasts from each of these patients. All had hepatomegaly, elevated serum aminotransferase activities and hyperlipoproteinemia. Histological examination of liver biopsy specimens before treatment revealed accumulation of fat within hepatocytes, bile duct epithelium and endothelial and Kupffer cells. Cholesterol crystals were recognized by their birefringence in frozen sections. A striking feature was the presence of markedly hypertrophied Kupffer cells and portal macrophages with foamy, tan-colored cytoplasm that stained readily with the periodic acid-Schiff reagent and aldehyde fuchsin. Periportal fibrosis was noted in all cases; incomplete cirrhosis was present in one case. Distinctive and hitherto undescribed lysosomal accumulations of triglyceride and cholesterol crystals were noted. The patients were treated with lovastatin, a cholesterol-lowering agent, for at least 12 mo. No significant changes were seen in serum lipoprotein concentrations or liver histopathology after therapy. Thus lovastatin did not have an obviously beneficial effect on abnormal lipid metabolism in these patients.
Explore the source record for details and available documents.
To determine the frequency of talc microcrystals in liver tissue of intravenous (IV) drug abusers and the significance of this finding, the authors reviewed, with light and polarizing microscopy, sections of liver tissue from 70 patients with chronic hepatitis and a history of active (45) or past (25) IV drug abuse. Birefringent crystalline particles consistent with talc were found in 44 cases (63%), 31 associated with active and 13 with past drug abuse. The microcrystals were situated predominantly in hypertrophied portal macrophages; there were no well-formed granulomas. Scanning electron microscopic and energy-dispersive spectrophotometry performed on eight of the positive cases showed the characteristic "flake-pastry" appearance and chemical composition (silicon and magnesium) of talc. For comparison, the authors similarly examined 70 cases of posttransfusion chronic hepatitis, all of which had negative findings for talc, and 70 cases of chronic hepatitis with no documented risk factors for viral hepatitis, of which two had positive findings for talc, even though IV drug abuse was denied by the two patients. The authors conclude that talc is frequently present in the liver of IV drug abusers and whenever encountered it strongly suggests IV drug abuse. Only two patients (1.4%) with a negative history also had talc.
In order to determine the morphologic spectrum of bile duct adenoma (BDA), we reviewed the clinical, gross, and histopathological features of 152 cases. All BDA were asymptomatic nodules discovered incidentally during intra-abdominal surgery (103 cases) or at autopsy (49 cases). They were usually subcapsular, ranged in size from 1 to 20 mm (mean, 5.8 mm), and were well circumscribed but nonencapsulated. Histologically, BDA was composed of benign, noncystic ductules and variable degrees of inflammation and fibrosis. The immunophenotype of these ductules was similar to that of interlobular bile ducts. Follow-up of 38 of the surgically treated patients confirmed the benign behavior of this lesion. BDA should be distinguished from an adenocarcinoma by the absence, in the former, of nuclear hyperchromasia, mitotic activity, and vascular invasion. The absence of bile and cystic changes and lack of association with polycystic disease of the liver and kidneys are the main features distinguishing BDA from von Meyenburg complex. We believe that BDA is a reactive process to a focal injury rather than a true neoplasm or a developmental anomaly.
A human monoclonal antibody (IgG2, lambda), 1B8.env, was produced, reactive with the envelope glycoprotein of human immunodeficiency virus (HIV). The antibody specifically stains cells infected with HIV, as assessed by indirect immunofluorescence analysis and reacts with determinants displayed on the surface of infected cells. In Western blot analysis, the antibody reacts with bands of 160 and 41 kD, consistent with the precursor and transmembrane forms of the HIV envelope glycoprotein. The antibody also reacts specifically in immunofluorescence and Western blot analysis with cells infected with the recombinant vaccinia virus VSC-25, which contains the envelope gene of HIV. With the lambda gt11 expression vector, the epitope recognized by 1B8.env was mapped to a region of 11 amino acids in the coding region of gp41. This domain is highly conserved between several otherwise highly variable HIV isolates. In addition, this epitope appears to be recognized by the vast majority of HIV seropositive individuals. Although antibody IB8.env does not neutralize HIV virion infectivity or virally mediated cell fusion, the results presented here demonstrate the feasibility of generating and characterizing human monoclonal antibodies to HIV with these techniques. Additional antibodies produced in this manner will help to further characterize the humoral response to HIV infection, define biologically significant determinants on HIV proteins, and may be useful in clinical applications.
Explore the source record for details and available documents.
We undertook a morphometric analysis of hepatocellular organelles in an attempt to correlate their changes with the clinical stages of patients with alcoholic hepatitis. Although hepatic ultrastructural alterations did not correlate with disease severity, we found significant differences between patient and control groups in the measured parameters of non-organelle cytoplasm, mitochondria, SER, RER, glycogen, and lipid.
The significance of megamitochondria in the alcoholic liver injury of humans was investigated as part of a large Veterans Administration cooperative study of the natural history of alcoholic hepatitis. Two hundred twenty patients were clinically stratified into the following three groups according to disease severity using serum bilirubin and prothrombin time as indicators: Group 1 (mild disease), serum bilirubin levels less than 5 mg/dl and prothrombin time prolonged for less than 4 s; group 2 (moderate disease), serum bilirubin levels greater than 5 mg/dl but prothrombin time prolonged for less than 4 s; and group 3 (severe disease), serum bilirubin levels greater than 5 mg/dl and prothrombin time prolonged for greater than 4 s. Megamitochondria were observed in 20% of the patients (45 of 220). Of these, 43 patients were in groups 1 and 2 of severity and only 1 patient belonged in group 3. The association of megamitochondria with cirrhosis was infrequent (33%, 15 of 45 patients). The differences in severity correlated with the differences in mortality: in patients with megamitochondria, only 1 had died at 6 mo compared with 40 deaths in patients without megamitochondria. By 12 mo, there were two deaths in patients with megamitochondria versus 51 deaths in those patients without. No complications were present in 72% of patients with megamitochondria versus 39% for those without. Infection, gastrointestinal bleeding, pancreatitis, hyperglycemia, azotemia, delirium tremens, seizures, and hepatic encephalopathy were all more common in patients without megamitochondria. The patients with megamitochondria appear to represent a subcategory of alcoholic hepatitis with a milder degree of clinical severity, lower incidence of cirrhosis, fewer complications, and good long-term survival.
Combined hepatocellular-cholangiocarcinoma is a rare form of primary liver cancer showing features of both hepatocellular and biliary epithelial differentiation. In a review of 24 cases of this tumor, three histologic types were encountered. Four cases were Type I or "collision tumors," apparently a coincidental occurrence of both hepatocellular carcinoma and cholangiocarcinoma in the same patient. Twelve cases were Type II or "transitional tumors," in which there were areas of intermediate differentiation and an identifiable transition between hepatocellular carcinoma and cholangiocarcinoma. Eight cases were Type III or "fibrolamellar tumors" which resembled the fibrolamellar variant of hepatocellular carcinoma but which also contained mucin-producing pseudoglands. Type III tumors differ from other combined tumors, occurring at a younger age, in the absence of cirrhosis, and having a slightly longer survival. Immunohistochemical (immunoperoxidase) staining for intracellular antigens showed that alpha-fetoprotein is a fairly specific, although insensitive, marker of hepatocellular differentiation in primary liver cancers, being present in 50% of typical hepatocellular carcinomas and in hepatocellular areas in 29% of combined tumors, but in no cholangiocarcinomas or cholangiocellular areas of combined tumors. Keratin is a good marker of biliary epithelial differentiation, being found in 90% of cholangiocarcinomas and in 52% of combined hepatocellular cholangiocarcinomas, but in no hepatocellular carcinomas. Alpha-1-antitrypsin, fibrinogen, IgG, and carcinoembryonic antigen may be found in both hepatocellular carcinoma, cholangiocarcinoma, and in combined tumors; these antigens are therefore of limited use in differential diagnosis.
Explore the source record for details and available documents.
The clinical, morphologic, and follow-up findings in 32 patients with a hitherto rarely reported tumor of the liver are reported. The study comprised 20 women (62.5 per cent) and 12 men (37.5 per cent) ranging in age from 19 to 86 years (average, 49.65 years). The tumors were discovered incidentally in four patients (12.5 per cent). Four patients (12.5 per cent) had jaundice attributable to the tumors; one of these patients experienced liver failure. One patient presented with an acutely painful abdomen due to hemoperitoneum. The remaining patients had nonspecific complaints. Grossly, the tumors were often multiple and involved both lobes of the liver. They were generally white and firm to hard. Microscopically, the neoplastic cells infiltrated sinusoids and intrahepatic veins of all sizes. Two types of tumor cells were identified--dendritic and epithelioid. Tumor cells were also vasoformative and synthesized Factor VIII-related antigen. Nine patients survived five years or longer. Two of these patients were alive five years, two nine years, one 12 years, and one 15 years after the onset of disease. Three patients died seven, ten, and 28 years, respectively, after the initial diagnosis. This vascular tumor has distinctive morphologic features that allow differentiation from sclerosing carcinoma and angiosarcoma. Although the prognosis is much more favorable than that for angiosarcoma, extrahepatic metastases occurred in nine of the patients (28 per cent) in this series. The biologic behavior of the tumor may be related in part to its matrix, which may show inflammation, dense sclerosis, and calcification.
A 37-year-old alcoholic presented to hospital with metabolic acidosis, hypoglycemia, hypoprothrombinemia, and markedly elevated SGOT level. Despite the absence of volunteered information, acetaminophen hepatotoxicity was considered the probable cause, and this diagnosis was eventually supported. This combination of findings appears to be highly suggestive of well-established acetaminophen hepatotoxicity and implies that the drug-induced lesion selectively impairs certain hepatocellular functions early in the progression of the injury.
We have studied five long-term survivors of allogeneic bone marrow transplantation. All exhibited prolonged serum biochemical evidence of hepatic dysfunction during 2- to 5-year periods of follow-up. Two patients developed chronic cholestasis without pruritus. The serum of a third patient became chronically positive for HBsAg. A fourth patient developed an acute hepatic syndrome and high titers of antibody to cytomegalovirus. Nuclear, mitochondrial, and smooth muscle antibodies were not detected. Seven liver biopsies, obtained from three of the patients, all revealed a hepatocellular necroinflammatory lesion suggestive of chronic active hepatitis, a paucity of interlobular bile ducts, and intrahepatic cholestasis. Possible etiologies for these hepatic changes include reactivation of chronic non-A, non-B hepatitis and chronic graft-versus-host disease per se. Our study emphasizes the diagnostic problems posed by hepatic dysfunction occurring in an immunosuppressed multiply-transfused patient after bone marrow transplantation.
Two patients developed a syndrome closely simulating the 'lupoid' form of chronic active hepatitis during prolonged therapy with macrocrystalline nitrofurantoin. Symptoms and biochemical indices of hepatocellular necrosis abated rapidly after discontinuation of drug therapy, but smooth muscle and antinuclear antibodies remained detectable more than 1 year later. The serologic features of the disease and a strongly positive lymphocyte transformation test in one of the patients suggest that the disorder may have been immunologically mediated.
Explore the source record for details and available documents.
Three cases of primary melanoma of the gallbladder are described to add to the five reported in the literature. As an organ of endodermal origin, the gallbladder appears to share the melanoblastic potentiality possessed by similarly derived organs, and hence, the development of a melanoma within the gallbladder is not unexpected. Presence of melanocytes within the gallbladder mucosa is absolute proof that the tumor is primary. Whether these cells originate from the neural crest and migrate to the gallbladder, or result from local differentiation from preexisting cells remains to be answered.