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Biomedical subjects

J Neuberger

Publications and source records attributed to J Neuberger.

At least 55 records · Page 3Linked to original sources
PubMed1987

Specific antibodies to halothane-induced liver antigens in halothane-associated hepatitis.

Antibodies to halothane-altered liver cell determinants (halothane antibodies) have previously been detected in serum of patients with fulminant hepatic failure after halothane anaesthesia. However, their diagnostic value has not been reported in patients with non-fulminant hepatitis. Sera from 39 patients who developed hepatitis following halothane anaesthesia between January 1983 and December 1985 were tested for antibodies to halothane-induced liver antigens using an ELISA; 22 of these patients had hepatitis without encephalopathy. Nineteen of the sera were from patients anaesthetized during 1985; four of the patients were aged 15 yr or less. All patients had undergone previous anaesthesia 17 days to 13 yr (median 3 yr) earlier. In 19 of the patients the final operation was a minor surgical procedure, lasting less than 45 min. In 13 patients a previous adverse reaction to halothane was documented in the case records. Twelve of the patients died. Halothane antibodies were detected in 12 of the 16 (75%) patients with hepatic encephalopathy and 16 of the 23 (70%) who did not develop encephalopathy, demonstrating that halothane antibodies are detectable in a wider spectrum of halothane-associated liver damage than previously appreciated.

Adolescent↗
PubMed1987

Identification by immunoblotting of three halothane-induced liver microsomal polypeptide antigens recognized by antibodies in sera from patients with halothane-associated hepatitis.

Previous studies have demonstrated that sera from patients with severe liver damage after halothane anesthesia ("halothane hepatitis") contain antibodies reacting with novel antigenic determinants expressed on hepatocytes from rabbits exposed previously to halothane. To determine the structure of the halothane-induced antigen(s), immunoblotting experiments were performed using patient sera and rabbit liver subcellular fractions. Three polypeptide antigens (Mr 100,000, 76,000 and 57,000) expressed in liver fractions from animals sacrificed 16 hr after exposure to 1% halothane in oxygen for 45 min, but not in fractions from unexposed animals, were identified. Analysis of fractions prepared by differential and sucrose density gradient centrifugation, and characterized by enzyme marker analysis, localized all three antigens to a microsomal subfraction relatively enriched in glucose-6-phosphatase activity, therefore, presumably derived from the endoplasmic reticulum. Antibodies to these antigens were detected in 19 of 24 sera from patients with halothane hepatitis, and four distinct patterns of antibody specificity were observed: 100,000 + 76,000 (seven patients), 100,000 alone (seven patients), 76,000 alone (three patients) and 57,000 alone (two patients). Such antibodies were not detectable in sera from 24 normal blood donors or 36 control patients. Thus, halothane induces expression of three distinct polypeptide antigens in liver, and patients with halothane hepatitis differ in patterns of recognition of these antigens by circulating antibodies.

Animals↗
PubMed1986

Oral contraceptives and hepatocellular carcinoma.

A series of 26 white women aged under 50 who developed hepatocellular carcinoma in a non-cirrhotic liver were studied for the possible role of oral contraceptives. Eighteen of the women had used the "pill" for a median of eight years. Over 1300 women whose use of the pill had been determined in another study served as controls. Patients and controls were divided into five age and four calendar groups and the relative risks associated with oral contraceptives calculated by multivariate analysis. Short term use of the pill was not associated with an increased risk of tumour development; nevertheless, use for eight years or more was associated with a 4.4-fold increased risk (p less than 0.01). When patients with markers of hepatitis B virus infection were excluded the relative risk was 7.2 (p less than 0.01). In both instances the absolute risk for developing hepatoma remained low.

Adult↗
PubMed1986

In vitro effects of lymphoblastoid interferon on lymphocyte activation and cell-mediated cytolysis in patients with chronic hepatitis B virus infection.

In addition to a direct anti-viral effect, interferons have important immunological properties including effects on cell-mediated immunity and antibody production as well as cell-mediated cytolysis. In chronic hepatitis B virus infection the host immune system is important for the elimination of replicating virus and in addition to directly inhibiting hepatitis B virus replication, interferons may affect host immune responses. We investigated the effect of lymphoblastoid interferon in vitro on lymphocyte activation and cell-mediated cytolysis in patients with chronic hepatitis B virus infection. The proliferative response to the mitogen PHA was significantly impaired in patients compared to controls. In addition supernatants of cultured mononuclear cells from patients stimulated with PHA contained less interleukin-2 activity than controls while the proportion of stimulated mononuclear cells expressing the interleukin-2 receptor was also reduced in patients. Prior incubation with 10(3) U ml-1 lymphoblastoid interferon increased both interleukin-2 activity and interleukin-2 receptor expression in patients and controls, although in patients the response was less marked. In contrast the proliferative response was unaffected. Natural killer cell activity against K562 cells was similar in patients and controls which in both groups was significantly augmented by prior incubation with 10(3) U ml-1 lymphoblastoid interferon; the increase was inversely proportional to baseline activity. In contrast incubation of target or effector cells with interferon did not augment T-cell cytotoxicity against autologous hepatocytes. The effects of lymphoblastoid interferon in vitro, were modest, but subtle changes in immunological status in addition to a direct effect on viral replication may be relevant to eventual clearance of the hepatitis B virus.

Cytotoxicity, Immunologic↗
PubMed1986

Use of a prognostic index in evaluation of liver transplantation for primary biliary cirrhosis.

In the Cambridge/King's College Hospital program, one of the main criteria for recommendation of a liver transplant for a patient with primary biliary cirrhosis (PBC), as in other types of end-stage liver disease, has been the overall assessment that survival was likely to be less than one year. In the present study, a recently developed prognostic model, based on six variables, was used retrospectively to estimate the likely survival without transplantation of the first 29 patients receiving a transplant for PBC. Median estimated survival time for the complete group of patients was five months and in only four patients was survival in the absence of transplantation estimated to be more than one year. Comparison of actual survival curves after transplantation with the estimated survival in the absence of such a procedure shows that, despite an initial higher mortality related to surgery and the immediate postoperative period, grafting was associated with a statistically significant improvement in overall survival. No correlation between the outcome after transplantation and the severity of preexisting liver disease, (as assessed by the expected survival) could be determined, but further assessment of preoperative variables is warranted.

Adult↗
PubMed1986

Ethanol metabolism in the generation of new antigenic determinants on liver cells.

Antibodies directed against ethanol altered liver cell components have been detected in the serum of nearly 50% of patients with alcoholic liver disease although the pathogenetic mechanisms are unclear. The importance of ethanol metabolism in the generation of new antigenic determinants on liver cells was investigated by in vivo inhibition of alcohol or acetaldehyde dehydrogenase and an induced cytotoxicity assay. There was a significant reduction in cytotoxicity to hepatocytes isolated from rabbits treated with ethanol 1 g/kg when the metabolism of ethanol to acetaldehyde by alcohol dehydrogenase was inhibited. In contrast when the oxidation of acetaldehyde was inhibited by disulfiram cytotoxicity was significantly enhanced. These results show that ethanol metabolism is integral to the expression of the ethanol related determinant and suggest that an impaired ability to metabolism acetaldehyde could lead to the development of immunological reactions to alcohol altered liver membrane antigens.

Alcohol Oxidoreductases↗
PubMed1986

In vitro effect of cyclosporin A on immunoglobulin production and concanavalin A induced suppression in primary biliary cirrhosis.

The in vitro effect of Cyclosporin A on the regulation of immunoglobulin production was investigated in 16 patients with primary biliary cirrhosis. A significant improvement in concanavalin A induced suppression of IgG and IgM producing cells was observed after prior incubation of mononuclear cells with 300 ng/ml Cyclosporin A for 30 minutes. No effect was seen on spontaneous or pokeweed mitogen induced immunoglobulin production, nor on con A induced suppression if Cyclosporin A was added after 24 hours. Incubation of mononuclear cells with a variable dose of Cyclosporin A showed an effect only at 250-500 ng/ml. Higher and lower doses had no effect. This dose dependent effect of Cyclosporin A is likely to be related to a differential inhibitory effect on T helper and T suppressor cells and may underlie the clinical benefit being observed in current clinical trials.

Aged↗
PubMed1986

The effect of prednisolone in vitro on immunoglobulin production in primary biliary cirrhosis.

Immunoglobulin production and its regulation have been investigated in 36 untreated patients with primary biliary cirrhosis and 14 healthy controls. Using a haemolytic plaque assay, the number of cells spontaneously producing IgG or IgM was normal, while in contrast, proliferation of both IgG and IgM producing cells in the presence of pokeweed mitogen was impaired (P less than 0.01). There was in addition a defect of Con A induced suppression of proliferation of IgG and IgM producing cells (P less than 0.01), which was more marked in those with early disease than in those with advanced disease. In vitro incubation of mononuclear cells with prednisolone, 5 X 10(-8) M, corrected the defect of Con A induced suppression, but had no effect on spontaneous or pokeweed mitogen stimulated immunoglobulin production. Prednisolone was only effective if added prior to exposure to Con A. There is anecdotal evidence that corticosteroids may be beneficial in primary biliary cirrhosis and the results of the present study study suggest that further investigation of their role is warranted.

Adult↗
PubMed1985

Sequential and diagnostic features in primary biliary cirrhosis based on serial histologic study in 209 patients.

Four forms of piecemeal necrosis--biliary, lymphocytic, ductular, and fibrotic--were identified in 605 liver biopsy specimens from 209 patients with primary biliary cirrhosis. Whereas lymphocytic piecemeal necrosis, often associated with lobular hepatitis, was most common in stages 2 and 3 of the classical histologic staging, biliary piecemeal necrosis was frequent in all stages, except stage 1, and the fibrotic form appeared to be a late, mainly cirrhotic feature. In 77% of patients cholestatic features predominated, whereas hepatitic changes producing some histologic overlap with chronic active hepatitis occurred in the remaining patients. These patterns tended to be maintained throughout the course of the disease. Large hypocellular scars found in 36% and 59% of stage 3 and 4 specimens, respectively, appeared to be a characteristic feature of biliary disease. The prevalence of classical features was assessed. The analysis of sequential biopsy specimens from those patients who died showed that cirrhotic transformation, increasing cholestasis (in particular with prominent hyaline inclusions), abundance of coarse collagen bundles, and "halo" formation at the margins of the fibrous septa were associated with a poor prognosis. We were unable to show that the presence of granulomas is associated with a more favorable course of the disease.

Adult↗
PubMed1985

Beneficial effect of azathioprine and prediction of prognosis in primary biliary cirrhosis. Final results of an international trial.

The effect of azathioprine on survival of patients with primary biliary cirrhosis was studied prospectively in a multinational, double-blind, randomized clinical trial including 248 patients of whom 127 received azathioprine and 121 placebo. There were 57 deaths in the azathioprine group and 62 in the placebo group. The actual survival was slightly longer during azathioprine than during placebo treatment. Using Cox multiple regression analysis and adjusting for slight imbalance between the two treatment groups, the therapeutic effect of azathioprine was statistically significant (p = 0.01), with azathioprine reducing the risk of dying to 59% of that observed during placebo treatment (95% confidence interval 40%-90%) or improving survival time by 20 mo in the average patient. Furthermore, azathioprine slowed down progressing incapacitation. Side effects of azathioprine were relatively few. The analysis revealed that the following five variables independently implied poor prognosis: high serum bilirubin, old age, cirrhosis, low serum albumin, and central cholestasis. These factors were combined to a "prognostic index" for prediction of outcome in new patients. The index was validated on independent patient data. On the basis of these results we recommend azathioprine as a routine treatment of primary biliary cirrhosis.

Actuarial Analysis↗
PubMed1985

Mononuclear cell complement receptor blockade in primary biliary cirrhosis.

Peripheral blood monocyte and lymphocyte receptors for Fc and C3b fragments were examined in vitro in patients with primary biliary cirrhosis and other chronic liver diseases using sheep red blood cells coated with anti-SRBC IgG1 (to detect Fc receptors) and with anti-SRBC IgM and complement (to detect C3b receptors). The number of C3b receptors detected on 100 monocytes was significantly lower in patients with primary biliary cirrhosis (23.0 +/- 12.0, mean +/- 1 SD) compared with normal controls (57.4 +/- 16.9) and other chronic liver disease (HBsAg negative chronic active hepatitis 62.0 +/- 17.0, alcoholic cirrhosis 50.9 +/- 4.0), while the number of Fc receptors detected on 100 monocytes was not significantly different in all the groups (primary biliary cirrhosis 72.8 +/- 28.6, chronic active hepatitis 74.7 +/- 14.0, alcoholic cirrhosis 58.0 +/- 13.5 and normal controls 69.6 +/- 19.9). When mononuclear cells isolated from normal individuals were pre-incubated with serum from patients with primary biliary cirrhosis before testing their receptor function there was a significant reduction in the number of C3b receptors detected per 100 monocytes (27.6 +/- 10.8) compared with pre-incubation with normal serum (72.0 +/- 18.0). This reduction in C3b-receptor function was again observed when the serum used for pre-incubation was depleted of circulating immune complexes; but when complement was further depleted from these sera, the number of C3b-receptors detected after pre-incubation was similar to normal values (64.0 +/- 11.8). Lymphocyte receptors showed a similar pattern of results. This implies a specific C3b receptor blockade on monocytes and lymphocytes from patients with primary biliary cirrhosis which appears to be because of blocking by serum factor(s) including complement fragments.

Adult↗