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Biomedical subjects

G J Alexander

Publications and source records attributed to G J Alexander.

At least 91 records · Page 5Linked to original sources
PubMed1994

Circulating IgA antibody against a 65 kDa heat shock protein in acute alcoholic hepatitis.

Heat shock proteins are known to be immunogenic in a number of diverse conditions and can be induced by hypoxia, tumour necrosis factor and alcohol--all potential triggers in patients with acute alcoholic hepatitis. In the present study, sera from 23 patients with acute alcoholic hepatitis, 18 liver disease controls, ten patients with inactive alcoholic liver disease and six alcoholics without liver damage were screened for the antibody to a 65 kDa heat shock protein using an ELISA technique. IgA antibody was found to be closely associated with alcoholic hepatitis; 20/23 patients were seropositive compared to 5/18 liver disease controls and 4/10 with inactive alcoholic cirrhosis. IgM and IgG antibodies to the 65 kDa heat shock protein were less closely associated with alcoholic hepatitis and were positive in nine and eight of the 23 patients, respectively, compared with six and seven of 18 liver disease controls. Neither antibody was detected in alcoholics without liver damage or normal controls. These data indicate that an IgA immune mediated response to the 65 kDa heat shock protein is characteristic of patients with acute alcoholic hepatitis and may be one mechanism underlying observed persistence of liver damage after cessation of alcohol consumption.

Acute Disease↗
PubMed1994

THF gamma 2 stimulates cytokine release by peripheral blood mononuclear cells of patients with chronic hepatitis B virus infection.

A recent study indicated that thymic hormones have antiviral effects in human hepatitis B virus infection and woodchuck hepatitis virus infection. These hormones are known to exert immunomodulatory effects on lymphocyte maturation and function; because these are abnormal in patients with chronic hepatitis B virus infection, we have examined the effects of a thymic hormone (THF gamma 2) on peripheral blood mononuclear cells from patients with chronic hepatitis B virus infection. THF gamma 2 (50 or 150 ng/ml) alone was without effect; in the presence of low doses of the mitogen phytohaemagglutinin, it had a broad effect in patients and controls. The effect on interleukin-2 production was greater in patients than controls with a significant increase in production at 150 ng/ml for patients alone (p = 0.037). Tumour necrosis factor alpha production was enhanced in all patients and controls, with a greater effect seen at 150 ng/ml THF gamma 2 than 50 ng/ml. There was no effect on interferon gamma production or on the expression of membrane markers of T-cell activation. THF gamma 2 has substantial immunomodulatory activity in chronic hepatitis B virus carriers and in vivo assessment of THF gamma 2 in chronic hepatitis B virus is indicated.

Antigens, CD↗
PubMed1993

Loss of HBsAg with interferon-alpha therapy in chronic hepatitis D virus infection.

Eleven patients with chronic hepatitis D virus (HDV) infection who had chronic active hepatitis and HDV antigen on liver biopsy were randomised in a crossover therapeutic trial of interferon-alpha 2b vs. no therapy. Nine patients had a history of intravenous drug use (drug free > 6 months before therapy), 8 had histological evidence of cirrhosis, and 7 out of 10 tested were found to be seropositive for antibody to hepatitis C virus (HCV). Six patients were randomised to receive interferon-alpha 2b therapy for 1 year, and 5 patients received no therapy for 1 year followed by the same regime of interferon-alpha 2b treatment. All patients with a history of intravenous drug use found self-injection stressful, 3 patients restarted using illicit drugs, and 2 patients with active cirrhosis developed severe thrombocytopenia during therapy and treatment was stopped in these patients. Of the 6 patients who completed at least 11 months of treatment, 4 lost serum hepatitis B surface antigen (HBsAg) with 3 developing antibody to HBsAg and one patient completing treatment. Among the 6 patients who had posttreatment liver biopsy, 5 showed an improvement in liver histology (3 of them lost serum HBsAg). These results provide further evidence that interferon-alpha is beneficial in chronic HDV infection although the psychological stress associated with the treatment, especially in patients with a previous history of intravenous drug use, is not inconceivable.

Adult↗
PubMed1993

Hepatic alpha-interferon expression in cytomegalovirus-infected liver allograft recipients with and without vanishing bile duct syndrome.

In previous studies cytomegalovirus (CMV) infection was identified as one risk factor in the development of vanishing bile duct syndrome (VBDS) after orthotopic liver transplantation (OLT), but its precise role in relation to the pathogenesis of tissue damage is uncertain. In the present study alpha-interferon (alpha-IFN) expression in the liver was studied as an indirect marker of viral infection in serial liver biopsies from 42 patients following OLT. alpha-IFN was identified more frequently in the bile duct cytoplasm of patients developing VBDS, with or without evidence of preceding CMV infection (7/8 and 4/5 cases, respectively), when compared with patients with acute CMV but without evidence of VBDS (6/19 cases; P < 0.05) or those with neither complication (2/10 cases; P < 0.01). alpha-IFN was detectable in bile duct cytoplasm for a longer period in patients developing VBDS than in those with acute CMV infection alone (median 14 weeks and range 9-19, median 6 weeks and range 1-11 weeks, respectively; P < 0.025). These data indicate that persistent CMV infection of bile duct cells is a likely co-factor linked to progression to VBDS, but the processes that allow persistent viral infection and bile duct destruction remain to be determined.

Bile Duct Diseases↗
PubMed1993

The safety and value of extradural intracranial pressure monitors in fulminant hepatic failure.

Thirty-six of 68 consecutive patients with fulminant hepatic failure (FHF) progressing to grade 4 encephalopathy who had extradural ICP monitors inserted were reviewed to determine the safety and the value of ICP monitoring. Only minor complications were encountered. These included local wound bleeding at the burrhole site in four patients and a small cerebral hemorrhage in relation to the monitor in one other patient. No significant long-term sequelae were related to the operative procedure. ICP monitoring identified rises in ICP unaccompanied by clinical signs and as a consequence treatment was given to the monitored patients more often than the non-monitored group (median 6 vs. 2 treatments, P < 0.01). The duration of survival from the onset of grade 4 encephalopathy was significantly greater in the ICP monitored group (median 60 vs. 10 h, P < 0.01) although overall survival was unchanged. Monitoring also provided important prognostic information since the peak ICP was higher in non-survivors than in survivors (median 45 vs. 35 mmHg, P = 0.051). The pattern of clinical signs accompanying episodes of intracranial hypertension differed between survivors and non-survivors. Pupillary abnormalities were detected more often in non-survivors while systolic hypertension occurred more frequently amongst survivors with the peak systolic blood pressure being significantly higher. ICP monitoring proved safe and effective, provided valuable information regarding subclinical intracranial hypertension and prognosis and should be regarded as part of the routine management of intracranial hypertension complicating FHF.

Cerebral Hemorrhage↗
PubMed1993

Identification of hepatitis B virus-DNA in the liver by in situ hybridization using a biotinylated probe. Relation to HBcAg expression and histology.

The cellular localisation of hepatitis B virus (HBV)-DNA in liver tissue was studied by in situ hybridisation using biotinylated and radiolabelled probes on samples from HBsAg carriers with a spectrum of disease and related to the presence of HBV-DNA in serum and intrahepatic HBcAg expression. Sixteen of the 31 patients studied were seropositive for HBV-DNA; nine had chronic active hepatitis and seven had chronic persistent hepatitis. HBV-DNA was detected in the liver tissue in seven of these patients. In each, HBV-DNA was detected in both cytoplasm and nuclei. All seven also had nuclear and/or cytoplasmic HBcAg which in six was associated with chronic active hepatitis. HBcAg (without tissue HBV-DNA) was detected in the remaining nine patients with an exclusively nuclear pattern in two. Fifteen patients were seronegative for HBV-DNA. HBV-DNA was not detected in the tissue of any of these. Three of these were HBcAg positive but in each this was confined to occasional nuclei and each had inactive disease. The close association between the presence of detectable HBV-DNA in tissue, cytoplasmic HBV-DNA expression and chronic active hepatitis in one group and a failure to detect HBV-DNA in those with nuclear HBcAg and benign disease suggests that there may be two distinct patterns of HBV replication in chronic HBV carriers which may influence the development of liver damage.

Biopsy↗
PubMed1993

Interferon-alpha therapy with and without interferon-alpha priming in patients with chronic hepatitis B infection.

To determine whether a priming course of lymphoblastoid interferon-alpha (IFN-alpha) enhances the efficacy of subsequent IFN-alpha therapy in the treatment of chronic hepatitis B, a randomized trial was conducted to compare IFN-alpha priming (IFN-alpha for one month; no treatment for one month) followed by IFN-alpha therapy for three months, with IFN-alpha therapy (10 MU thrice-weekly) given for three months. Thirty-seven patients seropositive for more than six months for HBsAg, HBeAg and HBV DNA, and with histological evidence of active liver inflammation, were recruited. Eight patients (40%) treated with a priming course of IFN-alpha responded to subsequent IFN-alpha therapy for three months with loss of HBV DNA and HBe seroconversion. This compared with five patients (29%), treated only with IFN-alpha therapy for three months, who lost HBV DNA and HBeAg (but only two [12%] developed anti-HBe). IFN-alpha was well tolerated, with only three patients withdrawing from the study because of 'flu'-like symptoms or inconvenience in the early phase. The better response, although not significant, may suggest a place for a short priming course of IFN-alpha in addition to the current IFN-alpha treatment regimen.

Adult↗
PubMed1993

Concentrations of interleukin 6 and tumour necrosis factor in serum and stools of children with Shigella dysenteriae 1 infection.

Serum interleukin 6 (IL-6) and tumour necrosis factor (TNF) were measured in children with dysentery during an epidemic caused by Shigella dysenteriae 1. IL-6 and TNF were also measured in fresh stool filtrates from children with acute gastroenteritis. The median serum IL-6 concentration was raised significantly in the children with complications (haemolytic uraemic syndrome, leukemoid reaction, thrombocytopenia, thrombocytosis, and severe colitis lasting more than one week) during the first week (n = 18, 9-7728 pg/ml; median 107) and in the second week (n = 13, 5-312 pg/ml; median 77), compared with convalescent sera (n = 10, < 3-85 pg/ml; median 39; p < 0.02 and < 0.05 respectively). The median IL-6 concentration during the first week was significantly higher in the group with complicated disease than in those with no complications (n = 8, < 3-37 pg/ml; median 5; p < 0.001). Although serum TNF concentrations were significantly raised in the complicated group during the first and second weeks of the illness and in the uncomplicated group compared with convalescence, there was no significant difference in the TNF concentrations between the complicated and uncomplicated groups. IL-6 was detectable in stool filtrates from eight of 13 children with S dysenteriae 1 infection and four of eight children with S flexneri infection. It was not detectable in Cryptosporidia, rotavirus, or adenovirus infections, those with pathogen-negative acute diarrhoea or controls. Seven of 13 children with S dysenteriae 1 and three of nine children with S flexneri infections had TNF detectable in stools. None of the children with Salmonella, Cryptosporidia, rotavirus of children with pathogen-negative diarrhoea and controls had detectable TNF in stool filtrates. It is postulated that the local and generalised vasculitis observed in shigellosis may be related to a direct effect of Shiga toxin on endothelial cells or caused by cytokine production stimulated by endotoxin, or both.

Child↗
PubMed1993

Detection of genomic and intermediate replicative strands of hepatitis C virus in liver tissue by in situ hybridization.

Nonisotopic in situ hybridization using a digoxigenin-labeled cDNA probe to the 3' nonstructural region (NS5) of hepatitis C virus (HCV) was performed on liver tissue from 33 patients. The results were compared with PCR detection of HCV RNA performed on 24 of the biopsies. Nonisotopic in situ hybridization correlated well with PCR findings. Hybridization signals were detected, within the cytoplasm and nuclei/nucleoli of hepatocytes, mononuclear, and biliary epithelial cells. In patients with clinically and histologically defined chronic active hepatitis related to active HCV infection, HCV genome was frequently detected in biliary epithelium and correlated well with biliary damage, an otherwise uncommon finding in chronic active hepatitis due to other hepatotropic viruses. Further studies using sense and antisense probes synthesized from the 5' non-coding region of the HCV genome confirmed the localization of positive strand of HCV in the above cell populations. The replicative intermediate strand was also present in all cells, although less frequently observed, apart from biliary epithelium, where negative strand of HCV was undetectable. The findings of HCV genome in liver biopsies of two patients with no significant histological abnormalities may suggest that the damage seen in chronic HCV infection is immune mediated, although the cytopathic effect of the virus may also be important.

Acute Disease↗
PubMed1993

Effects of immunosuppressive therapy on hepatic expression of hepatitis B viral genome and gene products.

To determine the effect of immunosuppressive therapy on hepatic expression of hepatitis B virus (HBV) DNA and antigens in vivo, serial biopsies from 12 patients with chronic active hepatitis B who had been given immunosuppressive therapy (prednisolone 10-15 mg +/- azathioprine 75-125 mg daily) in an earlier period were studied using immunohistochemistry and non-isotopic in situ hybridization. Four out of the 12 patients were positive for hepatic HBcAg/HBeAg/HBV DNA before immunosuppressive therapy. In these 4 patients positive for HBcAg, there was an increase in staining intensity and the proportion of liver cells positive for both HBcAg/HBeAg/HBV DNA and HBsAg during therapy. Of the 8 patients negative for hepatic HBcAg/HBeAg/HBV DNA before immunosuppressive therapy, hepatic HBcAg, HBeAg, and HBV DNA were detected in 2 patients, along with stronger and more diffuse hepatic expression of HBsAg. The other 6 patients also had an increase in hepatic HBsAg expression but without HBcAg. These data provide in vivo evidence that in some patients, immunosuppressive therapy enhances hepatic expression of both HBV genome and gene products.

Adult↗
PubMed1993

Hepatic 60-kD heat-shock protein responses in alcoholic hepatitis.

The precise mechanism of the pathogenesis of alcoholic hepatitis is unknown, but immune involvement may perpetuate and exacerbate the process. Heat-shock proteins, normally protective, may be immunogenic and have been shown to induce antibody formation in some inflammatory conditions. Alcohol, cellular hypoxia and tumor necrosis factor, all involved in alcoholic hepatitis, are potent inducers of heat-shock protein. In this study, we sought 60-kD heat-shock protein in liver tissue with a murine monoclonal antibody and measured circulating antibody to 60-kD heat-shock protein on ELISA. Fourteen of 20 livers from patients with acute alcoholic hepatitis expressed 60-kD heat-shock protein in hepatocyte cytoplasm in a diffuse pattern with superimposed clusters; other cell types were occasionally positive. Twelve of these patients had high-titer IgA 60-kD heat-shock protein antibody in serum. In contrast, 60-kD heat-shock protein was identified in only 2 of the 10 patients with alcoholic cirrhosis without hepatitis (p = 0.013). These two patients had severe liver disease, and one patient in this group was seropositive for IgA 60-kD heat-shock protein antibody. Eight alcoholic patients with fatty liver alone were negative for antigen, and all but one were negative for antibody. The 10 patients without liver damage were negative for antigen and antibody. The findings that 60-kD heat-shock protein is present in liver tissue of patients with acute alcoholic liver damage and that circulating IgA 60-kD heat-shock protein antibody levels are increased may point to one pathogenetic mechanism underlying development and progression of liver damage in alcoholic hepatitis.

Adult↗
PubMed1992

Effects of vasopressor agents and epoprostenol on systemic hemodynamics and oxygen transport in fulminant hepatic failure.

Hypotension is a serious complication in patients with fulminant hepatic failure, because it is associated with tissue hypoxia and a further compromise to end-organ function. In this study we investigated the effects of epinephrine and norepinephrine on hemodynamics and oxygen transport variables in 30 patients with fulminant hepatic failure. All had a mean arterial pressure of less than 60 mm Hg, despite adequate intravascular filling pressures. Both epinephrine (n = 15) and norepinephrine (n = 15) improved mean arterial pressure (p less than 0.001 epinephrine and norepinephrine), although this was not associated with a rise in oxygen delivery. Oxygen consumption fell (p less than 0.05 epinephrine, p less than 0.001 norepinephrine) because of a lower oxygen extraction ratio (p less than 0.01 epinephrine and norepinephrine). The addition of epoprostenol, a microcirculatory vasodilator, in 10 patients from each group led to an increase in oxygen consumption (p less than 0.001 epinephrine and norepinephrine) because of a rise in oxygen delivery (p less than 0.05 epinephrine, p less than 0.01 norepinephrine) and oxygen extraction ratio (p less than 0.01 epinephrine, p less than 0.001 norepinephrine), without a fall in mean arterial pressure. The fall in oxygen consumption after the institution of vasopressor therapy could exacerbate tissue hypoxia and thus contribute to further organ damage in an already susceptible patient. In patients with fulminant hepatic failure who are given vasopressor support, the addition of epoprostenol may prevent the development of tissue hypoxia.

Adolescent↗
PubMed1992

Cytomegalovirus infection persists in the liver graft in the vanishing bile duct syndrome.

Cytomegalovirus infection is one factor implicated in the cause of the vanishing bile duct syndrome complicating liver transplantation. To further investigate the role of cytomegalovirus in this syndrome, we studied serial liver biopsy material by in situ hybridization for cytomegalovirus DNA using a highly sensitive technique that allows the localization of viral replication. Cytomegalovirus DNA was identified in hepatocytes in 10 of 12 patients with the vanishing bile duct syndrome, 1 of whom had no serological evidence of cytomegalovirus infection. It was also present in all 18 patients with uncomplicated cytomegalovirus infection but was not identified in any of 10 subjects with transplants who had neither complication. Nine of the patients in this series underwent a diagnostic liver biopsy at 1 wk and subsequently had cytomegalovirus infection develop; cytomegalovirus DNA was identified in liver tissue of all nine patients, indicating that cytomegalovirus replication commences at an early stage. In those with uncomplicated cytomegalovirus, infection occurred earlier (p less than 0.05) but was eliminated more quickly (p less than 0.0005), and the number of infected hepatocytes was greater (p less than 0.05) when compared with those with the vanishing bile duct syndrome; in these, cytomegalovirus DNA was detectable until death or retransplantation. Cytomegalovirus DNA was never identified in either biliary or endothelial tissue. These data indicate that the vanishing bile duct syndrome is associated with persistent cytomegalovirus replication within hepatocytes.

Cholestasis↗
PubMed1992

Significance of serum IgM anti-HBc in chronic hepatitis B virus infection.

Because of widely differing reports on the significance of IgM anti-HBc in chronic hepatitis B virus (HBV) infection, paired sera and liver biopsies from 49 patients with chronic HBV infection were analysed for serum IgM anti-HBc, HBsAg titre, HBeAg/anti-HBe, HBV DNA, serum aspartate transaminase, intrahepatic HBcAg expression, and liver histology. High levels of IgM anti-HBc, in the diagnostic range of acute hepatitis B (greater than 1.2), were detected in seven patients (14.3%) and a total of 34 patients (69.6%) had an index of more than 0.2. No correlation was found between IgM anti-HBc and the serum markers of active viral replication or HBsAg titre but it correlated significantly with intrahepatic expression of cytoplasmic HBcAg (r2 = 0.165, P = 0.002). IgM anti-HBc also correlated with active liver histology (P = 0.015) but there was a considerable overlap of the IgM anti-HBc index values between the various disease groups, indicating a poor specificity. Serial assessment of IgM anti-HBc in eight patients treated with interferon-alpha (four responders) showed an increase in IgM anti-HBc in three out of four patients corresponding to the e-seroconversion period followed by a drop in IgM anti-HBc levels. However, an increase in IgM anti-HBc was also seen in one non-responder, indicating that this feature is not unique to interferon-alpha responders. These data indicate that serum IgM anti-HBc cannot be used alone as a certain diagnostic measure of HBV replication nor in the prediction of liver histology.

Adolescent↗