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Biomedical subjects

E A Fagan

Publications and source records attributed to E A Fagan.

At least 19 recordsLinked to original sources
PubMed1992

Toga virus-like particles in acute liver failure attributed to sporadic non-A, non-B hepatitis and recurrence after liver transplantation.

Toga virus-like particles (typically 60-70 nm: enveloped with small surface spikes) were detected in the native hepatectomy specimens in 7 of 18 patients grafted for acute liver failure attributed to sporadic non-A, non-B hepatitis and in 2 patients grafted for fulminant hepatitis attributed to anti-epileptic drug hepatotoxicity. These particles were not detected in the hepatectomies from 12 other patients grafted for other causes of acute liver failure, 12 for various chronic liver diseases, and 2 histologically normal livers. Acute hepatic failure, characterized histologically by severe haemorrhagic necrosis, developed 7 days after grafting in 5 patients, all in the non-A, non-B group with toga virus-like particles in native liver. Similar virus-like particles were detected in all grafts and were in greater abundance than in the native livers. The agent may be novel because pre- and post-grafting sera were negative for antibodies against representative panels of arboviruses and in first and second generation antibody tests for hepatitis C virus.

Adolescent↗
PubMed1991

Impaired binding properties of thyroxine-binding globulin in hepatocellular carcinoma and chronic liver disease.

To determine the factors underlying the apparent reduction in binding ability of thyroxine-binding globulin in hepatocellular carcinoma, hormone-binding characteristics were further examined in patients with this disease and in control subjects. No differences in affinity constants with respect to triodothyronine or serum thyroxine-binding globulin from hepatocellular carcinoma, cirrhotic and normal subjects were found. The affinity for thyroxine was significantly reduced in hepatocellular carcinoma (0.41 +/- 0.13 x 10(10) mol-1) and cirrhotic (0.65 +/- 0.1 x 10(10) mol-1) patients compared with normal subjects (0.94 +/- 0.7 x 10(10) mol-1). Investigations carried out on liver tissue obtained from patients with hepatocellular carcinoma and chronic liver disease showed that thyroxine-binding globulin within tumor tissue was elevated and bound less exogenous tracer hormone compared with that obtained from nontumor tissue. Tumor-derived thyroxine-binding globulin with altered binding properties is, at least partly, responsible for the abnormal behavior of the serum protein in patients with hepatocellular carcinoma.

Adult↗
PubMed1991

Prognostic significance of pre-S2 antigen and antibody in fulminant hepatitis B. Evidence for heterogeneous serological responses.

Serial sera were collected prospectively and from early on in the clinical course of ten patients with fulminant hepatitis B. These were analysed for HBV DNA (dot-blot technique), HBsAg, HBeAg, pre-S2-Ag and their respective antibodies. Two patterns emerged in nine of the patients. The first and well-recognised pattern of rapid clearance of antigens and appearance of antibodies was seen in four patients, all of whom survived. The second pattern seen in five patients was one of persistence of HBsAg and pre-S2 antigen and failure to detect antibodies but only one patient survived. The first pattern may reflect a more rapid cessation of virus replication and this may favour liver cell regeneration and recovery. In contrast, the second pattern may indicate continuing virus replication and liver cell damage which could contribute to the high mortality in some patients with fulminant hepatitis B.

Adolescent↗
PubMed1991

Cytoprotective effects of calcium channel blockers. Mechanisms and potential applications in hepatocellular injury.

Deregulation of calcium homeostasis is strongly implicated in the development of cellular injury, including in hepatocytes, and is thought to be the limiting step in transition to an irreversible stage. Calcium channel blockers appear to exert their cytoprotective effects through several mechanisms. These may involve blockade of L-(long-lasting)-type calcium channels, reduction of oxidative stress, antagonism at inflammatory mediator receptor sites and interaction at other intracellular sites. Studies relating to the liver are few but suggest that calcium channel blockers may have a role to play in limiting hepatocellular damage, especially those arising from exposure to a variety of toxic agents.

Animals↗
PubMed1991

Delayed calcium channel blockade with diltiazem reduces paracetamol hepatotoxicity in mice.

1. Diltiazem (30 mg kg-1 body weight, intraperitoneally) given to mice 9 h after paracetamol (450 mg kg-1, orally) reduced liver damage, as judged by plasma aspartate aminotransferase activity (median 186, range 6-602 IU 1(-1), n = 18 vs 466, range 23-3872 IU 1(-1) in 18 saline-treated controls; P less than 0.05) with comparable reductions in mortality (14% vs 33%, respectively; NS). 2. Regenerative activity, as judged by mitotic figures in tissue removed at 30 h after paracetamol, was significantly higher in mice treated at 9 h with diltiazem (median 0.83 per high power field vs 0.1 in saline-treated controls; P less than 0.05). 3. Diltiazem administered earlier or later than 9 h showed reduced efficacy and in some cases potentiated toxicity, as did nifedipine (40 mg kg-1 in divided doses up to 9 h).

Acetaminophen↗
PubMed1991

Association of a precore genomic variant of hepatitis B virus with fulminant hepatitis.

A variant of hepatitis B virus has been described recently in HBsAg+ Mediterranean patients who lack HBeAg and who have an unusual and severe form of chronic hepatitis. This variant is unable to produce HBeAg because of the presence of a novel translational stop codon at the end of the precore region of the genome. By direct sequencing of DNA, generated by the polymerase chain reaction, we have evaluated the association between infection with this variant and the fulminant course of hepatitis B. Eighteen patients with fulminant hepatitis B were studied. Of the 15 cases from whose serum viral DNA could be sequenced, the variant was found in the admission sera of 8 of 9 HBeAg- patients but in none of 6 HBeAg+ patients who had fulminant hepatitis B. Patients harboring the variant progressed more rapidly into hepatic encephalopathy, but those infected with the variant strain alone had a greater likelihood of survival than those infected with the normal strain or a mixture. The mutant strain may emerge spontaneously during fulminant hepatitis as occurs in chronic hepatitis B infection during seroconversion from HBeAg to antibody. Alternately, and perhaps less commonly, patients may be infected with the variant ab initio.

Base Sequence↗
PubMed1991

Detection of hepatitis B virus DNA sequences in liver in HBsAg seronegative patients with liver disease with and without anti-HBc antibodies.

Excluding studies from Brechot and co-workers, little support has been found for a role of the hepatitis B virus in the pathogenesis of HBsAg seronegative patients with predominantly chronic liver diseases, including primary liver cancer. In this study liver DNA from 59 predominantly British patients (four cases with paired biopsies, 6-12 months apart) with different, mostly chronic, liver diseases was analysed by molecular hybridization. All were seronegative for HBsAg and serum hepatitis B virus DNA (dot blot hybridization) and their liver diseases were believed to be unrelated to hepatitis B virus infection. Hepatitis B virus DNA was detected in liver of 11 (18.6 per cent) patients; nine had episomal (3.2 Kb) DNA and eight had higher molecular weight bands suggesting integrated forms. Six patients were also seronegative for anti-HBc. Patients of UK and non-UK origin were equally represented. Hepatitis B virus DNA was detected in serum of six of nine patients tested using the polymerase chain reaction. The detection of hepatitis B virus DNA in liver and in serum by this assay in a significant proportion of patients with chronic liver disease, hitherto unsuspected of being hepatitis B virus-related, suggests a possible role for this virus in low- as well as high-prevalence countries.

Adult↗
PubMed1990

HBV-DNA sequences in tumor and nontumor tissue in a patient with the fibrolamellar variant of hepatocellular carcinoma.

One patient with the fibrolamellar variant of hepatocellular carcinoma was found to be seropositive for HBsAg and anti-HBe. DNA from tumor and nontumor areas of the liver was examined by molecular hybridization for hepatitis B virus DNA sequences. Undigested DNA from the tumor gave a high-molecular-weight smear, and restriction-enzyme analysis indicated a single instance of integration. Nontumor liver tissue was analyzed from three separate areas. Hepatitis B virus DNA was detected in two of these; restriction-enzyme digestion suggested they contained different sites of viral integration. As with the typical hepatitis B virus-related hepatocellular carcinoma, analysis of hepatitis B virus DNA from nontumorous liver yielded a different pattern of high-molecular-weight bands, indicating that the virus genome had integrated at different chromosomal locations than that seen in the tumor. The finding of integrated hepatitis B virus DNA, especially in tumorous but also in nontumorous liver, would be consistent with an oncogenic role for hepatitis B virus in certain instances of fibrolamellar tumors and in the more typical hepatitis B virus-related hepatocellular carcinoma.

Adult↗
PubMed1990

Fulminant viral hepatitis.

In the United Kingdom and United States of America, fulminant viral hepatitis is due mainly to sporadic (non-parenteral) non-A, non-B hepatitis and hepatitis B whereas that caused by hepatitis A virus is very uncommon and by the herpes viruses remains rare. Recent advances in fulminant non-A, non-B hepatitis have come with the identification and cloning of a virus (27-34 nm) in the enteral variety (hepatitis E) which is prevalent in the Indian sub-continent, North Africa and elsewhere, especially in pregnant women. Virus-like particles (50-70 nm) with ultrastructural features similar to the togaviridae and flaviviridae have been identified in some patients with fulminant non-A, non-B hepatitis in the United Kingdom. The relation to hepatitis C virus, recently identified as a major cause of chronic post-transfusion (parenteral) non-A, non-B hepatitis, awaits serological analysis. The recent demonstration that persistence of active viral replication can occur in some cases of fulminant hepatitis types A and B using monoclonal antibody and molecular biology techniques challenges the classical views on the pathogenesis of these varieties of fulminant viral hepatitis.

Hepatic Encephalopathy↗
PubMed1989

Viruslike particles in liver in sporadic non-A, non-B fulminant hepatitis.

In a patient who followed the typical clinical course of fulminant hepatitis attributable to "sporadic" non-A,non-B (NANB) hepatitis and who finally received treatment by orthotopic liver grafting, three, apparently separate, virus-like agents (26, 45, and 80 nm) and cytoplasmic, reticular tubular structures (CTS) were identified in collapsed and regenerating areas of liver using electron microscopy. The 80-nm particles present within vacuoles, together with the finding of intranuclear rods in association with the smaller particles (26 nm), are similar to those found in the nuclei of cells infected with several different arboviruses. The third type of particle, existing as 45-nm spheres and rods, is similar in morphology only to some form of polyoma virus, which, hitherto, has not been reported as affecting the liver. Unlike typical polyoma virus, replication of the virus "cores" (25-26 nm) was extranuclear and appeared to be occurring in vacuoles. Although analysis for serological markers against a representative panel for arboviruses, flaviviruses, phleboviruses, arenavirus, and nairovirus was negative, an insect vector was implicated in the clinical history.

Adult↗
PubMed1989

Toga-like virus as a cause of fulminant hepatitis attributed to sporadic non-A, non-B.

Virus-like particles (60-70 nm) with spiked surfaces budding into cell vacuoles and rod-shaped inclusions were detected in nuclei of hepatocytes from a British patient transplanted for sporadic non-A, non-B fulminant hepatitis (NANB-FHF), probably contracted in Kenya. Identical particles were seen in two successive grafts (days 2 and 10) at regrafting for recurrent FHF. Ultrastructural features resembled those of the RNA-containing arbovirus, Rift Valley fever virus, but serological markers against a representative panel for arboviruses (Togaviruses) and transmission in mice proved negative. The particles shared features with the different arboviruses seen in the hepatectomy specimen of a second patient with NANB-FHF, and in both patients an insect vector was implicated in the clinical history. The particles were identical in size to those of a third patient with NANB-FHF, who had remained in the United Kingdom. These findings, together with the recent report of isolation of an RNA-containing virus resembling the Togaviridae, in parenteral NANB, suggest that several exotic virus-like agents resembling the arboviruses may be involved in the aetiology of NANB, including in the sporadic forms of FHF in the United Kingdom.

Adolescent↗
PubMed1989

Adoptive immunotherapy administered via the hepatic artery and intralesional interleukin-2 in hepatocellular carcinoma.

We assessed the feasibility of using lymphokine-activated killer cells (adoptive immunotherapy) with infusions of interleukin-2 when given regionally in three patients with unresectable primary hepatocellular carcinoma (PHC). In 2 patients, 2 cycles, which included a bolus of LAK (10(7) to 10(8) cells followed by a 4-hourly infusion of IL-2 were administered via selective arterial catheterization of the hepatic artery. One further patient received 3 cycles of IL-2 alone by direct intralesional and perilesional injections. Minimal toxicity was observed and side effects such as fever were comparable to those observed with systemic infusions of IL-2 alone. Serial alpha-fetoprotein (AFP) levels initially fell but subsequently rose within 2 to 4 weeks of therapy. AFP levels had not reached pre-treatment values at 4 months in 2 patients, 1 of whom was alive and well at 15 months follow-up.

Carcinoma, Hepatocellular↗
PubMed1988

Sequential studies of pre-S2 antigenemia and anti-pre-S2 antibodies in relation to viral replication in acute hepatitis B followed from the early incubation phase.

To determine the time sequence of expression of pre-S2 peptide (120-150) during the presymptomatic phase of acute hepatitis B, we used a monoclonal antibody radioimmunoassay in five subjects followed from 30 to 70 days before the onset of liver damage. Pre-S2 peptide was present in serum at low levels from the early incubation phase and started to increase immediately after the first detection of HBV-DNA in serum, in parallel with the increase in HBsAg levels. During the symptomatic phase, levels of pre-S2 peptide declined rapidly; it was no longer detectable after recovery. Anti-pre-S2 antibodies were detected, in four patients, only in the recovery phase. These results demonstrate that expression of pre-S2 peptide occurs very early in the incubation phase of acute HBV infection and is cleared in parallel with HBsAg. Anti-pre-S2 antibodies seem to play no role in viral clearance in these patients.

Adolescent↗
PubMed1988

Clearance of pre-S2 antigen: a marker of successful interferon therapy in hepatitis B virus infection.

The relation between viral replication, the presence of HBsAg and pre-S2 in serum and eventual clinical outcome has been investigated in fourteen patients undergoing treatment with lymphoblastoid interferon for chronic hepatitis B virus (HBV) infection. In four patients permanent loss of pre-S2 was accompanied by loss of serum HBV-DNA in association with a marked elevation of serum aspartate aminotransferase activity and in each of these cases HBsAg was subsequently cleared from serum. In contrast there was no significant fluctuation in the concentration of either pre-S2 or HBsAg in four cases not responding to therapy although substantial or complete inhibition of viral replication had been observed during treatment. In the third group, permanent loss of HBV-DNA was observed but in these cases pre-S2 and HBsAg persisted in serum, albeit at lower concentrations, while in this group loss of HBV-DNA from serum was not accompanied by a flare in disease activity. These results suggest first, that assay of pre-S2 is a further measure of the response to interferon and second that in some cases interferon enhances immune recognition of both the pre-S2 and HBsAg polypeptides.

Adult↗
PubMed1988

Lack of reverse transcriptase activity in serum in sporadic post-transfusional and presumed epidemic or water-borne forms of severe non-A, non-B hepatitis.

Reverse transcriptase (RT) activity was not detected in any serum sample taken from 22 patients with mainly severe non-A, non-B hepatitis (NANBH), using two assays selected to cover the range of known human and animal retroviruses. The study included patients with fulminant and sub-acute hepatic failure, which was was attributed to sporadic, post-transfusional, and presumed epidemic or water-borne epidemiological forms of NANBH. Although we cannot exclude the possibility that some of the agents implicated in NANBH are retroviruses, our negative findings suggest that other agents may be involved at least in the severe forms of NANBH.

Adolescent↗
PubMed1988

Review of hepatitis non-A, non-B: the potential hazards in dental care.

Several of the common viral agents that can cause hepatitis have been detected in body fluids, including saliva and blood, which may both form important routes for transmission of disease. The viruses most commonly implicated include hepatitis A virus (HAV), hepatitis B virus (HBV), cytomegalovirus (CMV), and Epstein-Barr virus. Hepatitis delta virus (HDV) can be found in persons positive for hepatitis B surface antigen (HBsAg) and presumably follows the same routes of transmission as HBV. Herpes simplex and echo viruses can cause hepatitis on rare occasion. Other agents, not yet positively identified but collectively referred to as non-A, non-B are also believed to follow the same routes as HBV and/or HAV. The aim of this reviews is twofold. First, we will discuss hepatotropic viruses other than HBV that may be spread via saliva and blood and, therefore, should be considered along with HBV as a potential health hazard to dental personnel and also to dental patients. The second aim is to highlight the epidemiology and the risk of transmission of these viral infections. The potential hazards are discussed in relation to those associated with HBV and human immunodeficiency viruses (HIV), implicated in the acquired immunodeficiency syndrome (AIDS).

Dental Care for Persons with Disabilities↗