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— Six patients with chronic hepatitis B virus (HBV)-induced liver disease were treated with human lymphoblastoid interferon. Daily, alternate day or thrice weekly regimens were employed in two, one and three patients respectively. Thrice weekly intra-muscular injections of 7.5 to 10 megaunits of interferon/m2 appeared to be as effective as daily injections in producing inhibition of HBV replication, were associated with fewer side effects and could be continued for up to 3 months. The effectiveness of this regimen in producing long-term inhibition of viral replication must now be determined.

In the monocrotaline (MCT) model of pulmonary hypertension, the pulmonary vascular endothelium is the likely early target of the reactive metabolite monocrotaline pyrrole (MCTP). Incubation of cultured bovine pulmonary arterial endothelial cells (BPAEC) with MCTP results in covalent binding to DNA, cell cycle arrest, and delayed but progressive cell death. The mode of cell death in MCTP-induced endothelial damage has not been addressed previously. Since DNA damage is frequently associated with apoptosis, the presence or absence of apoptosis in adherent BPAEC was determined by several techniques, including morphologic and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling. Two concentrations of MCTP (5 and 34.5 microgram/ml) along with a vehicle control were examined with each assay. Both concentrations of MCTP induced increasing numbers of cells to undergo apoptosis over time beginning as early as 6 h after exposure to MCTP in the high concentration group. Control and vehicle control cells exhibited small amounts of apoptosis (1-2%), which did not change over the duration of the experiment. Additionally, cell membrane integrity was assessed over time by either exposure to membrane-impermeant dyes or measuring LDH release. By either method, BPAEC had increased membrane permeability after about 48 h of either low or high concentration MCTP exposure. We conclude that both a low or high concentration of MCTP causes cell death in BPAEC by inducing apoptosis.

Hepatitis B virus (HBV) replicates via an intermediate RNA step. High frequency of polymerase errors with additional selection pressure leads to mutations in the HBV genome. We investigated the number, type, and antigenic effects of mutations in the coding region of the HBV surface antigen in eight patients who underwent orthotopic liver transplantation (OLT) for HBV-related end-stage liver disease and were experiencing infection of the graft and who received hepatitis B surface antigen antibody (anti-HBs) prophylaxis (hepatitis B immune globulin [HBIG]) after OLT. Controls were chronic HBV patients who underwent kidney transplantation and received the same immunosuppressive regime but no HBIG. The S-gene was amplified from serum before and after transplantation, sequenced, and changes in the genome were analyzed. In the five patients who experienced reinfection while receiving anti-HBs, clear mutations occurred in the S-gene. In the patient who did not receive HBIG and those who experienced reinfection only after termination of HBIG, no mutations were found in the S-gene. In the kidney recipients, mutations in the S-gene occurred in only one of eight patients. Because the a determinant contains neutralizing epitopes, this region was chosen for antibody binding to quantify antigenic effects of the mutations. The two patients who selected mutations in the a determinant and became reinfected while receiving HBIG had reduced antibody binding after OLT. Our results suggest that HBIG after OLT imposes a selection pressure on the S-gene, and that mutations are one mechanism for reinfection while receiving HBIG.

We report the discovery of a highly X-ray variable AGN, RX J2217.9-5941. This object was bright during the ROSAT All-Sky Survey (RASS), during which a decrease in the count rate by a factor of 12 was observed. It was found to be much fainter in follow-up HRI observations and is therefore an X-ray transient AGN candidate. On long time scales of years, its count rate decreased by a factor of about 30 between the RASS and the ROSAT HRI and ASCA observations in 1998. Analysis of the ASCA data, complicated by source confusion and poor statistics, tentatively indicates a steep spectrum in the faint state. There is no evidence for variability among 5 optical observations of the object obtained between 1992 and 1998. We discuss the variability of RX J2217.9-5941 and its possible X-ray transient nature., Comment: 10 pages (including 7 Figures), accepted for A&A, also available at http://www.xray.mpe.mpg.de/~dgrupe/research/refereed.html

BACKGROUND & AIMS: Lamivudine inhibits hepatitis B virus replication. This study investigated 6 months of lamivudine treatment at three doses. METHODS: Fifty-one patients (43% white, 49% Asian) with chronic hepatitis B were randomly assigned to receive 25, 100, or 300 mg of lamivudine orally once daily for 24 weeks with 24 weeks' follow-up. RESULTS: Serum hepatitis B DNA by liquid hybridization decreased in all patients and was undetectable at the end of the treatment in 7 of 12 (58%, 25 mg), 13 of 14 (93%, 100 mg), and 14 of 16 (88%, 300 mg) patients. Of the 36 patients with abnormal alanine aminotransferase (ALT) levels at baseline, 7 of 11 (64%, 25 mg), 5 of 11 (45%, 100 mg), and 5 of 14 (36%, 300 mg) normalized ALT at treatment completion. Quantitative decreases hepatitis Be antigen and hepatitis B surface antigen concentrations were observed at all doses. In most patients, markers of replication returned after treatment. Two patients (4%) were anti-HBe positive at the end of follow-up. Lamivudine was well tolerated. The incidence of adverse events was similar across all dose groups. However, 2 patients developed temporary hepatic decompensation after increase in transaminase levels after treatment. CONCLUSIONS: Lamivudine was well tolerated and induced sustained suppression of hepatitis B replication during treatment in all patients at all doses. These data support investigation of longer treatment durations of 100 mg once daily. (Gastroenterology 1997 Oct;113(4):1258-63)

Series Editor's Foreword. Preface. 1. Immunopathology and virus infections B. Askonas. 2. Immunopathology of hepatitis A and hepatitis E virus infections E.A. Brown, J. Ticehurst, S.M. Lemon. 3. Immunobiology of hepatitis B and D virus infections M.U. Mondelli, F. Negro. 4. Hepatitis C virus: infection and immunity J. Monjardino. 5. Human hepatoma associated antigens: opportunities for immunotherapy D. Shouval, R. Adler. 6. Mechanisms of autoimmunity M. Peakman, D. Vergani, A.L.W.F. Eddleston. 7. Autoantibodies and their cytoplasmic antigens in autoimmune chronic active hepatitis M.P. Manns, K.-H. Meyer zum Buschenfelde. 8. Primary biliary cirrhosis D.E.J. Jones, W.L. Gregory, M.F. Bassendine. 9. The immunology of primary sclerosing cholangitis R.W. Chapman. 10. Immune mechanisms in alcoholic liver disease R.D. Goldin, N.C.A. Hunt. 11. Immune-mediated drug hepatotoxicity J.G. Kenna. Index.

It is now well established that sequence variation of hepatitis B virus (HBV) occurs worldwide. Although variants have been classified into subtypes by means of antigenic specificities of the surface proteins, it may be that HBV can be better classified into genotypes by means of percentage nucleotide difference. HBV can be classified into at least four genotypes based on a divergence of >7% at the nucleotide level [1] and it is clear that, based on this definition, other genotypes will be described in the future. Whether genotyping in this fashion is a satisfactory method of classifying HBV, and whether this has any relevance to the pathogenesis of the liver disease, infectivity or spread remains to be seen. Subtypes, defined by antigens associated with specific amino acid changes, are distributed geographically and have no apparent ink with disease. Whether one subtype can infect a person previously infected with a different subtype is unclear; at least, it would seem to be quite uncommon.

Summary Severe potassium permanganate poisoning (more than 10 g of potassium permanganate) is invariably associated with massive systemic upset and death. Multiple organ damage has been recognized as an inevitable consequence of such an overdose, although pancreatitis has not been previously reported. Death due to cardiovascular collapse and profound hypotension is a common end point in those who reach hospital, but the pathogenesis is uncertain. We report a case of haemorrhagic pancreatitis following an overdose of potassium permanganate and suggest that this complication may be an unrecognized factor contributing to the extremely high mortality rate associated with this condition.

Antiviral therapy for chronic hepatitis B virus infection can result in clearance of replicating virus from the liver and prevention of progression to cirrhosis in a substantial proportion of patients. Adenosine arabinoside monophosphate, a potent inhibitor of HBV replication, is of limited usefulness because it causes significant neuromuscular toxicity. Acyclovir alone is relatively nontoxic, but is clinically ineffective in eliminating HBV from the liver. Lymphoblastoid or recombinant alpha-interferons are the best option at present and offer up to a 50% chance of long-term inhibition of HBV replication (with only minor side-effects) in patients who acquire the infection in adulthood. However alpha-interferon therapy alone is not effective when infection is acquired from birth. In this latter group of patients, prednisolone pre-treatment followed by alpha-interferon is currently under evaluation.

EDITOR, - Carol A Seymour's editorial1 and the papers on hepatitis C in the same issue illustrate the problems of defining chronic hepatitis C and of identifying patients who would benefit from regular follow up in a gastroenterology clinic. We and colleagues have found that only liver biopsy reliably identifies patients with chronic infection. Kate E Ryan and colleagues rightly question the effectiveness of counselling when so little is known of the natural course of this infection.2 Liver biopsy is not a minor procedure, and scarce and expensive medical resources should be used only when the patient will benefit. The patient must be given an accurate prognosis and treatment with interferon alfa and other antivirals should be offered when appropriate, although the long term effects of such intervention on the prognosis of liver disease associated with hepatitis C are unknown. Much of this information is not new. It has been known since the 1970s that a normal serum alanine aminotransferase activity in repeated samples taken over an extended period does not exclude the finding of non-A, non-B hepatitis on liver biopsy.3,4 Published studies of liver biopsies in blood donors positive for antibodies to hepatitis C virus show varying proportions with normal histological appearances and …

In patients with autoimmune chronic liver disease, a defect in the regulatory system of the immune response allows proliferation of clones of cells reacting with hepatocyte antigens. Identification of these target antigens, their isolation, and purification will allow further study of the nature of the immune diathesis and permit development of specific therapy designed to eliminate the malregulated clones of immunocytes. The mechanisms resulting in hepatocyte damage during chronic HBV infection are more complex. Both lobular focal and periportal piecemeal necrosis of hepatocytes is seen. Current evidence is consistent with the view that focal necrosis represents T-cell lysis of hepatocytes containing replicating virus, whereas piecemeal necrosis is a reflection of an autoimmune response to native liver membrane antigens, initiated by viral replication. The latter response would be expected to be greatest during viral replication, but because of the increase in suppressor T-cell concentrations that occurs at this time, the liver membrane antibody response is largely suppressed. When viral replication ceases, in patients with normal suppressor cells, the liver membrane antibody response is suppressed. In some patients, suppressor cells are relatively reduced and the liver membrane antibody response continues after cessation of viral replication. At this stage, the composition of the inflammatory infiltrate in the liver is similar to that seen in autoimmune (lupoid) chronic active hepatitis. The destruction of hepatocytes containing integrated HBV-DNA is probably dependent on an immune response to HBs antigen. Failure of this elimination process, for immunogenetic or environmental reasons, results in persistence of clones of cells from which malignantly derived cells may ultimately arise. Adequate therapy of this condition must not only stop the replication of the virus, thereby reducing hepatic inflammatory activity, but eliminate clones of cells containing integrated HBV-DNA so that the danger of malignant transformation of hepatocytes is removed.

Results of five nights of photoelectric UBV photometry of HZ Her and of simultaneous ultraviolet spectroscopy with IUE are presented.

Summary We describe a patient presenting with painless jaundice, anorexia and pruritus. The gall bladder was found to be lying above and behind a hypoplastic right lobe of liver. There was no evidence of cholangitis or biliary obstruction. The patient subsequently developed a bronchobiliary fistula with severe wheeze, cough and bile-stained sputum. Emergency percutaneous drainage of the gall bladder led to immediate cessation of bronchospasm and biloptysis, rendering the patient fit for definitive surgery.

The majority of oral infections with Candida albicans have a local cause. However some Candida infections, such as chronic muco-cutaneous candidosis, which may be widespread over skin and mucous membranes are associated with systemic disorders. Indeed, antibiotic or corticosteroid therapy and severe debilitating disease are proven causes of Candida infection while the association of various endocrinopathies with candidosis has now become well established. More recently, other systemic factors such as impaired cellular immunity and nutritional deficiency have been recognised as influencing Candida infections, and this knowledge is now being successfully applied to the treatment of the disease.

ASPLIN and Boyland (1947) and Turner and Kumaran (1949) have reported that certain pyrimidine sulfa compounds could induce testicular hyperplasia and enlarged combs in cockerels. Turner and Kumaran (1949) explained these facts by assuming an increased gonadotrophin secretion by the anterior pituitary gland. An alternative explanation for the observed phenomena is increased sensitivity of the gonads to endogenous gonadotrophins. Experiments reported in the present paper were designed to elucidate the mode of action of sulfamethazine, one of the sulfa pyrimidine compounds found by Turner and Kumaran (1949) to be effective in inducing precocious sexual maturity. During our experiments a marked effect was observed on the thyroid size and activity. MATERIALS AND METHODS Single Comb White Leghorn cockerels of an unselected population were used. The sulfamethazine was mixed with a 20% broiler mash at levels of 0.1 and 0.2%. Birds received feed and water ad libitum. At autopsy the combs, thyroids, …

Concentrated samples of saliva, urine, and seminal fluid from 23 men with chronic liver disease who were positive for hepatitis B e antigen were examined for the presence of hepatitis B virus deoxyribonucleic acid (HBV-DNA) by molecular hybridisation. HBV-DNA was detected in saliva from 15 of 17 men (88%), urine from 12 of 22 men (55%), and seminal fluid from 13 of 21 men (62%). The presence of hepatitis B virus in such secretions has important epidemiological implications for heterosexual and homosexual contact.

Primary biliary cirrhosis (PBC) is a granulomatous destructive disease involving the epithelium of the proximal intrahepatic biliary tree to the level of the interlobular ducts [34, 48]. More recently the polyglandular nature of the disease has become evident by the demonstration that 70–100% of patients also have lacrimal and salivary gland lesions [1,17], and pancreatic dysfunction is not uncommon [11,26]. It is predominantly the ductular components of these glands which are destroyed by an inflammatory or immunological process while the acinar elements are spared. In addition, dermal thickening (scleroderma-like) and pigmentation are prominent features, and the syndrome is accompanied by severe abnormalities of both cell- mediated and humoral immunity. Patients exhibit a generalised state of immune hyporesponsiveness being anergic to DNCB [15] and producing a diminished antibody response to parenteral antigenic challenge [16, 57]. They also exhibit failure of the immune response to convert from IgM to IgG antibody synthesis [57].

A randomised controlled trial was conducted in 29 HBV carriers who had been HBs and HBe antigen positive for more than six months. Fifteen patients were treated with ARA-AMP 10 mg/kg/day given as intramuscular injections 12 hours apart for five days followed by 5 mg/kg/day for 23 days. The 14 controls received no treatment. Serum HBV-DNA polymerase, and HBV-DNA decreased in all patients during therapy. Six treated patients lost serum HBV-DNA polymerase, HBV-DNA and HBeAg, HBsAg concentrations decreased, and five developed anti-HBe. One of these six patients lost HBsAg and developed anti-HBs. No such changes were observed in the control group over a similar 18 month period of observation. A four week course of ARA-AMP inhibits HBV replication and in a significant minority of patients this is long lasting and is associated with a reduced level of inflammatory activity in the liver.

In primary biliary cirrhosis, the primary immune response to the bacteriophage phi X 174 is normal but the secondary response is significantly reduced. The reduction is primarily of IgG antibody, while IgM is proportionately less affected. These changes may be the result of a reduction in helper T lymphocyte function and may contribute to the increase in the ratio of serum concentration of IgM to IgG.

There are approximately 200 million carriers of hepatitis B virus world-wide. This carriage rate is associated with a high incidence of chronic liver disease and a two hundred fold increased incidence of hepat-cellular carcinoma. These patients are those in whom acute infection has not been associated with clearance of the virus and development of immunity, but in whom this mechanism has broken down to produce the chronic carrier state. There are probably many reasons for the chronic carrier state. Approximately 5–10% of patients infected in adult life in the Western World (1) become chronic carriers whereas 90% of those in the Far East, infected around the time of birth, become carriers.(2). The hepatitis virus is not cytopathic and elimination depends on mobilisation of host defense mechanisms to lyse virus infected cells and to clear circulating virions (3). Lysis of virus infected cells requires recognition of viral proteins in association with HLA class I antigens on the surface of the cell and it is known that on both uninfected liver and in the chronic carrier state there is very little HLA protein display on the surface of the hepatocyte (4). In the animal model of acute viral hepatitis, this HLA display rises following the detection of interferon., in the circulation and the rise corresponds with biochemical evidence of liver damage.

Although the incidence of symptomatic hepatitis associated with jaundice in patients with congenital coagulation disorders is low1,2, several reports have demonstrated that many of these patients have asymptomatic liver disease. Mannucci et al., in 19755 showed increased transaminases in more than 40% of haemophiliacs and Levine et al., in 19764 found similar abnormalities in 68% of patients. The latter study included 33 intensively treated patients from the Royal Free Hospital who had received cryoprecipitate only and who had a 48.5% prevalence of abnormal liver function tests. More recently, in a survey of 76 patients with severe haemophilia A (Factor VIII < 1%) registered at the Royal Free Hospital Haemophilia Centre, 92% were found to have abnormal aspartate transaminase levels on random testing. The prevalence of abnormalities was similar in patients who had received NHS concentrate only (100%) and those who had received commercial Factor VIII preparations (96%), but slightly lower in those who had received cryoprecipitate only (80%). Seven untreated patients with mild haemophilia had normal liver function tests. Although the number of patients who had received NHS concentrate or cryoprecipitate only was smaller than the number who had received commercial concentrate, and patients receiving cryoprecipitate only were in general transfused less frequently than those receiving concentrate.

Patients with chronic active hepatitis or alcoholic cirrhosis have serum antibodies to many more serotypes of Escherichia coli than do patients with primary biliary cirrhosis or cryptogenic cirrhosis, or normal controls. They also have antibodies against more serotypes than cirrhotic patients with a portacaval shunt. These observations suggest that factors other than shunting of blood away from the liver are responsible for the increased range of antibodies. These factors are discussed. There was no correlation between the number of serotypes to which antibodies were present and the serum immunoglobulin concentration. In three patients, each with chronic active hepatitis, the antibodies were predominantly of the IgM class, while the elevation of globulin in general was mainly due to increased IgG and IgA levels. Antibodies to Escherichia coli, therefore, probably contribute only a small part of the increased globulin levels found in patients with chronic liver disease.

One hundred and six consecutive chronic hepatitis B virus (HBV) carriers were studied for the prevalence of delta markers in serum and tissue, and the clinical and histological features of those with and without delta infection were compared. Twenty (18.9%) patients were positive for anti-delta in serum or delta antigen in the liver or both. They presented at a younger age (30.3 v 38 years). All of them were symptomatic at the time of biopsy, in contrast to 35% of patients without delta infection who were not symptomatic. Those with delta infection had higher serum transaminase values and showed more severe liver damage on biopsy: chronic active hepatitis in 45% and cirrhosis in 55%. There was more pronounced disease activity both within the parenchyma and in the portal and periportal zones. The histological diagnosis of the 86 patients without delta infection included minimal disease (10%), chronic persistent hepatitis (9%), chronic active hepatitis (62%), and cirrhosis (19%). Delta infection in chronic HBV carriers is associated with a more active and progressive liver disease.

Groups of rats were submitted to end-to-side portacaval shunt, portacaval transposition or a control sham operation. There was an 18-fold increase of the IgA level in the serum of portacavally shunted rats (n = 7) at 3-6 weeks after surgery. Gel filtration revealed that this increase was predominantly due to dimeric and polymeric IgA. The serum IgM of these shunted rats, but not the IgG, was also significantly increased (twofold) above their control values. In rats subjected to portacaval transposition (n = 6), there was no significant increase of serum IgA, IgM or IgG when compared with their control values. These data confirm the active transfer, by the healthy rat liver, of IgA and, to a lesser extent, of IgM from the blood into bile. Impairment of this function, leading to the accumulation of polymeric IgA and IgM in the serum, in portacavally shunted but not portacavally transposed animals, may be related to impairment of hepatic flood flow and hepatic atrophy, shown earlier to occur in portacavally shunted but not transposed rats. Such reduction in liver cell mass could also explain the fall in transferrin levels in shunted rats.

The effects of chronic infection with hepatitis B virus (HBV) on the lives of 40 British patients were studied by means of a questionnaire. The aspects considered were: social, sexual, and family life, physical and psychological health, and work. Thirty six patients considered their lives to have been affected, nine mildly, 14 moderately, and 13 severely. The aspects of life most affected were: sexual (13), psychological (11), physical (5), work (3), social (2), and family (2). Most of the problems encountered were related to infectivity. The availability of vaccines against HBV and of successful antiviral treatment have solved some of the problems, but it remains important for the medical profession to be aware of the multifaceted impact of the carriage of HBV.

An immunoradiometric assay for hepatitis B surface antigen (HBsAg) that employs monoclonal antibodies directed against the common epitope(s) of HBsAg was used to analyse 3,694 samples of human serum. Further analysis of those sera identified as HBsAg-positive in this assay demonstrated that the findings with the monoclonal-antibody-based assay correlated with the presence of HBsAg as determined by Austria II. A small proportion of apparently false-positive reactions were observed, in that some sera, although reactive with the monoclonal antibodies, were not positive in conventional immunoassays using polyclonal antisera, nor were they neutralisable with polyclonal anti-HBs. The material purified by monoclonal immunoabsorbants from representative "true" and "false-positive" sera was run on polyacrylamide gels and examined under the electron microscope. The antigen in the apparently false-positive sera contained some polypeptides of similar size to those found in HBsAg, but no virus particles were seen by electron microscopy. The majority of patients with this monoclonal-antibody-reactive antigen gave either a history of hepatitis B virus (HBV) contact or had signs of liver disease.