["Accompanying hepatitis" in viral infections].
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Adult↗
Biomedical subjects
S Wirth
Publications and source records attributed to S Wirth.
Breaking tolerance leads to autoantibody production but not autoimmune liver disease in hepatitis B virus envelope transgenic mice.
Hepatitis B virus (HBV) transgenic mice containing the HBV envelope open reading frame under the transcriptional control of the mouse albumin promoter express hepatitis B surface Ag (HBsAg) in all of their hepatocytes and secrete HBsAg (10 to 40 ng/ml) into the circulation. Because these transgenic mice show no signs of spontaneous liver cell injury or autoimmunity toward the viral (self-) Ag, we asked whether the state of self-tolerance could be reversed by the induction of an acute necroinflammatory liver disease or by immunization with HBV envelope proteins, with the aim of creating a transgenic model for chronic, immune-mediated hepatitis. Our studies indicate that repetitive administration of bacterial LPS, IFN-gamma, or HBsAg-specific CTL, all of which were previously shown to cause liver cell injury and inflammation, does not break tolerance at the T or B cell level, suggesting that the intrahepatic lymphomononuclear cell infiltrate induced by these agents consists of HBsAg-nonspecific cells. The adoptive transfer of HBsAg-primed nontransgenic CD4+ T cells into transgenic mice did not induce anti-HBs autoantibody production by transgenic B cells, even though transgenic B cells were fully responsive to immunization with HBsAg when appropriate T cell help was provided in a nontransgenic environment. Immunization of transgenic mice with purified HBsAg in CFA and repetitive infection with rHBV envelope vaccinia virus led to production of T cell-dependent anti-HBs autoantibodies that cleared HBsAg from the serum, but not to activation of HBsAg-specific CTL. We conclude that HBV envelope transgenic mice are largely tolerant to the transgene product at the T cell but not at the B cell level, and that the activation of an anti-HBs response was not sufficient to induce an autoimmune liver disease in this HBV envelope transgenic mouse model.
Animals↗
Selective transmission of variant genomes from mother to infant in neonatal fulminant hepatitis B.
Hepatitis B virus (HBV) nucleotide sequences isolated from mother/child pairs were analyzed in three cases of neonatal fulminant hepatitis B (FHB). Heterogeneous HBV sequences consistent with both adw2 and ayw subtype were found in all three mothers. In one case, in which the child survived, both subtypes were transmitted. By contrast, only the ayw subtype was present in the two other children with a fatal course of FHB. In one fatal case, studied in greater detail, multiple HBV variants (viral quasi-species) were identified in both mother and child. A direct sequence comparison showed that only a subfraction of the virus pool from the mother was transmitted and that multiple new mutations emerged in the child. These data suggest that a minor HBV subpopulation from the mother may prevail as the dominant species in the child and that neonatal FHB is associated with the selection of mutant strains.
Adult↗
Invasive adenocarcinoma of the cervix following LLETZ (large loop excision of the transformation zone) for adenocarcinoma in situ.
Adenocarcinoma in situ (AIS) of the cervix is a controversial entity which is being encountered with increasing frequency. Current critical issues in its management are the safety of uterine preservation in younger patients and the use of LLETZ conization. A 28-year-old patient was diagnosed with AIS and managed with LLETZ. Despite apparently negative margins of resection in the initial conizations, the patient was found to have invasive adenocarcinoma 1 year later. It is concluded, after review of the pathologic features of AIS, that if conservative management of AIS is elected, then standard cold knife conization should be performed and not LLETZ. Further study is required to establish the overall safety of conservative treatment of cervical AIS, including the use of LLETZ.
Adenocarcinoma↗
Phenotypic variability in patients with generalised resistance to thyroid hormone.
Genetic linkage of generalised resistance to thyroid hormone (GRTH) to the human thyroid receptor beta 1 gene has been identified. To date 38 different mutations in several kindreds have been documented. We report on a family with GRTH displaying an adenine for guanine substitution at nucleotide 1234 resulting in a threonine for alanine substitution at codon 317 of exon 9. This mutation has been described for different phenotypes, suggesting that the heterogeneity in GRTH may be the result of multiple genetic factors.
Adult↗
[Children as witnesses of violence: consequences for determining reliability].
For many years testimony by children was considered to be of little value. The authors of the present article do not share the view that the credibility of children should generally be questioned. Different investigations show that even young children are able to make forensically relevant depositions. The roles of developmental stage, memory and suggestibility of children are discussed in detail. A case report of a child who witnessed the murder of both parents demonstrates the importance of age-related aspects of emotional experience, development of memory and the ability of children to recall memories. Even at the first hearings it is important to establish a nonthreatening atmosphere in which the child can feel safe and protected. An experienced child and adolescent psychiatrist should be consulted early on.
Child↗
Class I-restricted cytotoxic T lymphocytes are directly cytopathic for their target cells in vivo.
Although CD8-positive, class I-restricted CTL play a critical role in viral clearance and immunopathology in many model systems, they have not been shown to directly kill their target cells in vivo at the single cell level. Using a hepatitis B surface Ag transgenic mouse model of class I-restricted, CTL-mediated liver disease, we now demonstrate that CD8-positive, Ld-restricted hepatitis B surface Ag-specific CTL bind and kill their target cells in vivo by triggering them to undergo degenerative cytologic changes compatible with apoptosis. Unexpectedly, the data also indicate that the pathologic consequences of this direct, Ag-specific CTL effect are much less severe than the cytodestructive, Ag-nonspecific inflammatory response that they induce when they are activated by Ag recognition.
Animals↗
Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: a severe fatty acid oxidation disorder.
3-Hydroxyacyl-CoA dehydrogenase deficiency is a newly recognised fatty acid oxidation disorder with a usually fatal outcome. We present a further patient who presented with hypoketotic hypoglycaemia, hepatopathy, secondary carnitine deficiency and increased plasma long-chain acylcarnitines. 3-Hydroxydicarboxylic aciduria was present and the diagnosis confirmed in cultured skin fibroblasts. Our patient is compared with those reported in the literature with respect to clinical symptoms, differential diagnosis and possible therapeutic regimens.
3-Hydroxyacyl CoA Dehydrogenases↗
Proinflammatory cytokines in serum of patients with acute cerebral ischemia: kinetics of secretion and relation to the extent of brain damage and outcome of disease.
The release of the proinflammatory cytokines IL-1 beta, IL-6, TNF-alpha and soluble TNF-receptors p55 and p75 in peripheral blood was serially determined in 19 patients with acute cerebral ischemia. Only patients admitted within 4 h following onset of symptoms were studied. In contrast to serum levels of IL-1 beta, TNF-alpha and TNF-receptors, which did not exhibit a significant response, IL-6 showed a significant increase of serum levels already within the first hours following onset of disease and reached a plateau at 10 h until day 3 and returned to baseline by day 7. The increase of levels of this cytokine was significantly (P < 0.05) correlated with increasing volumes of brain lesion and was also significantly (P < 0.005) associated with poor functional and neurological outcome. The increase of levels of IL-6 despite a considerable dilution in peripheral blood shown in this preliminary study suggests an early inflammatory response in ischemic brain lesion.
Activities of Daily Living↗
Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis.
The molecular and cellular mechanisms responsible for cytotoxic T lymphocyte (CTL)-induced immunopathology are not well defined. Using a model in which hepatitis B surface antigen (HBsAg)-specific CTL cause an acute necroinflammatory liver disease in HBsAg transgenic mice, we demonstrate that class I-restricted disease pathogenesis is an orderly, multistep process that involves direct as well as indirect consequences of CTL activation. It begins (step 1) almost immediately as a direct antigen-specific CTL-target cell interaction that triggers the HBsAg-positive hepatocyte to undergo programmed cell death (apoptosis). It progresses (step 2) within hours to a focal inflammatory response in which antigen-nonspecific lymphocytes and neutrophils amplify the local cytopathic effect of the CTL. The most destructive pathogenetic function of the CTL, however, is to secrete interferon gamma when they encounter antigen in vivo, thereby activating the intrahepatic macrophage and inducing a delayed-type hypersensitivity response (step 3) that destroys the liver and kills the mouse. We propose that the principles illustrated in this study are generally applicable to other models of class I-restricted, CTL-induced immunopathology, and we suggest that they contribute to the immunopathogenesis of viral hepatitis during hepatitis B virus infection in humans.
Animals↗
[The treatment of chronic hepatitis B].
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Adult↗
Low level virus replication in infants with vertically transmitted fulminant hepatitis and their anti-HBe positive mothers.
Perinatal transmission of hepatitis B virus (HBV) occurs in about 10%-20% of anti-HBe seropositive mothers. The babies are at risk of developing fulminant hepatitis. In most cases no viral DNA has been detected in the sera of mothers and children by conventional hybridisation techniques. Thus, the aim of our investigation was to demonstrate HBV DNA in three children with liver failure and their anti-HBe positive mothers by more sensitive molecular hybridisation techniques. The babies were healthy at birth and did not receive vaccination. At 3 months of age they developed acute liver failure and died from liver insufficiency. Only in one child serum HBV DNA was detected by dot blot hybridisation, but polymerase chain reaction (PCR)-detectable HBV DNA was present in all sera. The liver specimen was negative for HBV DNA by Southern blot hybridisation, but showed a focal distribution of viral sequences as determined by in situ hybridisation. This finding was confirmed by PCR. Our results prove that chronic anti-HBe positive HBsAg carrier mothers and their babies show a low level virus replication. Fulminant hepatitis is due to vertical transmission of very small amounts of viral DNA, only detectable by most sensitive techniques like PCR and in situ hybridisation. Our findings underline the necessity to vaccinate all babies of HBsAg positive mothers regardless of HBeAg/anti-HBe status.
Adolescent↗
Interferon alfa-2b therapy in children with chronic hepatitis B.
Twenty nine children (mean age 8.3 years, 18 boys, 11 girls) who had biopsy proved chronic hepatitis B virus infection (HBV) with active viral replication were given a 16 week course of interferon alfa-2b treatment (9 million units (MU)/m2, thrice weekly). Fourteen children (48%) showed persistent loss of HBV-DNA 8 months after the end of treatment; 11 (38%) lost hepatitis B e antigen (HBeAg), and two (7%) hepatitis B surface antigen (HBsAg). Alanine aminotransferase activities returned to normal in 12 children. Those who responded had significantly higher initial transaminase activities than those who did not (p < 0.01) but similar serum HBV-DNA. Results were compared with the natural evolution of the disease in a group of 25 children (mean age 8.3 years) with identical initial mean serum HBV-DNA values, followed up during the same period. Two of these (8%) lost HBeAg and one (4%) HBsAg. The 23 remaining control subjects had no decrease in serum HBV-DNA or in transaminase activities compared with values 1 year earlier. It is concluded that treatment with interferon alfa-2b in children may lead to inhibition of HBV replication similar to that described in adults, and may thus shorten disease evolution. Further studies are necessary to establish the best protocols and to identify those patients who are the most likely to respond to treatment.
Alanine Transaminase↗
[Drug treatment of 7- to 14-year-old children. Results of a parent survey].
In comparison to other European countries, Germany has by far the highest availability of drugs. Consequently the fear is often expressed that drugs may be over-prescribed even for children and that educational measures or home remedies would often be equally effective. In particular, the issue of inappropriate prescribing of psychotropic drugs for children is often raised, even though epidemiological studies have failed to document such a practice. In a study conducted to obtain comprehensive data about the use of drugs by children, questionnaires were given to parents of children at four schools in Bavaria (2 industrial towns, 2 university towns). This anonymous inquiry was supported by the Ministry of Education and Cultural Affairs. Of the 1750 questionnaires distributed 1189 were evaluated (67.9% response rate). On an average, each child took 3.17 drugs per year, mainly for respiratory infections, fever, pain and gastrointestinal symptoms. Analgesics, nasal preparations, cough medicine, gastrointestinal medications and antibiotics were used frequently and psychotropic drugs only rarely (rank 20). For psychiatric conditions, only one child in 170 was given psychotropic drugs and only one in 108 used sedatives. Overall, drugs and home remedies were used with almost equal frequency (1.23:1). For psychiatric problems, home remedies were used three times more frequently, whereas for other problems drugs predominated. Of the parents who responded were 79.3% satisfied with the prescribed drugs; 9.1% stated that they changed the dosage of the prescribed drugs.
Adolescent↗
Molecular hybridization techniques in current diagnosis of chronic hepatitis B in childhood.
Following the cloning and sequencing of the hepatitis B virus genome, molecular hybridization techniques have been established to detect hepatitis B virus (HBV) DNA in serum and liver tissue. Analyses can be performed by dot blot, Southern blot and in situ hybridization. HBV DNA is regarded to be the most sensitive marker of viral replication and infectivity which was previously related to the presence of hepatitis B e antigen in serum and hepatitis B core antigen in liver cells. In liver tissue different molecular patterns can be recognized as free viral DNA and integrated sequences. Furthermore, introduction of the polymerase chain reaction allows the detection of very small amounts of viral DNA and has markedly improved diagnostic sensitivity. Thus the study of HBV DNA has become a valuable part of the routine diagnosis in chronic hepatitis B, providing a more reliable evaluation of virus replication and infectivity, and facilitating more precise statements about course and prognosis of the disease.
Child↗
Use of the polymerase chain reaction to demonstrate hepatitis B virus DNA in serum of children with chronic hepatitis B.
The polymerase chain reaction was used to investigate the presence of hepatitis B virus DNA in sera of 61 children with chronic hepatitis B and negative results on dot blot hybridization tests. Our results demonstrate that most chronic carriers of hepatitis B surface antigen in childhood have hepatitis B virus DNA detectable by polymerase chain reaction in their serum and must be considered infectious.
Adolescent↗
Detection of hepatitis B virus DNA in the liver of children with chronic hepatitis B by in situ hybridization and its relation to other viral markers.
The aim of the study was to detect hepatitis B virus (HBV) DNA by in situ hybridization (ISH) with a 35S-labeled radioactive probe in frozen liver biopsy tissue sections of 63 hepatitis B virus surface antigen (HBsAg)-positive children. The results were compared to other markers of viral replication. HBV DNA was detected in 48 children. Of the 15 negative cases, four had hepatitis B envelope antigen (HBeAg), 10 anti-HBe, and one neither HBeAg nor anti-HBe. Free HBV DNA in serum and liver was positive in one patient. Forty of the positive children were HBeAg- and six anti-HBe-positive; two were negative for both. Of 45 36 had HBV DNA in serum. In 38 of 47 HBV DNA and in 31 of 42 HBcAg could be detected in the liver. The HBV DNA signals were located mainly over the cytoplasm of hepatocytes. The distribution of HBV DNA in the tissue was classified as homogeneous, inhomogeneous with focal patches, and focal. It is concluded that in situ hybridization is a reliable method for detection of HBV DNA in liver tissue of children with chronic hepatitis B. The technique, which can be applied to small amounts of liver tissue, provides informations about the distribution of replicative viral sequences, complementing laboratory data, liver histochemistry, and histology.
Adolescent↗