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Biomedical subjects

S Wirth

Publications and source records attributed to S Wirth.

At least 55 records · Page 3Linked to original sources
PubMed1996

New point mutation (R243W) in the hormone binding domain of the c-erbA beta 1 gene in a family with generalized resistance to thyroid hormone.

Two years after the first mutation on exon 7 in the carboxy-terminal part of the hinge domain (D) was reported (Behr and Loos 1992), we have identified the second mutation on exon 7 in patients with GRTH. Interestingly, our mutation it is not located in the two previously described "hot spot regions", but instead very close to the hinge domain (D) of the receptor protein that is essential for the function of the hormone binding domain (E) (Lin et al., 1991). Confirming the observation that the majority of single base substitutions causing human genetic diseases or DNA polymorphisms follow the hot spot mutation rule of CG to TG and CG to CA transition (Barker et al., 1984), an additional CpG dinucleotide transition has been identified.

Adult↗
PubMed1996

Adenocarcinoma in situ of the uterine cervix: management and outcome.

OBJECTIVE: To retrospectively review the management of adenocarcinoma in situ of the uterine cervix, to determine the outcome of conization versus hysterectomy, and to compare the results achieved by different methods of conization. METHODS: We performed a retrospective pathology and chart review of 46 patients with cervical adenocarcinoma in situ from January 1980 to October 1994. RESULTS: Nine patients were managed during the first half of the study period and 37 were managed in the second half. The mean age of patients was 38.4 years (range 25-72). Forty-five of 46 patients were diagnosed as a result of an abnormal Pap smear, although only 19 smears indicated adenocarcinoma in situ or other glandular abnormalities. Cold knife conization resulted in a 33% rate of positive margins for adenocarcinoma in situ compared to 50% for large loop excision of the transformation zone (LLETZ). Among 24 conservatively managed patients with negative conization margins, there have been 2 (8.3%) recurrences of adenocarcinoma in situ. Among patients not undergoing hysterectomy as definitive treatment, 1 of 18 (6%) patients undergoing cold knife conization recurred, compared to 4 of 14 (29%) managed with LLETZ, despite a 63.4-month shorter mean follow-up interval for the LLETZ patients. CONCLUSIONS: Cold knife conization is associated with a lower rate of recurrence of cervical adenocarcinoma in situ compared to LLETZ. We recommend cold knife conization for patients who are not treated with hysterectomy.

Adenocarcinoma↗
PubMed1996

The diagnostic significance of IgG cow's milk protein antibodies re-evaluated.

UNLABELLED: The effect of different feeding regimens, notably the use of hydrolysed cow's milk formulas, on the development of allergic reactions and the development of cow's milk protein-IgG antibodies is still disputed. We prospectively compared the development of allergic manifestations and cow's milk protein-IgG antibodies in a total of 702 infants who were divided into six groups: 1. exclusively breast milk for at least 4 weeks (n = 206). 2. Breast milk plus initial partially hydrolysed formula (n = 104). 3. Breast milk plus extensively hydrolysed formula (n = 50). 4. Breast milk plus initial conventional cow's milk formula (n = 73). 5. Conventional cow's milk with or without breast milk throughout (n = 187). 6. Extensively hydrolysed cow's milk formula for 2 months, followed by conventional cow's milk (n = 82). Cow's milk protein antibodies were determined by an indirect immunofluorescent test. Antibody titres rose slowly in groups 1, 3 and 6. Children in group 5 showed two high peaks. There were no significant differences in the frequency and type of allergic manifestations between the groups. Introduction of cow's milk formula during the first trimenon resulted in elevated antibody titres in all breast fed infants compared with introduction at a later date. CONCLUSION: In contrast to a previous study from the same laboratory, there is no diagnostic significance of cow's milk protein-IgG antibodies for allergic manifestations. The occurrence of these antibodies is a physiological phenomenon: the shorter the breast feeding period and the earlier cow's milk formula is introduced, the higher the antibody levels.

Age Factors↗
PubMed1996

Long-term persistence of hepatitis B virus DNA in the serum of children with chronic hepatitis B after hepatitis B e antigen to antibody seroconversion.

To evaluate the prevalence and duration of viremia in relation to the features of liver disease, we investigated hepatitis B virus (HBV) DNA by the polymerase chain reaction in the serum of 39 children with chronic hepatitis B, after hepatitis B e antigen to antibody seroconversion. During a mean observation period of 8.2 +/- 3.8 years after seroconversion, all patients were asymptomatic; 36 had persistently normal alanine aminotransferase levels, and three had occasional mild alterations. Liver histology, checked in 21 patients, showed persistent hepatitis in nine, fibrosis in 10, and cirrhosis in two cases. HBV DNA was always undetectable by dot blot hybridization. Five children eventually cleared hepatitis B surface antigen, including one with cirrhosis who developed liver cancer at 19 years. HBV DNA was detected by polymerase chain reaction in 87% of children within 5 years of follow-up, in 58% of cases 6-10 years after seroconversion (p < 0.001), and in 50% of patients investigated later. Long-term viremia was found in two patients (40%) who cleared HBsAg, including the one who developed liver cancer. The chances of clearing viremia during follow-up were higher in children with acute hepatitis at the onset of illness (86%) than in those with asymptomatic onset (37%; p < 0.05). Our results show that low levels of HBV viremia, probably reflecting low levels of virus replication, persist for several years in children with chronic hepatitis B after hepatitis B e antigen to antibody seroconversion and remission of liver disease, even after the clearance of hepatitis B surface antigen. Persistent replication could support mild biochemical alterations and inflammatory liver lesions. It could allow late reactivation of liver disease and may play a role in the development of carcinoma.

Alanine Transaminase↗
PubMed1996

Cyclic adenosine monophosphate (cAMP) differentially regulates IL-4 in thymocyte subsets.

It was recently reported that cAMP upregulated IL-4 in T cell lines generated in vitro and expressing an unrestricted lymphokine pattern. In order to study the effect of cAMP on IL-4 released by freshly isolated T cell populations, we tested various T cell subsets that have previously been reported to synthesize this lymphokine. We found that cAMP upregulated IL-4 release from in vivo activated single CD4+ peripheral T cells and CD4+CD8-HSAlowNK1.1- thymocytes stimulated with ionomycin and phorbol ester. Furthermore, as in conventional single CD4+ or CD8+ thymocytes, cAMP enhanced IL-4 production in CD4+CD8-NK1.1+ thymocytes. This latter subset has recently been shown to belong to a independent T cell lineage that is positively selected by MHC class I molecules, recognizes CD1 and expresses a restricted T cell receptor repertoire. In contrast, cAMP appeared not to upregulate IL-4 in a third independent T cell lineage. This was suggested by the observation that cAMP did not increase IL-4 in CD3+CD4-CD8- thymocytes, which are thought not to give rise to conventional single CD4+ or CD8+ T cells. It therefore appears that cAMP is coupled differently to IL-4, depending on the T cell lineage. In contrast, in all IL-4 producing stages of conventional T cells, IL-4 is consistently upregulated by cAMP.

Animals↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

Selection of a precore mutant after vertical transmission of different hepatitis B virus variants is correlated with fulminant hepatitis in infants.

The incidence of perinatal transmission of hepatitis B virus (HBV) depends on the HBeAg/anti-HBe status of the mother. While children of HBeAg-positive mothers have a 90% probability of acquiring a chronic hepatitis B virus carrier state, babies of anti-HBe-positive mothers are more likely to develop fulminant hepatitis within the first 3 to 4 months of life. There is evidence that precore (pre-C) mutations of the HBV can be associated with fulminant hepatitis. The pre-C region was therefore examined in sera from nine infants with fulminant hepatitis after vertical transmission, one HBeAg-positive and seven anti-HBe-positive mothers by polymerase chain reaction (PCR) and direct sequence analysis. In five mother/infant pairs the virus populations were characterized in addition by analysing clones of the amplified products. All mothers were infected with two or four variants of HBV with mutations at different positions of the preC genome including position 1896, which results in a stop codon. While the precore stop codon was detected in a portion of the virus populations of the HBeAg-positive and of four anti-HBe-positive mothers the dominating viral strain was represented by the wild type virus in three. In contrast, the virus populations of all babies showed the 1896 precore variant as the prevalent virus strain during the phase of active disease. In the surviving baby only wild type sequences were detected after recovery. Subtype ayw was found in all mothers and infants and adw2 was present in three mothers and in the surviving child. The findings suggest that all mothers carried a wild type HBV population with a certain number of different HBV variants. After transmission of the mixed virus population a selection process was started in the baby. The association of subtype ayw with the precore mutations and with the fatal outcome of the hepatitis B might be the result of a directed selection of this variant with a particular advantage in the viral life cycle.

Adolescent↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

[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↗
PubMed1995

[Self-assessment of prescribing behavior of psychotropic drugs for children and adolescence. Results of a survey of established physicians].

All registered general practitioners, pediatricians, and neuropsychiatrists of lower franconia were asked to fill out a questionnaire regarding the ratio of 0-20 year old patients with psychiatric symptoms and their prescribing methods of psychopharmaca. Neuropsychiatrists treated less children and adolescents with psychiatric symptoms than pediatricians or general practitioners. Approximately 50% of the patients with psychiatric symptoms received psychopharmaca. The most frequently prescribed psychopharmaca were neuroleptics and antidepressants, followed by phytopharmaca with various ingredients, which were most frequently prescribed by general practitioners. The average duration of a psychopharmacotherapy was 9 weeks. A great deal of uncertainty regarding the prescription of psychopharmaca to children and adolescents has become evident. Despite the fact that an enuresis can not be diagnosed before the end of the 5th year, it was one of the most frequently treated symptom of the 2-5 year old children. On the other hand, approximately one third of all physicians principally do not treat children and adolescents with psychopharmaca.

Adolescent↗
PubMed1994

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↗
PubMed1994

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↗
PubMed1994

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↗
PubMed1993

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↗