T cell reactivity in neonates from an East and a West German city--results of the LISA study

BACKGROUND: Within an ongoing birth cohort study (LISA) the cytokine production of cord blood T cells was compared between neonates from Leipzig (East Germany) and Munich (West Germany). The aim of this study was to analyse regional differences and influencing factors of the immune status. METHODS: Cytokine production was measured in a randomly selected subgroup of 158 children from the LISA (Life style - Immune system - Allergy) cohort by intracellular cytokine staining. Information on family "atopy" history (FAH) and home characteristics was obtained from questionnaires. RESULTS: Reduced numbers of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) producing T cells were found in association with biparental FAH and housing renovation during pregnancy. In addition, cytokine production was influenced by season. In Munich, the frequency of biparental FAH and of renovation measures during pregnancy was significantly higher as compared to Leipzig. Neonates from Munich showed significantly decreased amounts of IFN-gamma and TNF-alpha and elevated levels of interleukin-4 (IL-4) producing T cells. Differences in cytokine production between Munich and Leipzig were influenced by season (IL-4) and housing renovation (IFN-gamma, TNF-alpha). CONCLUSIONS: Since differences in the T cell cytokine production of neonates in Munich and Leipzig are independent from FAH our findings may provide evidence for the impact of environmental factors upon the fetal immune system.     

Age-related changes in peripheral nerves

Semi-thin sections of the sural nerve from 200 autopsy specimens taken from individuals of both sexes, ages 10 to 91 were morphologically examined. Thickness of the endoneurial capillary walls, and of the perineurium, number of endoneurial capillaries, myelinated fiber density and distribution of myelinated fibers were determined. An additional ultrastructural examination of selected nerves with characteristic values was performed. The analysis revealed a statistically significant age dependence for the investigated features. Increasing age was associated with decreased myelinated fiber density and decreased number of endoneurial capillaries. There was an age dependent increase in the thickness of capillary walls and the perineurium as well as increasing loss of large myelinated fibers. The findings were discussed and compared with similar results from the literature. Age related changes in peripheral nerves have to be interpreted as the result of the cumulative, life-long effect of various pathogenic factors, modified by genetic determinants and by a gradual decrease in regenerative capacity.     

Test-ordering by multiple physicians increases unnecessary laboratory examinations

In modern teaching hospitals, patients typically receive direct care from a succession of different physicians, each of whom may order diagnostic tests on the same patient. We examined the association of test-ordering by multiple physicians with unnecessary duplication of 20-test chemistry profiles in 198 consecutively admitted patients. In a multivariate regression model, the number of duplicate chemistry profiles ordered for a patient was significantly correlated with the number of physicians ordering profiles after controlling for the overall intensity of profile testing. In a case-control analysis comparing duplicate with nonduplicate profiles, redundant tests were significantly more likely to have been ordered by a new physician who had not ordered a patient's previous profile than by the same physician who had ordered the previous chemistry panel. We conclude that test ordering by multiple physicians, the prevalent pattern in almost all teaching hospitals, predisposes to unnecessary laboratory examinations.     

Importance of immunohistochemistry for neuro-oncology. IV. Distribution model of beta human chorionic gonadotropins in intracranial germ cell tumors

beta-Human choriogonadotropic hormone (beta-HCG) is considered a good marker for trophoblastic differentiation of germ cell tumors. 34 primary intracranial germ cell tumors (15 germinomas, 6 mature teratomas, 1 embryonal carcinoma, 2 endodermal sinus tumors and 10 mixed germ cell tumors) were immunohistochemically evaluated for the presence of beta-HCG positive cells. In 8 of 15 germinomas and 6 of 10 mixed germ cell tumors beta-HCG cells were demonstrable. In the germinomas such cells included both syncytiotrophoblastic and mononuclear cells which histologically did not correspond to the cytotrophoblast. In one case the patient had exhibited a precocious puberty. Of the 6 beta-HCG positive mixed germ cell tumors, two contained elements of choriocarcinoma. In the cytotrophoblasts of the choriocarcinoma regions, beta-HCG was only sparsely demonstrable. Both of these patients had manifest precocious puberty clinically. The advantage of immunohistochemical demonstration of the beta-HCG compared to conventional histology is in the definite identification of trophoblastic differentiation, in particular the exact recognition of the choriocarcinoma segments, which can be critical for the prognosis. Demonstration of isolated syncytiotrophoblasts and beta-HCG positive mononuclear cells in the seminomas is of no prognostic significance and is primarily of theoretical interest.     

Verhandlungen ärztlicher Gesellschaften

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Identical mutations in the CSB gene associated with either Cockayne syndrome or the DeSanctis-cacchione variant of xeroderma pigmentosum

Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are two hereditary disorders in which photosensitivity is associated with distinct clinical and cellular phenotypes and results from genetically different defects. We have identified the primary molecular alteration in two patients in whom clinical manifestations strongly reminiscent of a severe form of XP were unexpectedly associated with the CS cellular phenotype and with a defect in the CSB gene. Sequencing of the CSB -coding region in both cDNA and genomic DNA showed that these patients had identical alterations to those in a patient with the clinical features of the classical form of CS. These data, together with fluorescence in situ hybridization analysis, demonstrated that the two siblings with XP as well as the CS patient were homozygous for the same CSB mutated allele, containing a silent C2830T change and a nonsense mutation C2282T converting Arg735 to a stop codon. The finding that the same inactivating mutation underlies different pathological phenotypes indicates that there is no simple correlation between the molecular defect and the clinical features. Therefore, alterations in the CSB gene give rise to the same repair defect at the cellular level but other genetic and/or environmental factors determine the pathological phenotype.     

In vitro study on the impact of fish sera on the survival and fine structure of the eel-pathogenic acanthocephalanParatenuisentis ambiguus

The effects of fish sera on the growth and fine structure of infective larvae of the eel-pathogenic acanthocephalanParatenuisentis ambiguus (Eoacanthocephala: Tenuisentidae) were studied under in vitro conditions using sera from the final hostAnguilla anguilla and from two accidental fish hosts as well as fetal calf serum. As controls larvae were also kept in medium in the absence of serum and in experimentally infected eels. Sera from the accidental fish hosts carp and rainbow trout exerted toxic effects on the acanthocephalans. Worms maintained in medium containing sera from these two fish were contracted and displayed inverted probosces. Moreover, the tegument exhibited vacuolization and the formation of necrotic areas, including lysis of the mitochondria. Due to these effects, the parasites died at 21 (rainbow trout) or 21–50 days (carp) postincubation. Eel sera had no toxic effect on the infective larvae. The growth of the larvae in medium depended on the composition of the latter, but was reduced as compared with that in the natural final host. Based on these results, we conclude that components of the hosts' blood sera play a role in the determination of the host specificity ofP. ambiguus.     

Charcot-Marie-Tooth neuropathy type 2 and P0 point mutations: two novel amino acid substitutions (Asp61Gly; Tyr119Cys) and a possible "hotspot" on Thr124Met

Mutations in the gene for the major protein component of peripheral nerve myelin, myelin protein zero (MPZ, P0), cause hereditary disorders of Schwann cell myelin such as Charcot-Marie-Tooth neuropathy type 1B (CMT1B), Dejerine-Sottas syndrome (DSS), and congenital hypomyelinating neuropathy (CHN). More recently, P0 mutations were identified in the axonal type of CMT neuropathy, CMT2, which is different from the demyelinating variants with respect to electroneurography and nerve pathology. We screened 49 patients with a clinical and histopathological diagnosis of CMT2 for mutations in the P0 gene. Three heterozygous single nucleotide changes were detected: two novel missense mutations, Asp61Gly and Tyr119Cys, and the known Thr124Met substitution, that has already been reported in several CMT patients from different European countries. Haplotype analysis for the P0 locus proved that our patients with the 124Met allele were not related to a cohort of patients with the same mutation, all of Belgian descent and all found to share a common ancestor. Our data suggest that P0 mutations account for a detectable proportion of CMT2 cases with virtually every patient harbouring a different mutation but recurrence of the Thr124Met amino acid substitution. The high frequency of this peculiar genotype in the European CMT population is presumably not only due to a founder effect but Thr124Met might constitute a mutation hotspot in the P0 gene as well.     

Biofeedback as a supportive method in weaning long-term ventilated critically ill patients

Weaning a patient from mechanical ventilation is occasionally a difficult process complicated by the patient's emotional state. Anxiety, agitation, depression and other emotional disturbances can start a vicious circle between fear of losing breath and dyspnea that impairs the process of withdrawing ventilatory support. A biocybernetic loop model is suggested that integrates psychological variables (e.g., capacity of self-control, self-confidence, sense of self-efficacy) as important factors for a successful weaning. The paradigm of biofeedback is regarded as a suited approach to strengthen these psychological factors. It means the externalization of physiological functions especially of those from the autonomous nervous system so that a patient becomes aware of them. In the case of the ventilated patient, it is assumed that the transformation of the respiratory activities into perceptible (acoustic and visual) signals supports the patient's self-controlling behaviour during the weaning process. He gets positive reinforcement for his efforts to influence his breathing intentionally and, by continuous and immediate information, he regains self-confidence to control his somatic functions effectively. The application of biofeedback is mainly described in single case studies. They all report a decrease in the respiratory rate and an increase in the tidal volume. The need for a controlled study is suggested that would answer the question of whether biofeedback is an appropriate psychological tool to facilitate the weaning process in mechanically ventilated patients.     

Time-dependent study of the antibody response to sperm-whale myoglobin: recognition of the antigenic sites is unaltered over an extended period of immunization

We have recently shown that the antigenic structure of sperm-whale myoglobin is not dependent on the host species in which the antisera are raised. The purpose of the present work was to determine whether or not the molecular immune recognition of a protein by antibody is subject to a time-dependency. We have investigated the recognition of the antigenic sites by serial antisera obtained in two rabbits at different times after the initial immunization, from the earliest bleeding with detectable antibodies (9 days) up to a year. The specificity of these antisera was determined by their cross-reactions with 13 myoglobins from different species. The reactivity was measured by quantitative immunoadsorbent titration studies from the amount of radioiodinated antibodies that could be bound maximally (i.e. plateau binding values) by immunoadsorbents of each myoglobin. From these studies and our recent structural analysis, which enabled us to identify for each of these myoglobins the regions retaining reactivity with antibodies to sperm-whale myoglobin, we have concluded that following maturation of the immune response the antigenic recognition of a protein (i.e. the regions that are recognized as antigenic) is not dependent upon the time antisera are obtained after the first immunization. In the early periods of the response, fluctuations are observed in the relative immunodominance of the sites. This further confirms our earlier conclusions that the antigenic sites on a protein are structurally inherent in the protein.