Congenital abnormalities in a Vermont County. Detection and medical care.

A retrospective cohort study of congenital abnormalities was undertaken on all the 1813 children born in 1952 to the residents of Chittenden County, Vermont. Multiple screening procedures were utilized and included questionnaires to parents, review of hospital charts, hospital pediatric-consultant records, death certificates, hospital pathological files and agencies for crippled and retarded children. Information was obtained for 1775 of the 1813 children (89 per cent). Two hundred and thirty-eight children with 270 malformations were discovered, and the incidence of malformations was 152.1 per 1000 live births; 42.6 per cent of the defects were discovered in the perinatal period. An additional 16.3 per cent were detected between the ages of one month and one year, and 36.3 per cent were discovered initially after one year of age. An assessment of the level of professional care required for the abnormalities discovered indicated that 33.6 per cent required no care, 42.9 per cent required short-term care, and 23.5 per cent required long-term continuing care. The early discovery of congenital defects in this study was accomplished less frequently than in many prospective studies in which screening was likely to be more comprehensive and less representative of reality. The only method of improving early medical care for children handicapped by congenital defects is by serial observation of families over long periods by trained personnel.     

Overexpression of connexin43 alters the mutant phenotype of midgestational wnt-1 null mice resulting in recovery of the midbrain and cerebellum

The midbrain-hindbrain (MHB) junction plays a key role in the patterning of the embryonic neural tube and the formation of brain structures such as the cerebellum. The mitogen wnt-1 is critical for cerebellar development, as evidenced by the lack of MHB region and cerebellar formation in the wnt-1 null embryo. We have generated wnt-1 null embryos overexpressing the gap junction gene connexin43 by crossing wnt-1 null heterozygotes into the CMV43 mouse line. We have confirmed that these mice show an increase in gap junctional communication by dye coupling analysis. Two-thirds of wnt-1 null CMV43(+) mouse embryos at E18.5 have a cerebellum. In addition, changes in the wnt-1 null phenotype in mouse embryos overexpressing connexin43 are observed as early as E9.5. At this stage, one-quarter of wnt-1 null CMV43(+) embryos display extra or expanded tissue present at the MHB boundary (a wnt-1 null enlarged phenotype). In situ hybridization studies conducted on these embryos have indicated no changes in the expression of embryonic brain positional markers in this region. We conclude from these studies that overexpression of the connexin43 gap junction restores cerebellar formation by compensating for the loss of wnt-1.     

Identification of the Yersinia enterocolitica urease beta subunit as a target antigen for human synovial T lymphocytes in reactive arthritis.

The local T-cell response to bacterial antigens is involved in the pathogenesis of reactive arthritis (ReA). Here, we have identified a 19-kDa antigen of Yersinia enterocolitica O:9 recognized by Yersinia-specific synovial fluid CD4+ T cells in two patients with Yersinia-induced ReA. N-terminal amino acid sequencing of this protein revealed that it was identical to the 19-kDa urease beta subunit of Y. enterocolitica O:9. This protein has previously been shown to be arthritogenic in preimmunized rats after intra-articular injection. Analysis of the T-cell response to this protein showed that it contains several T-cell epitopes, one of which cross-reacts with other enterobacteria not able to induce ReA. This indicates that the arthritogenicity of the 19-kDa antigen is not a property of the 19-kDa protein alone but is dependent on its expression in bacteria able to induce ReA.     

Predominance of Th1-type T cells in synovial fluid of patients with Yersinia-induced reactive arthritis.

The pathogenetic mechanisms underlying the development of reactive arthritis and the functional capacities of synovial T cells specific for Yersinia enterocolitica are still unclear. In this study we have determined the cytokine secretion patterns of 24 CD4+ synovial fluid (SF)-derived T cell clones from 2 patients with Yersinia-induced reactive arthritis, 16 clones specific for different Yersinia antigens and 8 clones as controls. The clones specific for Yersinia antigens predominantly belong to the T helper cell 1 (Th1) subset with production of interferon (IFN)-gamma and interleukin (IL)-2, but no IL-4, whereas SF T cells not reactive with Yersinia antigens produce IL-2, IL-4 and IFN-gamma and thus belonged to the Th0 subset. Moreover, short-term T cell lines established from SF and peripheral blood showed the same pattern. To further analyze the functional relevance of these data we investigated the influence of IFN-gamma and IL-4 on the intracellular killing of Yersinia in a human glioblastoma cell line. Our data show that the Th1 cytokine IFN-gamma promotes intracellular killing of Yersinia, whereas this effect is antagonized by the Th2 cytokine IL-4. Furthermore, the Th2 cytokine IL-10 inhibited the antigen-specific proliferative response and IFN-gamma and IL-2 production by the Th1 cells. These results provide insight into the antibacterial mechanisms at work in reactive arthritis after infection with Yersinia enterocolitica and, for the first time, reveal the cross-regulatory properties of cytokines derived from Th1 and Th2 cells in a human immune response to bacterial antigens.     

Tissue distribution of the T cell activation antigen Ta1. Serological, immunohistochemical and biochemical investigations.

The recently described Ta1 antigen is expressed by activated T cells in vitro and in vivo, as observed in patients with certain immune-mediated diseases, such as multiple sclerosis. In this paper we report on the tissue distribution of the Ta1 antigen. Serological testing of human tumour cell lines and immunohistochemical analysis of human tissue sections revealed a reactivity of the anti-Ta1 antibody with normal and malignant tissues of the upper gastro-intestinal tract, the biliary tract, exocrine pancreas and kidney. SDS-PAGE analysis of immunoprecipitates from 125I-labelled cells, employing the anti-Ta1 antibody, yielded a 113-115 kD band from three serologically Ta1 positive tumour cell lines, from a serologically Ta1 negative human EBV-transformed B lymphoblastoid cell line, from peripheral blood mononuclear cells (PBMC) and, as previously described, a 105 kD band from PHA activated T cells (Fox et al., 1984). After endoglycosidase F treatment similar bands of 85 kD were precipitated from activated T cells and from tumour cell lines. It is therefore likely that very similar glycoproteins, which differ only modestly in the size of carbohydrate chains, bear the Ta1 epitope on Ta1 positive tissues.     

Vom Werden und Wesen des Ärztlichen Berufes

Ohne ZusammenfassungDer Tag eines überlasteten Klinikers ist von zwingenden Pflichten restlos besetzt. Nur in kargen, seinem Beruf mühsam abgerungenen Abendstunden beschäftigte sich ERICH MEYER jahrelang mit dem Problem der vorliegenden Schrift: Vom Werden und Wesen des ärzbtlichen Berufes.Immer wieder unterbrach die gesetzesstarke menschliche Pflicht seines Berufes die ersehnte Sammlung zu seinem geplanten Werk, das er in der Stellungnahme zu den vielartigen Auffassungen der Gegenwart eine Entgegnung nannte. Alle Wege der Klärung wollte er gehen. Oft saß er bis in die Nacht hinein an dieser Arbeit, las eine Fülle historischer und philosophischer Bücher; nur weniges von den gewonnenen Anregungen und Zitaten konnte in diese Schrift aufgenommen werden. Vor allem beabsichtigte er ein stärkeres Gewicht auf die philosophischen Ausführungen zu legen. So hat er in letzter Zeit über das Verhältnis von mechanistisch-kausaler und teleologischer Betrachtungsweise des menschlichen Körpers eindringlich forschend, neue Anschauungen gewonnen. Er betonte als Gegengewicht gegen die aus philosophischer Halbbildung entstandenen Modeanschauungen über das Wesen der Medizin die Notwendigkeit einer philosophischen Durchbildung des Mediziners, durch die er sich ein schärferes Bewußtsein von der Tragweite und der Bedeutung klarer Begriffe erwerben müsse.Ein tragisches Geschick, das sein tatenreiches und tatenbereites Leben zerstörte, ließ ihn auch diese Arbeit nicht beenden. Er hinterließ nur Bruchstücke und Skizzen, die noch nicht zu einem organischen Ganzen durchgearbeitet waren. So blieb diese Schrift nur ein Entwurf, der aber dennoch seinen innerlichen Standpunkt klarstellt, der seine Stimme trägt, die nicht verstummen soll, die lebendig werben soll in dem Sinne des Mottos, das er zu dieser seiner Arbeit wählte:Wer aber durchschaut in das vollkommene Gesetz der Freiheit, und darin beharrt, und ist nicht ein vergeßlicher Hörer, sondern ein Täter, derselbe wird selig sein in seiner Tat. Buch Jacobi 1–2.     

Regulated activity of the IgH intron enhancer (E{micro}) in the T lymphocyte lineage

The activity of the IgH (E_µ) enhancer in the T lymphocytelineage has been investigated using both transgenic mice andtransfection studies. Thymocyte fractionation experiments indicatethat a transgene consisting of the bacterial chloramphenicolacetyl transferase (CAT) gene, linked to Eµ and the SV40early promoter (E_µ–CAT), is expressed only in thymocyteswith a mature medullary phenotype and not in immature cells.Transfection of this same construct into two thymoma cell linesrepresenting different stages of thymocyte development mimicsthe pattern of activity observed in vivo. Further transfectionexperiments suggest that this pattern of expression might beattributed to the differential activity of the E2E3 and octanucleotidemotifs of E_µ during development. In contrast, an Ig transgene(linked to E_µ and an Ig V promoter) is expressed in themajority of thymocytes. We envisage that the different patternsof expression of the two transgenes reflect interactions betweentheir respective promoters and the factors which are bound toE_µ at different stages of thymocyte development. Althoughdiffering in their pattern of expression within the thymus,the two transgenes share the property of extinction in peripheralT lymphocytes. These results indicate that the expression ofE_µ-linked transgenes in the thymus cannot simply be explainedby activation of the enhancer in a lymphoid progenitor cellprior to B/T lineage divergence. Rather, the enhancer (or componentsof it) must be independently activated (and inactivated) duringT lymphocyte development. Furthermore, this activity is consistentwith the developmental timing of Ig D_H–J_H rearrangementsin these cells.     

Relevance of apolipoprotein E polymorphism for coronary artery disease in the Saudi population

BACKGROUND: The apolipoprotein E alleles epsilon2 and epsilon4 have been reported as independent risk factors for coronary artery disease (CAD) and as predictors for the development of atherosclerosis. METHODS AND RESULTS: We determined by polymerase chain reaction the distribution of apolipoprotein E polymorphism in 320 Saudi blood donors (BD), 96 CAD patients, and 40 control subjects who had undergone angiography. Compared to controls, only epsilon4 was elevated in CAD patients. More than 61% (P <.0001) of the patients had angina, and 52.1% (P <.05) were diabetic; both of these factors were strongly associated with the presence of allele epsilon2. The epsilon2 allele was also associated with hypertension, elevated serum triglycerides, and total cholesterol. On the other hand, the allele epsilon4 appeared to be associated with increased risk of CAD and was also associated with hypertension, 3-vessel disease, and restenosis. CONCLUSIONS: Accordingly, epsilon4 may be associated with increased risk of CAD, whereas epsilon2 appears to be a predictor of several risk factors for atherosclerosis.     

Photoelectric recording of mechanical responses of cardiac myocytes

A method to monitor contraction of isolated myocytes by transmicroscopic photometry is illustrated. Two photodiodes are mounted inside an inverse microscope used for visual control of a cell. Illumination of one diode varies in proportion to changes in cell length. The contraction signal is amplified in a comparator circuit. Spatial resolution of the device is in the order of 1 m which corresponds to about 5% of cell shortening in the fully activated state of contraction. The method was tested on isolated myocytes from guinea-pig ventricle. Optical records of contraction in response to action potentials or during voltage clamp compare well with the contractile behaviour of multicellular preparations.     

Norepinephrine transporter (NET) promoter and 5'-UTR polymorphisms: association analysis in panic disorder

Several biochemical and pharmacological studies suggest that the catecholaminergic system involving the norepinephrine transporter (NET) is relevant for the pathogenesis of panic disorder. Three single nucleotide polymorphisms in the promoter or untranslated 5' region of the NET gene were investigated by means of RFLP analysis in a sample of 115 German patients with panic disorder and 115 matched controls. Statistical analysis failed to show association with the overall diagnosis of panic disorder. In the subgroup of patients with panic disorder without agoraphobia, however, two polymorphisms were found to be associated with the disease (G/C (rs2397771): p < 0.05; T/C (rs2242446): p < 0.01). While our data do not support a major function of the NET gene in the development of panic disorder, it may play a role in the subgroup of panic disorder without agoraphobia.