Missense mutations and evolutionary conserved amino acids at the human hypoxanthine phosphoribosyl-transferase locus.

Molecular characterization of in vivo mutation at the human hypoxanthine phosphoribosyltransferase (hprt) locus has revealed a broad spectrum of mutation, both with regard to germ-line mutation in Lesch-Nyhan and gout patients, and somatic mutation in 6-thioguanine resistant T-lymphocytes from healthy individuals. The pattern of missense mutation shows a non-random distribution with a preferential location to codons for amino acids which are identical in human and the two parasites Schistosoma mansoni and Plasmodium falciparum. Although these 'evolutionary conserved' amino acids account for only 32% of the amino acids in the human hprt protein, they are involved in 76% of the missense mutations at the hprt locus in human T-lymphocytes, 67% in Lesch-Nyhan patients (with severe hprt-deficiency), but only 43% in gout patients (with partial hprt deficiency). This observation supports the notion that evolutionary conserved amino acids constitute functionally important sites in the hprt enzyme, and missense mutations affecting these amino acids will often lead to complete loss of enzyme activity. Substitutions of 'non-conserved' amino acids cause less severe hprt-deficiency (as seen in the gout patients), or may even escape clinical diagnosis. These considerations are important for the understanding of structure-activity relationships in the hprt protein, possible differences between hprt mutational spectra in germ-line and somatic cells, and the mutational spectra induced by specific exogeneous mutagens.     

Children with deficits in attention,motor control and perception (DAMP) almost grown up: The contribution of various background factors to outcome at age 16 years

Fifty-six children with and forty-five children without deficits in attention, motor control and perception (DAMP) had been recruited from the general population at age 7 years. They were followed up neuropsychiatrically at age 16 years after intermediate term follow up at age 10 and 13 years. Cases were subdivided into those with good and not good outcome on the basis of absence or presence of psychiatric and personality disorders, multiple traumatic accidents and speech and language problems at age 16 years. The presence of DAMP in itself was the strongest predictor of poor outcome. High scores for minor neurological dysfunction, low performance IQ, autistic features at age 7 years and poor reading skills at age 10 and/or 13 years were important background factors in cases with poor outcome. In the small subgroup with poor outcome among those without DAMP at age 7 years, major life events was the most important background factor.

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Zusammenfassung 56 Kinder mit und 45 Kinder ohne Störungen der Aufmerksamkeit, der motorischen Kontrolle und der Wahrnehmung (DAMP) waren aus einer Gesamtpopulation 7jÄhriger rekrutiert worden. Sie wurden neuropsychiatrisch im Alter von 16 jahren nachuntersucht, nachdem zwischenzeitliche Untersuchungen im Alter von 10 und 13 Jahren erfolgt waren. Die Probanden wurden in solche mit gutem und nicht gutem Ausgang unterteilt, in AbhÄngigkeit vom Vorliegen psychiatrischer AuffÄlligkeiten, Persönlichkeitsstörungen, multiplen Traumata und Sprech- und Sprachproblemen im Alter von 16 Jahren. Das Vorhandensein von DAMP war der stÄrkste PrÄdiktor für einen schlechten Ausgang. Hohe Werte für leichte neurologische AuffÄlligkeiten, ein niedriger Handlungs-IQ, autistische Züge im Alter von 7 Jahren und schlechte LesefÄhigkeiten im Alter von 10 und/oder 13 Jahren waren wichtige Hintergrundfaktoren bei den Probanden mit einem schlechten Ausgang. In der kleinen Untergruppe mit einem schlechten Ausgang bei den Kindern, die im Alter von 7 Jahren kein DAMP ausgewiesen hatten, bildeten schwerwiegende Lebensereignisse den wichtigsten Hintergrundfaktor.

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Résumé Cinquante-six enfants atteints et quarante-cinq enfants non atteints de déficits de l'attention, du contrÔle moteur et de la perception (DAMP), ont été recrutés en population générale à l'âge de 7 ans. Ils ont été évalués sur la plan neuropsychiatrique à l'âge de 16 ans, après des évaluations intermédiaires à l'âge de 10 et 13 ans. Les cas ont été subdivisés entre bons et mauvais devenir sur la base de la présence ou de l'absence de troubles de la personnalité, l'importance du nombre d'accidents traumatiques, les difficultés d'élocution et de langage à 16 ans. La présence de DAMP était en soi, le facteur prédictif le plus important de mauvais devenir. Des scores élevés à des dysfonctionnements neurologiques mineurs, un QI bas, des traits autistiques à l'âge de 7 ans, et de mauvaises capacités en lecture à l'âge de 10 ou 13 ans ont été des facteurs importants dans les cas de mauvais devenir. Dans le petit sous-groupe à mauvais devenir caractérisé par une absence de DAMP à l'âge de 7 ans, des événements de vie marquants ont semblé Être des antécédents importants.

     

Selecting the proper management strategy

Formulating and implementing corporate strategy to guide the planning and operations of mental health centers is related to some degree to the center's initial scale of operations and its funding context. The results of a longitudinal study of centers in 15 states indicate that these aspects of a center's context favor a specific array of management strategies: the extent to which centers are diversifying their service operations, the percent of change in direct government and nongovernment revenue, and an emphasis on developing interagency ties and on reducing costs represent major strategy options which differentiate mental health centers.The research described was supported by a grant from the National Institute of Mental Health, Division of Biometry and Epidemiology, #5-R01-MH38069-02.     

Three new families with arterial tortuosity syndrome

Arterial tortuosity syndrome (ATS) is a rare condition with autosomal recessive inheritance characterized by connective tissue abnormalities. The most specific clinical findings are cardiovascular anomalies including tortuosity, lengthening, aneurysm, and stenosis formation of major arteries. Also ventricular hypertrophy is frequently present. Other anomalies are skin hyperextensibility and cutis laxa, joint laxity or contractures of the joints, and inguinal herniae. Histology shows disruption of elastic fibers of the media. These features suggest that ATS is a connective tissue disorder. A biochemical or molecular defect has not yet been identified. We describe here nine additional ATS patients from three consanguineous Moroccan families and review a total of 35 patients with this uncommon condition.     

Nonstimulatory peptides contribute to antigen-induced CD8-T cell receptor interaction at the immunological synapse

It is unclear if the interaction between CD8 and the T cell receptor (TCR)-CD3 complex is constitutive or antigen induced. Here, fluorescence resonance energy transfer microscopy between fluorescent chimeras of CD3zeta and CD8beta showed that this interaction was induced by antigen recognition in the immunological synapse. Nonstimulatory endogenous or exogenous peptides presented simultaneously with antigenic peptides increased the CD8-TCR interaction. This finding indicates that the interaction between the intracellular regions of a TCR-CD3 complex recognizing its cognate peptide-major histocompatibility complex (MHC) antigen, and CD8 (plus the kinase Lck), is enhanced by a noncognate CD8-MHC interaction. Thus, the interaction of CD8 with a nonstimulatory peptide-MHC complex helps mediate T cell recognition of antigen, improving the coreceptor function of CD8.     

Studies on the serum proteins of chimeras: III. Detection of donor-type C′5 in allogeneic and congenic post-irradiation chimeras

Allogeneic and congenic post-irradiation chimeras were produced by bone marrow transfer from C′5 active donor mice into C′5 defective recipients. During the first 4 weeks after transfer many of the chimeras contained haemolytic complement activity in their sera. B6AF₁→A chimeras developed higher levels of activity than did B10D2 (new line)→ B10D2 (old line).

Spleen tissue, but not liver tissue, taken from the chimeric animals during this time period incorporated [¹⁴C]amino acid into MuB1 as demonstrated by autoradiography of immunoelectrophoretic patterns, suggesting localization of the active donor cells in the spleen rather than in the liver. Formation of donor-type IgG remained demonstrable for a more extended period after induction of chimerism than formation of MuB1.

A transplantable hepatoma in C57L/J, a C′5 active mouse strain, also incorporated [¹⁴C]amino acid into MuB1.

     

Autosomal dominant inheritance of left ventricular outflow tract obstruction

Most nonsyndromic congenital heart malformations (CHMs) in humans are multifactorial in origin, although an increasing number of monogenic cases have been reported recently. We describe here four new families with presumed autosomal dominant inheritance of left ventricular outflow tract obstruction (LVOTO), consisting of hypoplastic left heart (HLHS) or left ventricle (HLV), aortic valve stenosis (AS) and bicuspid aortic valve (BAV), hypoplastic aortic arch (HAA), and coarctation of the aorta (CoA). LVOTO in these families shows a wide clinical spectrum with some family members having severe anomalies such as hypoplastic left heart, and others only minor anomalies such as mild aortic valve stenosis. This supports the suggestion that all anomalies of the LVOTO spectrum are developmentally related and can be caused by a single gene defect.     

Staffing patterns in rural health services for children and adolescents

This paper reviews several current human resources issues in delivering mental health services to children and adolescents, focusing primarily on the lack of systematic data regarding staff involved in these programs. Data from twenty counties in rural western Pennsylvania are then presented demonstrating the personal, educational, employment, and caseload characteristics of this group of staff, as well as their primary job functions and areas of job satisfaction. Professional staff were likely to have terminal master's degrees and to work primarily in outpatient services, whereas bachelor's-level staff were more likely to perform generalist functions, often without adequate supervision and clinical training. Paraprofessional staff were most numerous in community residential settings and performed a variety of functions. The implications of these findings for services development and staff training are discussed.Special thanks are extended to Jacki Herring, who performed the data analysis. An earlier version of this paper was presented at the annual meeting of the American Psychological Association. August 1983.