Missense mutation in a von Willebrand factor type A domain of the alpha 3(VI) collagen gene (COL6A3) in a family with Bethlem myopathy

The Bethlem myopathy is a rare autosomal dominant proximal myopathy characterized by early childhood onset and joint contractures. Evidence for linkage and genetic heterogeneity has been established, with the majority of families linked to 21q22.3 and one large family linked to 2q37, implicating the three type VI collagen subunit genes, COL6A1 (chromosome 21), COL6A2 (chromosome 21) and COL6A3 (chromosome 2) as candidate genes. Mutations of the invariant glycine residues in the triple-helical domain-coding region of COL6A1 and COL6A2 have been reported previously in the chromosome 21-linked families. We report here the identification of a G-->A mutation in the N-terminal globular domain-coding region of COL6A3 in a large American pedigree (19 affected, 12 unaffected), leading to the substitution of glycine by glutamic acid in the N2 motif, which is homologous to the type A domains of the von Willebrand factor. This mutation segregated to all affected family members, to no unaffected family members, and was not identified in 338 unrelated Caucasian control chromosomes. Thus mutations in either the triple-helical domain or the globular domain of type VI collagen appear to cause Bethlem myopathy.      

doublecortin is the major gene causing X-linked subcortical laminar heterotopia (SCLH)

Subcortical laminar heterotopia (SCLH), or 'double cortex', is a cortical dysgenesis disorder associated with a defect in neuronal migration. Clinical manifestations are epilepsy and mental retardation. This disorder, which mainly affects females, can be inherited in a single pedigree with lissencephaly, a more severe disease which affects the male individuals. This clinical entity has been described as X- SCLH/LIS syndrome. Recently we have demonstrated that the doublecortin gene, which is localized on the X chromosome, is implicated in this disorder. We have now performed a systematic mutation analysis of doublecortin in 11 unrelated females with SCLH (one familial and 10 sporadic cases) and have identified mutations in 10/11 cases. The sequence differences include nonsense, splice site and missense mutations and these were found throughout the gene. These results provide strong evidence that loss of function of doublecortin is the major cause of SCLH. The absence of phenotype-genotype correlations suggests that X-inactivation patterns of neuronal precursor cells are likely to contribute to the variable clinical severity of this disorder in females.      

Plasma lipids and lipoproteins and essential hypertension

In recent years there have been many studies demonstrating a correlation between increased arterial blood pressure and altered lipid profiles, and there has been an especially positive correlation between high cholesterol levels and blood pressure. There are differences between the various reports that are important. In our study the lipid distribution in 105 hypertensive patients with mild or moderate arterial hypertension according to WHO criteria without clinically or ultrasonographically apparent atherosclerosis was compared to the lipid distribution in 65 age-matched healthy persons. On the epidemiological level a significant, positive association was found between LDL serum levels (P 0.001), Apo B serum levels (P 0.001), serum triglyceride levels (P 0.05) and VLDL serum levels (P 0.01) and arterial hypertension. However, in contrast to recent reports, no significant difference was found between total serum cholesterol levels in normotensives and hypertensives, and there was no difference in HDL serum levels. No evidence could be found for a significant increase in lipoprotein (a) serum levels in hypertensives.Abbreviations LDL low density lipoprotein - VLDL very low density lipoprotein - HDL high density lipoprotein - Apo B 100 apolipoprotein B 100 - Apo A I apolipoprotein A I Correspondence to: H. Vetter     

Neopterin in AIDS,other immunodeficiencies,and bacterial and viral infections

Summary An increase in total urinary neopterin was observed in 12 of 13 patients with acquired immunodeficiency syndrome (AIDS), seven of 13 patients with lymphadenopathy, one of six healthy homosexual males, seven of ten adult patients with staphylococcal pneumonia, 11 of 12 children with viral infections, four of seven children with bacterial infections, and 12 of 13 children with various immune defects. Extremely high values of total urinary neopterin and monapterin were observed in severely ill patients with AIDS and those with familial hemophagocytic lymphohistiocytosis. Neopterin excretion was normal in two AIDS patients with Kaposi's sarcoma, but without opportunistic infections at that time. On reexamination of one of these patients later on, elevated neopterin values were noted. Parallel increases in neopterin and monapterin were found, whereas biopterin was usually normal. The increase in total neopterin was mainly due to 7,8-dihydroneopterin and was accompanied by an increase in 3-hydroxysepiapterin. Increased neopterin in urine is assumed to reflect the increase in GTP pool and GTP cyclohydrolase I activity as observed in stimulated monocytes. Thus, neopterin, as a measure of the activation of the nonspecific cellular immune system, may be used diagnostically to detect allograft rejection after transplantations and to follow-up HTLV-III positive patients.

---

Neopterin bei AIDS, anderen Immundefekten, Bakteriellen und viralen Infektionen

Abbreviations AIDS acquired immunodeficiency syndrome - ARC AIDS related complex - BH₄ tetrahydrobiopterin - GTP guanosine triphosphate Supported by the Swiss National Science Foundation, project 3.266-0.82 and 3.601-0.84     

Smoking as a risk factor for lung cancer and cardiac infarct as mediated by psychosocial variables. A prospective investigation

In 1965-66, a prospective psychosomatic investigation was started with 1,353 relatively old inhabitants of the village of Crvenka, Yugoslavia. The present article reports on the relevance of smoking for the incidence of lung cancer and cardiac infarct. The main results are: (1) The relevance of smoking is reduced, but not eliminated, by introducing psychosocial control variables, suggesting that the latter have direct influences both on smoking and on the diseases. (2) The relevance of smoking interacts very strongly with psychosocial background conditions: it is nearly reduced to zero when the latter are favorable, and is correspondingly high when they are unfavorable. The results are also interpreted in biochemical terms.     

Interchromosomal duplications of the adrenoleukodystrophy locus: a phenomenon of pericentromeric plasticity

A 9.7 kb segment encompassing exons 7-10 of the adrenoleukodystrophy (ALD) locus of the X chromosome has duplicated to specific locations near the pericentromeric regions of human chromosomes 2p11,10p11, 16p11 and 22q11. Comparative sequence analysis reveals 92-96% nucleotide identity, indicating that the autosomal ALD paralogs arose relatively recently during the course of higher primate evolution (5-10 million years ago). Analysis of sequences flanking the duplication region identifies the presence of an unusual GCTTTTTGC repeat which may be a sequence-specific integration site for the process of pericentromeric- directed transposition. The breakpoint sequence and phylogenetic analysis predict a two-step transposition model, in which a duplication from Xq28 to pericentromeric 2p11 occurred once, followed by a rapid distribution of a larger duplicon cassette among the pericentromeric regions. In addition to facilitating more effective mutation detection among ALD patients, these findings provide further insight into the molecular basis underlying a pericentromeric-directed mechanism for non- homologous interchromosomal exchange.      

Human mini-chromosomes in mouse embryonal stem cells

We have introduced human mini-chromosomes of 4 Mb and approximately 15 Mb in size into mouse embryonal stem cells. Although these human mini- chromosomes are stable in hamster and chicken cells, they re-arrange or segregate aberrantly in the embryonal stem cells and are rapidly lost in the absence of selection. However, one of the mini-chromosomes re- arranged, acquired mouse centromeric sequences and was then stably maintained for at least 60 population doublings in culture. This mini- chromosome, which is 4 Mb in size, is a candidate for a mouse germ line chromosome vector.      

Bestimmung der Plasma-Renin-Konzentration mittels Radioimmunoassays für Angiotensin I

Zusammenfassung Ein Radioimmunoassay für Angiotensin I und seine Anwendung für die Messung der Reninkonzentration im Plasma werden beschrieben. Die zur Herstellung von Angiotensinantikörpern und radioaktiv markiertem Angiotensin sowie zur Trennung von gebundenem und freiem Hormon benutzten Verfahren werden mitgeteilt. Die Empfindlichkeit der Methode erlaubt den Nachweis von zwanzig Pikogramm Angiotensin I.Zur Messung der Reninkonzentration wurde substratfreies Plasma mit Schafsubstrat im Überschuß versetzt und in Anwesenheit von Inhibitoren von converting enzyme und Angiotensinasen bei 37°C inkubiert. Das gebildete Angiotensin wurde in 20 µl des proteinfreien Inkubationsgemisches bestimmt. Die initiale Geschwindigkeit der Angiotensinbildung wurde zur Berechnung der Reninkonzentration herangezogen. Als eine Einheit wurde die Reninmenge definiert, die ein Nanogramm Angiotensin I pro Stunde Inkubation bildet.Normalwerte unter kontrollierter natriumreicher und natriumarmer Diät wurden ermittelt.Die Empfindlichkeit der Methode erlaubt die Messung der Reninkonzentration im Plasma von Patienten mit primärem Aldosteronismus.Mit Unterstützung der Deutschen Forschungsgemeinschaft.     

A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophy

Background  

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder with monogenic mutations setting the stage for successful gene therapy treatment. We have completed a study that directly deals with the following key issues that can be directly adapted to a gene therapy clinical trial using rAAV considering the following criteria: 1) A regional vascular delivery approach that will protect the patient from widespread dissemination of virus; 2) an approach to potentially facilitate safe passage of the virus for efficient skeletal muscle transduction; 3) the use of viral doses to accommodate current limitations imposed by vector production methods; 4) and at the same time, achieve a clinically meaningful outcome by transducing multiple muscles in the lower limb to prolong ambulation.     

Attachment representations in 6-year-olds: related longitudinally to the quality of attachment in infancy and mothers' attachment representations

A new method to assess attachment representations in children by applying a story completion procedure in doll play (SCPDP) is presented. Transmission and continuity of attachment were tested in 28 German families by using the Strange Situation procedure (SS) with the mother and her infant, the Adult Attachment Interview (AAI) with the mother when the child is 5 years old, and the attachment representations (SCPDP) of the 6-year-olds. Relying on the twofold distinction (secure/insecure), results revealed a significant continuity of attachment from 1 to 6 years of age, and a correspondence between maternal AAI and child's attachment quality in SS, as well as a correspondence between maternal AAI and the 6-year-olds' attachment representations. Using configural frequency analysis, we found continuity in patterns of security and insecurity when looking across the measures of infant and pre-school attachment and maternal adult attachment. Processes underlying the high match of mothers' and children's attachment representations are discussed.