Regulation of the p21Ras-MAP kinase pathway by factor VIIa.

BACKGROUND: In recent years it has become clear that factor (F)VIIa is not a passive mediator involved in the linear transduction of the coagulation cascade, but actively engages target cells to induce signal transduction and that this signal transduction fulfills critical functions in angiogenesis, arteriosclerosis and inflammatory processes. OBJECTIVES: The details of coagulation factor-dependent signal transduction are among the least understood in biology and thus we set out to establish the molecular events responsible for MAP kinase activation induced by the interaction of FVIIa with its cellular binding partner tissue factor (TF). METHODS: Two different TF-expressing cell types, BHKTF and HaCaT cells, were assayed for p21Ras activation using a pull-down assay that is specific for activated Ras. This activation was visualized by means of Western blotting. In addition, the upstream pathways leading to FVIIa-induced Ras activation were characterized using phosphospecific antibodies and specific inhibitors. RESULTS: We observed that in both BHKTF and HaCaT cells FVIIa-induced MAP kinase activation correlates with p21Ras activation, and that this p21Ras activation is essential for FVIIa-induced MAP kinase activation. In BHKTF cells, early p21Ras activation was mediated by the activation of protein kinase C (PKC), whereas late p21Ras activation employed alternative mechanisms. In HaCaT cells, stimulation of the Src kinase family mediated FVIIa-dependent p21Ras activation. Finally, in both cell types, Raf activity was mandatory for MAP kinase activation. CONCLUSIONS: p21Ras activation is instrumental in FVIIa signal transduction and the FVIIa-dependent activation of p21Ras involves either PKC or Src-dependent mechanisms, depending on the cell type investigated.

Mutations in SCO2 are associated with a distinct form of hypertrophic cardiomyopathy and cytochrome c oxidase deficiency.

Mutations in SCO2, a cytochrome c oxidase (COX) assembly gene located on chromosome 22, have recently been reported in patients with fatal infantile cardio-encephalomyopathy and severe COX deficiency in heart and skeletal muscle. The Sco2 protein is thought to function as a copper chaperone. To investigate the extent to which mutations in SCO2 are responsible for this phenotype, a complete sequence analysis of the gene was performed on ten patients in nine families. Mutations in SCO2 were found in three patients in two unrelated families. We detected two missense mutations, one of which (G1541A) results in an E140K substitution adjacent to the highly conserved CxxxC metal-binding site. The other (C1634T) results in an R171W substitution more distant from the copper-binding site. A nonsense codon was found on one allele in two siblings presenting with a rapidly progressive fatal cardio-encephalomyopathy. Interestingly, all patients so far reported are compound heterozygotes for the G1541A mutation, suggesting that this is either an ancient allele or a mutational hotspot. The COX deficiency in patient fibroblasts (approximately 50%) did not result in a measurable decrease in the steady-state levels of COX complex polypeptide subunits and could be rescued by transferring chromosome 22, but not other chromosomes. These data indicate that mutations in SCO2 cause a fatal infantile mitochondrial disorder characterized by hypertrophic cardiomyopathy and encephalopathy, and point to the presence of one or more other genes, perhaps in the copper delivery pathway, in this clinical phenotype.

["Allergy testing" with "Dr. Voll electroacupuncture"]. / "Allergiestestung" mit der "Elektroakupunktur nach Dr. Voll".

Electroacupuncture according to Dr. Voll (EAV) is one of the numerous unconventional methods propagated for allergy testing in Germany. From an experimental examination for "drug testing" of this method, it can be concluded that EAV is unsuitable for any form of allergy testing.

[Oral nickel provocation and a nickel-free diet. Indications and practical implementation]. / Orale Nickelprovokation und nickelarme Diät. Indikation und praktische Durchführung.

In spite of some unsolved questions, an influence of orally ingested nickel on some forms of chronic eczema is generally accepted. In cases of chronic relapsing dermatitis with typical location, positive nickel patch test and positive oral nickel challenge, a nickel-restricted diet may be recommended for a limited period of time. Regional nutritional habits should be considered in the design of diets. Indications, practice and evaluation criteria for oral nickel challenge and nickel-reduced diets are described.