Sul meccanismo di azione della streptomicina

Summary A study was undertaken on the variations of the redox potential level produced by streptomycinin vitro andin vivo. We have been able to show that, owing to an oxidative effect, streptomycin produces an increase of the redox potential level. This oxidative effect varies in degree according to the condition of the patient.We also found that in the blood and in the spinal fluid of patients suffering from tubercular meningitis factors are present which inhibit the action of streptomycin.The results of our findings lead to the conclusion that the dose of streptomycin must be varied according to the condition of the patient if the constant level required for an efficient therapy is to be maintained in the blood and in the spinal fluid.     

Kondensationsprodukte von Oxyketonen und Aminoketonen mit 2,4,5-Triamino-6-oxy-pyrimidin

Summary By condensing 2:4:5-triamino-6-hydroxy-pyrimidine with dihydroxyacetone (diacetate), diaminoacetone or acetone-1,3-di (p-formylaminobenzoic acid) not the expected 8- or 9-oxymethyl resp. -aminomethyl-pteridines but 8-or 9-methyl-pteridines were obtained. With p-tolyl-d-isoglucosamine not a tetrahydroxybutyl-pteridine but a trihydroxybutyl-pteridine was formed. For an explanation of these results it is supposed that from the dihydro-pteridines formed at first by intramolecular splitting off of H₂O or R·NH₂ aromatization takes place.     

Tissue-specific and reversible RNA interference in transgenic mice

Genetically engineered mice provide powerful tools for understanding mammalian gene function. These models traditionally rely on gene overexpression from transgenes or targeted, irreversible gene mutation. By adapting the tetracycline (tet)-responsive system previously used for gene overexpression, we have developed a simple transgenic system to reversibly control endogenous gene expression using RNA interference (RNAi) in mice. Transgenic mice harboring a tet-responsive RNA polymerase II promoter driving a microRNA-based short hairpin RNA targeting the tumor suppressor Trp53 reversibly express short hairpin RNA when crossed with existing mouse strains expressing general or tissue-specific 'tet-on' or 'tet-off' transactivators. Reversible Trp53 knockdown can be achieved in several tissues, and restoring Trp53 expression in lymphomas whose development is promoted by Trp53 knockdown leads to tumor regression. By leaving the target gene unaltered, this approach permits tissue-specific, reversible regulation of endogenous gene expression in vivo, with potential broad application in basic biology and drug target validation.     

A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome

Opitz-Kaveggia syndrome (also known as FG syndrome) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation. We report here that the original family for whom the condition is named and five other families have a recurrent mutation (2881C>T, leading to R961W) in MED12 (also called TRAP230 or HOPA), a gene located at Xq13 that functions as a thyroid receptor-associated protein in the Mediator complex.     

Phytanic acid impairs mitochondrial respiration through protonophoric action

Refsum disease is a rare, inherited neurodegenerative disorder characterized by accumulation of the dietary branched-chain fatty acid phytanic acid in plasma and tissues caused by a defect in the alphaoxidation pathway. The accumulation of phytanic acid is believed to be the main pathophysiological cause of the disease. However, the exact mechanism(s) by which phytanic acid exerts its toxicity have not been resolved. In this study, the effect of phytanic acid on mitochondrial respiration was investigated. The results show that in digitonin-permeabilized fibroblasts, phytanic acid decreases ATP synthesis, whereas substrate oxidation per se is not affected. Importantly, studies in intact fibroblasts revealed that phytanic acid decreases both the mitochondrial membrane potential and NAD(P)H autofluorescence. Taken together, the results described here show that unesterified phytanic acid exerts its toxic effect mainly through its protonophoric action, at least in human skin fibroblasts. Received 4 August 2007; received after revision 26 September 2007; accepted 10 October 2007 J. C. Komen, F. Distelmaier: These authors contributed equally to this work.