Biomedical subjects
Publications and source records attributed to K Müller.
The extract of the bark of Mahonia aquifolium is an inhibitor of keratinocyte growth with an IC50 of 35 microM. Of its main alkaloids tested, berberine inhibited cell growth to the same extent as did the Mahonia extract, while the benzylisoquinoline alkaloids berbamine and oxyacanthine were more potent inhibitors by a factor of three.
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Antipsoriatic anthrones are probably the most commonly used topical agents in the treatment of psoriasis. There is growing evidence that the biochemical basis for their mechanism of action at the molecular level is related to their redox activity leading to the production of active oxygen species, which include singlet oxygen, superoxide anion radical, and hydroxyl radical. These species are involved in a variety of oxidative effects affecting cellular targets that have been implicated both in the mode of action and the skin-irritating properties of antipsoriatic anthrones: interaction with DNA, inhibition of various enzyme systems associated with cell proliferation and inflammation, such as glucose-6-phosphate dehydrogenase and inflammation, such as glucose-6-phosphate dehydrogenase and 5-lipoxygenase, and destruction of membrane lipids. Furthermore, the application of this information to the design of novel derivatives is discussed. In particular, compounds with diminished oxygen radical-generating properties have been developed, which may permit a separation of antipsoriatic and inflammatory effects. Some of the novel anthrone analogs which produced significantly less amounts of oxygen radicals than dithranol compared favorably in biological tests with this known antipsoriatic drug as an alternative method of treating psoriasis.
The isolated traumatic dislocation of the triquetrum is an extremely rare injury. The clinical signs are unspecific. Roentgenograms of the wrist in posteroanterior and lateral views, possibly complemented by oblique views, will help to provide the diagnosis. The best therapy appears to be the open reduction and fixation with Kirschner wires. With the presented case report, the difficulties in using the classification carpal injuries are discussed. Finally, corresponding to the carpus ring theory, the plausibility of additional injuries to carpal ligaments in such trauma is pointed out.
BACKGROUND: Multiple organ failure (MOF) is becoming the most common cause of death in patients in surgical intensive care units. In this respect, a multicenter study in four different groups of patients in surgical intensive care units was done to evaluate the role of phospholipase A2 (PLA2) in comparison with C-reactive protein (CRP) and polymorphonuclear (PMN) elastase. STUDY DESIGN: A total of 223 patients entered the study: 73 patients with multiple injuries, 46 patients with diffuse peritonitis, 52 patients with sepsis, and 52 patients in a control group who were at a higher risk for postoperative sepsis after defined surgical interventions. The patients underwent a daily monitoring of PLA2, CRP, and PMN elastase for seven days. RESULTS: Phospholipase A2 activity remained within the normal range in patients with multiple injuries and patients in the control group, indicating that this parameter is not influenced by the postaggression metabolism. In contrast, in patients with peritonitis, high PLA2 values were found from the beginning. The efficiency for predicting a lethal MOF was 85 percent for PLA2 (cut-off 80 U/L) in patients if determined at the day of operation. A comparably favorable efficiency (84 percent) was demonstrated for PMN elastase in patients with multiple injuries (cut-off 205 micrograms/L) measured at day one. CONCLUSIONS: These efficiency rates of PLA2 in peritonitis and PMN elastase in multiple injuries were comparable or even better than multifactorial scoring systems used in the study. C-reactive protein did not contribute to an early estimation of the prognosis in all groups analyzed. Therefore, the measurement of PLA2 in patients with diffuse peritonitis and PMN elastase in patients with multiple injuries, as single parameters, is recommended to estimate the individual risk for the occurrence of lethal MOF.
Using continuous multigasmonitoring on the basis of photoacoustic spectralanalysis a mean concentration of ammonia of 8.1 ppm, nitrous oxide of 2.1 ppm and carbon dioxide of 0.12 Vol.-% was measured in a deep litter system for fattening pigs with additives. In slatted floor system with liquid manure storage the average concentration of ammonia (11.9 ppm) was significantly higher at the same period, whereas the concentration of nitrous oxide was appr. 0.2 ppm. Concentration of carbon dioxide in liquid manure system was lower (0.10 Vol.-%) than in deep litter system.
Thrombin, a serine protease, plays a central role in the initiation and propagation of thrombotic events. An extensive search for new thrombin inhibitors was performed, using an unconventional approach. Screening of small basic molecules for binding in the recognition pocket of thrombin led to the discovery of (aminoiminomethyl)piperidine (amidinopiperidine) as a weak, but intrinsically selective, thrombin inhibitor. Elaboration of this molecule provided compounds which inhibit thrombin with Ki's in the range of 20-50 nM and with selectivities of 1000-4000 against trypsin. These inhibitor compounds show a new and unexpected binding mode to thrombin. Modification of the central building block and then of one of the hydrophobic substituents led to the discovery of a new family of thrombin inhibitors which has reverted to the former binding mode to thrombin. This last class of compounds shows inhibitory activities in the picomolar range, low toxicity, and a short plasma half life which favors its use for an intravenous application. From this series of thrombin inhibitors, 19f(Ro 46-6240) was selected for clinical development as an antithrombotic agent for intravenous administration.
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We have investigated the transbilayer movement of phospholipids in the plasma membrane of ram sperm cells using spin- and fluorescence-labeled lipid analogues. After incorporation into the outer leaflet, phosphatidylcholine (PC) and sphingomyelin (SM) moved slowly to the inner cytoplasmic leaflet, whereas phosphatidylserine (PS) and phosphatidylethanolamine (PE) rapidly disappeared from the exoplasmic monolayer. Variation of the initial velocity of the relocation kinetics vs the amount of analogue incorporated into the membrane suggests a saturability of the transbilayer movement of aminophospholipids. ATP depletion or pretreatment with N-ethylmaleimide of ram sperm cells reduced the fast inward motion of PS and PE, indicating a protein-mediated aminophospholipid translocation. The results suggest for the plasma membrane of ram sperm cells the presence of an aminophospholipid translocase and an asymmetric transversal lipid distribution with aminophospholipids preferentially located in the inner leaflet and choline-containing phospholipids in the outer leaflet. The relevance of the transversal segregation of phospholipids for membrane fusion processes occurring during fertilization is discussed.
The results of 178 extraarticular proximal phalangeal fractures in 154 patients treated in our institution during the last 10 years were reviewed and evaluated clinically and radiologically. Prime goal of treatment was stable fixation of all injured structures to enable immediate functional after treatment. Postoperative follow-up was 12 months. Fracture union and range of motion were assessed. The results after monodigital isolated fractures scored best, showing more compromise in PIP than in MP motion. Mobility decreased with involvement of other, neighbouring rays or other structures in the same finger. Among the concomitant lesions, injuries to the flexor or extensor tendons were of major negative influence. However, in the later stage as well a favourable functional outcome resulted if early functional postoperative treatment could be guaranteed.
The phospholipid transmembrane distribution and movement in the plasma membrane of rainbow trout spermatozoa was determined with spin-labelled phospholipid analogues. After initial incorporation in the outer membrane leaflet, only the aminophospholipids, phosphatidylserine (PS) and phosphatidylethanolamine (PE) redistributed towards the inner leaflet. At equilibrium, more than 90% PS and approximately 80-85% PE were located in the cytoplasmic leaflet. The inward motion was significantly faster for PS (t1/2 approximately 5 min) than for PE (t1/2 approximately 60 min). Both the velocity and the extent of this redistribution were dependent on the cellular ATP level, arguing for the involvement of the aminophospholipid translocase. Comparison of the electron paramagnetic resonance spectra recorded from analogues located in either one of the leaflet showed an important difference of microviscosity between the cytoplasmic and the extracellular bilayer leaflets. Assuming that the analogue distribution reflects the asymmetry of the endogenous phospholipids, the higher probe mobility in the inner leaflet could be correlated to a higher degree of unsaturation of the fatty acids present in this hemi-leaflet.
A novel series of 2- and 3-substituted 1,8-dihydroxy-9(10H)-anthracenones were synthesized and tested for their inhibitory activity against 5-lipoxygenase (5-LO) in bovine polymorphonuclear leukocytes and the growth of human keratinocytes. Structure-activity relationships are discussed with respect to the following redox properties of the compounds: reactivity against 2,2-diphenyl-1-picrylhydrazyl, generation of hydroxyl radicals as measured by deoxyribose degradation, and inhibition of lipid peroxidation in model membranes. Inhibition of cell proliferation seemed to be related to these properties, whereas 5-LO inhibition was not. Within a class of structural analogs the activity against 5-LO, which was markedly improved as compared to that of the antipsoriatic drug anthralin, correlated well with the overall lipophilicity. Even though a number of compounds in this series enhanced oxidative damage to nonlipid molecules such as deoxyribose, their antioxidant properties predominate in membrane lipids. Among the prooxidant compounds were also the most potent antiproliferative agents (IC50 values in the 10(-7) M range).
The maturation of the fastest afferent and efferent central and peripheral pathways was analysed using the recording of somatosensory evoked potentials of the median nerve stimulation for afferent conduction and magnetoelectrical stimulation of motor cortex to the thenar muscles for efferent conduction. Both afferent and efferent central pathways showed a prolonged maturational pattern with adult values being reached by the age of 5 to 7 years for the afferent and by the age of around 10 years for the efferent pathway. In contrast, the maturation for peripheral afferent and efferent pathways showed a similar trend with a fairly constant conduction velocity reached around the age of 3 years. There was no evidence for a constancy of central conduction delays in both afferent and efferent pathway which has been supposed as a possible mechanism for a temporal stability in feedback loops involved in motor learning processes during development. It is concluded that the prolonged maturational central conduction time precludes the usage of a fixed temporal timing pattern during development in the human sensory motor system.
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We have investigated the pharmacologic effects of a new bisphosphonate compound, CGP 42'446 [2-(imidazol-1-yl)-1-hydroxyethylidene-1,1-bisphosphonate], on bone metabolism. The compound exhibited potent inhibitory activity on the bone resorption induced by 1,25-dihydroxyvitamin D3 both in vivo in the thyroparathyroidectomized rat (ED50 0.072 microgram/kg SC) and in vitro in mouse calvarial cultures (IC50 0.002 microM). A comparison of the in vivo and in vitro inhibitory potencies of a total of nine bisphosphonates revealed an excellent correlation between the two assays (r = 0.97). CGP 42'446 also potently inhibited calvarial bone resorption induced by parathyroid hormone (1-34), parathyroid hormone-related protein (1-34), and recombinant human interleukin-1 beat. Short-term treatment of growing rats with CGP 42'H446 dose-dependently increased the radiographic density of the tibial proximal metaphysis (ED50 1.7 micrograms/kg SC) as well as increasing the calcium and hydroxyproline content of femoral trabeculae (ED50 values 0.17 and 1.1 micrograms/kg SC, respectively), but there was no detectable effect on cortical bone. On a molar basis in this range of in vivo screening assays, CGP 42'H446 was between 940-fold (thyroparathyroidectomized rat) and 87-fold (rat femoral trabecular calcium content) more potent than pamidronate. It is concluded that CGP 42'446 is a promising new, highly potent bisphosphonate for the suppression of the increased bone resorption associated with various diseases.
Single crystals of three different isoenzymes of (R)-(+) mandelonitrile lyase (hydroxynitrile lyase) from almonds (Prunus amygdalus) have been obtained by hanging drop vapor diffusion using polyethylene glycol 4000 and isopropanol as co-precipitants. The crystals belong to the monoclinic space group P2(1) with unit cell parameters a = 69.9, b = 95.1, c = 95.6 A, and beta = 118.5 degrees. A complete set of diffraction data has been collected to 2.6 A resolution on native crystals of isoenzyme III.
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