Interaction between thiol-modifying agents and P1075, a KATP channel opener, in rat isolated aorta

In vascular smooth muscle, openers of ATP-dependent potassium channels (K _ATP channels), such as P1075 (N-cyano-N’-(1,1-dimethylpropyl)-N’’-3-pyridylguanidine), produce relaxation. In this study we have investigated the effects of thiol-modifying agents on the binding of P1075 and on the ⁸⁶Rb⁺ efflux stimulating and vasorelaxant effects of the opener in rat aortic rings. The increase in ⁸⁶Rb⁺ efflux induced by P1075 was taken as a qualitative measure of K⁺ channel opening. The hydrophilic SH-group-oxidizing substance, thimerosal (1 to 100μM), abolished specific binding of [³H]-P1075 with an IC₅₀ value of 7.6±1.2μM; at 30μM, the half time for inhibition was 38min. Two other thiol-oxidizing agents, PMB (4-hydroxy-mercuribenzoic acid) and DTBNP (2,2’-dithio-bis(5-nitropyridine)), inhibited binding up to 86% and 44%, respectively. The disulphide bond reducing substance, DTT (1,4-dithiothreitol, 0.1 to 1mM), reduced [³H]-P1075 binding by up to 20% and partially reversed the inhibitory effect of thimerosal. In ⁸⁶Rb⁺ efflux experiments, thimerosal (3 to 100μM) concentration-dependently increased basal efflux but inhibited P1075-stimulated tracer efflux with an IC₅₀ value of 7±1μM. The inhibitory effect occurred with a half-time of approximately 8min and was essentially reversed by DTT. In rings precontracted with noradrenaline, thimerosal inhibited the vasorelaxant effect in a noncompetitive manner, shifting the concentration-relaxation curves to the right and reducing maximum relaxation.The data show that oxidation of thiol groups interferes with the binding of the K _ATP channel opener, P1075; concomitantly, the ⁸⁶Rb⁺ efflux stimulating and the vasorelaxant effects are inhibited. Reduction of disulphide bonds by DTT has only minor effects on the action of P1075. Collectively, the results suggest that intact thiol groups are essential for the functioning of the K_ATP channel in rat aorta. The different kinetics governing the inhibition of opener binding and of opener-stimulated ⁸⁶Rb⁺ efflux suggest that the SH-groups involved in the two processes differ in their accessibility to thimerosal and/or in their reactivity. Received: 7 April / Accepted: 9 July 1997     

Age, socioeconomic status, and health

Analysts dispute what roles biomedical, psychosocial, and other factors play in determining the duration of morbidity and disability over the life course. Cross-sectional data from two national surveys of adults aged 25 years and over not only show, however, that age and socioeconomic status (SES) are significant predictors of self-reported physical health; they also demonstrate that the relation of age to health varies with SES features. Longitudinal research is needed to test the finding that enduring functional limitations in terms of time are actually compressed in higher SES groups. To improve well-being in our society, moreover, requires specifying why SES differences occur, and perhaps ultimately reducing socioeconomic inequality itself.     

Reaming versus non-reaming in medullary nailing: Interference with cortical circulation of the canine tibia

Summary Medullary nails have only been used with reluctance in the treatment of open fractures since reaming interferes with the cortical circulation. The technique of interlocking offers the interesting possibility of inserting a relatively stiff nail which does not necessarily require reaming. The effects of reaming prior to nail insertion upon the cortical circulation was investigated in the canine tibia. Intravital staining with procion red was used to trace areas of disturbed circulation. Nail insertion without reaming provided clear advantages for the bone's blood supply, while reaming disturbed perfusion in two-thirds of the cortical area and regionally extended through the entire thickness of the cortex. The disturbance without reaming was limited to the inner layer of the cortex and involved only one-third of the cortical cross-section.     

Treatment of defects of the long bones using distraction osteogenesis (Ilizarov) and intramedullary nailing. Theoretic principles, animal experiments, clinical relevance

For large shaft defects of tibia and femur, distraction-compression osteosynthesis (Ilizarov) provides an ideal autologous bone graft. Combination of this with an intramedullary interlocking nail instead of an external fixator could improve patient comfort, because transport with a small external device takes only one-third of the total fixation period. Using 21 adult female sheep we created standardized tibia shaft defects 20 mm (medium size) and 45 mm (large size) in length. The tibiae were stabilized with non-reamed intramedullary interlocking nails. Following corticotomy by chisel, segments were transported using subcutaneous traction wires with a screw as a fulcrum to maintain stationary skin exit points without soft tissue problems. The external traction devices were removed after 12 or 16 weeks. Animals were sacrificed after 12 or 24 weeks with medium-size defects, and after 16 or 32 weeks with large defects. We evaluated the results clinically, by standardized weekly X-rays and, after sacrifice, by quantitative computed tomography (QCT). No animals had to be excluded from the study. Despite primary destruction of the intramedullary circulation all distraction gaps were spanned with bone. X-Rays showed typical signs of good quality of distraction bone regeneration (narrow radiolucent zone in the middle of the regenerate, longitudinal structure), continuous calcification, and cortex formation. QCT cross sections showed completely circular bone regeneration with small and large defects. Bone regeneration was faster on the dorsal side, where more bone was formed than ventrally. Small defects can remain ventrally in the regenerate; these close secondarily.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential Stripping: Determination of the Amount of Topically Applied Substances Penetrated into the Hair Follicles

The determination of penetration pathways of topically applied substances into the skin is the subject of several investigations. Recently, follicular penetration has become a major focus of interest. To date, a direct, non-invasive quantification of the amount of topically applied substance penetrated into the follicles had not been possible. The development of such a method was the aim of this study. Therefore, the advantages of both stripping techniques, tape stripping and cyanoacrylate skin surface biopsy, were combined and evaluated. Tape stripping was used to remove the part of the stratum corneum that contained the topically applied dye. Subsequently, the follicular contents were ripped off by cyanoacrylate skin surface biopsy. The combined method termed "differential stripping" was evaluated in vitro and in vivo , and the amount of topically applied fluorescent dye penetrated into the hair follicles was quantified after different penetration times. After 30 min, 5% of the recovered concentration of sodium fluorescein was found in the follicular infundibula, where it was still detectable after 48 h. Altogether, the results of this investigation revealed that differential stripping is a new method that can be used to study the penetration of topically applied substances into the follicular infundibula non-invasively and selectively.     

Endovaskuläre Brachytherapie als neue Therapieoption zur Prophylaxe der Rezidivstenose nach peripherer Katheterintervention

The therapeutic concept of irradiation of the vessel wall for prevention of restenosis after endovascular procedures is based on increasing knowledge about the pathophysiology of the process leading to restenosis. There is until now only a limited number of studies concerning the use of brachytherapy (BT) in the peripheral circulation, which is in contrast to the already large experience in the coronary circulation. In the peripheral trials the radiation dose was administered by a remote afterloader using a gamma source. According to the available data, vascular BT is a promising technology with the potential to reduce the restenosis rate. The Vienna-2-Trial was the first randomised study to demonstrate the efficacy of endovascular BT for prophylaxis of restenosis after femoropopliteal percutaneous transluminal angioplasty. However, we have to await further supportive data from ongoing clinical trials before definitive recommendations can be given. Currently, endovascular BT seems already justified in patients with recurrent interventions or after long-segment femoropopliteal angioplasty because of the high risk of restenosis in these patients. The next years will demonstrate the ultimate role of endovascular BT in comparison to the rapidly evolving field of drug-eluting stents.     

Decreased stability of triglycerides and increased free glycerol in serum from heparin-treated patients

Triglycerides usually are stable in serum. However, for a few patients, we noted marked decreases in measured triglycerides when the same serum specimen was analyzed on successive days. This was found to be ascribable to intravenous administration of heparin. Measured triglyceride in serum of 11 patients being treated with heparin decreased 34% (SD 17%) in samples stored for one day at room temperature. Triglyceride values for sera from control patients remained unchanged. Increases in free glycerol corresponded to the observed decreased in triglycerides. Measurement of free glycerol thus provides a means of recognizing this problem.     

Neue Entwicklungen in der systemischen Psoriasistherapie

The current standard systemic therapeutic modalities for psoriasis have many potential side effects. Progress made in the understanding of the pathophysiology of psoriasis as a T‐cell‐mediated dermatosis provide options for new more precise therapeutic approaches. These immunological therapeutic strategies involve the inhibition/depletion of activated T‐lymphocytes, the inhibition of antigen presentation and thus the regulation of T‐cell activation, the inhibition of adhesion of inflammatory cells, the inhibition of effects of proinflammatory mediators and the administration of antiinflammatory cytokines. This article summarizes these new systemic therapeutic approaches. Clinical results in the early studies have been mixed. In the next years further results of phase II‐ and phase III‐studies may be expected, which should allow better assessment of the potential of those particular approaches. Some of these approaches could lead to the approval of new drugs to treat psoriasis and to enhance or replace already existing therapeutic options. Furthermore results of therapeutic experiments should contribute to a better understanding of the disease. As we learn which mechanisms are more or less important for the disease, we will be better able to plan intervention strategies.