Time-, voltage-, and state-dependent block by quinidine of a cloned human cardiac potassium channel.

The interaction of quinidine with a cloned human cardiac potassium channel (HK2) expressed in a stable mouse L cell line was studied using the whole-cell tight-seal voltage-clamp technique. Quinidine (20 microM) did not affect the initial sigmoidal activation time course of the current. However, it reduced the peak current and induced a subsequent decline, with a time constant of 8.2 +/- 0.8 msec, to 28 +/- 6% of control (at +60 mV). The concentration dependence of HK2 block at +60 mV yielded an apparent KD of 6 microM and a Hill coefficient of 0.9. The degree of block was voltage dependent. Block increased from 0.60 +/- 0.09 at 0 mV to 0.72 +/- 0.06 at +60 mV with 20 microM quinidine and from 0.39 +/- 0.20 to 0.48 +/- 0.16 with 6 microM. Paired analysis in seven experiments with 20 microM quinidine indicated that the voltage-dependent increase in block was significant (difference, 12 +/- 4%; p less than 0.001). This voltage dependence was described by an equivalent electrical distance delta of 0.19 +/- 0.02, which suggested that at the binding site quinidine experienced 19% of the applied transmembrane electrical field, referenced to the inner surface. Quinidine reduced the tail current amplitude and slowed the time course relative to control, resulting in a "crossover" phenomenon. These data indicate that 1) the charged form of quinidine blocks the HK2 channel after it opens, 2) binding occurs within the transmembrane electrical field (probably in or near the ion permeation pathway), and 3) unbinding is required before the channel can close.     

Arzneimitteltherapiesicherheit im Krankenhaus

Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Arzneimittelbezogene Probleme (ABP) sind eine signifikante und häufig vermeidbare Ursache für Morbidität und...     

A simple signaling rule for variable life‐adjusted display derived from an equivalent risk‐adjusted CUSUM chart

The variable life‐adjusted display (VLAD) is the first risk‐adjusted graphical procedure proposed in the literature for monitoring the performance of a surgeon. It displays the cumulative sum of expected minus observed deaths. It has since become highly popular because the statistic plotted is easy to understand. But it is also easy to misinterpret a surgeon's performance by utilizing the VLAD, potentially leading to grave consequences. The problem of misinterpretation is essentially caused by the variance of the VLAD's statistic that increases with sample size. In order for the VLAD to be truly useful, a simple signaling rule is desperately needed. Various forms of signaling rules have been developed, but they are usually quite complicated. Without signaling rules, making inferences using the VLAD alone is difficult if not misleading. In this paper, we establish an equivalence between a VLAD with V‐mask and a risk‐adjusted cumulative sum (RA‐CUSUM) chart based on the difference between the estimated probability of death and surgical outcome. Average run length analysis based on simulation shows that this particular RA‐CUSUM chart has similar performance as compared to the established RA‐CUSUM chart based on the log‐likelihood ratio statistic obtained by testing the odds ratio of death. We provide a simple design procedure for determining the V‐mask parameters based on a resampling approach. Resampling from a real data set ensures that these parameters can be estimated appropriately. Finally, we illustrate the monitoring of a real surgeon's performance using VLAD with V‐mask.     

Neue Versuche zur Züchtung der im Pansen von Wiederkäuern lebenden Ophryoscoleciden (Ciliata)

Ohne ZusammenfassungIch schließe diese Arbeit mit tiefem Dankgefühl gegen Herrn Professor Dr.Schulze, Direktor des Zoologischen Institutes der Universität Rostock, und gegen Herrn Professor Dr.Winterstein, jetzigen Direktor des Physiologischen Universitäts-Institutes Breslau. - Ich danke Herrn Professor Dr.Schulze für die Überlassung des Themas, für die in reichem Maße erwiesenen Anregungen und für die Förderung der Arbeit, Herrn Professor Dr.Winterstein f ür die Erlaubnis zur Vornahme der p_H-Messungen mittels der Gaskettenmethode im hiesigen Physiologischen Institut der Universität. Die Arbeit wurde im Landestierseuchenamt Rostock angefertigt.     

Different testosterone metabolism by immortalized embryonic and postnatal hippocampal neurons from C57BL/6 mice: a crucial role for androstenedione

Steroid hormones influence the development of undifferentiated brain during ontogenesis. In the present study we investigated the metabolic pathway of testosterone in immortalized embryonic and postnatal hippocampal neurons from C57BL/6 mice. Both cell lines are capable of metabolizing testosterone to 6alpha-hydroxytestosterone, 6beta-hydroxytestosterone and androstenedione. The formation was found to correlate with protein concentration and time of incubation. These linearities were significant for all metabolites except androstenedione that was the main metabolite in embryonic hippocampal neurons and nearly absent in postnatal neurons. Moreover, only embryonic cells react to testosterone with a decrease of beta-tubulin expression, that was a typical effect indicating induced neuronal maturation. Application of androstenedione caused the same decrease of beta-tubulin expression as testosterone did before. Our results of hippocampal testosterone metabolism in vitro confirm that not only estradiol and 5alpha-dihydrotestosterone could impact neural tissue but also androstenedione is a powerful metabolite involved in prenatal neuronal differentiation.