Molecular Interaction of Droperidol with Human Ether-a-go-go-related Gene Channels: Prolongation of Action Potential Duration without Inducing Early Afterdepolarization

Background: The cardiac safety of droperidol given at antiemetic doses is a matter of debate. Although droperidol potently inhibits human ether-a-go-go-related gene (HERG) channels, the molecular mode of this interaction is unknown. The role of amino acid residues typically mediating high-affinity block of HERG channels is unclear. It is furthermore unresolved whether droperidol at antiemetic concentrations induces action potential prolongation and arrhythmogenic early afterdepolarizations in cardiac myocytes.

Methods: Molecular mechanisms of HERG current inhibition by droperidol were established using two-electrode voltage clamp recordings of Xenopus laevis oocytes expressing wild-type and mutant channels. The mutants T623A, S624A, V625A, Y652A, and F656A were generated by site-directed mutagenesis. The effect of droperidol on action potentials was investigated in cardiac myocytes isolated from guinea pig hearts using the patch clamp technique.

Results: Droperidol inhibited currents through HERG wild-type channels with a concentration of half-maximal inhibition of 0.6-0.9 [mu]m. Droperidol shifted the channel activation and the steady state inactivation toward negative potentials while channel deactivation was not affected. Current inhibition increased with membrane potential and with increasing duration of current activation. Inhibition of HERG channels was similarly reduced by all mutations. Droperidol at concentrations between 5 and 100 nm prolonged whereas concentrations greater than 300 nm shortened action potentials. Early afterdepolarizations were not observed.     

Epilepsie im Kindesalter: Wann kann die antiepileptische Therapie abgesetzt werden?

Zusammenfassung Der richtige Zeitpunkt für das Absetzen der Antiepileptika (AE) im Kindesalter ist unbekannt. Anl?sslich ihrer Jahrestagung haben die Mitglieder des K?nigsteiner Arbeitskreises (KA) eigene und publizierte Absetzstrategien diskutiert. Da Studien zu diesem Thema rar und widersprüchlich sind, wurde beschlossen, die Diskussionsergebnisse im Sinne einer Meinungs?u?erung zu publizieren. Bei Neugeborenen besteht übereinstimmung, AE innerhalb von 2 bis 12 Wochen nach dem letzten Anfall abzusetzen. Bei BNS-Epilepsie wird Vigabatrin nach 6 bis 12 und Sultiam nach 6 bis 36 Monaten abgesetzt. Nach erfolgreicher Steroidtherapie setzt die Mehrheit des KA die AE-Therapie für zwei Jahre fort. Für die Rolando-Epilepsie sind 1 bis 3 Jahre Anfallsfreiheit ausreichend, auch wenn fokale Spike-Waves persistieren. Im Falle einer symptomatisch fokalen Epilepsie ist die Grunderkrankung mitentscheidend für das Absetzen. Die Behandlung der Absencen-Epilepsie kann nach zwei Jahren beendet werden, w?hrend bei myoklonisch- astatischer Epilepsie meist eine 2- bis 5-j?hrige Anfallsfreiheit vorausgesetzt wird. Konsens besteht darüber, dass die Juvenile- Myoklonus-Epilepsie ein sehr hohes Rückfallrisiko birgt. Dennoch ziehen einzelne neurop?diatrische Mitglieder einen Absetzversuch nach 2- bis 3-j?hriger Anfallsfreiheit in Betracht. Die überwiegende Mehrheit des KA führt aber bei gesicherter Diagnose keinen Absetzversuch durch. Bezüglich der Absetzgeschwindigkeit wird ein langsames (3 bis 12 Monate) Ausschleichen favorisiert. Nur zwei Mitglieder praktizieren ein rascheres Absetzen (<3 Monaten). Das EEG spielt für die Entscheidung eine untergeordnete Rolle und bleibt auf bestimmte Epilepsieformen (z. B. Absencen-Epilepsie) beschr?nkt. Das vorliegende Papier gibt die Meinung des KA wieder und eignet sich nicht im Sinne einer Leitlinie. Für die Entscheidung AE abzusetzen, ist immer eine individuelle Abw?gung von Grunderkrankung, Epilepsieform und psychosozialen Umst?nde erforderlich.      

Coil embolization of major bleeding after femoral fracture: A case report

Successful internal arterial embolization with steel coils in life-threatening bleeding after femoral fracture is described in an older patient.     

Primitive neuroectodermal tumors after prophylactic central nervous system irradiation in children. Association with an activated K-ras gene.

Three patients had supratentorial malignant brain tumors 7 to 9 years after prophylactic central nervous system (CNS) treatment for acute lymphocytic leukemia or malignant T-cell lymphoma. Therapy was administered at the age of 3 to 8 years and included cranial irradiation (total dose, 1800 to 2400 cGy) and intrathecal methotrexate. The brain tumors had histologic and immunohistochemical features of primitive neuroectodermal tumors (PNET), including neuroblastic rosettes, rhythmic arrangement of tumor cells, and immunohistochemical expression of glial, and in one patient neuronal, marker proteins. Using polymerase chain reaction-mediated DNA amplification from paraffin-embedded tissues and subsequent DNA sequence analysis, an activating point mutation was detected in the K-ras protooncogene in one tumor. This mutation was a G to A transition in position 2 of codon 12, substituting aspartate (GAT) for glycine (GGT). This type of mutation has not been observed before in human brain tumors, but it is frequent in radiation-induced murine lymphomas. These observations suggest that PNET can be induced after completion of the embryonal and fetal development of the human CNS. Oncogene-activating point mutations may represent a pathogenetic mechanism involved in the genesis of radiation-induced brain tumors.     

Effects of exposure to an estrous female on forebrain monoaminergic neurotransmission in the non-copulating male rat

Regional changes in the rate of brain monoamine synthesis were monitored in male rats exposed to, but prevented from physical contact with, an estrous or an ovariectomized female. The in vivo rate of tyrosine and tryptophan hydroxylase activities were estimated by measuring the accumulation of DOPA and 5-HTP following inhibition of cerebral aromatic l-amino acid decarboxylase by means of 3-hydroxybenzylhydrazine (NSD-1015) treatment (100 mg/kg i.p.) 5 min upon NSD-1015 treatment, the males were exposed to an intact estrous female or an ovariectomized female for 20 min before decapitation and brain dissections. Exposure to an estrous female produced an increased rate of tyrosine and tryptophan hydroxylase activity in the medial prefrontal cortex, the dorso-lateral neostriatum and in the ventral neostriatum, in comparison with home-cage controls. By the same comparison, exposure to an ovariectomized female resulted in an increased rate of tyrosine hydroxylase activity in the medial prefrontal cortex, byt not in the neostriatal areas, whereas tryptophan hydroxylase activity was unaffected. Finally, exposure to the empty test cage, with no stimulus females present, did not produce any statistically significant changes in the rate of tyrosine or tryptophan hydroxylase activity in any of the brain areas sampled. Taken together with recent findings from this laboratory, the present results demonstrate that the level of sexual motivation brought about by the olfactory, auditory and/or visual stimulation of a receptive female is associated with an increased demand on catecholamine and 5-hydroxytryptamine synthesis in the limbic forebrain of the male rat. The finding that the presence of an unestrous female produced an enhanced demand on tyrosine hydroxylase activity in the medial prefrontal neocortex demonstrates that the sexual incentive provided by the estrous female may not be the only factor responsible for all the effects observed in the present study. In fact, there is a distinct possibility that the intense challenge produced by sexually significant stimuli is but an endpoint, and that the changes found in forebrain monoamine synthesis is a reflection of an environmental challenge not necessarily specifically linked to the sexual behavior.     

Corneal D.C. recordings of slow ocular potential changes such as the ERG c-wave and the light peak in clinical work

A set-up for D.C. recordings of slow ocular potentials such as the c-wave of the electroretinogram (ERG) as well as the fast oscillation (FO), the light peak (LP) and the dark trough (DT) in both clinical and experimental work is described. It includes matched calomel half-cells connected by saline-agar bridges to a corneal contact lens on the eye and a reference chamber on the forehead, a low-drift differential-input D.C. amplifier, an A/D converter, a computer, a thermoprinter, a flexible disc memory, a plotter, and a device for light stimulation controlled by the computer.Examples of the usefulness of the set-up in clinical work are shown in the form of D.C. c-wave ERGs of normal subjects as well as of patients with vitelliform macular degeneration, choriocapillaris atrophy, and retinitis pigmentosa. The direct corneal recording of the FO and LP is demonstrated as well. The different origins of the standing potential (SP) of the eye, the ERG c-wave, the FO and the LP are reviewed briefly.     

Die zweizeitige Unterkieferrekonstruktion mit einer 2,7-mm-Überbrückungsplatte

The two-phase reconstruction of the mandible with a 2.7-mm-Martin-reconstruction-plate creates a tumor free period that is followed by bone grafting to the embedded plate. We have treated 61 patients following this pattern from 2000 to 2005, follow-up was done in 56. 14 patients had received radiotherapy of 70?Gy. 43 plates healed in without any complications. Until 2005 bone grafting had been performed in 18 patients, in ten patients the plate had been removed.