Stereoselectivity of actions of the calcium sensitizer [+]-EMD 60263 and its enantiomer [-]-EMD 60264

The thiadiazinone derivative [+]-EMD 60263 ((+)-5-(1-(α-ethylimino-3,4-dimethoxybenzyl)-1,2,3,4- tetrahydroquinoline-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4 -thiadiazine-2-on) is a Ca²⁺-sensitizing agent with only minor phosphodiesterase inhibitory activity. Our aim was to characterize the inotropic and electrophysiological effects of [+]-EMD 60263 and its enantiomer [-]-EMD 60264 in several cardiac muscle preparations. The Ca²⁺-sensitizing activity resided in the [+]-enantiomer only. [+]-EMD 60263 (3 μM) shifted the EC₅₀ of Ca²⁺ for contractile activation of skinned fibers of pig heart from 2.41 μM to 0.73 μM, whereas [-]-EMD 60264 (30 μM) was ineffective. In Langendorff-perfused guinea pig hearts, [+]-EMD 60263 and [-]-EMD 60264 induced concentration-dependent positive and negative inotropic effects, respectively; both enantiomers reduced spontaneous heart rate but did not influence perfusion pressure. The maximum increase in force of human atrial trabeculae was 35 % of pre-drug control with [+]-EMD 60263 in comparison to 113 % with forskolin. In guinea-pig papillary muscles, [+]-EMD 60263 and [-]-EMD 60264 had opposite inotropic responses, however, both agents similarly prolonged action potential duration. Both enantiomers concentration-dependently blocked the rapidly activating component I_Kr of the delayed rectifier in guinea-pig myocytes. The block saturated at potentials positive to +30 mV, closely resembling the effects of the antiarrhythmic agent E-4031 which had been originally used to define I_Kr. It is concluded, that the positive inotropic action of [+]-EMD 60263 can be explained by prevalence of the Ca²⁺-sensitizing effect. The accompanying prolongation in action potential duration is caused by block of the I_Kr component of the delayed rectifier. While the inotropic effects are stereoselective, most of the electrophysiological actions are clearly independent of sterical configuration. The combination of Ca²⁺-sensitizing with class-III antiarrhythmic action may provide an interesting pharmacological profile of potential therapeutic use. Received: 7 January 1997 / Accepted: 25 February 1997     

Herzoperationen wegen Herztumoren in Deutschland – Ergebnisse eienr Umfrage für das Jahr 1996

Zusammenfassung Zahlen zur H?ufigkeit von Herztumoren im operativen Krankengut liegen bisher für die Bundesrepublik Deutschland nicht vor. Um einen entsprechenden überblick für das Jahr 1996 zu erhalten, wurde allen 77 herzchirurgischen Zentren der Bundesrepublik Deutschland ein standardisierter Fragebogen zugesandt. Daten von 65 der 77 Herzzentren (=84%) waren schlie?lich verfügbar: 187 Patienten waren wegen Myxomen, lediglich 44 wegen nichtmyxomat?sen Tumoren, davon 28 wegen malignen prim?ren oder sekund?ren Herztumoren, operiert worden. Im Jahr 1996 waren somit 0,32% (231/72 763) der Eingriffe mit Herz-Lungen-Maschine (erfa?t 72 763 von insgesamt 87 372) wegen eines Herztumors vorgenommen worden. Ausgehend von diesen operativen Daten liegt die Inzidenz ausschlie?lich der prim?ren Tumoren des Herzens zumindest bei 3 Tumoren pro 1 Million Einwohner pro Jahr (253 Tumoren/81,814 Millionen Einwohner). Wenn auch kleine Tumoren asymptomatisch und unentdeckt bleiben k?nnen, wird heute doch die Mehrzahl prim?rer kardialer Tumoren durch Echokardiographie, Computer- und Kernspintomographie bereits zu Lebzeiten des Patienten diagnostiziert, und diese Patienten werden in aller Regel einer Operation zugeführt. Somit werden gut 0,3% aller Eingriffe mit Herz-Lungen-Maschine in Deutschland wegen Herztumoren durchgeführt, wobei es sich weit überwiegend um Myxome handelt. Eingegangen: 23. September 1997, Akzeptiert: 11. Februar 1998     

Recurrent dislocation of the patella and the Goldthwait operation

In this study 17 patients with recurrent dislocation of the patella were followed up 10 years after their Goldthwait operation. The subjective and clinical findings were excellent or good in 70%. X-radiographs indicated osteoarthritis of the femoropatellar joint in 60%. Concerning the aetiopathological factors, we found an increased external torsion of the afflicted extremity (measured by computed tomography).     

Tessier type VI-VII cleft combination associated with congenital bimaxillary fusion and anophthalmia.

Congenital intermaxillary fusion is a rare anomaly. Combination of the anomaly with any type of facial cleft is extremely rare. Death in a majority of these patients as a result of feeding and aspiration problems in early life may have caused the reports to be limited. In this article a 5-year-old patient, probably the first in the literature having Tessier type VI-VII facial cleft combination associated with bimaxillary fusion and anophthalmia on the right side, is presented. The patient has survived on fluid meal through a very small opening for 5 years. The features of the case are presented, and the time and method of the management of such a rare anomaly are discussed with a review of the literature.     

HIV transmission by needle stick and eczematous lesion — Three cases from Germany

Summary Two cases of documented HIV-1 transmission by needle stick and one case of probable transmission by eczematous lesion in three nurses in Germany are reported in the period 1988 to 1991. In two of the cases the nurse knew of the AIDS status of the index patient. A review of the three cases reiterates the importance of repeated training on the prevention of accident and on measures to be taken after an accident, as well as the need to keep the workplace free of additional burden when AIDS or HIV-infected patients are treated.

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HIV-Übertragung durch Nadelstichverletzung und über offenes Ekzem. Drei Fälle aus Deutschland

Zusammenfassung Zwei dokumentierte HIV-Übertragungen über Nadelstichverletzung und eine Übertragung über ein offenes Hautekzem der Hand bei zwei Krankenschwestern und einem Pfleger aus den Jahren 1988 bis 1991 werden geschildert. Diese Übersicht der drei Fälle weist auf die Bedeutung von wiederholten Übungen hin, um einen Unfall zu verhüten und auf Maßnahmen die nach einem Unfall zu ergreifen sind. Unter anderem auf die Notwendigkeit den Arbeitsplatz von zusätzlichen Gegenständen freizuhalten, wenn AIDS- oder HIV-infizierte Patienten behandelt werden.

     

Tumor induction by ras and myc oncogenes in fetal and neonatal brain: modulating effects of developmental stage and retroviral dose

Introduction into fetal rat brain cells of a replication-defective retroviral vector harboring v-Ha-ras and v-gag-myc rapidly causes the induction of highly malignant undifferentiated neuroectodermal tumors following transplantation into the brains of syngeneic hosts [Wiestler, et al. (1992) Cancer Res. 52: 3760–3767]. In the present study, we have investigated the modulating effect of the developmental stage of neural target cells and of the dose of the retroviral vector used in the grafting experiments. Exposure of fetal cells from embryonic day (E)12 or E14 produced a 100% incidence of malignant neuroectodermal tumors which led to the death of recipient animals after a median latency period of 32 days. A 100-fold reduction of the virus dose from 2.062×10⁶ to 2.062×10⁴ focus-forming units/ml resulted in a lower tumor incidence of 25%. Of six neural grafts exposed to v-Ha-ras and v-myc at E16, only one showed evidence of tumorigenesis (low-grade astrocytoma and hemangioma). All other transplants were morphologically normal for observation periods of 26 weeks, indicating a marked loss of transforming activity of ras and myc in more advanced stages of brain development. In retrovirus-exposed donor cells which caused the development of neural tumors in recipient rats, malignant transformation was also evident during culture in vitro, usually after 9–12 days. Oncogene complementation was also studied in the newborn rat brain. After microinjection of the retroviral vector into the brain at postnatal day (P)0, P1 and P3, 5 out of 20 animals (25%) developed a total of seven brain tumors. Histopathologically, three of these neoplasms were malignant neuroectodermal tumors which, in contrast to those induced in fetal brain transplants showed evidence of focal glial and/or neuronal differentiation. In addition, we observed one oligodendroglioma, two hemangiomas and a malignant hemangioendothelioma. These data indicate that neural precursor cells and endothelia of the rat brain represent the major target cells for the complementary action of ras and myc and that the use of target cells from later developmental stages (E16 and postnatal) leads to the induction of both primitive and more differentiated neoplasms.These studies were supported by the Fonds zur Förderung der wissenschaftlichen Forschung in Österreich (Erwin Schrödinger fellowship, JO501-MED), by the Swiss National Science Foundation and by the Cancer League of the Kanton of Zürich     

Dural arteriovenous malformations at the base of the anterior cranial fossa: report of nine cases

Nine men with dural arteriovenous malformations (DAVM) at the base of the anterior cranial fossa are described. Four patients had intracerebral haemorrhage and four had seizures, associated with haemorrhage in two. In three cases the fistula was an incidental finding. In five cases the diagnosis could be made before angiography, on the basis of CT findings. Angiographically, venous drainage was always seen into ascending cortical veins. Five cases demonstrated drainage via the olfactory vein into the basal vein of Rosenthal; in four this way was the principal route of drainage. Five patients underwent surgery, the therapy of choice. One fistula closed spontaneously after angiography. Two patients refused treatment and one was not treated because of his poor general condition. Because arterial supply was usually bilateral, from small branches of the ophthalmic artery, embolisation seemed to be more dangerous. Compared to dural fistulae in other locations the DAVM of the anterior cranial fossa have a higher risk of complications and should be treated even if asymptomatic at the time of diagnosis.     

Uptake of Adriamycin in tumour and surrounding brain tissue in patients with malignant gliomas

Summary Eight patients with malignant gliomas verified on CT scan, received an intravenous injection of 50 mg of Adriamycin R, 24 hours prior to surgical removal of the tumour. Peroperatively, both tumour and surrounding tissue specimens were obtained for determination of the tissue concentrations of Adriamycin and its reduced metabolite Adriamycinol. It was found that Adriamycin could be detected in tumour tissue from all patients. The concentration varied between 0,9 and 4,6 nmol/g tissue. In contrast, Adriamycin could only be detected in surrounding brain tissue from one patient.In anin vitro study a human malignant glioma cell line (U-251 MG) was exposed to various concentrations of Adriamycin for 24 hours. It was found that an intracellular drug concentration above 30 nmol/g cells caused a concentration dependent inhibition of cell growth. Thus, it is likely that the poor effect of Adriamycin on patients with malignant gliomas is due to an ineffective drug accumulation in the tumour tissue.     

Uses and risks of drainage following elective colon resection. A prospective, randomized and controlled clinical study

The results of a controlled randomized and prospective clinical study including 113 patients from March 1987 until August 1988 showed that prophylactic drainage in elective resection for cancer of the colon was not necessary. 60 patients received a drain, 53 patients were not drained. The drain turned out to be ineffective even concerning its expected function of draining intraabdominal fluid: its diagnostic and therapeutic value failed in clinical practice. The rate of surgical complications--i.e. anastomotic leakage, impaired wound healing and relaparotomy--was significantly higher in the drained group. In elective colon resection the use of a drain as a routine procedure cannot be recommended.