Stimulus properties of the L-type calcium channel agonist BAY k 8644 in rats

Calcium (Ca(2+)) channels appear to be involved in the regulation of ethanol (EtOH) intake, as indicated by the effectiveness of both L-type Ca(2+) channel antagonists and agonists in reducing EtOH intake in animals. The present study was aimed to investigate rewarding/aversive and discriminative stimulus effects of the Ca(2+) channel agonist BAY k 8644, a compound showing pronounced anti-alcohol effects in rats. Therefore, a series of conditioned taste aversion (CTA), conditioned place preference (CPP) and two-lever drug discrimination (DD) experiments were conducted in Wistar rats, with (+/-)-BAY k 8644 and its enantiomers. After i.p. application, (+/-)-BAY k 8644 (0.0625-1mg/kg), (-)-BAY k 8644 (0.125-1mg/kg) and (+)-BAY k 8644 (2.5-20mg/kg) all induced a dose-dependent CTA. The minimal effective doses (MED) for (+/-)-, (-)- and (+)-BAY k 8644 were 0.25, 0.25 and 10mg/kg, respectively. In a CPP study, however, (+/-)-BAY k 8644 (0.25-2mg/kg, i.p.) showed neither aversive nor rewarding stimulus properties. Rats were trained to discriminate (-)-BAY k 8644 (0.3mg/kg, i.p.), the enantiomer acting as a high potency Ca(2+) channel agonist, from vehicle, in a two-lever DD procedure (ED(50)) value: 0.05mg/kg); full generalisation: 0.1mg/kg). The (-)-BAY k 8644 cue dose-dependently generalized to (+/-)-BAY k 8644 and (+)-BAY k 8644, the enantiomer acting as a low potency Ca(2+) channel antagonist, with ED(50) values of 0.06 and 0.28mg/kg, respectively. Both (+/-)- and (+)-BAY k 8644 produced full generalization at 1mg/kg, the latter compound showing an inverted U-shaped curve (i.e., this was the only dose showing >80% drug lever selection). The stimulus patterns of BAY k 8644 and its enantiomers appear to resemble the anti-alcohol profiles of these compounds. Therefore, commonalities between the stimulus properties of the agonistic and antagonistic enantiomers might provide a clue for the mechanism underlying the anti-alcohol effects of L-type Ca(2+) channel antagonists and agonists.     

Stepwise development of a clinical expert system in rheumatology

Summary The evaluation of computer expert systems, a promising diagnostic tool for future application in clinical medicine, is of great importance. We present here the evaluation of our expert system, RHEUMA. It is stressed, that repeated retrospective testing and updating of an expert system and its subsequent repeated assessment in clinical use and surroundings is mandatory. This increases the diagnostic accuracy of the system. For our system this is demonstrated under three separate conditions. In the first study the information available for the computer system (mainframe) came from medical histories only. Here an error rate of about 25% — similar to that of physicians themselves using the same information — was observed in 358 outpatients, compared to the final diagnoses of physicians also relying solely on information from medical histories. In a second step a completely new system on a personal computer was developed with all relevant diagnostic information. The error rate of this system (0.4%) was much too optimistic because the knowledge base was changed during the study, affecting about 30% of the 282 prospectively recruited outpatients. In a third step the efficacy of the expert system was tested in an additional hospital without the diagnostic involvement of the first testing clinic. The error rate of the system without changing the knowledge base reached 11% in 51 outpatients in this rheumatology clinic. This result reflects the diagnostic accuracy of the system today. Its ability to specify the same diagnoses which clinical experts reached approached 90%. Considerable time is needed for such prospective testing, with repeated updating of the knowledge base — in our case for both the two systems and field studies of 2 years each. Further prospective field testing with physicians not specialized in rheumatology and with a larger number of patients is necessary before the system can be used in clinical routine.Dedicated to Prof. Dr. N. Zöllner on the occasion of his 70th birthday     

The effect of prenatal diazepam exposure on TNF-α production by rat splenocytes

Prenatal exposure to diazepam and other benzodiazepines (BDZ) has been found to result in a marked reduction of T-lymphocyte proliferation during postnatal development of rats. In search for pathogenic changes underlying this effect, we investigated the mitogen lipopolysaccharide (LPS) and concanavalin A (ConA) stimulated release of tumour necrosis factor (TNF)- by mixed splenocytes of male offspring from Long Evans rats treated with 1.25 mg/kg per day diazepam from gestational day 14 to 20. In response to LPS, TNF- release was found to be significantly lower in mixed splenocytes of two- and four-week-old treated than in control offspring. However, at eight weeks of age, prenatally diazepam-treated animals showed a significantly higher LPS-induced TNF- release than control rats. Since monocytes/macrophages represent a major source of TNF-, additional experiments were performed on purified spleen macrophages and lymphocytes stimulated with LPS. TNF- release was only detectable in supernatants of adherent spleen macrophages and not in supernatants of lymphocytes. Thus, our data indicate that a disturbance in TNF- release from macrophages is involved in the deficient immune response of prenatally diazepam-exposed rats.     

10. Einführung zum Thema

Zusammenfassung Der fortgeschrittene Organkrebs ist eine systemische Krankheit. Die chirurgische Therapie mu durch interdisziplinäre Kooperation ergänzt werden. Jetzt gilt es, entsprechende Arbeitsgemeinschaften zu bilden, um die heute und morgen gegebenen Möglichkeiten standardisierter Chirurgie, Chemotherapie, Radiotherapie, immunologischer Therapie und Rehabilitation optimal nutzen zu können. Eine einheitliche Dokumentation nach dem TNM-System ist dabei eine notwendige Voraussetzung.     

Apoliprotein E and multiple sclerosis: impact of the epsilon-4 allele on susceptibility, clinical type and progression rate

The purpose of this study was to investigate the relation between APOE genotype and Multiple Sclerosis (MS) in a genetically homogeneous population. We examined 240 patients consulting the MS-clinic during a period of 3 years (1996 - 1999). The mean age of the patients was 41.7 years (range 19 - 80 Y, SD 10.0 Y). As a measure of the progression rate (PR) the last registered Expanded Disability Status Scale (EDSS) score was divided by the time span (years) from disease onset until the latest assessment. The APOE genotype was determined from saliva and/or blood samples using PCR-techniques. The prevalence of different APOE genotypes was compared with the allele-distribution in a population of 361 persons from a Danish cross-sectional population study. The frequency of APOE-epsilon 4/epsilon 4 homozygotes was significantly higher in the MS-group as compared to controls (P<0.05, odds ratio: 2.3), whereas the frequency distribution of other genotypes did not differ significantly. The rate of progression was significantly faster in the APOE-epsilon 4/epsilon 4 homozygotes compared to other genotypes in the MS group (P<0.05). This study suggests that the APOE-epsilon 4/epsilon 4 homozygotes have an increased risk of developing MS. MS patients with the APOE-epsilon 4/epsilon 4 allele may also have an increased rate of disease progression. Multiple Sclerosis (2000) 6 226 - 230     

Extracorporal therapy with AN69 membranes in combination with ACE inhibition causing severe anaphylactoid reactions: still a current problem?

The negatively charged membrane AN69 is known to evoke anaphylactoid reactions both without and with concomitant ACE inhibition. Underlying reasons are mainly the induction of bradykinin release due to the negatively charged membrane and the reduced degradation of bradykinin due to ACE inhibition. This complication has been reported repeatedly, but anaphylactoid reactions still occur in clinical practice. We recently had to treat two patients who suffered anaphylactoid reactions during extracorporal therapy with an AN69 membrane and simultaneous ACE inhibition. The first incident occurred in a patient on hemodialysis, the second was in a patient on continuous venovenous hemofiltration. An anaphylactoid reaction induced by an AN69 membrane during continuous, extracorporal treatment in combination with ACE inhibition has not been reported so far. Our report intends to serve as a reminder that the potentially lethal combination of AN69 membranes with ACE inhibitor treatment should be avoided.     

17 Alpha-oestradiol and 17 beta-oestradiol do not affect basal and follicle-stimulating hormone-stimulated inhibin B secretion by highly purified rat Sertoli cells

The effects of 17 alpha-oestradiol and 17 beta-oestradiol on basal and follicle-stimulating hormone (FSH)-stimulated inhibin B secretion by rat Sertoli cells were studied. Sertoli cells were isolated and cultivated from testes of 18-day-old Wistar rats in the presence and absence of FSH and different doses of oestrogens. On day 4 of culture, secreted inhibin was measured by enzyme-linked immunosorbent assay. Neither 17 alpha-oestradiol nor 17 beta-oestradiol had any effect on the secreted inhibin level in either the presence or absence of FSH. It is concluded that these oestradiols do not play an essential role in regulatory processes involving inhibin or FSH.