Oestradiol enhances the vulnerability threshold for schizophrenia in women by an early effect on dopaminergic neurotransmission

In a representative sample of 392 first hospital admissions for schizophrenia from a population of 1.5 million we assessed the "true" age of onset by a semi-standardized interview "IRAOS". We demonstrated that the mean age at onset of the disease is 3-4 years higher in females than in males, with the lifetime risk being exactly equal. In males, the rates of onset show a steep increase - starting from school age and reaching their maximum value in the age group 15-24 years - followed by a steady decrease. Females reach the first peak with a clear delay between 20 and 29 years. After the decrease, a second smaller peak is observed consistently in females within the age group 45-49 years and over. After having excluded competing explanations, we hypothesized that the effect of oestradiol on the dopaminergic system enhances the vulnerability threshold, which is lowered again during the menopause. Alternatively, we assumed that testosterone reduces the vulnerability threshold and thus furthers the earlier onset of the disease in males. We tested the hypotheses in three animal models by examining the effect of gonadal hormones on haloperidol-induced catalepsy and on apomorphine-induced stereotypies in both neonatal and adult rats. No clear influence by testosterone was shown. Oestradiol caused a significant reduction of both dopamine-agonist and dopamine-antagonist induced behaviour. The effects were stronger in neonatal rats. Since oestradiol caused the dopamine (DA) receptor affinity for sulpiride to be reduced by a factor of 2.8, we assumed that the behavioural changes due to oestradiol were accounted for by a down-regulation of DA receptor sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)     

The relation between the current underlying pacemaker activity and beta-adrenoceptors in cardiac Purkinje fibres: A study using adrenaline,procaine, atenolol and penbutolol

Summary The pacemaker current — i _K2 — in cardiac Purkinje fibres was analysed using the voltage clamp technique described by Deck et al. (1964). (–)-Adrenaline (5.5 · 10^–6 M) causes the wellknown shift of the Hodkin-Huxley kinetics in the depolarizing direction. Procaine (7.3·10^–4 M) does not cause any further shift of s in the presence of adrenaline. Atenolol (3.8·10^–5 M) causes a backshift of the kinetics in the negative direction in the presence of adrenaline and procaine. The instantaneous current-voltage relationship ( ) is altered neither with adrenaline, nor with procaine or atenolol. The results exclude the possibility that the local anaesthetic side effect of many beta-adrenoceptor blocking agents may be involved in the backshift of the s-kinetics. The voltage dependence of the reciprocals of the time constants is shifted in a similar way as s by the sympathomimetic or blocking drugs. Following the application of (–)-adrenaline (5.5·10^–6 M) the (–)-isomere of penbutolol (1.7 and 3.5·10^–6 M) is about equally effective in shifting the kinetics back as the (+)-isomere (3.5·10^–5 M). In the presence of (–)-adrenaline, the (+)- and (–)-forms of penubutolol cause virtually no change of the instantaneous current-voltage relationship, . Thus, (–)-adrenaline and (+)- and (–)-penbutolol are aiming for the s-kinetics whose voltage dependence is controlled by the electric field near the i _K2-channel of the membrane and do not influence the number of the i _K2-channels. These findings suggest that the sympathomimetic or blocking agents influence the s-kinetics of the pacemaker current i _K2 by altering the electric field; the fully activated current-voltage relationship which is proportional to the number of the open i _K2-channels is not subject to any appreciable modification. The results conclusively show that the kinetics of the pacemaker current can be controlled by beta-adrenoceptors.     

European Society of Medical Oncology membership survey

Market research is a popular instrument used by industry tolearn more about the profile and expectations of potential clients.Scientific and professional societies, the European Societyof Medical Oncology (ESMO) included, also need to be acquaintedwith their members’ characteristics—their background,working conditions, activities, needs and expectations. Thesewere among the considerations that prompted ESMO to undertakea membership survey. Last year, a questionnaire was designedand sent out by mail to 3457 ESMO members of whom 393 (11.4%)returned the completed files. Although the response rate was     

Chromosomal instability rather than p53 mutation is associated with response to neoadjuvant cisplatin-based chemotherapy in gastric carcinoma.

PURPOSE: The objective of the study was to evaluate microsatellite alterations [microsatellite instability (MSI) and loss of heterozygosity (LOH)] and mutation in the p53 gene in relation to response and patient survival to a cisplatin-based neoadjuvant chemotherapy in gastric cancer. EXPERIMENTAL DESIGN: Fifty-three pretherapeutic gastric carcinoma biopsies were analyzed with 11 microsatellite markers. The entire coding region of the p53 gene (exons 2-11) was analyzed for mutations by denaturing high-pressure liquid chromatography and sequencing. p53 protein expression was evaluated by immunohistochemistry. Patients were treated with a cisplatin-based, neoadjuvant chemotherapy regimen. Therapy response was evaluated by computed tomography scan, endoscopy, and endoluminal ultrasound. The median follow-up of the patients was 45.6 months. RESULTS: p53 mutations were identified in 19 of the 53 (36%) analyzed tumors. No significant association with response or survival was found for p53 mutation or for p53 protein expression. MSI (either high-grade MSI or low-grade MSI) did not show a correlation with response. With respect to LOH, LOH at chromosome 17p13 showed a significant association with therapy response (P = 0.022) but did not reach statistical significance in terms of patient survival. The global LOH rate, expressed as fractional allelic loss (FAL), was assessed, and tumors were classified into tumors with a high (>0.5), medium (>0.25-0.5), and low (0-0.25) FAL value. A statistically significant association of FAL with therapy response was found (P = 0.003), with a high FAL being related to therapy response. The sensitivity, specificity, positive predictive value, and negative predictive value for FAL > 0.5 were 45%, 93%, 82%, and 72%, respectively. CONCLUSIONS: A high level of chromosomal instability (high FAL value) defines a subset of patients who are more likely to benefit from cisplatin-based neoadjuvant chemotherapy. p53 mutation status is not significantly associated with therapy response and is not a useful marker for response prediction.     

Milrinone therapy in catecholamine-dependent critically ill patients with heart failure

BACKGROUND: Treatment with the PDE-III inhibitor milrinone improves hemodynamics in patients with heart failure. We examined whether therapy with milrinone is safe and effective in critically ill patients with catecholamine-dependent heart failure and whether treatment with milrinone facilitates weaning from prolonged catecholamine therapy. METHODS: Twenty adult patients with reduced left ventricular function and prolonged (7+/-4 days) catecholamine therapy in whom attempts at catecholamine weaning had failed were examined. Patients were prospectively randomised either to group A (addition of a fixed dose of 0.5 microg x kg(-1) x min(-1) milrinone to catecholamine therapy) or to group B (continued catecholamine therapy without milrinone). Dobutamine and norepinephrine treatment and fluid intake were titrated according to predefined hemodynamic goals. Hemodynamic parameters, fluid requirements and catecholamine dose were monitored. RESULTS: After 24 h of study treatment goup A showed a significant increase in cardiac index (2.2+/-0.4 1 min(-1) x m(-2) to 2.7+/-0.51 min(-1) x m(-2); P<0.005), a decrease in systemic vascular resistance (1,427+/-609 dyn x s x cm(-5) to 951+/-184 dyn x s x cm(-5); P<0.005), required lower doses of dobutamine (5.9+/-4.2 microg x kg(-1) x min(-1) to 2.2+/-3.3 microg x kg(-1) x min(-1); P<0.02), but showed a tendency for higher vasoconstrictor (0.14+/-0.16 microg x kg(-1) x min(-1) to 0.29+/-0.43 microg x kg(-1) x min(-1); P=n.s.) and fluid requirements (+1,404+/-2,257 ml/24 h to +2,508+/-1,873 ml/ 24 h; P=n.s.). No significant changes occurred in group B. Weaning from catecholamine therapy was more often achieved in group A and more milrinone treated patients were discharged alive from the ICU (80% vs. 30%; P<0.05). CONCLUSIONS: Milrinone improves central hemodynamics and may facilitate weaning from prolonged catecholamine support in critically ill patients with heart failure. Its administration in this subset of critically ill patients is safe, but eventually is associated with additional vasoconstrictor and fluid requirements.     

Emergence of behavioural states in fetuses of type-1-diabetic women

The aim of this study was to investigate the effects of tightly controlled maternal (type-1-)diabetes mellitus on the development of fetal behavioural states. Seventeen diabetic women, who required insulin (White's class C predominantly) and were treated with continuous subcutaneous insulin infusion (CSII) therapy, participated in the study. Adjustment to an insulin-pump occurred before conception or during early pregnancy. In all diabetic women (near-)normoglycemia was achieved during pregnancy, with glycosylated hemoglobin-values within the normal range (6-8.5%). Fifty-three 2-h recordings of fetal heart rate, uterine contractions and of real-time ultrasound scanning for fetal body movements, breathing and eye movements were obtained from the 17 fetuses. The fetuses were longitudinally studied between 32 and 40 weeks post menstrual age, at intervals of 2 weeks. The 3 state variables, fetal heart rate, body movements and eye movements, were analyzed for the presence of combinations meeting the definitions of the four fetal behavioural states. Findings in the fetuses of diabetic women were compared with those obtained from 28 low risk fetuses. The criteria of states were met in only 3 of 8 fetuses studied at 38 weeks and in one of two studied at 40 weeks. For comparison: in low risk fetuses studied at 38 and 40 weeks, states were present in 70% and 90% of the cases, respectively. This poorly developed state organization exhibited by the near term fetuses of the diabetic group, was related to maternal parity, but not to pre- or postconceptional onset of CSII-treatment. Fetuses of nulliparous diabetic women showed more often asynchrony of transitions (greater than 3 min) and interruption of periods of concordant association. This resulted in significantly higher percentages of 'no-coincidence' and in low incidence of behavioural states as compared with control fetuses of nulliparous women. In the few multiparous diabetic cases studied near term the development of fetal behavioural states was normal. We conclude therefore that, despite tight control of maternal diabetes, the development of behavioural states is disturbed in fetuses of nulliparous diabetic women.     

Response of proopiomelanocortin and gonado- or lactotroph systems to in-vitro fertilisation procedures stress

Objective

To analyse for the first time the response of the corticotroph-type and the melanotroph-type pituitary proopiomelanocortin (POMC) system with regard to in-vitro fertilisation (IVF) treatment using self-developed highly specific non-cross-reacting radioimmunoassay.

Study design

Setting: University hospital. Patients: A total of 28 patients undergoing IVF oocyte retrieval. Cross sectional exploratory study, one factorial design with repeated measurements on one factor, non-parametric tests. Blood was collected before anaesthesia (t_A) (n = 28) and immediately after oocyte retrieval (t_B) (n = 28). Main outcome measure(s): β-endorphin immunoreactive material (IRM), acetyl-N-β-endorphin IRM, β-lipotropin IRM, ACTH, cortisol, estradiol, progesterone, prolactin, luteinizing hormone, and follicle-stimulating hormone. For determination of authentic β-endorphin [β-endorphin (1–31)] a highly specific two-site fluid phase immunoprecipitation radioimmunoassay was developed, which did not cross-react with any β-endorphin derivative or any other opioid peptide tested.

Results

No response of acetyl-N-β-endorphin IRM and of authentic β-endorphin (1–31) was observed to oocyte retrieval in contrast to a significant increase of corticotroph-type proopiomelanocortin derivatives. A significant rise in prolactin plasma concentration indicates a pronounced lactotroph response to oocyte retrieval stress. No significant correlation between POMC derivates and prolactin and between POMC derivatives and gonadotropins or sexual steroids except for ACTH and progesterone and for β-endorphin IRM and estradiol was observed.

Conclusion

IVF treatment stress led to significant corticotroph-type POMC and lactotroph responses, but not to responses of authentic β-endorphin or melanotroph-type POMC in women undergoing oocyte retrieval.