Modulatory effects of phosphatidylserine on the binding of muscarinic cholinergic receptor ligands

The modulation of the binding of muscarinic cholinergic receptor ligands by phosphatidylserine purified from bovine cerebral cortex (BC-PS) was examined in vitro and in vivo. The enrichment of bovine cerebral cortical synaptosomal membranes with BC-PS, using a fusion technique, produced a concentration-dependent decrease in the affinity (increase in K _d ) of [³H]quinuclidinyl benzylate (³H-QNB) specific binding to muscarinic acetylcholine receptors (mAChR), without changes in their maximal number (Bmax). Similar results were observed when [³H]oxotremorine (³H-OXO) was used to label a high affinity subpopulation of mAChR. On the other hand, preincubation of BC-PS liposomes with synaptosomal membranes in a nonoptimum fusion condition (at pH 7.4) did not alter the binding properties of both radioligands. Fusion experiments using a pure phosphatidylserine preparation from spinal cord revealed a similar decrement in the affinity of³H-QNB specific binding. Five day’s intraperitoneal (i.p.) administration of 15 mg/kg of BC-PS liposomes in rats increased the maximal number of cerebral cortical binding sites for³H-OXO. Scatchard analysis revealed no changes in the apparent dissociation constant. This modification is selective in relation to the neural structure studied. Thus, BC-PS treatment did not modify³H-OXO binding in the hippocampal formation and cerebellum. In contrast, parallel experiments using the muscarinic antagonist³H-QNB showed no alteration in the binding properties of mAChR. Five day’s i.p. administration of 15 mg/kg/d of phosphatidylcholine from bovine cerebral cortex (BC-PC) liposomes produced quite similar results to those obtained with BC-PS. These results indicate that mAChR are under the modulatory action of phosphatidylserine (PS) and phosphatidylcholine (PC), and suggest that this endogenous phospholipids may play a regulatory role on the mAChR. The possible implications of these findings on the effects of PC or PS treatment in neurological disorders involving a decrease in central cholinergic functions are discussed.     

Surface-Attached Polymer Networks Made from Cationic Poly(diitaconates): Synthesis,Surface Characterization,and Bioactivity

Facially amphiphilic polymers carrying cationic and hydrophobic groups on the same repeat unit have shown promising antimicrobial activity and biocompatibility, yet they are prone to suffer from protein adhesion which may induce biofilm formation. To overcome this problem, poly(diitaconate)-based copolymers with cationic/hydrophobic and protein-repellent/charge-neutral repeat units are synthesized. The bioactivity profile of surface-attached polymer networks made from these copolymers depends on the ratio of the cationic and charge-neutral repeat units. In all cases, the protein adhesion is substantially reduced compared to purely cationic polymers. At a 50:50 ratio, the polymer coatings are partially protein-repellent and antimicrobial, yet slightly cell toxic. At an intermediate composition of 30:70, they are still antimicrobial and the cell compatibility is substantially improved. The long-term stability of these materials still has to be determined to judge their suitability for medical applications.     

Lasting reduction in mesolimbic dopamine neuronal activity after morphine withdrawal

The activity of mesolimbic dopaminergic neurons was investigated in rats at various times after a chronic regimen of morphine, which produced, upon suspension, a marked somatic withdrawal syndrome. Single-cell extracellular recording techniques, coupled with antidromic identification from the nucleus accumbens, were used to monitor neuronal activity while behavioural observations allowed quantification of the somatic signs of morphine withdrawal. Temporal correlation of electrophysiological indices, such as firing rate and burst firing, with scores obtained through behavioural assessments proved negative, in that somatic signs were pronounced at 24 h after suspension of treatment and then subsided to control values at 72 h after the last morphine injection. In contrast, the firing rate and burst firing of mesolimbic dopaminergic neurons were found to be reduced at 1, 3 and 7 days after morphine withdrawal. After 14 drug-free days, electrophysiological analysis revealed an apparent normalization of various parameters. However, at this time, intravenous administration of morphine produced an increment of electrical activity which was significantly higher than that obtained in control (saline treated) rats. Further, administration of the opiate antagonist naltrexone, administered without prior morphine, at 3, 7 and 14 days after the last morphine administration, failed to alter dopaminergic neuronal activity. The results indicate: (i) that the activity of mesolimbic dopaminergic neurons remains reduced well after somatic signs of withdrawal have disappeared; (ii) after 14 days of withdrawal, the augmented magnitude of the electrophysiological response to exogenous morphine suggests an increased sensitivity of opiate receptors; and (iii) the lack of relationship between dopaminergic activity and somatic signs of withdrawal corroborates the notion that dopaminergic activity in the mesolimbic system does not participate in the neurobiological mechanisms responsible for somatic withdrawal. The present results may be relevant to the phenomenon of drug addiction in humans and consequent relapse after drug-free periods.     

The impact of student-generated learning issues on individual study time and academic achievement

OBJECTIVES: The aim of this study was twofold. The first question concerns the way students make use of the learning issues they generate (as strict guidelines or as global guidelines) and whether this changes across years of training. The second question concerned the relationship between the way students make use of learning issues and the time spent on individual study and achievement on two tests of knowledge. DESIGN: A questionnaire was developed, containing seven items that measured to what extent students study strictly according to the student-generated learning issues and six items that measured to what extent students study beyond the student-generated learning issues. The questionnaire also contained one question in which students had to estimate the mean time spent on individual study. Achievement was measured by two forms of tests of knowledge, a block test assessing course content and a progress test assessing long-term functional knowledge. SETTING: Medical School of Maastricht University, the Netherlands. SUBJECTS: Medical students (response=69%) from the problem-based curriculum at the Maastricht University. RESULTS: During their first year students study strictly according to the content of the learning issues, whereas in later years students studied more according to their own learning needs and interests. In addition, students who tended to study beyond the generated learning issues spent more time on individual study and achieved better on both tests. CONCLUSIONS: Students in a problem-based curriculum seem to become better self-directed learners during the years of training.     

Does a student log provide a means to better structure clinical education?

CONTEXT: In order to optimize student learning during clinical rotations, the learning situation could be better structured. A student log was developed in order to improve the structure of clinical education. In this log, students systematically register essential learning activities. Students record daily the patient problems with which they had been confronted and in which fashion (passive, active, without or with feedback). OBJECTIVES/RESEARCH QUESTIONS: Two questions were addressed. Firstly, did the log provide insight into the content and nature of students' learning experiences and did these learning experiences differ between hospitals? Secondly, was the log used by students, supervisors and the faculty to improve the structure of student learning during clinical education? METHOD: Three student logs, used in an ear, nose and throat, an ophthalmology and a paediatrics clerkship at the Medical School of the University of Maastricht, were developed and implemented. In order to answer the first question, a number of completed student logs were analysed. In order to answer the second question, students were asked to rate the log on five evaluative statements. In addition, the clerkship coordinators were interviewed. RESULTS: The results showed that the logs provided the clerkship coordinators with a useful overview of the content and nature of students' learning experiences in the hospitals. The differences between hospitals were small. However, the logs were not used by students, supervisors and faculty to improve the structure of student learning. CONCLUSIONS: In order to be effective, i.e. to better structure clinical education, a student log should be integrated into the supervision activities.     

Clozapine potently stimulates mesocortical dopamine neurons

The effects of clozapine on dopamine neurons projecting to the medial-prefrontal cortex, nuclei accumbens and caudatus were compared. Clozapine (1.25 mg/kg i.v.) maximally stimulated the firing rate and burst activity of dopamine neurons projecting to the medialprefrontal cortex. Much higher doses (5 and 10 mg/kg i.v.) were needed to stimulate mesoaccumbens and nigrostriatal dopamine neurons. The results suggest that the activation of mesocortical dopamine neurons is responsible for clozapine-induced dopamine release in the prefrontal cortex.     

Multivariate Analysis of Left Ventricular Mass Determinants in Adults: Different Patterns in Men and Women

Echocardiographic left ventricular mass (LVM) estimates are strong predictors of subsequent mortality and cardiovascular events. It is known that blood pressure (BP), weight (WT), and age are significantly correlated with LVM. We hypothesized that stroke volume (SV) measured by Doppler echocardiography would also be correlated with LVM. Two hundred and thirteen patients referred for routine echocardiography had determination of LVM, cuff BP, and Doppler SV. Those with localized LV disease, valvular disease, or cor pulmonale were excluded. In both men and women, systolic BP (SBP) was more closely correlated with LVM than was diastolic blood pressure or mean arterial pressure, and SV was more closely correlated with LVM than cardiac output or cardiac index. Stepwise regression, followed by multiple regression showed that four variables (WT, SV, SBP, and AGE) explained 32.3% of the variability in LVM in men and 48.5% of the variability in LVM in women. WT and SV were significant determinants of LVM in both men and women. Age was also significant in men and SBP was also significant in women. For both men and women, SV was more significantly correlated with LVM than was SBP. The changes in LVM associated with 1 SD increments of SV and SBP, respectively, were 8 and 5 g for men and 13 and 11 g for women. We conclude that men and women have different patterns of variables influencing LVM. Doppler echocardiographic SV is a newly described determinant of LVM that has a greater correlation with LVM than does SBP. This study reemphasizes the importance of WT as the major determinant of LVM. (ECHOCARDIOGRAPHY, Volume 13, January 1996)     

Comparison of left ventricular performance in healthy young women and men during exercise

Background

Previous studies show sex-related differences in left ventricular (LV) response to exercise. It is not clear, however, whether these differences are also seen in younger healthy subjects.

Methods and Results

This study examined the changes in LV performance during dynamic upright exercise in 11 healthy men and 19 healthy young women according to the Bruce protocol and an individualized ramp protocol. There were no significant differences between the two protocols for either men or women in heart rate, blood pressure, LV ejection fraction (EF) (measured by ambulatory nuclear detector), and measured oxygen consumption. The peak oxygen consumption was higher in men than in women (44±13 vs 36±9 ml/kg/min; p<0.05), but the peak heart rate, systolic blood pressure, and EF were similar. The change in EF (from rest to exercise) was 19%±8% in men and 19%±11% in women with the Bruce protocol (difference not significant) and 26%±9% in men and 19%±6% in women with the ramp protocol (difference not significant). At peak exercise, both men and women showed an increase in end-diastolic volume (29%±14% vs 23%±11%; difference not significant) and a decrease in end-systolic volume (41%±15% vs 43%±21%) (difference not significant). The increase in cardiac output during exercise was due to an increase in heart rate and stroke volume in both men and women. At submaximal exercise, however, the decrease in end-systolic volume was less in women than in men (p<0.05).

Conclusions

There are no sex-related differences in compensatory mechanism during dynamic execise in healthy subjects. The changes in contractility and LV volume are not affected by the exercise protocol.     

Informed consent does not demand full disclosure of risks

British law on informed consent does not require as high a standard of disclosure as do American and Canadian law. In a recent decision, Hills v. Potter, the judge held that a physician has a duty to inform a patient according to the practice adopted by a competent body of his peers, rather than an absolute duty of full disclosure. Brahams argues that the patient is entitled to all the information that will enable him or her to weigh the risks and benefits of the proposed therapy, even if this disclosure leads to rejection of beneficial treatment.