Regulation of natural antibiotic expression by inflammatory mediators and mimics of infection in human endometrial epithelial cells

The natural antibiotic molecules, beta-defensins 1 and 2 (HBD1/2) and secretory leukocyte protease inhibitor (SLPI), have an important role in mucosal defence and are present in the uterus. This study details their regulation in primary endometrial epithelial cells and in two endometrial cell lines (MFE/HES). Cells were treated with proinflammatory molecules and mimics of infection [lipopolysaccharide (LPS) and lipoteichoic acid (LTA)]. mRNA for HBD1, HBD2 and SLPI was detected in primary endometrial epithelial cells using real-time quantitative PCR. HBD1 mRNA was present at very low levels preventing conclusive study of its regulation. However, HBD2 mRNA expression was increased by interferon-gamma, interleukin (IL)-1beta alone and IL-1beta+tumour necrosis factor (TNF)-alpha. SLPI mRNA was not affected by proinflammatory mediators, although protein levels fell in the presence of IL-1beta+TNFalpha. LPS had little effect on antimicrobial expression. However, there was a trend towards increased expression with LTA treatment for 4-8 h. Antimicrobial expression in endometrial cell lines was similar to that in primary cells, although SLPI was increased by IL-1beta+TNFalpha treatment. These results suggest that in endometrium some natural antibiotics (e.g. SLPI) may be constitutively expressed providing a basal level of protection, while others (e.g. HBD2) are inducible allowing maximal antimicrobial activity during infection. Natural antimicrobials will have an important role in endometrium in protecting against infection.     

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.     

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.     

Mathematical Ability and Lateral Asymmetry

The hypothesis that special ability in mathematics is associated with a reduction in bias to dextral preference and skill was examined in several samples of students and in 97 male and 27 female teachers of mathematics, mainly in Universities and Polytechnics. The maths students and maths teachers differed from controls, both general and academic, in the direction predicted and several comparisons were statistically significant. Differences were in most cases clearer for males than females.An analysis of the findings in relation to the right shift (RS) theory of handedness (Annett, 1972, Annett, 1978) suggests that the incidence of left preference and skill is slightly raised in mathematicians not because of any intrinsic advantage of left preference but rather because extreme bias to the right, as expected in those carrying a hypothesised rs++ genotype, is disadvantageous for mathematical thinking. If the role of mathematics can be regarded as one of developing languages to describe those aspects of human experience which otherwise could be understood only in visuo-spatial images, it can be seen to require a coordination of those aspects of human intelligence which have been distinguished as depending differentially on the left and right cerebral hemispheres. The present findings suggest that this process might be impeded by a double dose of a gene which promotes left hemisphere language specialisation.