Potentiation of human alpha4beta2 neuronal nicotinic receptors by a Flustra foliacea metabolite

The effects of various Flustra foliacea metabolites on different types of human neuronal nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes were investigated. Whereas most of the compounds tested had a small blocking effect, one of them, deformylflustrabromine, selectively increased the current obtained in alpha4beta2 receptors when co-applied with acetylcholine (ACh). The current increase was reversible and concentration-dependent. This potentiating effect was still present at saturating concentrations of acetylcholine, and no changes in single-channel conductance or reversal potential were observed, thus suggesting a modification in the gating of alpha4beta2 receptors. Dwell time analysis of single channel records indicates that the mechanism of action of deformylflustrabromine could be both an increase of the opening rate constant and a decrease of the closing rate constant on alpha4beta2 receptors. Thus, deformylflustrabromine may constitute an excellent starting point for the future development of related agents able to potentiate human neuronal nicotinic receptor function.     

Severe meningococcal disease is characterized by early neutrophil but not platelet activation and increased formation and consumption of platelet-neutrophil complexes

Approximately 25% of polymorphonuclear leukocytes (PMNL) circulate in heterotypic complexes with one or more activated platelets. These platelet-neutrophil complexes (PNC) require platelet CD62P expression for their formation and represent activated subpopulations of both cell types. In this study, we have investigated the presence, time course, and mechanisms of PNC formation in 32 cases of severe pediatric meningococcal disease (MD) requiring intensive care. There were marked early increases in PMNL CD11b/CD18 expression and activation, and reduced CD62L expression compared with intensive care unit control cases. Minimal platelet expression of the active form of alphaIIbbeta3 (GpIIb/IIIa) was seen. PNC were reduced on presentation and fell to very low levels after 24 h. Immunostaining of skin biopsies demonstrated that PNC appear outside the circulation in MD. In vitro studies of anticoagulated whole blood inoculated with Neisseria meningitidis supported these clinical findings with marked increases in PMNL CD11b/CD18 expression and activation but no detectable changes in platelet-activated alphaIIbbeta3 or CD62P expression. In vitro PMNL activation with N. meningitidis (or other agonists) potentiated the formation of PNC in response to platelet activation with adenine diphosphate. Therefore, in severe MD, PMNL activation is likely to promote PNC formation, and we suggest that the reduced levels of PNC seen in established MD reflect rapid loss of PNC from the circulation rather than reduced formation.     

Psychiatric disorders associated with risk for the development of eating disorders during adolescence and early adulthood

Longitudinal data were used to investigate whether anxiety, depressive, disruptive, personality, or substance use disorders are associated with risk for the development of eating disorders during adolescence or early adulthood. Psychiatric disorders were assessed among 726 youths from a random community sample during adolescence and early adulthood. Depressive disorders during early adolescence were associated with elevated risk for the onset of eating disorders, dietary restriction, purging behavior, and recurrent weight fluctuations after preexisting eating problems and other psychiatric disorders were controlled statistically. Disruptive and personality disorders were independently associated with elevated risk for specific eating or weight problems. The present findings suggest that depressive disorders during early adolescence may contribute to the development of eating disorders during middle adolescence or early adulthood.     

Moderation of physiological stress responses by personality traits and daily hassles: less flexibility of immune system responses

Previously we demonstrated that stressors varying on the dimension of mental effort and controllability have distinctive effects on cardiovascular, endocrine and immune system responses. The purpose of the present study was to relate individual differences in physiological stress responsivity to task appraisal and stress-induced mood changes (issue 1), trait characteristics (issue 2) and daily hassles (issue 3). Appraisal and mood changes did not mediate the differential effects of the stressors. The trait characteristics, aggression and external locus of control and daily hassles moderated the effect of the stressor on physiological parameters, especially immune parameters. Moreover, the moderation effect was different in the high versus the low effort stress task. High aggression, high external locus of control and more daily hassles were associated with increased reactivity in the low effort condition and decreased reactivity in the high effort condition, which is suggested to reflect less differentiated responding to changing task demands and hence, less flexibility in the immune system.     

Monoclonal antibodies to enterobacterial common antigen and to Escherichia coli lipopolysaccharide outer core: demonstration of an antigenic determinant shared by enterobacterial common antigen and E. coli K5 capsular polysaccharide.

We established hybridoma cell lines producing monoclonal antibodies against enterobacterial common antigen (ECA) and a substructure of the outer core of different Escherichia coli lipopolysaccharides (LPSs). Anti-ECA antibodies 865 and 898 reacted with ECA in extracts of heated E. coli and with ECA-bound R1 and R4 core-containing LPS preparations, as well as with a purified sample of ECA from Salmonella montevideo. Antibody 865, but not antibody 898, cross-reacted with K5 capsular polysaccharide, suggesting that 4-linked alpha-N-acetylglucosamine is part of an antigenic determinant shared by both K5 polysaccharide and ECA. Anti-LPS antibody 786 recognized an outer core structure common to E. coli K-12, B, R2, and R4 core type LPS, but not to R1 and R3 core type LPS. Its most probable target is the trisaccharide sequence Hexp(1----2)-alpha-D -Glcp(1----3) alpha-D-Glcp----(Hepp) (where Hex is hexose, p is phosphate, Glc is glucose, and Hep is heptose), the first glucose being the immunodominant moiety. These monoclonal antibodies may be used not only for the detection of ECA, K5, and LPS core structures but also for analysis of the molecular forms resolved on polyacrylamide gels (banding patterns) of both ECA and LPS, independently of one another.     

A general practice-based study examining the absolute risk of cardiovascular disease in treated hypertensive patients.

BACKGROUND: When managing hypertension, the assessment of the absolute risk of a cardiovascular' event is now advocated as the most accurate way in which the risks and benefits of anti-hypertensive therapy should be judged. Most studies that have examined control of hypertension have relied solely on the blood pressure level attained after treatment, with no measurement of the likely absolute risk in individual patients. AIM: To assess control of hypertension by quantifying the 10-year absolute risk of cardiovascular disease in patients treated by their general practitioners, and to assess which risk factors are associated with uncontrolled hypertension in this group of patients. METHOD: A cross-sectional study was made of patients on drug treatment for hypertension in 18 Oxfordshire general practices subscribing to the VAMP (value-added medical products) computer system. The absolute risk of suffering a cardiovascular event in the following 10 years was measured according to each individual's risk factor profile. Factors associated with uncontrolled hypertension were ascertained using multiple logistic regression analysis. RESULTS: Overall, 40.9% (37.6% to 44.1%) of the hypertensive population had an absolute risk exceeding 20% of having a cardiovascular event in the following 10 years. The distribution of risk factors varies throughout the population. A higher blood pressure reading was strongly associated with an increased likelihood of high absolute risk, but high blood pressure readings in individual patients did not necessarily equate to a high absolute risk. The factors independently associated with uncontrolled hypertension were age, sex, past history of stroke, ischaemic heart disease and transient ischaemic attack, a body mass index greater than 30, diabetes, and current smoking. CONCLUSIONS: Absolute risk assessment maximizes the risk-benefit ratio in treated hypertensive patients. Individual control and management requires multifactorial assessment and management. Treatment of hypertension according to blood pressure reading alone is not a reliable way of reducing the absolute risk of cardiovascular disease.     

Influence of dietary protein level on protein self-selection and plasma and brain amino acid concentrations

Control of protein intake was studied in young rats that were allowed to choose between either protein-free and 55% casein diets or 15% and 55% casein diets. Animals on the protein-free vs. 55% casein regimen exhibited a lower weight gain, a lower cumulative energy intake and a greater cumulative total protein intake during the 13-day study compared to rats selecting between 15% and 55% casein. The daily average proportion of total food selected as casein by animals choosing between protein-free and 55% casein diets increased from 15% to 38% during the course of the study. In contrast, rats choosing between 15% and 55% casein chose 18-22% of total food as protein throughout the entire study. Long-term protein intake or protein selection did not correlate significantly with whole-brain contents of 5-HT or 5-HIAA. Our results suggest that protein intake is not regulated at a constant proportion of total calories, but is controlled between a minimum level that will support rapid growth and a maximum that, if exceeded, would require the animal to undergo substantial metabolic adaptation. The mechanism controlling protein selection may involve diet-induced changes in the brain content of total free indispensable amino acids.     

Complement studies in membranoproliferative glomerulonephritis

Detailed studies of the complement system were carried out in fifteen patients with membranoproliferative glomerulonephritis. The findings of reduced levels of C3 and C7 and of circulating breakdown products of C3 in fresh plasma suggested in vivo complement activation. Low C3 levels were associated with the presence of a serum factor (the C3 nephritic factor C3NeF) which was capable of breaking down C3 in normal serum in vitro. Metabolic studies using radioactive iodine labelled C3 showed no evidence of accelerated in vivo breakdown of parenterally administered C3 suggesting that hypocomplementaemia is either maintained by diminished C3 synthesis or that accelerated catabolism is occurring in a pool that does not freely exchange with parenterally given C3. The C3 nephritic factor has so far only been identified in patients with membranoproliferative nephritis and is therefore of major diagnostic significance in patients with glomerular disease.