Role of conformational constraints of position 7 of the disulphide bridge of h-alpha-CGRP derivatives in their agonist versus antagonist properties

<p>Previous structure-activity studies have shown that the disulphide bridge of calcitonin gene-related peptide (CGRP) is important for the highly potent, CGRP receptor-mediated effects of this peptide. In this study penicillamine (Pen) was substituted for one or both of the cysteinyl residues to determine conformational and topographical properties of the disulphide bridge favourable for binding to CGRP receptors and/or receptor activation. Pen constrains the conformational flexibility of disulphide bridges in other peptides. Binding affinities were measured using a radioligand binding assay with membranes prepared from pig coronary arteries and I-125-h-alpha-CGRP. Functional effects were characterized using a previously reported pig coronary artery relaxation bioassay. The binding affinity of [Pen(2)]h-alpha-CGRP was not significantly different from that of h-alpha-CGRP. All other analogues showed reduced affinity for CGRP receptors. [Pen(2)]h-alpha-CGRP also caused relaxation of coronary arteries. The remaining analogues either caused relaxation with significantly reduced potency or failed to relax the arteries at concentrations up to 1 x 10(-5) M. All analogues that did not relax coronary arteries contained a D-Pen in position 7 and inhibited CGRP-induced relaxation. [D-Pen(2,7)]h-alpha- CGRP was the most potent antagonist with a K-B value of 630 nM. This affinity is similar to that of the classical CGRP receptor antagonist, h-alpha-CGRP(8-37), on these arteries (K-B, 212 nM). These studies show that modifying the topography of the disulphide bridge can cause large and variable effects on ligand binding and activation of CGRP receptors. The contribution of position 7 to the conformation and topography of the disulphide bridge of h-alpha-CGRP is crucial to the future design of agonists of CGRP receptors. Furthermore, position 7 is important for the development of new CGRP receptor antagonists with structures based on the whole sequence of h-alpha-CGRP.p>

Occupational stress in the chef profession

Purpose – The purpose of this paper is to consider the occupational stress experienced by chefs and the moderating influence of coping behaviour and locus of control on stress outcomes. Design/methodology/approach – A total of 40 working chefs were surveyed. They were asked to complete an occupational stress questionnaire, the General Health Questionnaire. Differences werer/>sought between gender and locus of control and stress measures, and correlations were carried out between key variables. Findings – The reported stress was markedly higher than in previous research. Excessive workload,r/>feeling undervalued and communication issues were common and bullying and threats of violence were present for some. Unexpectedly, locus of control was unable to predict stress experiences. Explanations were offered, such as the possibility that those who perceive they have a strong sense of control may believe that this, paradoxically, affords them the opportunity to engage in unhealthy behaviours. Research limitations/implications – Limitations of the research include the influence of the wider environment, specifically the history of political violence in the province, and its possible effect on stress outcomes. However, this may be negated by the many positive effects peace has brought over the last decade. In drawing conclusions it is important to note the limitations of the sample size and the self-reporting nature of survey responses. Further research could usefully incorporate well-being as well as stress measures, including physiological ones. It would be worth exploring further how one’s sense of control affects perceptions of stress and, in turn, the coping behaviours engaged in. Practical implications – Practical implications include the need for managers and head chefs to provide more feedback to employees, to validate their good work and to foster a supportive working environment. Norms in the working environment endorsing aggressive behaviour must be challenged.r/>Staff appraisals should consider the need to have work that involves variety and challenge, especially where changes involve increases in workload. Originality/value – This paper identifies some important ingredients to reduce distress and it will be of value to chefs and other kitchen staff and, more broadly, to those involved in people management.

Obesity associated severe asthma represents a distinct clinical phenotype - Analysis of the British Thoracic Society Difficult Asthma Registry patient cohort according to body mass index

BACKGROUND: Obesity has emerged as a risk factor for the development of asthma and it may also influence asthma control and airways inflammation. However, the role of obesity in severe asthma remains unclear. OBJECTIVE: To explore the association between obesity (defined by BMI) and severe asthma. METHODS: Data from the National Registry for dedicated UK Difficult Asthma Services were used to compare patient demographics, disease characteristics and healthcare utilisation between three body mass index (BMI) categories (normal weight: 18.5 -24.99, overweight: 25 -29.99, obese: =30) in a well characterised group of severe asthmatic adults. RESULTS: The study population consisted of 666 severe asthmatics with a median BMI of 29.8 (interquartile range 22.5 -34.0). The obese group exhibited greater asthma medication requirements in terms of maintenance corticosteroid therapy (48.9% versus 40.4% and 34.5% in the overweight and normal weight groups, respectively), steroid burst therapy and short-acting ß2-agonist (SABA) use per day. Significant differences were seen with gastro-oesophageal reflux disease (GORD) (53.9% versus 48.1% and 39.7% in the overweight and normal weight groups, respectively) and proton pump inhibitor (PPI) use. Bone density scores were higher in the obese group, whilst pulmonary function testing revealed a reduced FVC and raised Kco. Serum IgE levels decreased with increasing BMI and the obese group were more likely to report eczema, but less likely to have a history of nasal polyps. CONCLUSIONS: Severe asthmatics display particular characteristics according to BMI that support the view that obesity associated severe asthma may represent a distinct clinical phenotype.1Royal Brompton Hospital, London, UK;2Department of Computing, Imperial College, UK3Airways Disease, National Heart &amp; Lung Institute, Imperial College, UK;4Centre for infection and immunity, Queen's University of Belfast, UK;5University of Leicester, UK;6The University of Manchester and University Hospital of South Manchester, UK;7Birmingham Heartlands Hospital, University of Birmingham, UK;8Gartnavel General Hospital, University of Glasgow, UK;9Glasgow Royal Infirmary, Glasgow, UKCorrespondence: Dr Andrew N. Menzies-Gow, Royal Brompton Hospital, Fulham Road, London SW3 6HP.