1,721,275 research outputs found
Pharmacological regulation of mast cell mediator release in asthma
No full textThis thesis presents the investigation into the pharmacological regulation of mast cell mediator release in asthma, in vivo. The immediate airway response to inhaled allergen has been used as an in vivo model of mast cell activation in atopic asthma and changes in the circulating levels of histamine in plasma and high molecular weight neutrophil chemotactic activity (NCA) in serum as markers of mast cell activation. Both allergenic reactivity and non-specific bronchial reactivity were found to be determinants of the immediate airway response to allergen, the level of non-specific bronchial reactivity determining the pattern of circulating mediator changes following allergen inhalation challenge. In this respect, changes in serum NCA were more sensitive a marker for mast cell activation than changes in plasma histamine. Changes in plasma histamine were only detectable in patients with relatively unreactive airways to non-specific stimuli, indicative of the greater degree of intrapulmonary mast cell degranulation required in these subjects to produce bronchoconstriction. Plasma histamine changes, when they occurred, were, however, significantly greater outside the variance of the baseline measurements than those changes identified with serum NCA, identifying that plasma histamine changes are a more precise marker of intrapulmonary mast cell activation. These changes in plasma histamine were repeatable both within and between subjects. Although basophil derived histamine was found to be an important determinant of resting plasma histamine levels, basophils were not found to contribute to the immediate increments in histamine following allergen inhalation. Using this model, astemizole, a potent and specific oral H1-receptor antagonist, attenuated the immediate airway response to allergen, without influencing mast cell degranulation. Both inhaled salbutamol and sodium cromoglycate were found to inhibit mast cell degranulation in vivo and inhaled ipratropium bromide, which produced equivalent bronchodilatation to salbutamol, had no significant effect on either the airway or mediator responses to allergen inhalation. Salbutamol was found to be more active, as an inhibitor of immunologically stimulated mast cell mediator release, but the inhaled rather than the oral route, despite dose equivalents producing comparable effects on non-specific bronchial reactivity, illustrating the importance of the mucosal mast cell in the immediate interaction with allergen. Although dose equivalents were not calculated, by inhalation, salbutamol was at least 100 times more potent than sodium cromoglycate in inhibiting immunologically stimulated mast cell degranulation. The relevance of these findings to the model of allergic asthma are discussed and question the role of the mast cell in the genesis of allergen induced airway inflammation and bronchial hyperreactivity in asthma.</p
Repeated high-dose inhalation allergen challenge in asthma
No full textIntroduction:? Inhalation allergen challenge in humans is used to investigate lung pathophysiology and responses to novel therapies. However, the single high-dose allergen challenges that are commonly performed do not mimic repeated symptomatic environmental allergen exposure.Objectives:? To develop and evaluate the safety of a repeated high-dose symptomatic inhalation allergen challenge model.Methods:? Sixteen subjects with atopic asthma were recruited. Each underwent three inhalation allergen challenges using house dust mite (Dermatophagoides pteronyssinus) antigen at 48-h intervals with a target of symptom induction and an early asthmatic reaction fall in forced expiratory volume in 1 s (FEV1) of 15% from baseline.Results:? All of the subjects completed the three-challenge protocol and the target immediate airway bronchoconstrictor response was achieved in all the subjects at all challenges. There were no adverse events recorded. The early asthmatic reaction was similar for the three challenges whether measured as mean maximal fall in FEV1 or mean area under the curve. The late asthmatic reaction was also similar over the three challenges with no evidence of priming or desensitisation. Symptom scores and reliever medication use significantly increased over the time of the challenges. Baseline lung function and reversibility was unchanged 4 days after the last challenge.Conclusion:? We demonstrate that repeated high-dose inhaled house dust mite allergen challenge in human volunteers with mild asthma is safe, repeatable and acceptable. This allows the use of this model in further studies focused on understanding the pathophysiology of allergen induced asthma and the impact of therapeutic interventions.<br/
MicroRNAs and respiratory diseases
No full textMicroRNAs (miRNA) are a family of endogenous, small, noncoding RNA molecules that modulate physiological and pathological processes by post-transcriptional inhibition of gene expression. They were first recognised as regulators of development in worms and fruitflies. In recent years extensive research has explored their pivotal role in the pathogenesis of human diseases. Over 1000 human miRNAs have been discovered to date, however the biological function and protein targets for the majority remain to be uncovered. Within the respiratory system, miRNAs are important in normal pulmonary development and maintaining lung homeostasis. Recent studies have also begun to reveal that altered miRNA expression profiles may be associated with pathological processes within the lung and lead to the development of various pulmonary diseases ranging from inflammatory diseases to lung cancers. Advancing our understanding of the role of miRNAs in the respiratory system will help provide new perspectives on disease mechanisms and reveal intriguing therapeutic targets and diagnostics for respiratory disorders
Exhaled volatile organic compounds in adult asthma: a systematic review
No full textThe search for biomarkers that can guide precision medicine in asthma, particularly those that can be translated to the clinic, has seen recent interest in exhaled volatile organic compounds (VOCs). Given the number of studies reporting "breathomics" findings and its growing integration in clinical trials, we performed a systematic review of the literature to summarise current evidence and understanding of breathomics technology in asthma.A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)-oriented systematic search was performed (CRD42017084145) of MEDLINE, Embase and the Cochrane databases to search for any reports that assessed exhaled VOCs in adult asthma patients, using the following terms (asthma AND (volatile organic compounds AND exhaled) OR breathomics).Two authors independently determined the eligibility of 2957 unique records, of which 66 underwent full-text review. Data extraction and risk of bias assessment was performed on the 22 studies deemed to fulfil the search criteria. The studies are described in terms of methodology and the evidence narratively summarised under the following clinical headings: diagnostics, phenotyping, treatment stratification, treatment monitoring and exacerbation prediction/assessment.Our review found that most studies were designed to assess diagnostic potential rather than focus on underlying biology or treatable traits. Results are generally limited by a lack of methodological standardisation and external validation and by insufficiently powered studies, but there is consistency across the literature that exhaled VOCs are sensitive to underlying inflammation. Modern studies are applying robust breath analysis workflows to large multi-centre study designs, which should unlock the full potential of measurement of exhaled volatile organic compounds in airways diseases such as asthma.</p
Asthmatic and normal respiratory epithelial cells respond differently to mechanical apical stress
No full textClinical assessment of speech correlates well with lung function during induced bronchoconstriction
No full textClinical assessment of asthma often includes a crude assessment of speech, for example whether the patient can speak in full sentences. To date, this statement, despite appearing in national asthma guidelines, has not been related to lung function testing in asthma exacerbation. Seven asthmatics underwent a bronchial challenge and were then recorded reading a standardised text for 1?min. The recordings were played to 88 healthcare professionals who were asked to estimate FEV1% predicted. Health care professionals' estimations showed moderate correlation to FEV1% predicted (rho=0.61 P<0.01). There were no significant differences between professionals grouped by seniority or speciality. Speech can intuitively be estimated by health care professionals with moderate accuracy. This gives an evidence basis for the assessment in speech in acute asthma and may provide a new avenue for monitorin
Severe acute respiratory syndrome coronavirus 2 infection in those on mepolizumab therapy
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Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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