957 research outputs found
A new look at the pathogenesis of asthma
No full textAsthma is an inflammatory disorder of the conducting airways that has strong association with allergic sensitization. The disease is characterized by a polarized Th-2 (T-helper-2)-type T-cell response, but in general targeting this component of the disease with selective therapies has been disappointing and most therapy still relies on bronchodilators and corticosteroids rather than treating underlying disease mechanisms. With the disappointing outcomes of targeting individual Th-2 cytokines or manipulating T-cells, the time has come to re-evaluate the direction of research in this disease. A case is made that asthma has its origins in the airways themselves involving defective structural and functional behaviour of the epithelium in relation to environmental insults. Specifically, a defect in barrier function and an impaired innate immune response to viral infection may provide the substrate upon which allergic sensitization takes place. Once sensitized, the repeated allergen exposure will lead to disease persistence. These mechanisms could also be used to explain airway wall remodelling and the susceptibility of the asthmatic lung to exacerbations provoked by respiratory viruses, air pollution episodes and exposure to biologically active allergens. Variable activation of this epithelial-mesenchymal trophic unit could also lead to the emergence of different asthma phenotypes and a more targeted approach to the treatment of these. It also raises the possibility of developing treatments that increase the lung's resistance to the inhaled environment rather than concentrating all efforts on trying to suppress inflammation once it has become established.<br/
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/
δ Orionis: Further temporal variability and evidence for small-scale structure in the interstellar medium
No full textWe report here the detection of both spatial and temporal variations in interstellar absorption in the line of sight to δ Orionis. First, we present new high-resolution (R≈110 000) observations of the interstellar D lines of Na i towards both δ Ori A and C. Comparison of these spectra highlights variations in absorption between the two stars, indicative of small-scale spatial structure in the interstellar medium in this direction over distances of less than ≈15 000 au (the projected separation of the two stars). Components with the largest Na i column densities and lowest velocity dispersions are, in general, found to be subject to the greatest differences; in fact the narrowest component detected is only observed in one of the sightlines. This effect has also been reported by Meyer & Blades. Secondly, we present new ultra-high-resolution (R≈900 000) Na i D1 observations and high-resolution (R≈110 000) Ca ii H & K observations of δ Ori A which, through ultra-high-resolution work conducted between 1994 and 2000, has been shown to exhibit a time-variable interstellar Na i absorption component. These new observations, while revealing the further reduction in intensity of the time-variable Na i absorption, indicate constant Ca ii absorption over the same period. This results in a dramatic reduction in the Na°/Ca+ abundance ratio, perhaps indicating the line of sight to be gradually probing a less-dense outer region of an absorbing filament
Airway inflammation in atopic patients: a comparison of the upper and lower airways
No full textObjective. The purpose of this study was to understand and assess the inflammatory response within the upper and lower airways in patients suffering from both asthma and allergic rhinitis. Study Design. Cross-sectional study. Setting. A laboratory-based study of patients with allergic rhinitis and asthma. Subjects and Methods. Glycol methacrylate resin-embedded specimens from 10 patients with allergic rhinitis and asthma taken from the nose and bronchi were assessed by immunohistochemistry. Monoclonal antibodies directed against specific cell markers for mast cells (AA1), eosinophils (EG2), neutrophils (NOE), and lymphocytes (CD3(+), CD4(+), CD8(+)) were studied. Cells were counted blind (as cells/mm(2)) in the submucosal matrix. Mann-Whitney U test was used for analyses. P values of .05 or lower were considered statistically significant. Results. There was a significant increase in CD4(+) (P = .05) and CD8(+) cell counts (P = .001) in the lower airway compared to the upper airway. There were no differences between the 2 groups in the number of neutrophils, mast cells, eosinophils, and the CD3(+) cell counts. Conclusion. The upper and lower airways have parallel inflammation with possible bidirectional extension of inflammation in patients suffering from asthma and allergic rhinitis. There is increased lymphocytic infiltration in the lower airway, suggesting a possible preponderance for development and maintenance of allergic disease in the lower airway
Analysis of allergen immunotherapy studies shows increased clinical efficacy in highly symptomatic patients
No full textBackground: the assessment of allergen immunotherapy (AIT) efficacy in the treatment for seasonal allergic rhinoconjunctivitis (SAR) symptoms is challenging. Allergen immunotherapy differs from symptomatic therapy in that while symptomatic therapy treats patients after symptoms appear and aims to reduce symptoms, AIT is administered before symptoms are present and aims to prevent them. Thus, clinical studies of AIT can neither establish baseline symptom levels nor limit the enrolment of patients to those with the most severe symptoms. Allergen immunotherapy treatment effects are therefore diluted by patients with low symptoms for a particular pollen season. The objective of this analysis was to assess the effect possible to achieve with AIT in the groups of patients presenting the most severe allergic symptoms.Methods: study centres were grouped into tertiles categorized according to symptom severity scores observed in the placebo patients in each centre (low, middle and high tertiles). The difference observed in the average score in each tertile in active vs placebo-treated patients was assessed. This allowed an estimation of the efficacy that could be achieved in patients from sites where symptoms were high during the pollen season.Results: an increased treatment effect was observed in the most severe patients and was independent of the study analysed and symptom score used.Conclusions: the use of a tertile approach to analyse efficacy in AIT in SAR clinical studies can give a more accurate assessment of potential clinical benefi
Evaluation of a rapid lateral flow immunoassay for Staphylococcus aureus detection in respiratory samples
No full textRapid point-of-care pathogen detection remains a challenge in routine diagnostics. A Staphylococcus aureus-specific lateral flow immunochromatography (LFI) test has been developed using a specific monoclonal antibody to the S. aureus cell-wall peptidoglycan. The LFI test was shown to be specific for S. aureus with no signal development for other Staphylococcal species or common respiratory pathogens. Evaluation of S. aureus isolates spiked into induced sputum and bronchoalveolar lavage samples derived from severe asthmatic patients showed a detection limit of 10(6) CFU/mL for the LFI. The test was also shown to successfully detect S. aureus in 1 sample independently determined to be S. aureus positive by quantitative polymerase chain reaction. The ability of the LFI test to rapidly detect S. aureus in clinical respiratory samples suggests that it might be a useful platform for further development of point-of-care diagnostic applications
Transforming growth factor-beta promotes rhinovirus replication in bronchial epithelial cells by suppressing the innate immune response
No full textRhinovirus (RV) infection is a major cause of asthma exacerbations which may be due to a deficient innate immune response in the bronchial epithelium. We hypothesized that the pleiotropic cytokine, TGF-?, influences interferon (IFN) production by primary bronchial epithelial cells (PBECs) following RV infection. Exogenous TGF-?(2) increased RV replication and decreased IFN protein secretion in response to RV or double-stranded RNA (dsRNA). Conversely, neutralizing TGF-? antibodies decreased RV replication and increased IFN expression in response to RV or dsRNA. Endogenous TGF-?(2) levels were higher in conditioned media of PBECs from asthmatic donors and the suppressive effect of anti-TGF-? on RV replication was significantly greater in these cells. Basal SMAD-2 activation was reduced when asthmatic PBECs were treated with anti-TGF-? and this was accompanied by suppression of SOCS-1 and SOCS-3 expression. Our results suggest that endogenous TGF-? contributes to a suppressed IFN response to RV infection possibly via SOCS-1 and SOCS-3
Elevation of Candida IgG antibodies in patients with medically unexplained symptoms
No full textBackground: The hypothesis that an immunologic reaction to Candida yeasts, present in the gastrointestinal tract, causes a diffuse collection of multisystem symptoms is not generally accepted within conventional medicine. A questionnaire, the Fungus Related Disease Questionnaire (FRDQ-7), was previously developed and used to identify patients for a randomized, placebo-controlled trial of the nonabsorbed antifungal drug nystatin. Nystatin was superior to placebo in relieving these symptoms. This provides some support for the hypotheses that underpin the "Candida syndrome". Aim: The aim of this study was to identify a population with a high (>9) FRDQ-7 score and symptom-free controls and, subsequently, to explore the relationship between FRDQ-7 scores and Candida immunoglobulin (Ig)A, IgG, and IgM levels. Design: This was a case-controlled study. Methods: Santelmann has suggested that the FRDQ-7 describes people with Candida syndrome if the FRDQ-7 score is >9; 35 patients with medically unexplained symptoms, between ages 18 and 64, were selected for the study if they scored > 9 on the FRDQ-7 questionnaire. Serum Candida IgA, IgG, and IgM measurements were undertaken both for this group and a group of 45 healthy age- and gender-matched controls, and the Ig concentrations were compared. Results: Candida IgG concentration was significantly higher in the noncontrol group than in the control group (p < 0.001). No significant difference was found for Candida IgA or IgM concentrations. Conclusions: Further studies are required to identify whether there is a causal link for the elevation of serum IgG found in this subgroup of patients with increased FRDQ-7 scores, or whether these two observations are parallel manifestations of a common underlying disorder
Expression of c-erbB receptors and ligands in human nasal epithelium
No full textBackground: The epidermal growth factor (EGF) family of growth factors plays an important role in maintenance and repair in a variety of epithelial tissues. However, very little is known about coexpression of these factors and their receptors, the c-erbB family of receptor tyrosine kinases, in human nasal epithelium. Objective: We sought to investigate the expression of these molecules in cultured nasal epithelial cells and nasal mucosa from healthy individuals. Methods: Identification of c-erbB receptors and their ligands was sought by using reverse transcription PCR, Western blotting, and immunohistochemistry. Results: Messenger RNA encoding the EGF receptors (EGFR) c-erbB2 and c-erbB3, but not c-erbB4, was detected in primary cultures of human nasal epithelial cells. Transcripts encoding EGF, heparin-binding EGF, transforming growth factor (TGF) ?, and amphiregulin were also detected. Receptor and ligand expression was confirmed by using immunocytochemical staining of the cells and Western blotting of the cell lysates. Immunohistochemical analysis of tissue sections obtained from biopsy specimens of nasal mucosa revealed intense membrane staining for the EGFR within the respiratory nasal epithelium, which was predominantly localized at the level of the columnar epithelial layers. Similar staining patterns were observed for c-erbB2 and c-erbB3 in the respiratory nasal epithelium. Evidence for EGF, transforming growth factor ?, heparin-binding EGF, amphiregulin, and betacellulin immunostaining in the nasal epithelium was also obtained; their staining patterns paralleled that of EGFR immunostaining. Conclusion: Colocalization of c-erbB receptors and ligands establishes a basis on which to investigate c-erbB receptor– mediated effects in human nasal epithelium
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