Search PubMed⌕ Search

Biomedical subjects

S T Holgate

Publications and source records attributed to S T Holgate.

At least 199 records · Page 11Linked to original sources
PubMed1998

Duration of growth suppressive effects of regular inhaled corticosteroids.

The growth of 50 children receiving regular inhaled corticosteroids was segregated into divisions of six weeks from the start of treatment and compared with their growth when not receiving regular corticosteroids using a random effects regression model. Growth suppression was most marked during the initial six weeks after starting treatment, with most suppression occurring during the initial 18 weeks. Thereafter the children's growth was similar to their growth when not receiving treatment. These findings have important consequences for patterns of treatment of asthma in children.

Anti-Asthmatic Agents↗
PubMed1998

The natural history of respiratory symptoms in a cohort of adolescents.

A cohort of 2,289 children, previously studied at the age of 6-8 yr, were followed up by means of a postal questionnaire when aged 14 -16 yr to examine the association between potential risk factors and the natural history of respiratory symptoms. Children with current symptoms, persistent symptoms, and late-onset symptoms were identified and multivariate analyses were performed to determine the independent association between risk factors and these various symptom-based subgroups. Personal and family history of atopy was significantly associated with all symptom groups and with the presence of doctor-diagnosed asthma. Smoking, either active or passive, was shown to be significantly associated with current, persistent, and late-onset symptoms. Other factors shown to be significantly associated with certain symptom groups were gender (late-onset wheeze), single-parent households (current cough, persistent cough), social class (late-onset wheeze), number of children in the household (persistent wheeze, late-onset cough), number of furry pets in the household (current wheeze), birth weight (late-onset wheeze), and gas cookers (current wheeze, persistent wheeze). In a subgroup of children studied in more detail in 1987, bronchial hyperresponsiveness in 1987 was positively associated with persistent wheeze in 1995, whereas positive skin-prick testing in 1987 was not.

Adolescent↗
PubMed1998

Effects of 0.2 ppm ozone on biomarkers of inflammation in bronchoalveolar lavage fluid and bronchial mucosa of healthy subjects.

Short-term exposure to ozone at peak ambient levels induces neutrophil influx and impairs lung function in healthy humans. In order to investigate the mechanisms contributing to neutrophil recruitment and to examine the role of T-cells in the acute inflammatory response, we exposed 12 healthy humans to 0.2 parts per million (ppm) of ozone and filtered air on two separate occasions for 2 h with intermittent periods of rest and exercise (minute ventilation = 30 L x min(-1)). Fibreoptic bronchoscopy was performed 6 h after the end of exposures. Total protein, tryptase, histamine, myeloperoxidase, interleukin (IL)-8 and growth-related oncogene-alpha (Gro-alpha) were measured and total and differential cell counts were performed in bronchoalveolar lavage (BAL) fluid. Flow cytometry was performed on BAL cells to study total T-cells, T-cell receptors (alphabeta and gammadelta), T-cell subsets (CD4+ and CD8+ cells) and activated T-cell subsets (CD25+). Using immunohistochemistry, neutrophils, mast cells, total T-cell numbers, T-cell subsets, CD25+ T-cells and leukocyte endothelial adhesion molecules including P-selectin, E-selectin, intercellular adhesion molecule (ICAM)-1 and vascular adhesion molecule (VCAM)-1 were quantified in the bronchial biopsies. Paired samples were available from nine subjects. Following ozone exposure there was a threefold increase in the proportion of polymorphonuclear neutrophils (PMNs) (p=0.07) and epithelial cells (p=0.05) in BAL fluid. This was accompanied by increased concentrations of IL-8 (p=0.01), Gro-alpha (p=0.05) and total protein (p=0.058). A significant positive correlation was demonstrated between the two chemokines and proportion of PMNs in BAL fluid. After ozone exposure there was a significant decrease in the CD4/CD8 ratio (p=0.05) and the proportion of activated CD4+ (p=0.01) and CD8+ T-cells (p=0.04). However, no significant changes were demonstrable in any of the inflammatory markers studied in the biopsies. Short-term exposure of healthy humans to 0.2 ppm ozone induced a neutrophil influx in peripheral airways at 6 h post exposure, but no apparent inflammatory response in proximal airways. This response seems to be mediated at least in part by interleukin-8 and growth-related oncogene-alpha.

Adult↗
PubMed1998

Nasal cavity lining fluid ascorbic acid concentration increases in healthy human volunteers following short term exposure to diesel exhaust.

To determine if diesel exhaust (DE) exposure modifies the antioxidant defense network within the respiratory tract lining fluids, a randomized, single blinded, crossover control study using nasal lavage and flexible video bronchoscopy with bronchial and bronchoalveolar lavage was performed. Fifteen healthy, non-smoking, asymptomatic subjects were exposed to filtered air or diluted diesel exhaust (300mg m(-3) particulates, 1.6ppm nitrogen dioxide) for one hour on 2 separate occasions, at least three weeks apart. To examine the kinetics of any DE-induced antioxidant reactions, nasal lavage fluid and blood samples were collected prior to, immediately after, and 5 1/2 hours post exposure. Bronchoscopy was performed 6 hours after the end of DE exposure. Ascorbic acid, uric acid and reduced glutathione (GSH) concentrations were determined in nasal, bronchial, bronchoalveolar lavage and plasma samples. Malondialdehyde (MDA) and protein carbonyl concentrations were determined in plasma and bronchoalveolar lavage samples. Nasal lavage ascorbic acid concentration increased 10-fold during DE exposure [1.02 (0.26-2.09) Vs 7.13 (4.66-10.79) micromol/L(-1)], but returned to basal levels 5.5 hours post-exposure [0.75 (0.26-1.51) micromol/L(-1)]. There was no significant effect of DE exposure on nasal lavage uric acid or GSH concentration. DE exposure did not influence plasma, bronchial wash, or bronchoalveolar lavage antioxidant concentrations and no change in MDA or protein carbonyl concentrations were found. The physiological response to acute DE exposure is an increase in the level of ascorbic acid in the nasal cavity. This response appears to be sufficient to prevent further oxidant stress in the respiratory tract of normal individuals.

Adult↗
PubMed1998

Adhesion molecules and relationship to leukocyte levels in allergic eye disease.

PURPOSE: To evaluate the conjunctival expression of leukocyte cell adhesion molecules (CAMs) and their relationship to leukocyte patterns on the microvasculature in the different clinical subtypes of allergic eye disease. METHODS: Immunohistochemical analysis, using appropriate monoclonal antibodies, was applied to glycolmethacrylate-embedded biopsies of bulbar and tarsal conjunctival tissue. The proportion of total blood vessels expressing a particular CAM was derived and related to individual cell types identified by cell-specific markers, such as mast cells, eosinophils, neutrophils, T cells, and macrophages. Statistical analysis was used to correlate adhesion molecule expression and, ultimately, cell type. RESULTS: There was a basal expression of intercellular adhesion molecule-1 (ICAM-1) (21% bulbar, 18% tarsal), E-selectin (15% bulbar, 21% tarsal), and vascular cell adhesion molecule-1 (VCAM-1) (13% bulbar and tarsal) in normal controls. In seasonal and perennial (bulbar and tarsal conjunctival) allergic tissue, ICAM-1 and E-selectin were expressed in 40% to 78% of vessels; in chronic disease, they were expressed in 45% to 80% of vessels; and in vernal giant papillae, they were expressed in as many as 90% of vessels. There was also increased expression of endothelial VCAM-1 in all forms of allergic eye disease; the greatest values were found in vernal giant papillae (64%). Biopsies taken in winter from seasonal sufferers demonstrated a marked reduction in levels of all three CAMs compared with those taken in the pollen season. This is almost consistent with values found in normal conjunctiva. Positive correlations were found between the levels of ICAM-1 and E-selectin expression and the degree of granulocyte and lymphocyte infiltration, although VCAM-1 expression correlated most closely with eosinophil numbers. CONCLUSIONS: Increased levels of cell adhesion molecules on the microvasculature and the factors that regulate them are likely to be responsible for the infiltration of cells bearing their ligands and may perpetuate inflammation in the chronic forms of allergic eye disease.

Adult↗
PubMed1998

Theophylline inhibits the release of eosinophil survival cytokines--is Raf-1 the protein kinase A target?

Increased numbers of activated eosinophils in bronchial tissue is a feature of asthma and may, in part, be attributed to the prolonged cytokine-dependent survival of eosinophils within the inflamed microenvironment. Low-dose oral theophylline was previously shown to reduce the number of activated eosinophils within the sub-mucosa following allergen exposure. A number of inhibitory actions of theophylline have been described which relate to eosinophil recruitment and activation, including inhibition of cell migration and release of granule basic proteins. In this study we investigated the ability of theophylline to inhibit the release of preformed GM-CSF and IL-8 from eosinophils in vitro, as these cytokines may serve an autocrine function in eosinophil survival in vivo. Eosinophils rapidly released GM-CSF and IL-8 spontaneously, and release was further enhanced in response to sIgA-coated beads. Theophylline inhibited the stimulated, but not the spontaneous, release of both cytokines. We previously reported the role of protein kinase A in inhibition of arachidonic acid mobilization and LTC4 synthesis. Therefore we speculate that cAMP-dependent activation of protein kinase A following theophylline treatment of eosinophils resulted in inhibition of Raf-1 and MAPK/MAPKK dependent activation of phospholipase A2 and consequently inhibition of degranulation and cytokine release.

Bronchodilator Agents↗
PubMed1997

Effect of inhaled corticosteroids on episodes of wheezing associated with viral infection in school age children: randomised double blind placebo controlled trial.

OBJECTIVES: To determine the effect of regular prophylactic inhaled corticosteroids on wheezing episodes associated with viral infection in school age children. DESIGN: Randomised, double blind, placebo controlled trial. SETTING: Community based study in Southampton. SUBJECTS: 104 children aged 7 to 9 years who had had wheezing in association with symptoms of upper and lower respiratory tract infection in the preceding 12 months. INTERVENTIONS: After a run in period of 2-6 weeks children were randomly allocated twice daily inhaled beclomethasone dipropionate 200 micrograms or placebo through a Diskhaler for 6 months with a wash out period of 2 months. Children were assessed monthly. MAIN OUTCOME MEASURES: Forced expiratory volume in 1 second (FEV1); bronchial responsiveness to methacholine (PD20); percentage of days with symptoms of upper and lower respiratory tract infection with frequency, severity, and duration of episodes of upper and lower respiratory symptoms and of reduced peak expiratory flow rate. RESULTS: During the treatment period there was a significant increase in mean FEV1 (1.63 v 1.53 1; adjusted difference 0.09 1 (95% confidence interval 0.04 to 0.14); P = 0.001) and methacholine PD20 12.8 v 7.2 mumol/l; adjusted ratio of means 1.7 (1.2 to 2.4); P = 0.007) in children receiving beclomethasone dipropionate compared with placebo. There were, however, no significant differences in the percentage of days with symptoms or in the frequency, severity, or duration of episodes of upper or lower respiratory symptoms or of reduced peak expiratory flow rate during the treatment period between the two groups. CONCLUSIONS: Although lung function is improved with regular beclomethasone dipropionate 400 micrograms/day, this treatment offers no clinically significant benefit in school age children with wheezing episodes associated with viral infection.

Administration, Inhalation↗
PubMed1997

Age specific trends in asthma mortality in England and Wales, 1983-95: results of an observational study.

OBJECTIVE: To determine trends in asthma mortality by age group in England and Wales during 1983-95. DESIGN: Observational study. SETTING: England and Wales. SUBJECTS: All deaths classified as having an underlying cause of asthma registered from 1 January 1983 to 31 December 1995. MAIN OUTCOME MEASURE: Time trends for age specific asthma deaths. RESULTS: Deaths in the age group 5-14 years showed an irregular downward trend during 1983-95; deaths in the age groups 15-44, 45-64, and 65-74 years peaked before 1989 and then showed a downward trend; and deaths in the age group 75-84 years peaked between 1988 and 1993 and subsequently dropped. Trends were: age group 5-14 years, 6% (95% confidence interval 3% to 9%); 15-44 years, 6% (5% to 7%); 45-64 years, 5% (4% to 6%); 65-74 years, 2% (1% to 3%). Deaths in the 75-84 and 85 and over categories plateaued. CONCLUSIONS: There are downward trends in asthma mortality in Britain, which may be due to increased use of prophylactic treatment.

Adolescent↗
PubMed1997

Differential inhibitory effect of regular inhaled corticosteroid on airway responsiveness to adenosine 5' monophosphate, methacholine, and bradykinin in symptomatic children with recurrent wheeze.

Indirect tests of bronchial responsiveness to agents such as adenosine 5'-monophosphate (AMP) or bradykinin might be more specific markers of a therapeutic responses to anti-inflammatory treatment than a test of direct responsiveness to agents such as methacholine. In children selected from the community on the basis of mildly symptomatic wheeze, we compared in a randomized, double-blind study design the effect of 400 micrograms/day of beclomethasone dipropionate (BDP) or placebo on three separate ways of provoking bronchial responsiveness, using methacholine, bradykinin, and AMP as the provoking agents. Following pretreatment bronchial challenges, 29 children received paired monthly methacholine and AMP challenges for 3 months, while for the same period another 33 children received paired monthly methacholine and bradykinin challenges. Compared with placebo-treated subjects, FEV1 increased significantly in the children receiving BDP. This improvement was observed in those randomized to either the AMP challenge or the bradykinin challenge. In children challenged with AMP, the PD20 AMP increased significantly after 1 month and 2 months of BDP therapy when compared with placebo, while under similar conditions the PD20 methacholine was not significantly affected. In children challenged with bradykinin, BDP therapy did not significantly alter either the PD20 bradykinin or PD20 methacholine. We conclude that a bronchial challenge with AMP appears to be a more sensitive predictor of response to anti-inflammatory treatment than either methacholine or bradykinin.

Adenosine Monophosphate↗
PubMed1997

Asthma: a dynamic disease of inflammation and repair.

It is now widely accepted that asthma in its varied forms is an inflammatory disorder of the airways in which mediator release from activated mast cells and eosinophils plays a major role. T lymphocytes take a primary role in orchestrating these processes through their capacity to generate a range of cytokines of the interleukin 4 gene cluster encoded on the long arm of chromosome 5. Additional cytokines derived from mast cells and eosinophils also play a key role, especially tumour necrosis factor alpha, which is responsible for initiating the up-regulation of vascular adhesion molecules involved in the recruitment of eosinophils and other inflammatory cells from the circulation. The importance of C-X-C and C-C chemokines as local chemoattractants and activating stimuli is also recognized. In addition to releasing an array of pharmacologically active autacoids, the inflammatory response in asthma results in the generation of proteolytic activities from mast cells (tryptase, chymase), eosinophils (MMP-9) and the epithelium itself (MMP-2, MMP-9), which exert tissue-destructive and cell-signalling effects. The epithelium is also highly activated, as evidenced by the up-regulation of cytokine production, inducible enzymes and soluble mediators. Increased surface expression of the epithelial isoform of CD44 (9v) and subepithelial proliferation of myofibroblasts are indicative of a simultaneous active repair process and the laying down of new interstitial collagens. Together, inflammatory and repair processes create the complex phenotype that characterizes asthma and its progression.

Asthma↗
PubMed1997

Pattern of usage and somatic hypermutation in the V(H)5 gene segments of a patient with asthma: implications for IgE.

The V(H)5 family contains two functional genes, V5-51 and V(H)32, and appears to be over-represented in IgE antibodies from patients with allergic disease. Previous sequence analysis of V(H)5 gene segments in IgE has revealed a substantial level of somatic hypermutation, with evidence for hotspots. To assess characteristics of V(H)5 gene behavior, V(H)5 gene segments in combination with C mu, C gamma, C alpha, and C epsilon have been amplified from blood B lymphocytes of a patient with atopic asthma. Sequence analysis revealed strong preferential usage of one of the two V(H)5 gene segments (V5-51) by IgM, IgG, and IgA. In contrast, IgE used both genes equally. Levels of somatic mutation were higher following all isotype switches, particularly to IgA. Mutational hotspots were identifiable in all isotypes, leading to several common replacement amino acids. The dominant mutational site in IgM was a common hotspot at Ser31. IgG, IgA, and IgE-derived sequences had mainly common hotspots, with few distinct sites. The results indicate that mutational hotspots are a feature of the V(H)5 gene, are identifiable at an early stage of somatic hypermutation, and are not a unique feature of IgE. Generation of IgE antibodies appears to involve three processes: the preferential use of V(H)5 genes, consistent with superantigen stimulation; the accumulation of somatic mutations in common hotspots, some of which are in complementarity-determining regions (CDR); and the acquisition of non-hotspot mutations in CDR, accounting for approximately 50% of replacement amino acids in these sites, and presumably contributing to affinity maturation.

Adult↗
PubMed1997

Immunoreactive endothelin in bronchial biopsy specimens: increased expression in asthma and modulation by corticosteroid therapy.

BACKGROUND: The human endothelin (ET) family comprises three 21-amino-acid peptides, which are potent bronchoconstrictors and have a number of other biologic properties relevant to the pathophysiology of asthma. OBJECTIVE: We sought to compare the expression of immunoreactive ET in bronchial biopsy specimens from subjects with asthma treated only with inhaled beta2-agonists, subjects with asthma treated with beta2-agonists and corticosteroids, and control subjects without asthma. METHODS: Biopsy specimens were obtained by fiberoptic bronchoscopy and stained immunohistochemically with a specific ET antiserum. Epithelial ET expression was quantitated by using a computer-assisted system of image analysis. Numbers of inflammatory cells and depth of subepithelial collagen deposition were also determined. RESULTS: Immunoreactive ET was principally localized in the airway epithelium. The proportion of epithelium immunostained was significantly increased in the subjects with asthma not treated with steroids (35.4% +/- 3.8%) compared with that of both the control subjects (16.2% +/- 1.9%, p < 0.0001) and the subjects with asthma treated with steroids (14.3% +/- 2.0%, p < 0.0001). The last two groups did not differ significantly from one another. There were no significant correlations between ET expression and either physiologic parameters or indexes of airway inflammation and remodeling. CONCLUSION: Bronchial epithelial expression of immunoreactive ET is increased in subjects with asthma receiving treatment only with beta2-agonists but not in subjects with asthma also receiving corticosteroid therapy. These findings are consistent with the hypothesis that ET is implicated in the pathophysiology of asthma.

Adrenal Cortex Hormones↗
PubMed1997

The glutamine 27 beta2-adrenoceptor polymorphism is associated with elevated IgE levels in asthmatic families.

BACKGROUND: The beta2-adrenoceptor polymorphisms occurring at amino acid positions 16 (arginine to glycine) and 27 (glutamine to glutamate) are known to be functionally relevant and also disease-modifying in subjects with asthma. However, the contribution of these polymorphisms to the development of the asthmatic phenotype or other markers for allergic disease remains to be established. OBJECTIVE: This large family study examines the contributions of these polymorphisms in determining the heritable component of markers for allergic disease in asthmatic families. METHODS: Three hundred twenty-four individuals from 60 families multiplex for asthma selected by means of an asthmatic proband were characterized for the following markers of allergic disease: asthma, atopy, and serum IgE. The polymerase chain reaction was used to generate a 234 base pair fragment spanning the region of interest, and the beta2-adrenoceptor polymorphism was then defined by allele-specific oligonucleotide hybridization. Segregation analysis was then performed. RESULTS: We found a significant association (p = 0.009) between the glutamine 27 beta2-adrenoceptor polymorphism and elevated levels of IgE, which was supported by the observation of linkage between IgE and beta2-adrenoceptor polymorphisms at locus 27 (p = 0.037). However, there was no association between either the arginine-glycine 16 or the glutamine-glutamate 27 beta2-adrenoceptor polymorphism and an increased risk of asthma or atopy per se. CONCLUSION: The glutamine 27 beta2-adrenoceptor polymorphism appears to contribute to IgE variability in families with asthma. However, it seems that although both amino acid 16 and 27 beta2-adrenoceptor polymorphisms are disease-modifying in subjects with asthma, they do not contribute markedly to the development of the asthmatic phenotype.

Adult↗