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Biomedical subjects

N C Barnes

Publications and source records attributed to N C Barnes.

At least 19 recordsLinked to original sources
PubMed2006

Antibiotics for exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: Most patients with an exacerbation of chronic obstructive pulmonary disease (COPD) are treated with antibiotics. However the value of their use remains uncertain. Some controlled trials of antibiotics have shown benefit (Berry 1960; Pines 1972) while others have not (Elmes 1965b; Nicotra 1982). OBJECTIVES: To conduct a systematic review of the literature estimating the value of antibiotics in the management of acute COPD exacerbations. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2005); MEDLINE (1966 to December 2005); EMBASE (1974 to December 2005); Web of Science (December 2005), and other electronically available databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) in patients with acute COPD exacerbations comparing antibiotic (for a minimum of five days) and placebo. DATA COLLECTION AND ANALYSIS: Data were analysed using Review Manager software. Continuous data were analysed using weighted mean differences (WMD) and 95% confidence intervals (CI). Relative risks (RR) (and 95% CI) were calculated for all dichotomous data. Where appropriate, number needed to treat to benefit (NNT) and 95% CI were calculated. MAIN RESULTS: Eleven trials with 917 patients were included. Ten trials used increased cough, sputum volume and purulence diagnostic criteria for COPD exacerbation. Eight-hundred and fifty-seven patients provided data for outcomes including mortality, treatment failure, increased sputum volume, sputum purulence, PaCO(2), PaO(2), peak flow and adverse events. Antibiotic therapy regardless of antibiotic choice significantly reduced mortality (RR 0.23; 95% CI 0.10 to 0.52 with NNT of 8; 95% CI 6 to 17), treatment failure (RR 0.47; 95% CI 0.36 to 0.62 with NNT of 3; 95% CI 3 to 5) and sputum purulence (RR 0.56; 95% CI 0.41 to 0.77 with NNT of 8; 95% CI 6 to 17). There was a small increase in risk of diarrhoea with antibiotics (RR 2.86; 95% CI 1.06 to 7.76). Antibiotics did not improve arterial blood gases and peak flow. AUTHORS' CONCLUSIONS: This review shows that in COPD exacerbations with increased cough and sputum purulence antibiotics, regardless of choice, reduce the risk of short-term mortality by 77%, decrease the risk of treatment failure by 53% and the risk of sputum purulence by 44%; with a small increase in the risk of diarrhoea. These results should be interpreted with caution due to the differences in patient selection, antibiotic choice, small number of included trials and lack of control for interventions that influence outcome, such as use of systemic corticosteroids and ventilatory support. Nevertheless, this review supports antibiotics for patients with COPD exacerbations with increased cough and sputum purulence who are moderately or severely ill.

Anti-Bacterial Agents↗
PubMed2006

Variability of bronchial inflammation in chronic obstructive pulmonary disease: implications for study design.

There is variability in the distribution of inflammatory cells in bronchial tissue in chronic obstructive pulmonary disease (COPD). Better strategies for biopsy sampling of the airway mucosa may improve the capacity to show a difference between study populations where variability in distribution exists. The current authors have examined sources of biological variability in the quantification of inflammatory cells in endobronchial biopsies using immunostained samples taken from 51 subjects with COPD, with a mean forced expiratory volume in one second of 1.71 L, 55% predicted. The distribution of variance contributed by different sources was similar for different inflammatory cell types. For CD8+ cells, a key inflammatory cell in COPD, the largest contribution to intra-subject variability (39%) was time (i.e. 10 weeks between biopsies of placebo-treated subjects), followed by airway generation (23%), biopsy (2.5%), zone (within section; 1.4%) and section (0.4%). Power calculations demonstrated that examining one section from one biopsy, from each of two airway generations, would require a sample size of 32 subjects per group to show a difference of one doubling or halving in CD8+ cells, compared with 47 subjects per group if only one airway generation was sampled. Therefore, biopsies from more than one airway generation should be examined in order to maximise statistical power to detect a difference between study groups.

Adult↗
PubMed2005

Raft localisation of FcgammaRIIa and efficient signaling are dependent on palmitoylation of cysteine 208.

Ligand-dependent aggregation of FcgammaRIIa initiates multiple biochemical processes including the translocation to detergent resistant membrane domains (DRMs) and receptor tyrosine phosphorylation. Palmitoylation of cysteine residues is considered to be one process that assists in the localisation of proteins to DRMs. Within the juxtamembrane region of FcgammaRIIa there is cysteine residue (C208) that we show to be palmitoylated. Mutation of this cysteine residue results in the disruption of FcgammaRIIa translocation to DRMs as empirically defined by insolubility at high Triton X-100 concentrations. This study also demonstrates that the lack of lipid raft association diminishes FcgammaRIIa signaling as measured by receptor phosphorylation and calcium mobilisation functions suggesting that FcgammaRIIa signaling is partially dependent on lipid rafts.

Animals↗
PubMed2005

Unscheduled healthcare resource use among asthma patients receiving low-dose inhaled corticosteroids maintenance treatment.

This survey describes asthma control and unscheduled healthcare resource use (HCRU) among patients receiving low-dose inhaled corticosteroids (ICS) alone in five European countries and the USA. Physicians and patients completed forms collecting data on asthma symptoms, sudden increase in chest/respiratory symptoms, asthma-related HCRU, quality of life (QoL) and drug therapy. Fifty-seven per cent of patients on low-dose ICS alone had physician-rated moderate or severe asthma. Only 13% of patients receiving low-dose ICS alone achieved asthma control; 36% reported nocturnal wakening and 22% reported unscheduled healthcare services in the past year. Gender, symptom frequency, episodes of sudden increase in chest/respiratory symptoms and impaired QoL were all related to unscheduled healthcare resource utilisation. Many patients receiving low-dose ICS alone do not have adequate asthma control. Some patient characteristics were found to be significantly different, but not exclusive, between unscheduled healthcare resource users and non-users.

Adolescent↗
PubMed2005

Sputum induction in corticosteroid-dependant asthmatics: risks and airway cellular profile.

Sputum induction with nebulized hypertonic saline is increasingly being used to evaluate airway inflammation. We investigated the procedure-associated risk in 16 asthmatics that were still symptomatic despite on high doses of regular corticosteroid (CS) therapy (7 on daily inhaled CS > or = 800 microg budesonide or equivalent; 9 on additional daily oral CS) and their sputum cellular profile. For comparison, 12 mild stable asthmatics and 10 normal healthy subjects were included. All subjects inhaled 3%, 4% and 5% hypertonic saline sequentially via ultrasonic nebulizer as a means to induce sputum. Maximal percentage fall of Forced Expiratory Volume on One Second (FEV1) during sputum induction was significantly greater in CS-dependent asthmatics (median % [IQR]: 16.0 [11.0-32.3]) than in mild asthmatics (5.3 [4.2-10.8], p = 0.002] and in normal subjects (4.6 [3.4-6.4]), p = 0.0001). The maximal percentage FEV1 fall was inversely correlated with baseline FEV1 (Rs= -0.69; p < 0.0001). Compared to mild asthmatics, induced sputum from CS-dependant asthmatics had proportionately fewer eosinophils (2.2 [0.8-7.0] versus 23.3% [10.7-46.3], p = 0.003) and greater neutrophils (64.2 [43.9-81.2] versus 28.7 [19.0-42.6], p = 0.009). Sputum neutrophils showed a significant inverse correlation to FEV1 (Rs = -0.51, p = 0.01). We concluded that sputum induction using nebulized hypertonic saline should be performed with caution in CS-dependant asthmatics. The airway cellular profile observed suggests that the immunopathology underlying CS-dependant asthmatics may be different or a consequence of CS therapy.

Adrenal Cortex Hormones↗
PubMed2004

Safety of research bronchoscopy, biopsy and bronchoalveolar lavage in asthma.

Bronchoscopy with endobronchial biopsy (EBB) and/or bronchoalveolar lavage (BAL) has become an important research tool in asthma. A recent report has suggested audit and reporting of the safety of these procedures. A total of 159 asthmatic patients (84 males, 75 females), aged 18-52 (median 27) yrs, forced expiratory volume in one second 53-120 (median 88) % predicted, underwent 273 bronchoscopies in six clinical research studies. On 228 occasions, EBB and BAL were performed and, on 45 occasions, EBB was performed alone. On 48 occasions, bronchoscopy was performed 24 h post-allergen challenge. Adverse events occurred on 34 out of 273 occasions, none of which were following allergen challenge. Post-EBB and BAL, four patients developed pleuritic chest pain, shortness of breath and fever. A further two patients experienced pleuritic chest pain alone post-EBB/BAL. Bronchospasm or worsening of asthma symptoms occurred on 14 occasions, 13 post-EBB/BAL and on one occasion post-EBB alone. Fever/flu-like symptoms were reported on nine occasions following EBB and BAL. One subject had haemoptysis post-EBB/BAL, but required no intervention. In conclusion, bronchoscopy, endobronchial biopsy and bronchoalveolar lavage can be performed safely in asthmatic patients. Most of the complications were seen where bronchoalveolar lavage and endobronchial biopsy were both performed, suggesting that bronchoalveolar lavage accounts for most of the adverse events.

Adult↗
PubMed2003

Inspiratory muscle training for asthma.

BACKGROUND: In moderate to severe chronic obstructive pulmonary disease there is good evidence of a generalised loss of muscle bulk (including the respiratory muscles). It is possible that similar loss of respiratory muscle strength occur particularly in more severe asthma related in part to the effects of steroid therapy. Thus the respiratory muscle function may well be of relevance in asthma and if dysfunctional, may be a suitable target for training. OBJECTIVES: To evaluate the efficacy of inspiratory muscle training with an external resistive device in patients with asthma. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2002), MEDLINE (January 1966 to March 2002), EMBASE (January 1985 to March 2002), CINAHL (to March 2002) and the UK National Research Register of trials (January 1982 to March 2002) and reference lists of articles. We also searched on line respiratory journals and contacted manufacturers of training devices to obtain trials. SELECTION CRITERIA: All randomised-controlled trials that involved the use of an external inspiratory muscle training device versus a control (sham or no inspiratory training device) were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected articles for inclusion, evaluated methodological quality of the studies and abstracted data. MAIN RESULTS: Five studies were included in the review with four of the studies being produced by the same group. PI(max) (maximum inspiratory pressure) reported in three studies with 76 patients showed significant improvement with inspiratory muscle training when compared to the control group (WMD 23.07 cmH(2)O, 95%CI 15.65 to 30.50). Unfortunately, due to the paucity of included studies and data no other outcome was reported by more than one study. Therefore it is not possible to confirm whether this increase seen with PI(max) translates into any measurable clinical benefit. REVIEWER'S CONCLUSIONS: Currently there is insufficient evidence to suggest that inspiratory muscle training provides any clinical benefit to patients with asthma. Due to the limited availability of studies in this area there is a need for further trials evaluating the efficacy of inspiratory muscle training devices in patients with asthma. These studies should investigate asthmatics with a range of severity. They should investigate clinically relevant outcomes such as lung function, symptoms, exacerbation rate and concomitant medications.

Asthma↗
PubMed2003

Cyclosporin A, apoptosis of BAL T-cells and expression of Bcl-2 in asthmatics.

The late asthmatic reaction is characterised by elevated numbers of interleukin-4/interleukin-5/CD4-positive T-helper cells type 2 in bronchoalveolar lavage fluid (BALF). Cyclosporin A (CsA) is known to inhibit T-cell proliferation, induce apoptosis of CD4-positive T-cells and downregulate cytokine gene expression. It was assessed whether CsA-induced inhibition of the late asthmatic reaction was associated with apoptosis of BALF T-lymphocytes and other cell types, as well as expression of the antiapoptotic protein B-cell leukaemia/lymphoma 2 gene product (Bcl-2). BALF cells were obtained from asthmatics at baseline and 24 h after allergen-inhalation challenge following prior administration of CsA (n=13) or placebo (n=11). The number of apoptotic CD3-positive T-lymphocytes increased in the CsA but not the placebo group. The numbers of Bcl-2-positive cells were significantly reduced in the CsA but not the placebo group. The majority of Bcl-2-positive cells were CD3-positive T-lymphocytes. The beneficial effect of cyclosporin A in asthma may be related to its inhibitory effect on the late asthmatic reaction via induction of T-cell apoptosis and decreased B-cell leukaemia/lymphoma 2 gene product levels.

Apoptosis↗
PubMed2003

Variation of CD8+ T-lymphocytes around the bronchial internal perimeter in chronic bronchitis.

The variation of CD8+ cells has been determined around the internal perimeter of intrapulmonary bronchi in smokers with chronic bronchitis (CB), and the amount of tissue required to confidently estimate the true mean has been calculated. Lung specimens were obtained from 10 smokers with CB. Paraffin sections of intrapulmonary bronchi were immunostained and CD8+ cells counted in the epithelium and subepithelium in up to 10 sequential 1-mm segments around the internal perimeter of each airway. The percentage of counts falling between +/-20% of the final mean was 43.0% for epithelium and 40.9% for subepithelium. In 90% of subjects, the cumulative mean was stable after examination of subepithelial tissue associated with 5 mm of reticular basement membrane. There is considerable variation in the counts of CD8+ cells between adjacent 1-mm airway mucosal segments in chronic bronchitis. In order to achieve a representative count and to maximise statistical power to detect differences between study populations, subepithelial tissue including a minimum of 5 mm of reticular basement membrane length should be examined.

Aged↗
PubMed2001

Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common, progressive respiratory disease that causes great morbidity and mortality despite treatment. There is evidence for airway inflammation in COPD. Cilomilast is an orally active, potent, selective phosphodiesterase type 4 inhibitor, which in vitro can affect cells thought to be of clinical importance in COPD. Our aim was to assess the safety, efficacy, and dose response of cilomilast in the treatment of patients with this disease. METHODS: We did a 6-week, randomised, dose-ranging study in 424 patients with COPD (forced expiratory volume in 1 s [FEV(1)] 46.8% of predicted, FEV(1)/forced vital capacity [FVC] 54.6%, and postsalbutamol reversibility 5.4%). We randomly assigned individuals at 60 European centres to receive cilomilast 5 (n=109), 10 (n=102), or 15 (n=107) mg twice daily, or placebo (n=106). The main outcome measure was trough FEV(1) before and after use of a bronchodilator. Analyses were by intention to treat. FINDINGS: Cilomilast 15 mg twice daily significantly improved FEV(1) compared with placebo (mean 130 mL vs -30 mL [95% CI 90-240] at week 6, p<0.0001). FVC and peak expiratory flow were also improved (p=0.001 and p<0.0001, respectively). Quality of life measures did not differ significantly between the groups. There were no significant differences in serious adverse events between the groups. INTERPRETATION: Cilomilast 15 mg twice daily might be an effective maintenance treatment for COPD. Further clinical studies are underway.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

The effects of an anti-CD4 monoclonal antibody, keliximab, on peripheral blood CD4+ T-cells in asthma.

CD4+ T-cells are likely to be involved as a source of pro-inflammatory cytokines in asthma. This study assessed the effects of an infusion of keliximab (IDEC CE9.1), an anti-CD4+ monoclonal antibody, on peripheral blood CD4+ T-cells in corticosteroid-dependent asthmatics. Three cohorts of patients (termed C0.5: n=6, C1.5: n=5, and C3.0: n=5) received a single infusion of 0.5, 1.5 or 3.0 mg x kg(-1), respectively, with a fourth receiving placebo (Cpl: n=6), and were followed-up for 4 weeks. By flow cytometry in peripheral blood, pre- and postinfusion assessment was made of: a) CD4 and CD8 counts and mean fluorescence; b) CD25, human leukocyte antigen-DR (HLA-DR), CD45RO and CD45RA expression on CD4+ T-cells; and c) interferon (IFN)-gamma, interleukin (IL)-4 and IL-5 expression in CD4+ T-cells. Keliximab's in vitro effects on allergen-specific peripheral blood mononuclear cells (PBMC) proliferation in atopic asthmatics were also evaluated. There was a significant increase in lung function (peak expiratory flow rate) in the C3.0 group. Following infusion in C0.5, C1.5 and C3.0 but not Cpl: 1) the CD4, but not CD8 count was significantly decreased; 2) there was total loss of Leu3a staining; 3) there were significant reductions in the mean fluorescence of OKT4 binding; and 4) there were significant reductions in the numbers of CD25, HLA-DR, CD45RO and CD45RA/CD4+ cells. There were no changes in CD4+ cell expression of IFN-gamma, IL-4 or IL-5. Keliximab caused a significant reduction in T-cell proliferation as compared to a control monoclonal antibody. Keliximab, as an anti-CD4 monoclonal antibody, leads to a transient reduction in the number of CD4+ T-cells and modulation of CD4+ receptor expression in severe asthmatics. The effects of keliximab may be mediated through a decrease in CD4+ surface expression and T-lymphocyte numbers, in addition to a reduction in allergen-induced proliferation.

Adult↗
PubMed2001

What are the alternatives to increasing inhaled corticosteroids for the long term control of asthma?

The Global Initiative for Asthma (GINA) guidelines stated the therapeutic goals for the management of asthma and, through a stepwise approach to treatment, defined the various grades of asthma severity and the therapeutic options available to the clinician at each step. This article considers the options at step 3; the management of a patient with poorly controlled asthma who is already taking low-dose inhaled corticosteroids. Before considering a change in therapy, the clinician should rule out alternative diagnoses, confirm compliance with treatment, explore potential exacerbants in the patient's environment and, where possible, remove them. If a change in medication is necessary, the choice of drug will depend on the therapeutic goal that needs to be achieved. If the most important goal is the control of symptoms and optimisation of lung function, most studies support the addition of a long-acting beta(2)-agonist to low dose inhaled corticosteroids. If recurrent severe exacerbations are a major feature of the poor control, increasing the dosage of inhaled corticosteroids may be most effective. The addition of a leukotriene antagonist may be the best choice if exercise-induced symptoms are prominent or in the setting of aspirin-sensitive asthma. General recommendations supported by the findings of large therapeutic trials do not allow for significant variability in the individual response to a particular drug. Receptor polymorphisms have recently been discovered that may account for variability in the response to beta(2)-agonists and leukotriene receptor antagonists. However, until more is known about the reasons behind this variability, a therapeutic trial may be the most effective way of determining the best drug for an individual patient. One of the key developments in asthma over the past decade has been the acceptance of the concept of asthma as a chronic inflammatory disorder of the airways. However, the long term significance of this inflammation is not clear and the importance of control of inflammation beyond the suppression of symptoms, reduction of exacerbation frequency and the optimisation of lung function has not been established.

Adrenal Cortex Hormones↗
PubMed2000

Basophils, eosinophils, and mast cells in atopic and nonatopic asthma and in late-phase allergic reactions in the lung and skin.

BACKGROUND: Previous studies used indirect methods to identify basophils in the bronchi in asthma, and the numbers were not compared with eosinophils and mast cells. Furthermore, differences in basophil numbers between atopic and nonatopic asthma at baseline and between late-phase skin and asthmatic reactions have not been previously documented. OBJECTIVE: The basophil granule-specific mAb BB1 was used to identify basophils in (1) bronchial biopsy specimens from atopic asthmatic subjects and nonatopic asthmatic subjects and control subjects, (2) biopsy specimens from atopic asthmatic subjects before and after inhalational allergen challenge, and (3) late-phase skin reactions. Basophil numbers were compared with EG2(+) eosinophils and tryptase(+) mast cells. METHODS: Cells were enumerated in bronchial and skin biopsy specimens by means of immunohistochemistry with the alkaline phosphatase-antialkaline phosphatase method. RESULTS: There were elevated numbers of basophils in baseline biopsy specimens in atopic asthmatic subjects compared with atopic control subjects or normal control subjects, although eosinophils and mast cells were 10-fold higher. There was an intermediate number of basophils in nonatopic asthmatic subjects. Basophils increased after allergen inhalation, but again basophils were less than 10% of eosinophils. In contrast, basophils in cutaneous late-phase reactions were approximately 40% of infiltrating eosinophils. The peak of basophil accumulation was at 24 hours, whereas maximal eosinophil infiltration occurred at 6 hours. One third of cutaneous basophils had morphologic appearances suggestive of degranulation. CONCLUSION: Numerous basophils infiltrated cutaneous late-phase reactions in atopic subjects. However, this cell was not prominent in bronchial biopsy specimens of asthmatic subjects, either at baseline or after allergen challenge.

Adult↗
PubMed2000

The anti-inflammatory profile of inhaled corticosteroids: biopsy studies in asthmatic patients.

The beneficial effects of inhaled corticosteroids in the treatment of asthma are well established. A potent topical anti-inflammatory action is assumed to underlie the therapeutic effect, given that these agents alter the number and function of a range of inflammatory cells and markers in airway biopsies. This activity profile is shown by all inhaled corticosteroids, in a variety of patient types and study designs. Thus, treatment with inhaled corticosteroids leads to consistent reductions in the number and activation of mast cells and eosinophils in biopsy specimens. Other relevant findings include reductions in T-lymphocytes, which contribute to chronic inflammation via the secretion of pro-inflammatory cytokines (some of which are responsible for eosinophil accumulation and activation). Inhaled corticosteroids may therefore act by down-regulating immunoreactivity, so reducing activation of T lymphocytes and (consequently) eosinophils. There is considerable interest in whether corticosteroids can inhibit or reverse some structural changes in the airways, including basement membrane thickening, collagen deposition and increased airway vascularity; it has been suggested that these changes may contribute towards airway hyperresponsiveness and irreversible airway obstruction. In summary, inhaled corticosteroids have a broad spectrum of anti-inflammatory activity in asthma patients, but the relationship between changes in clinical and immunopathological parameters, particularly in the long-term, requires further study.

Administration, Inhalation↗
PubMed2000

Effect of leukotriene receptor antagonist therapy on the risk of asthma exacerbations in patients with mild to moderate asthma: an integrated analysis of zafirlukast trials.

BACKGROUND: Asthma exacerbations contribute substantially to morbidity, and their reduction is an important therapeutic objective. In this integrated analysis the risk of asthma exacerbations was assessed during treatment with the leukotriene receptor antagonist zafirlukast. METHODS: Data were collected from all five double blind, multicentre, randomised, placebo controlled, 13 week trials of zafirlukast 20 mg twice daily performed in steroid-naive patients with mild to moderate asthma. Exacerbation data were collected prospectively during monitoring of adverse events and concomitant medication use. Pooled data were used to assess the relative risk of asthma exacerbations using three definitions: worsening of asthma leading to withdrawal from the study; requirement for additional anti-asthma therapy (excluding increased short acting beta(2) agonist use); and requirement for oral corticosteroid therapy. RESULTS: The proportion of patients with an asthma exacerbation leading to withdrawal was consistently lower in the group treated with zafirlukast 20 mg twice daily than in the placebo group. Overall, the risk of an asthma exacerbation requiring withdrawal from zafirlukast therapy was approximately half that of placebo (odds ratio 0.45; 95% CI 0.26 to 0.76; p = 0.003). Similar results were observed for exacerbations requiring additional control medication (odds ratio = 0.47; 95% CI 0.30 to 0.74; p = 0.001) and oral corticosteroid rescue (odds ratio = 0.53; 95% CI 0.32 to 0.86; p = 0.010). CONCLUSIONS: Zafirlukast in a dose of 20 mg twice daily reduces the risk of asthma exacerbations and the need for additional anti-asthma therapies, fulfilling an important goal of control medication in patients with mild to moderate asthma.

Adolescent↗