bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exercise and dyspnoea in COPD
Authors: Calverley P. M. A. 
Published: September 2008

Dyspnoea provoked either by exercise or during a disease exacerbation is one of the most feared symptoms of the chronic obstructive pulmonary disease (COPD) patient. It contributes to impaired quality of life and patients who are more limited by exertional dyspnoea are more likely to die. The physiological mechanisms responsible for these two outcomes vary in different settings, but in both situations, changes in the resting lung volume and increased activation of the respiratory muscles relative to their maximum capacity is the final common pathway.Although increased metabolic carbon dioxide production from weak or poorly conditioned muscles is an important cofactor, most patients limited by exertional dyspnoea exhibit dynamic hyperinflation that parallels their symptom intensity. This results from the longer respiratory time constant of the lungs in COPD and coexisting expiratory flow limitation during tidal breathing. The response of the chest wall muscles to this change in lung volume is variable: most patients with more severe COPD allow chest wall volume to increase, while others try to defend chest wall volume. The latter is not a good breathing strategy as the patient’s exercise capacity is very limited.Treatment with bronchodilators reduces operating lung volumes and delays the time until tidal volume is mechanically limited by the inspiratory reserve volume. Breathing oxygen and heliox gas mixtures further increases exercise endurance and slows the rate at which end-expiratory lung volume increases.During exacerbations there is a consistent increase in end-expiratory lung volume and this parallels the reduction in forced vital capacity. This suggests that gas trapping due to airway closure is the main mechanism involved here, although changes in lung volume still track the symptomatic improvement in dyspnoea reported by patients both as the episode resolves and after nebulised bronchodilator treatment.
Lung hyperinflation in COPD: the impact of pharmacotherapy
Authors: O'Donnell D. E. , Laveneziana P. 
Published: September 2008

Improvement in airway function in response to bronchodilator therapy is generally confirmed by simple spirometry. However, improvements in maximal expiratory flow rates have been shown to correlate poorly with important patient-centred outcomes, such as reduced exertional dyspnoea and improved exercise performance. Recent studies have suggested that attendant reductions in end-expiratory lung volume as a result of bronchodilator-induced improvements in lung emptying may be more closely associated with symptom relief and increased exercise capacity than traditional spirometric indices. To the extent that chronic lung hyperinflation and the superimposition of acute dynamic hyperinflation (in response to increased ventilation or expiratory flow limitation) result in excessive loading and weakening of the inspiratory muscles, then pharmacological lung volume reduction should have important mechanical and sensory benefits for the patient.The present article will examine the mechanisms of lung deflation following short-term bronchodilator therapy. The physiological links between reduced hyperinflation, improved dyspnoea and exercise endurance will be examined, and the emerging evidence for the additive effects of combining various modern pharmacological therapies will be reviewed.
Asthma: a comparison of animal models using stereological methods
Authors: Hyde D. M. , Miller L. A. , Schelegle E. S. , Fanucchi M. V. , Van Winkle L. S. , Tyler N. K. , Avdalovic M. V. , Evans M. J. , Kajekar R. , Buckpitt A. R. , Pinkerton K. E. , Joad J. P. , Gershwin L. J. , Wu R. , Plopper C. G. 
Published: September 2008

Asthma is a worldwide health problem that affects 300 million people, as estimated by the World Health Organization. A key question in light of this statistic is: “what is the most appropriate laboratory animal model for human asthma?”The present authors used stereological methods to assess airways in adults and during post-natal development, and their response to inhaled allergens to compare rodents and nonhuman primates to responses in humans.An epithelial–mesenchymal trophic unit was defined in which all of the compartments interact with each other. Asthma manifests itself by altering not only the epithelial compartment but also other compartments (e.g.interstitial, vascular, immunological and nervous). All of these compartments show significant alteration in an airway generation-specific manner in rhesus monkeys but are limited to the proximal airways in mice. The rhesus monkey model shares many of the key features of human allergic asthma including the following: 1) allergen-specific immunoglobulin (Ig)E and skin-test positivity; 2) eosinophils and IgE+ cells in airways; 3) a T-helper type 2 cytokine profile in airways; 4) mucus cell hyperplasia; 5) subepithelial fibrosis; 6) basement membrane thickening; and 7) persistent baseline hyperreactivity to histamine or methacholine.In conclusion, the unique responses to inhaled allergens shown in rhesus monkeys make it the most appropriate animal model of human asthma.
Quantitative morphology using bronchial biopsies: FIGURE 1.
Authors: Woodruff P. G. , Innes A. L. 
Published: September 2008

Bronchoscopy with bronchial biopsies allows sampling of airway tissue in prospective clinical studies and is increasingly applied for the study of airway inflammation and remodelling.It is important to recognise that there are limitations inherent to the use of bronchial biopsies, including the inability to randomly sample the airway and susceptibility to the “reference trap”. Nonetheless, certain stereological principles can be applied to the analysis of these specimens, which may improve the validity of the results obtained. These principles relate to choice of reference space, adequacy of sampling and treatment of tissue orientation in the estimation of thickness and surface area.With attention to these principles, the present authors have developed protocols for the assessment of multiple measures of airway remodelling in bronchial biopsies, including airway epithelial mucin content, epithelial goblet cell size, reticular basement membrane thickness and smooth muscle morphological outcomes. They have also developed protocols for the enumeration of inflammatory cells important in the study of asthma and chronic obstructive pulmonary disease, including eosinophils and neutrophils.In the present article, relevant stereological principles and the details of these specific protocols will be reviewed.
Development of a biomarker for lung inflammation in COPD through analysis of labelled leukocyte transit through the lung circulation
Authors: Baker EmmaH. , Irwin Andrew , Brennan AmandaL. , Trost Brian , Britten Alan , Heenan Sue , Peterson Barry 
Published: September 2008

Measurement of pulmonary leukocyte margination could be a useful biomarker of lung inflammation in COPD, but analysis is complicated by recirculation of labeled leukocytes.15 minutes of planar nuclear images were obtained after injecting autologous99mTc-labeled leukocytes in 4 never-smoked controls, 6 stable mild/moderate and 2 exacerbating COPD patients. COPD patients were also imaged for 10 minutes afterin vivored blood cell (RBC) labeling with99mTc and were re-imaged 2 weeks later to determine reproducibility. Activity as a function of time was measured in regions of interest over lungs and heart.A multi-compartment mathematical model was used to correct for recirculation but failed to provide a biomarker that clearly separated controls from COPD. A simpler model for activity in lungs and heart as a function of time (A(t)) was applied only to time points before recirculation: [A(t) = X1x (1-exp(-X2x t)) x exp(-X3x t), where Xiare adjusted to match the data]. The ratio (R) of X3(downslope of curve) in the lungs to X3in the heart was investigated as a biomarker of margination. Values of R were reasonable (1.06±0.08 (SE)) for RBC (i.e.no margination) and 0.76±0.10 for controls (∼25% margination). In stable COPD patients R was significantly smaller (0.19±0.09, p<0.01) than controls and was reproducible (0.25±0.10). R during exacerbation was surprisingly large (0.88±0.22), possibly due to steroid treatment, but R was similar to stable COPD patients 2 weeks later (0.09±0.04).R requires only 2–3 minutes of imaging and may be a useful biomarker of margination. However it remains to be shown whether R truly reflects inflammation in COPD.
Role of purinergic receptors in the activation of human airway smooth muscle cells by the antimicrobial peptide LL-37
Authors: Zuyderduyn Suzanne , Ninaber DennisK. , Hiemstra PieterS. , Rabe KlausF. 
Published: September 2008

Inflammatory cells that infiltrate and surround the airway smooth muscle (ASM) layer express antimicrobial peptides including the cathelicidin LL-37. LL-37 has been shown to activate epithelial cells by transactivation of the epidermal growth factor receptor (EGFR). Previously, we have shown that LL-37-induced IL-8 release by ASM cells was not dependent on either formyl peptide receptors or the EGFR (ATS 2005). In monocytes LL-37 induces processing of IL-1β through activation of the purinergic P2X7receptor. Therefore, the aim of our study was to evaluate the role of purinergic receptors in LL-37-induced activation of ASM cells, and to explore the involvement of several intracellular signalling pathways.ASM cells were cultured and serum-deprived 24 hours before stimulation with LL-37 (10 μg·ml−1). The purinergic receptor antagonist suramin and inhibitors of ERK1/2, p38, Src and PI3K were preincubated for one hour. ERK1/2 phosphorylation was assessed by Western Blot, and IL-8 release was determined in supernatants using a sandwich ELISA. RT-PCR was performed for P2X7on untreated ASM cells. LL-37 induced ERK1/2 phosphorylation and IL-8 release; both were inhibited by suramin (IL-8: 86%). Inhibitors of ERK1/2, p38 and Src signalling also reduced LL-37-induced IL-8 release (by 67%, 63% and 76%, respectively), suggesting a role for these pathways. P2X7mRNA was expressed in ASM cells.These data show that LL-37-induced IL-8 release is mediated via purinergic receptors, ERK1/2 activation, p38 and Src signalling. Our PCR data are in line with the hypothesis that also in ASM P2X7is the purinergic receptor involved in LL-37 signalling, although this needs further investigation.
The effects of ELTGOL on mucociliary clearance in patients with COPD
Authors: Martins JocimarA. , Andrade ArmèleD. , Assis RodrigoS. , Lara Rovilson , Parreira VerônicaF. 
Published: September 2008

Excessive tracheobronchial secretion is a common complication of chronic obstruction pulmonary disease (COPD) and its presence is associated with lower survival, greater hospitalization and death. Slow expiration with the glottis open in a lateral posture (ELTGOL) is a chest physiotherapy procedure for the removal of lung secretions. Studies which have assessed ELTGOL through pulmonary scintigraphy were not found [1]. The aim this study was to evaluate the effects of ELTGOL on the mucociliary clearance in patients with COPD.Twelve patients with COPD aged 45 to 75 years were studied. After inhaling 20 mCi of 99mTc-DTPA [2], six posterior static scintigraphy images were taken in intervals of 0, 20, 40, 60, 80 and 120 minutes (figure 1).The study was carried out in two stages (control and experimental) in a randomized order with a minimum interval of one week between the stages. In the experimental stage, ELTGOL was carried out after the first image. The right lung was studied, comparing the percentage of retention [3] of radioactive aerosol obtained during the control stage with the experimental condition, for each interval studied. The study was approved by the local ethics committee and all patients gave their written consent participate. The t test was used for data analysis with a significance level of α<0.05.As shown in figure 2, significant differences between groups were found between all time intervals.The present results showed the ELTGOL significantly increased the mucociliary clearance suggesting that ELTGOL is an effective technique to improve secretion removal in patients with COPD.
A Disintegrin and Metalloprotease 33polymorphisms and lung function decline in the general population
Authors: van Diemen CleoC. , Postma DirkjeS. , Vonk JudithM. , Bruinenberg Marcel , Schouten JanP. , Marike Boezen H. 
Published: September 2008

ADAM33(A Disintegrin and Metalloprotease 33) has been identified as a susceptibility gene for asthma and single nucleotide polymorphisms (SNPs) in this gene have been associated with excess decline of lung function in asthmatics.To assess whether SNPs inADAM33are associated with accelerated lung function loss in the general population and with chronic obstructive pulmonary disease (COPD).We have collected DNA from subjects of the Vlagtwedde/Vlaardingen cohort participating in the last survey in 1989/1990 after a follow up of 25 years. Information was collected every 3 years, including lung function measurements. We defined COPD as GOLD stage 2 or higher at the last survey. 1390 subjects from the cohort were genotyped for the following SNPs inADAM33: F+1, Q−1, S_1, S_2, T_1, T_2, V_4, ST+5. Differences in prevalence of SNPs were analyzed with chi-square tests. Linear mixed effects models were used to analyze FEV1decline according to genotype.In the whole population mean adjusted decline was 18.7 and 12.7 ml·y−1in females and males respectively. Individuals homozygous for minor alleles of SNPs S_2 and Q−1 and heterozygous for SNP S_1 had a significantly accelerated decline in FEV1of respectively 4.9, 9.6 and 3.6 ml·y−1compared with wild type. We found a significantly higher prevalence of SNPs F+1, S_1, S_2 and T_2 in subjects with COPD.We demonstrated that SNPs inADAM33are associated with accelerated lung function decline in the general population. These SNPs are also risk factors for COPD.
Diminished peroxisome proliferator-activated receptor (PPAR) regulation as a potential mechanism for the persistent inflammation in chronic obstructive pulmonary disease
Authors: Drost E. M. , Poland C. A. , Donaldson K. , MacNee W. 
Published: September 2008

Persistent inflammation is the main pathological process that underlies COPD. Understanding this inflammatory response is a key focus of COPD research with the aim of discovering new therapeutic targets. The nuclear hormone receptor, PPAR is now a recognised modulator of inflammation in various chronic inflammatory conditions, but its role in the persistent airways inflammation in COPD has not been examined. Control of the inflammatory response by PPARα has been shown by antagonising inflammatory signalling pathways, such as NF-κB and AP-1.PPARα protein levels in lung tissue from patients with COPD were assessed by Western blot.In vitroassays using the human type II alveolar epithelial cell line were performed to assess the effect of PPARα agonist treatment on inflammatory cytokine generation.An increase in PPARα protein levels was seen for healthy smokers compared with non-smokers (Ratio to β-actin loading control, non-smokers 0.61±0.1, n = 10; healthy smokers 0.97±0.3, n = 11, p>0.05). No increase was seen for current smoker or ex-smoker COPD patients (0.36±0.08, n = 12; 0.49±0.1, n = 8 respectively).In vitroexperiments with a human type II alveolar epithelial cell line demonstrated a diminished inflammatory response to TNFα, as measured by the generation of the pro-inflammatory cytokine IL-8, following pre-treatment with the PPARα agonist, WY-14643 (IL-8 generation, control 823±22 pg·ml−1, TNFα 7491±530 pg·ml−1p<0.001, WY-14643 2559±46 pg·ml−1p<0.05, n = 3).We propose PPAR agonists as a potential therapy for reducing the NF-κB-regulated inflammation in COPD airways.Supported by GlaxoSmithKline
How different measures of cold weather affect chronic obstructive pulmonary disease (COPD) hospital admissions in London
Authors: Marno P. , Bryden C. , Bird W. , Watkin H. A. 
Published: September 2008

Many COPD sufferers find that their symptoms become worse during colder weather, which can lead to an exacerbation resulting in hospital admission. This study investigates different measures of cold, assessing which most strongly relate to COPD admissions and whether they can be used to forecast risk of exacerbation.COPD admissions (ICD10 J40–J44) for the five Strategic Health Authorities (SHAs) in London and corresponding meteorological data were extracted for October–March 1997–2003. Correlations and regressions were used to compare the effects on admissions of:daily mean, maximum and minimum temperature;significant drops in temperature;weekly average maximum temperature;“cumulative cold”, summing the number of degrees the daily maximum temperature was below a threshold across a week;different windchill indices.All measures of cold showed significant negative correlations with COPD admissions. Daily relationships were weaker than weekly ones (R =  −0.19, p<0.001 for daily maximum temperature, R =  −0.36, p<0.001 for weekly average maximum temperature) but are most significant with an 8-day lag. Windchill had the strongest correlation with one-week lag (R =  −0.397, p<0.001) accounting for 20% of the variation in admissions. “Cumulative cold” is also significant at p<0.001, ranging from R = 0.28 for a 3°C threshold to R = 0.36 for 18°C.Cold measures explain sufficient variation in COPD hospital admissions to be used in a forecast model of risk of exacerbation. The Met Office uses such a model in a health forecasting and anticipatory care service in England.
Challenging cases in PH
Authors: Hoeper M. M. , Laenger F. 
Published: September 2008

The requirement for a timely diagnosis of pulmonary arterial hypertension (PAH) to maximise the benefits achieved with appropriate therapy is hampered by the insidious nature of the disease and consequently the late presentation of the majority of patients. Therefore, it is critical to maintain a high index of suspicion in cases of unexplained dyspnoea and to employ a structured and systematic diagnostic strategy.Pulmonary hypertension (PH) has been classified clinically into PAH, PH associated with left heart diseases, PH associated with hypoxaemia or disorders of the respiratory system, PH caused by chronic thrombotic or embolic disease and PH caused by disorders of the pulmonary vasculature, such as sarcoidosis. These different classes of diseases may have similar presentations despite differing physiologies and aetiologies. Moreover, in some cases, incorrect diagnosis and instigation of an inappropriate course of action can have serious consequences.This paper illustrates two particularly challenging clinical cases that can be encountered in patients with pulmonary hypertension.
Pharmacokinetic optimisation of β-lactams for the treatment of ventilator-associated pneumonia
Authors: Drusano G. L. 
Published: September 2008

Rational therapy of ventilator-associated pneumonia requires choosing the right drug at the right dose. The choice of dose depends on the microbiological goal, the range of minimum inhibitory concentrations (MICs) for likely pathogens, the extent of the drug's protein binding and, in humans, pharmacokinetics.If protein binding and the distribution of pharmacokinetic parameters are known, as well as the likely pathogens and MICs in a given setting, Monte Carlo simulations can be used to calculate the likelihood that a given dose will attain an identified microbiological goal. For β-lactams, the antibacterial effect depends on the percentage of time (%T) during the dosing interval that the free (nonprotein bound) antibiotic concentration remains above the MIC (%T >MIC); the required values are smaller for carbapenems than for penicillins or cephalosporins.Data show that infusion of ani.v.β-lactam over an extended period may greatly increase %T >MIC, and hence efficacy, at a given dose. Alternatively, it may provide the same efficacy at a lower total dose, reducing cost and potential toxicity. In a real-life setting, a 4-h infusion of 3.375 g piperacillin-tazobactamq8 h(every 8 h; 3 times daily); proved more effective for severePseudomonas aeruginosainfections than a 30-min infusion of 3.375 gq6 h(every 6 h; 4 times daily) orq4 h(every 4 h; 6 times daily).Data for doripenem, an investigational carbapenem, suggest that its stability following reconstitution may render it particularly suitable for extended infusion.
The rationale for treating allergic asthma with anti-IgE
Authors: Hamelmann E. 
Published: September 2008

An estimated two-thirds of asthma is allergic and >50% of severe asthma has an allergic component. An increased immunoglobulin (Ig)E production in response to environmental allergens (atopy) is the strongest detectable predisposing factor for the development of asthma, particularly when sensitisation occurs early in life.IgE binds to high-affinity receptors (FcϵRI) on effector cells, such as mast cells and basophils. Allergen binds to IgE and initiates an inflammatory cascade resulting in release of pro-inflammatory mediators that contribute to the acute and chronic symptoms of allergic airway diseases. By reducing serum IgE levels and FcϵRI receptor expression on key cells in the inflammatory cascade, omalizumab blocks the release of inflammatory mediators from mast cells and reduces the infiltration of inflammatory cells, notably eosinophils, into the airway. In patients with allergic asthma, omalizumab inhibits both the early and late asthmatic response and several other markers of inflammation, including the requirement for inhaled or oral corticosteroids.The anti-inflammatory effects of omalizumab provide proof-of-concept of the key role played by immunoglobulin E in allergic respiratory disease. Omalizumab represents a novel approach to the treatment of asthma, inhibiting the inflammatory cascade before it starts.
Inflammation in COPD: a link to systemic comorbidities
Authors: Rennard S. I. 
Published: September 2008

Chronic obstructive pulmonary disease (COPD) has been defined as a preventable and treatable disease characterised by progressive airflow limitation that is not fully reversible and associated with an abnormal inflammatory response in the lungs.Results from a large number of recent studies have characterised the inflammatory processes underlying COPD. Inflammatory cells, most notably CD8+ T-lymphocytes, macrophages and neutrophils, as well as a large number of chemokines, cytokines and proteinases, are believed to play a role.The inflammatory processes in COPD contribute to remodelling of pulmonary tissues, leading to the irreversible airflow limitation characteristic of this disease. Inflammation may also contribute to the comorbidities often observed in COPD patients. Patients with COPD often have cardiovascular disease, changes in body composition, osteoporosis and anaemia. The same inflammatory processes that characterise COPD are also risk factors for these comorbidities.Ongoing studies are evaluating a wide range of new therapies for chronic obstructive pulmonary disease. Some of these have the potential to blunt the inflammatory processes underlying chronic obstructive pulmonary disease and potentially the associated comorbid conditions. These therapies may significantly improve survival, function and quality of life for patients with this disease.