bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic disruption of p38α Tyr323 phosphorylation prevents T-cell receptor–mediated p38α activation and impairs interferon-γ production
Authors: Jirmanova Ludmila , Sarma Dandapantula N. , Jankovic Dragana , Mittelstadt Paul R. , Ashwell Jonathan D. 
Published: November 2008

AbstractT cells possess a p38 activation alternative pathway in which stimulation via the antigen receptor (T-cell receptor [TCR]) induces phosphorylation of p38α and β on Tyr323. To assess the contribution of this pathway to normal T-cell function, we generated p38α knockin mice in which Tyr323 was replaced with Phe (p38αY323F). TCR-mediated stimulation failed to activate p38αY323F as measured by phosphorylation of the Thr-Glu-Tyr activation motif and p38α catalytic activity. Cell-cycle entry was delayed in TCR-stimulated p38αY323F T cells, which also produced less interferon (IFN)–γ than wild-type T cells in response to TCR-mediated but not TCR-independent stimuli. p38αY323F mice immunized with T-helper 1 (Th1)–inducing antigens generated normal Th1 effector cells, but these cells produced less IFN-γ than wild-type cells when stimulated through the TCR. Thus, the Tyr323-dependent pathway and not the classic mitogen-activated protein (MAP) kinase cascade is the physiologic means of p38α activation through the TCR and is necessary for normal Th1 function but not Th1 generation.
Glucocorticoid therapy increases COX-2 gene expression in nasal polypsin vivo
Authors: Pujols L. , Benitez P. , Alobid I. , Martinez-Antón A. , Roca-Ferrer J. , Mullol J. , Picado C. 
Published: November 2008

The aim of the present study was to evaluate thein vivoregulation of cyclooxygenase-2 in nasal polyps.In total, 65 patients with nasal polyps were randomly (3:1) treated with (n = 51; 33 with asthma) or without (n = 14) oral prednisone and intranasal budesonide for 2 weeks plus intranasal budesonide for 10 additional weeks. Biopsies were obtained at baseline and after 2 and 12 weeks of treatment. All samples were analysed for cyclooxygenase-1 and cyclooxygenase-2 mRNA. Attempts were made to detect cyclooxygenase-2 protein.At baseline, cyclooxygenase-1 and cyclooxygenase-2 expression did not differ between polyps from nonasthmatic and asthmatic patients. Cyclooxygenase-1 mRNA was unchanged by glucocorticoid treatment, while cyclooxygenase-2 mRNA increased in glucocorticoid-treated patients at week 2 compared with baseline and then decreased at week 12. Within subgroups, increased cyclooxygenase-2 mRNA was found at week 2 in polyps from nonasthmatic and asthmatic patients compared with baseline. At week 12, cyclooxygenase-2 expression remained high in nonasthmatics while it decreased in asthmatics. Cyclooxygenase-2 protein was not detected under any circumstances.Glucocorticoid therapy enhances cyclooxygenase-2 expressionin vivoin nasal polyps, a finding that does not follow the generally accepted assumption that cyclooxygenase-2 expression is suppressed by glucocorticoids.
Occurrence ofChlamydia trachomatisandChlamydia pneumoniaein paediatric respiratory infections
Authors: Webley W. C. , Tilahun Y. , Lay K. , Patel K. , Stuart E. S. , Andrzejewski C. , Salva P. S. 
Published: November 2008

An emerging body of evidence suggests that half of asthma in both children and adults is associated with chronic lung infection. The aim of the present study was to determine the frequency of viableChlamydia pneumoniae(Cp) andC. trachomatis(Ct) in the respiratory tracts of paediatric patients with chronic respiratory diseases.Bronchoalveolar lavage fluid (BALF) samples obtained from 182 children undergoing bronchoscopy for clinical reasons were assayed using PCR analysis,in vitrotissue culture and immunofluorescence staining for the presence ofCpandCt.Chlamydia-specific DNA was detected by PCR in 124 (68%) out of 182 patients; 79 were positive forCp, 77 positive forCtand 32 for both organisms; 75 patients had cultivableChlamydia. CtDNA prevalence decreased, whereasCppositivity generally increased with age. A total of 59 out of 128 asthma patients and 16 out of 54 nonasthmatics wereChlamydiaculture positive. When the patients were divided into inflammatoryversusnoninflammatory airway disease, there were 69 (46%) out of 150 and six (18%) out of 32 BALF samples with cultivableChlamydia, respectively.ViableChlamydia pneumoniaeandChlamydia trachomatisoccur frequently in children with chronic respiratory diseases and may be more prevalent in asthma patients. To the current authors’ knowledge, this is the first report of viableChlamydia trachomatisin the lungs of children.
Physical activity in patients with COPD
Authors: Watz H. , Waschki B. , Meyer T. , Magnussen H. 
Published: November 2008

The present study aimed to measure physical activity in patients with chronic obstructive pulmonary disease (COPD) to: 1) identify the disease stage at which physical activity becomes limited; 2) investigate the relationship of clinical characteristics with physical activity; 3) evaluate the predictive power of clinical characteristics identifying very inactive patients; and 4) analyse the reliability of physical activity measurements.In total, 163 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I–IV; BODE (body mass index, airway obstruction, dyspnoea, exercise capacity) index score 0–10) and 29 patients with chronic bronchitis (normal spirometry; former GOLD stage 0) wore activity monitors that recorded steps per day, minutes of at least moderate activity, and physical activity levels for 5 days (3 weekdays plus Saturday and Sunday).Compared with patients with chronic bronchitis, steps per day, minutes of at least moderate activity and physical activity levels were reduced from GOLD stage II/BODE score 1, GOLD stage III/BODE score 3/4 and from GOLD stage III/BODE score 1, respectively. Reliability of physical activity measurements improved with the number of measured days and with higher GOLD stages. Moderate relationships were observed between clinical characteristics and physical activity. GOLD stages III and IV best predicted very inactive patients.Physical activity is reduced in patients with chronic obstructive pulmonary disease from Global Initiative for Chronic Obstructive Lung Disease stage II/ body mass index, airway obstruction, dyspnoea, exercise capacity score 1. Clinical characteristics of patients with chronic obstructive pulmonary disease only incompletely reflect their physical activity.
Early short-termversusprolonged low-dose methylprednisolone therapy in acute lung injury
Authors: Silva P. L. , Garcia C. S. N. B. , Maronas P. A. , Cagido V. R. , Negri E. M. , Damaceno-Rodrigues N. R. , Ventura G. M. , Bozza P. T. , Zin W. A. , Capelozzi V. L. , Pelosi P. , Rocco P. R. M. 
Published: November 2008

The present study compared the effects of early short-term with prolonged low-dose corticosteroid therapy in acute lung injury (ALI).In total, 120 BALB/c mice were randomly divided into five groups. In the control group, saline was intratracheally (i.t.) instilled. In the ALI group, mice receivedEscherichia colilipopolysaccharide (10 μgi.t.). ALI animals were further randomised into four subgroups to receive saline (0.1 mLi.v.) or methylprednisolone (2 mg·kg−1i.v.) at 6 h, 24 h or daily (for 7 days, beginning at day 1). At 1, 3 and 8 weeks,in vivoandin vitrolung mechanics and histology (light and electron microscopy), collagen and elastic fibre content, cytokines in bronchoalveolar lavage fluid and the expression of matrix metalloproteinase (MMP)-9 and -2 were measured.In vivo(static elastance and viscoelastic pressure) andin vitro(tissue elastance and resistance) lung mechanics, alveolar collapse, cell infiltration, collagen and elastic fibre content and the expression of MMP-9 and MMP-2 were increased in ALI at 1 week. Methylprednisolone led to a complete resolution of lung mechanics, avoided fibroelastogenesis and the increase in the expression of MMP-9 and MMP-2 independent of steroid treatment design.Thus, early short-term, low-dose methylprednisolone is as effective as prolonged therapy in acute lung injury.
Do childhood respiratory infections continue to influence adult respiratory morbidity?
Authors: Dharmage S. C. , Erbas B. , Jarvis D. , Wjst M. , Raherison C. , Norbäck D. , Heinrich J. , Sunyer J. , Svanes C. 
Published: November 2008

The aim of the present study was to examine the influence of childhood respiratory infections on adult respiratory health.In 1992–1994, the European Community Respiratory Health Survey recruited community based samples of 20–44-yr-old people from 48 centres in 22 countries. Study participants completed questionnaires and underwent lung function testing. On average, 8.9 yrs later, 29 centres re-investigated their samples using similar methods. Mixed effects models comprising an estimate for the random variation between centres were used to evaluate the relevant associations.In total, 9,175 patients participated in both studies, of whom 10.9% reported serious respiratory infections (SRI) before 5 yrs of age and 2.8% reported hospitalisation for lung disease (HLD) before 2 yrs if age. SRI was associated with current wheeze (odds ratio (OR) 1.9, 95% confidence interval (CI) 1.7–2.2), asthma (OR 2.5, 95% CI 2.2–3.1), and lower forced expiratory volume in one second (FEV1; 89 mL; 95% CI 54–126), forced vital capacity (FVC; 49 mL; 95% CI 8–90) and FEV1/FVC ratio (−1.2%; 95% CI −1.8– −0.6). Childhood respiratory infections were also associated with new asthma (OR 1.5, 95% CI 1.03–2.0), new wheeze (OR 1.5, 95% CI 1.0–2.4) and persistent wheeze (OR 2.2, 95% CI 1.4–3.6) but not with a decline in lung function. Similar findings were observed for HDL. These associations were significantly consistent across centres. SRI was associated with lower FEV1when excluding ever asthmatics and current wheezers. The impact of early infections was significantly larger in subjects exposed to maternal or active smoking.The impact of childhood respiratory infections on the respiratory system may not only last into adulthood but also influence development and persistence of adult respiratory morbidity.
Air pollution during pregnancy and lung function in newborns: a birth cohort study
Authors: Latzin P. , Röösli M. , Huss A. , Kuehni C. E. , Frey U. 
Published: November 2008

Post-natal exposure to air pollution is associated with diminished lung growth during school age. The current authors aimed to determine whether pre-natal exposure to air pollution is associated with lung function changes in the newborn.In a prospective birth cohort of 241 healthy term-born neonates, tidal breathing, lung volume, ventilation inhomogeneity and exhaled nitric oxide (eNO) were measured during unsedated sleep at age 5 weeks. Maternal exposure to particles with a 50% cut-off aerodynamic diameter of 10 μm (PM10), nitrogen dioxide (NO2) and ozone (O3), and distance to major roads were estimated during pregnancy. The association between these exposures and lung function was assessed using linear regression.Minute ventilation was higher in infants with higher pre-natal PM10exposure (24.9 mL·min−1per μg·m−3PM10). The eNO was increased in infants with higher pre-natal NO2exposure (0.98 ppb per μg·m−3NO2). Post-natal exposure to air pollution did not modify these findings. No association was found for pre-natal exposure to O3and lung function parameters.The present results suggest that pre-natal exposure to air pollution might be associated with higher respiratory need and airway inflammation in newborns. Such alterations during early lung development may be important regarding long-term respiratory morbidity.
Sex-specific association of epidermal growth factor gene polymorphisms with acute respiratory distress syndrome
Authors: Sheu C. C. , Zhai R. , Su L. , Tejera P. , Gong M. N. , Thompson B. T. , Chen F. , Christiani D. C. 
Published: November 2008

Epidermal growth factor (EGF) is involved in alveolar epithelial repair, lung fluid clearance and inflammation, and is regulated by sex hormones. An unmatched, nested case–control study was conducted to evaluate the associations ofEGFvariants with acute respiratory distress syndrome (ARDS) and the role of sex on the associations betweenEGFvariants and ARDS.Patients with ARDS risk factors upon intensive care unit admission were enrolled. Cases were 416 Caucasians who developed ARDS and controls were 1,052 Caucasians who did not develop ARDS. Cases were followed for clinical outcomes and 60-day mortality. One functional single nucleotide polymorphism (SNP), rs4444903, and six haplotype-tagging SNPs spanning the entireEGFgene were genotyped.No individual SNP or haplotype was associated with ARDS risk or outcomes in all subjects. Sex-stratified analyses showed opposite effects ofEGFvariants on ARDS in malesversusin females. SNPs rs4444903, rs2298991, rs7692976 and rs4698803, and haplotypes GGCGTC and ATCAAG were associated with ARDS risk in males. No associations were observed in females. Interaction analysis showed that rs4444903, rs2298991, rs7692976 and rs6533485 significantly interacted with sex for ARDS risk.The present study suggests that associations of epidermal growth factor gene variants with acute respiratory distress syndrome risk are modified by sex. The current findings should be replicated in other populations.
Fluctuation analysis of lung function as a predictor of long-term response to β2-agonists
Authors: Thamrin C. , Stern G. , Strippoli M-P. F. , Kuehni C. E. , Suki B. , Taylor D. R. , Frey U. 
Published: November 2008

The response to β2-agonists differs between asthmatics and has been linked to subsequent adverse events, even death. Possible determinants include β2-adrenoceptor genotype at position 16, lung function and airway hyperresponsiveness. Fluctuation analysis provides a simple parameter α measuring the complex correlation properties of day-to-day peak expiratory flow. The present study investigated whether α predicts clinical response to β2-agonist treatment, taking into account other conventional predictors.Analysis was performed on previously published twice-daily peak expiratory flow measurements in 66 asthmatic adults over three 6-month randomised order treatment periods: placebo, salbutamol and salmeterol. Multiple linear regression was used to determine the association between α during the placebo period and response to treatment (change in the number of days with symptoms), taking into account other predictors namely β2-adrenoceptor genotype, lung function and its variability, and airway hyperresponsiveness.The current authors found that α measured during the placebo period considerably improved the prediction of response to salmeterol treatment, taking into account genotype, lung function or its variability, or airway hyperresponsiveness.The present study provides further evidence that response to β2-agonists is related to the time correlation properties of lung function in asthma. The current authors conclude that fluctuation analysis of lung function offers a novel predictor to identify patients who may respond well or poorly to treatment.
Inhibition of phosphodiesterase 4 enhances lung alveolarisation in neonatal mice exposed to hyperoxia
Authors: Woyda K. , Koebrich S. , Reiss I. , Rudloff S. , Pullamsetti S. S. , Rühlmann A. , Weissmann N. , Ghofrani H. A. , Günther A. , Seeger W. , Grimminger F. , Morty R. E. , Schermuly R. T. 
Published: November 2008

Bronchopulmonary dysplasia (BPD) is characterised by impaired alveolarisation, inflammation and aberrant vascular development. Phosphodiesterase (PDE) inhibitors can influence cell proliferation, antagonise inflammation and restore vascular development and homeostasis, suggesting a therapeutic potential in BPD.The aim of the present study was to investigate PDE expression in the lung of hyperoxia-exposed mice, and to assess the viability of PDE4 as a therapeutic target in BPD.Newborn C57BL/6N mice were exposed to normoxia or 85% oxygen for 28 days. Animal growth and dynamic respiratory compliance were reduced in animals exposed to hyperoxia, paralleled by decreased septation, airspace enlargement and increased septal wall thickness. Changes were evident after 14 days and were more pronounced after 28 days of hyperoxic exposure. At the mRNA level, PDE1A and PDE4A were upregulated while PDE5A was downregulated under hyperoxia. Immunoblotting confirmed these trends in PDE4A and PDE5A at the protein expression level. Treatment with cilomilast (PDE4 inhibitor, 5 mg·kg−1·day−1) between days 14 and 28 significantly decreased the mean intra-alveolar distance, septal wall thickness and total airspace area and improved dynamic lung compliance.Pharmacological inhibition of phosphodiesterase improved lung alveolarisation in hyperoxia-induced bronchopulmonary dysplasia, and thus may offer a new therapeutic modality in the clinical management of bronchopulmonary dysplasia.
Potent bronchodilation and reduced stiffness by relaxant stimuli under dynamic conditions
Authors: Ansell T. K. , McFawn P. K. , Noble P. B. , West A. R. , Fernandes L. , Mitchell H. W. 
Published: November 2008

Airway relaxation in response to isoprenaline, sodium nitroprusside (SNP) and electrical field stimulation (EFS) was compared under static and dynamic conditions. The capacity of relaxants to reduce airway stiffness and, thus, potentially contribute to bronchodilation was also investigated.Relaxation responses were recorded in fluid filled bronchial segments from pigs under static conditions and during volume oscillations simulating tidal and twice tidal manoeuvres. Bronchodilation was assessed from the reduction in carbachol-induced lumen pressure, at isovolume points in pressure cycles produced by volume oscillation, and stiffness was assessed from cycle amplitudes.Under static conditions, all three inhibitory stimuli produced partial relaxation of the carbachol-induced contraction. Volume oscillation alone also reduced the contraction in an amplitude-dependent manner. However, maximum relaxation was observed when isoprenaline or SNP were combined with volume oscillation, virtually abolishing contraction at the highest drug concentrations. The proportional effects of isoprenaline and EFS were not different under static or oscillating conditions, whereas relaxation to SNP was slightly greater in oscillating airways. All three inhibitory stimuli also strongly reduced carbachol-induced airway stiffening.The current authors conclude that bronchoconstriction is strongly suppressed by combining the inhibitory stimulation of airway smooth muscle with cyclical mechanical strains. The capacity of airway smooth muscle relaxants to also reduce stiffness may further contribute to bronchodilation.
Occupational exposures and COPD: an ecological analysis of international data
Authors: Blanc P. D. , Menezes A. M. B. , Plana E. , Mannino D. M. , Hallal P. C. , Toren K. , Eisner M. D. , Zock J-P. 
Published: November 2008

The occupational contribution to chronic obstructive pulmonary disease (COPD) has yet to be put in a global perspective. In the present study, an ecological approach to this question was used, analysing group-level data from 90 sex-specific strata from 45 sites of the Burden of Obstructive Lung Disease study, the Latin American Project for the Investigation of Obstructive Lung Disease and the European Community Respiratory Health Survey follow-up. These data were used to study the association between occupational exposures and COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II or above.Regression analysis of the sex-specific group-level prevalence rates of COPD at each site against the prevalence of occupational exposure and ever-smoking was performed, taking into account mean smoking pack-yrs and mean age by site, sex, study cohort and sample size.For the entire data set, the prevalence of exposures predicted COPD prevalence (0.8% increase in COPD prevalence per 10% increase in exposure prevalence). By comparison, for every 10% increase in the proportion of the ever-smoking population, the prevalence of COPD GOLD stage II or above increased by 1.3%. Given the observed median population COPD prevalence of 3.4%, the model predicted that a 20% relative reduction in the disease burden (i.e.to a COPD prevalence of 2.7%) could be achieved by a 5.4% reduction in overall smoking rates or an 8.8% reduction in the prevalence of occupational exposures. When the data set was analysed by sex-specific site data, among males, the occupational effect was a 0.8% COPD prevalence increase per 10% change in exposure prevalence; among females, a 1.0% increase in COPD per 10% change in exposure prevalence was observed.Within the limitations of an ecological analysis, these findings support a worldwide association between dusty trades and chronic obstructive pulmonary disease for both females and males, placing this within the context of the dominant role of cigarette smoking in chronic obstructive pulmonary disease causation.
Extracorporeal pumpless interventional lung assist in clinical practice: determinants of efficacy
Authors: Müller T. , Lubnow M. , Philipp A. , Bein T. , Jeron A. , Luchner A. , Rupprecht L. , Reng M. , Langgartner J. , Wrede C. E. , Zimmermann M. , Birnbaum D. , Schmid C. , Riegger G. A. J. , Pfeifer M. 
Published: November 2008

Respiratory acidosis can become a serious problem during protective ventilation of severe lung failure. A pumpless arteriovenous interventional lung assist (iLA) for extracorporeal carbon dioxide removal has been used increasingly to control critical respiratory situations. The present study sought to evaluate the factors determining the efficacy of iLA and calculate its contribution to gas exchange.In a cohort of 96 patients with severe acute respiratory distress syndrome, haemodynamic parameters, oxygen consumption and carbon dioxide production as well as gas transfer through the iLA were analysed.The measurements demonstrated a significant dependency of blood flowviathe iLA device on cannula size (mean±sd1.59±0.52 L·min−1for 15 French (Fr), 1.94±0.35 L·min−1for 17 Fr, and 2.22 ±0.45 L·min−1for 19 Fr) and on mean arterial pressure. Oxygen transfer capacity averaged 41.7±20.8 mL·min−1, carbon dioxide removal was 148.0±63.4 mL·min−1. Within two hours of iLA treatment, arterial oxygen partial pressure/inspired oxygen fraction ratio increased significantly and a fast improvement in arterial carbon dioxide partial pressure and pH was observed.Interventional lung assist eliminates ∼50% of calculated total carbon dioxide production with rapid normalisation of respiratory acidosis. Despite limited contribution to oxygen transfer it may allow a more protective ventilation in severe respiratory failure.