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Background: Physical activity (PA) is low in patients with Chronic Obstructive Pulmonary Disease (COPD). Identifying modifiable and non-modifiable correlates of PA give understanding of the individual behavior and provide future directions for PA enhancing interventions. As PA is complex and multidimensional, it should be embedded within a thorough framework., Objective: To identify correlates of PA in a comprehensive COPD population based on a broad ecological model, including physiological, psychological, socio-demographic and environmental dimensions., Methods: PA was objectively measured using the Dynaport Movemonitor and a comprehensive data collection of physiological, psychological, socio-demographic and environmental factors were collected. Bivariable and multivariable regression analyses (including principle component analysis) were executed., Results: For this cross-sectional analysis, we included 148 patients with COPD and valid PA data (mean (SD) age 68 (7) years, FEV1 57 (17) % predicted, 5613 (3596) steps per day). Significant bivariable associations were found for physiological (exercise capacity, muscle force, lung function, symptoms, comorbidities), psychological (e.g. fatigue, motivation, perceived difficulty with PA), socio-demographic (dog owning, use of activity tracker) and environmental (season, daylight, temperature) factors. Based on the multivariable regression model, exercise capacity, beliefs on motivation, importance and self-confidence regarding PA and weather conditions were independent correlates of mean steps per day (R 2  = 0.35). Movement intensity during walking was only independently associated with exercise capacity and age (R 2  = 0.41)., Conclusion: Although a wide range of potential influence factors were evaluated, variance in PA was only partly explained, supporting that PA is a complex behavior which is difficult to predict., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Astrid Blondeel reports financial support was provided by Research Foundation Flanders. Heleen Demeyer reports financial support was provided by Research Foundation Flanders. Fien Hermans reports financial support was provided by Research Foundation Flanders. Marieke Wuyts reports financial support was provided by Research Foundation Flanders., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are associated with changes in the sputum microbiome, including an increased prevalence of pathogenic bacteria. Vaccination against the most frequent bacteria identified in AECOPD might reduce exacerbation frequency. We assessed the efficacy, safety, and immunogenicity of a candidate vaccine containing surface proteins from non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat) in patients with COPD., Methods: This multicentre, randomised, observer-blinded, placebo-controlled, proof-of-concept, phase 2b trial recruited patients with stable COPD, moderate-to-very severe airflow limitation (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 2, 3, or 4), at 67 clinical sites in Belgium, Canada, France, Germany, Italy, Spain, UK, and USA. Eligible patients were aged 40-80 years and had a history of at least one moderate or severe exacerbation in the previous year. Patients were allocated (1:1) using a minimisation algorithm to receive two intramuscular injections of NTHi-Mcat vaccine or placebo 60 days apart, in addition to standard care. The allocation algorithm considered age category, number of previous exacerbations, COPD severity at study entry, and country as minimisation factors, to guarantee treatment balance within each factor. Vaccine recipients and those responsible for evaluating study endpoints were masked to group allocation. In the analysis of efficacy, the primary outcome was the rate of any moderate or severe AECOPD occurring within a 1-year period, starting 1 month after the second dose in patients who received two vaccine doses (modified total vaccinated cohort). Safety was assessed in the total vaccinated cohort. The trial is registered with ClinicalTrials.gov, number NCT03281876, and is complete., Findings: Between Nov 27, 2017, and Nov 30, 2018, 606 adults were enrolled and included in the total vaccinated cohort (304 in the NTHi-Mcat vaccine group, 302 in the placebo group); 571 received two doses and were included in the primary efficacy analysis (279 in the NTHi-Mcat vaccine group, 292 in the placebo group). 23 participants dropped-out in the NTHi-Mcat vaccine group and 39 in the placebo group; this included 4 patients in the NTHi-Mcat vaccine group and 15 in the placebo group who withdrew from the study because of an adverse event. The primary analysis included 340 exacerbations (in follow-up time 102 123 days) in the NTHi-Mcat vaccine group and 333 (in 104 443 days) in the placebo group, with a yearly rate of moderate or severe AECOPD of 1·22 in the NTHi-Mcat vaccine group and 1·17 in the placebo group, with vaccine efficacy in reducing the yearly rate of moderate or severe AECOPD estimated to be zero (vaccine efficacy point estimate 2·26% [87% CI -18·27 to 11·58]; p=0·82). Solicited local adverse events were more frequent in the NTHi-Mcat vaccine group (216 [72%] of 301 patients) than with placebo (34 [11%] of 299 patients), and the frequency of solicited general adverse events was similar between groups (239 [79%] of 301 vs 235 [79%] of 299 patients). There was one death in the NTHi-Mcat vaccine group (acute respiratory failure, not related to vaccination) and ten in the placebo group (seven due in part to COPD or respiratory failure). There were 158 serious adverse events (89 [29%] of 304 patients) in the NTHi-Mcat vaccine group, not related to vaccination, and 214 (99 [33%] of 302 patients) in the placebo group., Interpretation: NTHi-Mcat vaccine administered to patients with COPD did not show efficacy in reducing the yearly rate of moderate or severe exacerbations. No safety concerns were identified., Funding: GlaxoSmithKline Biologicals SA., Competing Interests: Declaration of interests SA reports grants and personal fees from Boehringer Ingelheim, grants from Pfizer, and personal fees from Novartis, AstraZeneca, the GlaxoSmithKline (GSK) group of companies, Chiesi, and Merini, outside of the submitted work. AKA, DC, GDM, ML, LM, SS, and AT are employees of the GSK group of companies. MT was an employee of the GSK group of companies when this study was conducted and is now an employee of Janssen–Cilag SpA. ML and SS also hold shares in the GSK group of companies. GB reports having received honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, the GSK group of companies, Novartis, and Teva, and for advisory boards from Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, the GSK group of companies, Novartis, Sanofi–Regeneron, and Teva, all outside of the submitted work. WJ reports grants from AstraZeneca, Chiesi, Roche, and Boehringer Ingelheim outside of the submitted work. EK has served on advisory boards and received consulting fees and travel reimbursements from Amphastar, AstraZeneca, Boehringer Ingelheim, Chiesi, Connect Biopharmaceuticals, the GSK group of companies, Mylan, Novartis, Sunovion, and Theravance, outside of the submitted work. AP reports receiving fees for board membership, consultancy, payment for lectures, grants for research, travel expense reimbursement from Chiesi, AstraZeneca, the GSK group of companies, Boehringer Ingelheim, and Teva; fees for board membership, consultancy, payment for lectures, travel expense reimbursement from Mundipharma, Novartis, Zambon, and Sanofi–Regeneron; and grants for research, payment for lectures, travel expenses reimbursement from Menarini, fees for board membership, consultancy, travel expenses reimbursement from Roche, grants for research from Fondazione Maugeri, Fondazione Chiesi, and consultancy fees from Edmondpharma, all outside of the submitted work. LP-M reports, outside of the submitted work, financial support for educational activities and advisory from AstraZeneca, financial support for educational activities and a grant for non-committed investigation from the GSK group of companies, investigation grant from Esteve and Menarini, travel bourses from Boerhinger Ingelheim and Teva, travel bourse, and personal fees for educational activities from Novartis, financial support for educational activities from Chiesi, and personal fees for advisory from Merck Sharpe & Dohme and Boston Scientific. DS, BP, and LB declare no financial and non-financial relationships and activities and no conflicts of interest. HW reports a grant to his employer from the GSK group of companies during the conduct of this study, and grants or personal fees from the GSK group of companies, AstraZeneca, Boehringer Ingelheim, Novartis, Chiesi, Menarini, Takeda, and Bayer outside of the submitted work. TMAW received grants from the GSK group of companies during the conduct of this study. TMAW also received grants from AstraZeneca, Synairgen, UK Research and Innovation, and MyMHealth, and fees or non-financial support from Boehringer Ingelheim, Chiesi, and AstraZeneca, outside of the submitted work. TMAW is an inventor on patent applications: 2018 US Patent application 62/479562—immunogenic composition, use and methods of treatment—a novel vaccine to prevent exacerbations of COPD pending to the GSK group of companies; and US patent application 62/479550 (novel COPD vaccine). TMAW is the founder and director of MyMHealth Ltd. FM reports a grant paid to his institution by the GSK group of companies during the conduct of this study, and grants paid to his institution by the GSK group of companies, AstraZeneca, Sanofi; unrestricted grant paid to his institution by Novartis, Boehringer Ingelheim, Grifols; personal fees for participating in speaker bureau from the GSK group of companies, Boehringer Ingelheim, Grifols, Novartis; and financial participation in Oxynov, all outside of the submitted work., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Physiological lung ageing is associated with a gradual decline in dynamic lung volumes and a progressive increase in residual volume due to diminished elastic recoil of the lung, loss of alveolar tissue, and lower chest wall compliance. However, the effects of ageing on the small airways (ie, airways <2·0 mm in diameter) remain largely unknown. By using a combination of ex-vivo conventional CT (resolution 1 mm), whole lung micro-CT (resolution 150 μm), and micro-CT of extracted cores (resolution 10 μm), we aimed to provide a multiresolution assessment of the small airways in lung ageing in a large cohort of never smokers., Methods: For this cross-sectional study, we included donor lungs collected from 32 deceased never-smoking donors (age range 16-83 years). Ex-vivo CT and whole lung high-resolution CT (micro-CT) were used to determine total airway numbers, stratified by airway diameter. Micro-CT was used to assess the number, length, and diameter of terminal bronchioles (ie, the last generation of conducting airways); mean linear intercept; and surface density in four lung tissue cores from each lung, extracted using a uniform sampling approach. Regression β coefficients are calculated using linear regression and polynomial models., Findings: Ex-vivo CT analysis showed an age-dependent decrease in the number of airways of diameter 2·0 mm to less than 2·5 mm (β coefficient per decade -0·119, 95% CI -0·193 to -0·045; R 2 =0·29) and especially in airways smaller than 2·0 mm in diameter (-0·158, -0·233 to -0·084; R 2 =0·47), between 30 and 80 years of age, but not of the larger (≥2·5 mm) diameter airways (-0·00781, -0·04409 to 0·02848; R 2 =0·0007). In micro-CT analysis of small airways, the total number of terminal bronchioles per lung increased until the age of 30 years, after which an almost linear decline in the number of terminal bronchioles was observed (β coefficient per decade -2035, 95% CI -2818 to -1252; R 2 =0·55), accompanied by a non-significant increase in alveolar airspace size (6·44, -0·57 to 13·45, R 2 =0·10). Moreover, this decrease in terminal bronchioles was associated with the age-related decline of pulmonary function predicted by healthy reference values., Interpretation: Loss of terminal bronchioles is an important structural component of age-related decline in pulmonary function of healthy, non-smoking individuals., Funding: Research Foundation-Flanders, KU Leuven, Parker B Francis Foundation, UGent, Canadian Institutes for Health., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Given the recent development in the field of particle and fibre toxicology, parallels have been drawn between Carbon nanotubes (CNTs) and asbestos. It is now established that both multi-walled (MWCNTs) and single-walled (SWCNTs) carbon nanotubes might contribute to pulmonary disease. Although multiple mechanisms might be involved in CNT induced pathogenesis, systematic understanding of the relationship between different CNT exposure (MWCNT vs SWCNT) and autophagy/ apoptosis/ necrosis, in human lung epithelial cells remains limited. In this study, we demonstrate that exposure to MWCNT (NM-400), but not SWCNT (NIST-SRM2483), leads to an autophagic response after acute exposure (24 h). MWCNT exposure was characterized by an increase in anti-apoptotic BCL2, downregulation of executor Caspase-3/7 and increase in expression of genes from the autophagy machinery. For SWCNT exposure however, we observed an overexpression of executor Caspase-3/7 and upregulation of pro-apoptotic BAX; enrichment for processes like cornification, apoptotic process, cell differentiation from proteomic analysis. These results clearly indicate a major difference in the pathways initiated by the CNTs, in vitro. While the present study design provides mechanistic understanding after an acute exposure for the tested CNTs, we believe that the information obtained here would have relevance in better understanding of CNT toxicity and pathogenesis in general., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Spirometry is the current gold standard for diagnosing and monitoring the progression of Chronic Obstructive Pulmonary Disease (COPD). However, many current and former smokers who do not meet established spirometric criteria for the diagnosis of this disease have symptoms and clinical courses similar to those with diagnosed COPD. Large longitudinal observational studies following individuals at risk of developing COPD offer us additional insight into spirometric patterns of disease development and progression. Analysis of forced expiratory maneuver changes over time may allow us to better understand early changes predictive of progressive disease. This review discusses the theoretical ability of spirometry to capture fine pathophysiologic changes in early airway disease, highlights the shortcomings of current diagnostic criteria, and reviews existing evidence for spirometric measures which may be used to better detect early airflow impairment., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Anxiety is a highly prevalent psychological comorbidity in patients with chronic obstructive pulmonary disease (COPD) and has detrimental effects on pulmonary rehabilitation (PR) outcomes. It has been suggested that disease-specific fears could play an even more important role in COPD patients' disease progression. However, little is known about how different disease-specific fears impact COPD. This study examined how different disease-specific fears relate to different PR outcome measures in COPD patients and how these relationships evolve over the course of PR. Before and after a 3-week inpatient PR program, COPD patients (N = 104) underwent a 6-min walking test to measure functional exercise capacity. Disease-specific fears (fear of physical activity, fear of dyspnea, fear of disease progression, fear of social exclusion) were assessed with the COPD-Anxiety-Questionnaire-Revised. Health-related quality of life (HQoL), COPD health status, dyspnea in daily life, depression, and anxiety were measured using validated questionnaires. Multiple regression showed that greater disease-specific fears at the start of PR were associated with worse functional exercise capacity, HQoL, health status, and depression at the start and end of PR (controlling for age, sex, lung function, smoking status, and general anxiety). Patients who showed a stronger decrease in disease-specific fears improved more in PR outcome measures over the course of PR. Furthermore, different disease-specific fears were related to different PR outcome measures. The results show that disease-specific fears are associated with treatment outcome measures, both cross-sectionally and prospectively. Therefore, disease-specific fears should be addressed in COPD patients as they might play a significant role in disease progression., (Copyright © 2018. Published by Elsevier Ltd.)

The molecular mechanisms underlying the pathogenesis of chronic obstructive pulmonary disease (COPD) are still unclear, however signaling pathways associated with lung development, such as the transforming growth factor (TGF)-β superfamily, could be implicated in COPD. Growth differentiation factor (GDF)-15, a member of the TGF-β superfamily, is involved in inflammation, mucus secretion, and cachexia. We analyzed the pulmonary expression of GDF-15 in smokers and patients with COPD, in cigarette smoke (CS)-exposed cultures of primary human bronchial epithelial cells (pHBECs), and in CS-exposed mice. Next, we exposed GDF-15 KO and control mice to air or CS and evaluated pulmonary inflammation. GDF-15 levels were higher in sputum supernatant and lung tissue of patients with COPD and smokers without COPD compared with never smokers. Immunohistochemistry revealed GDF-15 staining in the airway epithelium. Increased expression and secretion of GDF-15 was confirmed in vitro in CS-exposed pHBECs compared with air-exposed pHBECs. Similarly, GDF-15 levels were increased in lungs of CS-exposed mice. Importantly, GDF-15 deficiency attenuated the CS-induced pulmonary inflammation. These results suggest that increased GDF-15-as observed in lungs of smokers and patients with COPD-contributes to CS-induced pulmonary inflammation.

Background: There is a wide variability in measurement methodology of physical activity. This study investigated the effect of different analysis techniques on the statistical power of physical activity outcomes after pulmonary rehabilitation., Methods: Physical activity was measured with an activity monitor armband in 57 patients with COPD (mean ± SD age, 66 ± 7 years; FEV1, 46 ± 17% predicted) before and after 3 months of pulmonary rehabilitation. The choice of the outcome (daily number of steps [STEPS], time spent in at least moderate physical activity [TMA], mean metabolic equivalents of task level [METS], and activity time [ACT]), impact of weekends, number of days of assessment, postprocessing techniques, and influence of duration of daylight time (DT) on the sample size to achieve a power of 0.8 were investigated., Results: The STEPS and ACT (1.6-2.3 metabolic equivalents of task) were the most sensitive outcomes. Excluding weekends decreased the sample size for STEPS (83 vs 56), TMA (160 vs 148), and METS (251 vs 207). Using 4 weekdays (STEPS and TMA) or 5 weekdays (METS) rendered the lowest sample size. Excluding days with < 8 h wearing time reduced the sample size for STEPS (56 vs 51). Differences in DT were an important confounder., Conclusions: Changes in physical activity following pulmonary rehabilitation are best measured for 4 weekdays, including only days with at least 8 h of wearing time (during waking hours) and considering the difference in DT as a covariate in the analysis., Trial Registry: ClinicalTrials.gov; No.: NCT00948623; URL: www.clinicaltrials.gov.

Abundant laboratory findings show the important role vitamin D has in the innate and adaptive immune system. In human beings, observational studies have associated vitamin D deficiency with an increased risk for different inflammatory, infectious, and autoimmune diseases. With regard to chronic obstructive pulmonary disease (COPD), conflicting data have been reported. Most epidemiological studies have been restricted by their design, and larger longitudinal studies of population-based samples and of cohorts with COPD are warranted. An alternative explanation for the discordant results in COPD might be related to the complexity of the intracellular vitamin D signalling pathway, which is not shown in systemic levels of the precursor 25-hydroxyvitamin D. For COPD in particular, we speculate that local downregulation of vitamin D signalling from and beyond the receptor might clarify why pro-inflammatory processes in the airways are not or are insufficiently countered by vitamin D-dependent control mechanisms. In a disease already characterised by glucocorticoid resistance, the potential activation and reactivation of an intrinsic comprehensive system of immune control should attract more attention to design appropriate interventions with promising therapeutic potential., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Few studies of the diagnostic value of pulmonary function testing are available. We assessed the diagnostic contribution of four basic pulmonary function tests: spirometry, lung volume, airway resistance, and diffusing capacity., Methods: In this prospective cohort study, we enrolled patients presenting to a pulmonologist with respiratory symptoms but no clear diagnosis from 33 hospitals in Belgium. Each patient had spirometry, lung volume, airway resistance, and diffusing capacity testing and all other tests necessary for a definitive diagnosis. Clinical history and pulmonary function data were presented to local focus groups, who established differential diagnoses and a preferred diagnosis after each test-the focus groups were masked to additional investigations. The final diagnosis was established by the attending physician on the basis of all the investigations done, and validated as the gold standard diagnosis by the local focus group. The primary outcome was a score calculated by 1/number of differential diagnoses, corrected for the accuracy of the diagnosis. Secondary outcomes were the number of differential diagnoses for patients with a correct preferred diagnosis and the proportion of preferred diagnoses that were correct. The study is registered at ClinicalTrials.gov, number NCT01297881., Findings: We screened 1285 people, of whom 1023 were enrolled and 979 analysed. The primary outcome score was 0·226 after spirometry, increasing to 0·296 after measurement of lung volume, 0·373 after airway resistance test, and 0·540 after measurement of diffusing capacity (p<0·0001 for each step). The number of differential diagnoses decreased after each step (4·2, 3·4, 3·0, and 2·4; p<0·0001 for each step) and the proportion of correct preferred diagnoses increased (61%, 65%, 70%, and 77%; p<0·0001 for each step)., Interpretation: The increase in scores shows a progressive reduction of the number of differential diagnoses and an increased accuracy of the preferred diagnosis. Each of the four classic pulmonary function tests contributes significantly and independently to the final diagnosis in new patients with respiratory symptoms seen by pulmonologists. Thus, funding of these tests is justified in that setting., Funding: Belgian Society of Pneumology., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: This study explores spirometry quality and reproducibility in the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT(®)) trial., Methods: Four-year, randomized, double-blind, placebo-controlled, multicenter trial in 5993 patients with chronic obstructive pulmonary disease. Within-test variability of pre- and post-bronchodilator forced expiratory volume in 1 s (FEV(1)) was compared across study visits. Between-test variability of best pre- or post-FEV(1) values between two visits 6 months apart was compared at the start, middle and end of the trial., Results: Three or more acceptable maneuvers were obtained in 93% of visits. Within-test variability of pre- and post-FEV(1) (mean standard deviation: 0.092 and 0.098 L) decreased during the trial. Between-test variability also decreased: pre-FEV(1) (visit 3-5 = 0.141 ± 0.138 L; visit 9-11 = 0.129 ± 0.121 L; visit 17-19 = 0.121 ± 0.122 L); post-FEV(1) (0.139 ± 0.140, 0.126 ± 0.123, 0.121 ± 0.122 L, respectively), and was dependent on age, sex, smoking status and disease stage, but not on bronchodilator response or study treatment., Conclusion: Spirometry quality in UPLIFT(®) was good and improved during the trial. Between-test variability across patient subgroups suggests that relevant cut-offs for individual disease monitoring are difficult to establish., Trial Registration Number: NCT00144339., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Results of epidemiological studies have shown that chronic obstructive pulmonary disease (COPD) is frequently associated with comorbidities, the most serious and prevalent being cardiovascular disease, lung cancer, osteoporosis, muscle weakness, and cachexia. Mechanistically, environmental risk factors such as smoking, unhealthy diet, exacerbations, and physical inactivity or inherent factors such as genetic background and ageing contribute to this association. No convincing evidence has been provided to suggest that treatment of COPD would reduce comorbidities, although some indirect indications are available. Clear evidence that treatment of comorbidities improves COPD is also lacking, although observational studies would suggest such an effect for statins, β blockers, and angiotensin-converting enzyme blockers and receptor antagonists. Large-scale prospective studies are needed. Reduction of common risk factors seems to be the most powerful approach to reduce comorbidities. Whether reduction of so-called spill-over of local inflammation from the lungs or systemic inflammation with inhaled or systemic anti-inflammatory drugs, respectively, would also reduce COPD-related comorbidities is doubtful., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow obstruction that is only partly reversible, inflammation in the airways, and systemic effects or comorbities. The main cause is smoking tobacco, but other factors have been identified. Several pathobiological processes interact on a complex background of genetic determinants, lung growth, and environmental stimuli. The disease is further aggravated by exacerbations, particularly in patients with severe disease, up to 78% of which are due to bacterial infections, viral infections, or both. Comorbidities include ischaemic heart disease, diabetes, and lung cancer. Bronchodilators constitute the mainstay of treatment: β(2) agonists and long-acting anticholinergic agents are frequently used (the former often with inhaled corticosteroids). Besides improving symptoms, these treatments are also thought to lead to some degree of disease modification. Future research should be directed towards the development of agents that notably affect the course of disease., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

COPD and osteoporosis are strongly associated because of common risk factors such as age, smoking, and inactivity. In addition, COPD-related systemic inflammation, vitamin D deficiency, and the use of systemic corticosteroids enhance ongoing bone destruction. Osteoporosis, in turn, may cause fragility fractures, which further impair mobility and increase morbidity and mortality. Vertebral compression fractures and rib cage fractures in patients with COPD may also reduce pulmonary function or enhance exacerbations. Early prevention and treatment of osteoporosis in COPD is, therefore, important and should be based on integrated risk assessment tools such as FRAX, which take bone mineral density, history of fragility fractures, and population-specific clinical factors into account. As long as intervention studies focusing on the bone in COPD are lacking, a more rigorous application of existing treatment guidelines of osteoporosis in general is mandatory.

Background: Fractional exhaled NO (Fe,NO) has yielded inconsistent results in COPD. Measuring exhaled NO at multiple flow rates however, allows to dissect exhaled NO in an alveolar (CAlv,NO) and bronchial (J'aw,NO) fraction, which are claimed to better reflect the bronchial and alveolar inflammation in COPD. We examined whether the use of Fe,NO, CAlv,NO and J'aw,NO may contribute to the clinical diagnosis of COPD., Methods: One hundred and fifty one patients were included in this case-control design: 28 healthy nonsmokers, 39 healthy smokers, 55 COPD nonsmokers and 29 COPD smokers. Prior to spirometry, exhaled NO was measured at three different flow rates (50, 100 and 200 ml/s; NIOX-FLEX) from which Fe,NO, CAlv,NO and J'aw,NO were calculated., Results: Mean Fe,NO, mean CAlv,NO and mean J'aw,NO of healthy individuals were not significantly different from COPD patients and none of these variables correlated with FEV(1). In both healthy and COPD patients, current smoking significantly reduced Fe,NO, J'aw,NO and CAlv,NO. Multivariate analysis demonstrated that in contrast to gender, age, BMI, GOLD stage and the use of inhaled corticosteroids, current smoking was the only variable affecting CAlv,NO. (p=0.0115), Conclusion: We conclude that similar to single breath exhaled NO, exhaled NO at different flow rates does not contribute to the diagnosis of COPD in standard respiratory practice., (Copyright 2010 Elsevier Ltd. All rights reserved.)

The use of dissimilar chromatographic systems in drug impurity profiling can be very advantageous. Screening a new-drug impurity mixture on those systems not only enhances the chance that all impurities are revealed, but also allows choosing a suited system for further method development. In this paper several strategies were evaluated to predict the optimal pH (of the buffer used in the mobile phase) from the screening results. Four or five dissimilar stationary phases were screened at four pH values (between 2.5 and 9.4), in order to obtain maximal information about the composition of the sample and to select one column for the subsequent optimization. Different linear models (straight lines, 2nd and 3rd degree polynomials) based on these experiments were tested for their ability to predict the retention times (t(R)) of the impurities at intermediate pH values. The predicted t(R) values were then used to calculate minimal resolutions and eventually to select an optimal pH at which the highest minimal resolution is predicted. None of the applied models is accurate enough to predict correctly which peaks are worst separated at the indicated optimal pH. However, the best strategy (applying a second degree polynomial describing the t(R) measured at 3 consecutive screening pH values) did succeed in indicating an optimal pH at which a good separation of the impurities is obtained. Unfortunately, the resulting separation quality is not or only slightly better than the best separation obtained during screening. Therefore, it can be concluded that the most (time-) efficient approach to develop an impurity profile of a new drug is to screen it on four or five dissimilar columns at four different pH values and to retain the best screening conditions (without making predictions for intermediate conditions) for further optimization of the organic modifier composition of the mobile phase, and occasionally the temperature and the gradient. This is at least the case when the profiles have a complexity similar to those studied.

Listeria monocytogenes is an important bacterial pathogen in immunocompromised patients, the elderly, pregnant women and transplant patients, but until now it has not been reported in lung transplants. We report the first case of listeriosis in a lung transplant recipient who presented with a pleural effusion 8 days after transplantation. After the introduction of a thorax drain and the administration of intravenous antibiotics during 3 weeks, the patient recovered completely. This case highlights the increased risk for uncommon respiratory infections in lung transplant patients and examines the specific management of listeria pleuritis.

The influence of genetic selection for improved feed conversion (FC) and fast growth (GL) in broiler chickens, on the hepatic growth hormone receptor was investigated as a function of age. Selection for improved feed conversion resulted in lean chickens, whereas selection for fast growth resulted in fat chickens. Growth hormone receptor characteristics were determined in liver microsomal fractions and plasma GH concentrations were measured by radioimmunoassay. Embryos from the FC line showed higher specific GH binding than GL embryos at day 16 of embryonic development only (P < 0.05). On day 18 of embryonic development, the FC line had slightly more GH receptors than the GL line (P < 0.05), whereas simultaneous plasma GH concentrations were greater in the GL line. The effect of selection on hepatic growth hormone binding was greatest in 4 week old growing chicks at which age the GL line showed a 2- to 3-fold higher % of specific binding than the FC line (P < 0.001). The difference at this stage is probably due to down regulation of the receptor by the significantly higher GH concentrations in the FC line. The adult GL chickens also showed higher specific binding than FC, but the difference was less pronounced than in the growing stage (P < 0.05). This was due to a higher number of GH receptors, while receptor affinity was unchanged. Because no line difference in plasma GH concentrations was found in adult hens, other unknown mechanisms probably play a role in determining differences in GH receptor binding between these selected lines at older ages.

BM 13.177, a sulphonamide derivative, prevented platelet aggregation by thromboxane A2 in vitro and selectively inhibited contraction of isolated rabbit femoral arteries induced by two stable endoperoxide analogues. In a double-blind placebo-controlled study, oral BM 13.177 inhibited platelet aggregation induced by arachidonic acid, low dose collagen, and the two stable endoperoxide analogues, and slightly prolonged the bleeding time. Generation of thromboxane or of other prostaglandins was not affected. No side-effects were seen. BM 13.177 appears selectively and safely to block platelet and vessel wall thromboxane receptors and should be useful in elucidating the role of thromboxane A2 in disease.

Concentrations of droperidol which caused a shift to the right of the dose-response curve to noradrenaline in the pulmonary artery and the saphenous vein of the dog did not affect myogenic activation by K+; they did not inhibit spontaneous activity of portal-mesenteric veins. Droperidol inhibited the contractile response to nerve stimulation, but did not affect the evoked release of 3H-noradrenaline. These experiments indicate that the vasodilator properties of smaller doses of droperidol are a result of its ability to block alpha-adrenergic receptors.