Nasal mucociliary clearance in subjects with COPD after smoking cessation

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Avaliação do significado social, econômico e cultural do tabagismo em mulheres profissionais do sexo

Pós-graduação em Enfermagem - FMB

Tobacco in adolescence: importance to knowledge the health hazards and preventive measures

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Smoking cessation and bronchial epithelial remodelling in COPD: a cross-sectional study

Abstract Background Chronic Obstructive Pulmonary Disease (COPD) is associated with bronchial epithelial changes, including squamous cell metaplasia and goblet cell hyperplasia. These features are partially attributed to activation of the epidermal growth factor receptor (EGFR). Whereas smoking cessation reduces respiratory symptoms and lung function decline in COPD, inflammation persists. We determined epithelial proliferation and composition in bronchial biopsies from current and ex-smokers with COPD, and its relation to duration of smoking cessation. Methods 114 COPD patients were studied cross-sectionally: 99 males/15 females, age 62 ± 8 years, median 42 pack-years, no corticosteroids, current (n = 72) or ex-smokers (n = 42, median cessation duration 3.5 years), postbronchodilator FEV1 63 ± 9% predicted. Squamous cell metaplasia (%), goblet cell (PAS/Alcian Blue+) area (%), proliferating (Ki-67+) cell numbers (/mm basement membrane), and EGFR expression (%) were measured in intact epithelium of bronchial biopsies. Results Ex-smokers with COPD had significantly less epithelial squamous cell metaplasia, proliferating cell numbers, and a trend towards reduced goblet cell area than current smokers with COPD (p = 0.025, p = 0.001, p = 0.081, respectively), but no significant difference in EGFR expression. Epithelial features were not different between short-term quitters (<3.5 years) and current smokers. Long-term quitters (≥3.5 years) had less goblet cell area than both current smokers and short-term quitters (medians: 7.9% vs. 14.4%, p = 0.005; 7.9% vs. 13.5%, p = 0.008; respectively), and less proliferating cell numbers than current smokers (2.8% vs. 18.6%, p < 0.001). Conclusion Ex-smokers with COPD had less bronchial epithelial remodelling than current smokers, which was only observed after long-term smoking cessation (>3.5 years). Trial registration NCT00158847

Smoking, apolipoprotein E genotypes, and mortality (the Ludwigshafen RIsk and Cardiovascular Health study).

AIMS The genetic polymorphism of apolipoprotein E (APOE) has been suggested to modify the effect of smoking on the development of coronary artery disease (CAD) in apparently healthy persons. The interaction of these factors in persons undergoing coronary angiography is not known. METHODS AND RESULTS We analysed the association between the APOE-genotype, smoking, angiographic CAD, and mortality in 3263 participants of the LUdwigshafen RIsk and Cardiovascular Health study. APOE-genotypes were associated with CAD [ε22 or ε23: odds ratio (OR) 0.56, 95% confidence interval (CI) 0.43-0.71; ε24 or ε34 or ε44: OR 1.10, 95% CI 0.89-1.37 compared with ε33] and moderately with cardiovascular mortality [ε22 or ε23: hazard ratio (HR) 0.71, 95% CI 0.51-0.99; ε33: HR 0.92, 95% CI 0.75-1.14 compared with ε24 or ε34 or ε44]. HRs for total mortality were 1.39 (95% CI 0.39-0.1.67), 2.29 (95% CI 1.85-2.83), 2.07 (95% CI 1.64-2.62), and 2.95 (95% CI 2.10-4.17) in ex-smokers, current smokers, current smokers without, or current smokers with one ε4 allele, respectively, compared with never-smokers. Carrying ε4 increased mortality in current, but not in ex-smokers (HR 1.66, 95% CI 1.04-2.64 for interaction). These findings applied to cardiovascular mortality, were robust against adjustment for cardiovascular risk factors, and consistent across subgroups. No interaction of smoking and ε4 was seen regarding non-cardiovascular mortality. Smokers with ε4 had reduced average low-density lipoprotein (LDL) diameters, elevated oxidized LDL, and lipoprotein-associated phospholipase A2. CONCLUSION In persons undergoing coronary angiography, there is a significant interaction between APOE-genotype and smoking. The presence of the ε4 allele in current smokers increases cardiovascular and all-cause mortality.

Association of long-term nicotine abstinence with normal metabotropic glutamate receptor-5 binding

BACKGROUND Nicotine addiction is a major public health problem and is associated with primary glutamatergic dysfunction. We recently showed marked global reductions in metabotropic glutamate receptor type 5 (mGluR5) binding in smokers and recent ex-smokers (average abstinence duration of 25 weeks). The goal of this study was to examine the role of mGluR5 downregulation in nicotine addiction by investigating a group of long-term ex-smokers (abstinence >1.5 years), and to explore associations between mGluR5 binding and relapse in recent ex-smokers. METHODS Images of mGluR5 receptor binding were acquired in 14 long-term ex-smokers, using positron emission tomography with radiolabeled [11C]ABP688, which binds to an allosteric site with high specificity. RESULTS Long-term ex-smokers and individuals who had never smoked showed no differences in mGluR5 binding in any of the brain regions examined. Long-term ex-smokers showed significantly higher mGluR5 binding than recent ex-smokers, most prominently in the frontal cortex (42%) and thalamus (57%). CONCLUSIONS Our findings suggest that downregulation of mGluR5 is a pathogenetic mechanism underlying nicotine dependence and the high relapse rate in individuals previously exposed to nicotine. Therefore, mGluR5 receptor binding appears to be an effective biomarker in smoking and a promising target for the discovery of novel medication for nicotine dependence and other substance-related disorders.

Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort

U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach.This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements.Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids.Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of "omic" datasets that are at the core of this systems medicine approach.

Effect of nicotine on brain activation during performance of a working memory task

Nicotine influences cognition and behavior, but the mechanisms by which these effects occur are unclear. By using positron emission tomography, we measured cognitive activation (increases in relative regional cerebral blood flow) during a working memory task [2-back task (2BT)] in 11 abstinent smokers and 11 ex-smokers. Assays were performed both after administration of placebo gum and 4-mg nicotine gum. Performance on the 2BT did not differ between groups in either condition, and the pattern of brain activation by the 2BT was consistent with reports in the literature. However, in the placebo condition, activation in ex-smokers predominated in the left hemisphere, whereas in smokers, it occurred in the right hemisphere. When nicotine was administered, activation was reduced in smokers but enhanced in ex-smokers. The lateralization of activation as a function of nicotine dependence suggests that chronic exposure to nicotine or withdrawal from nicotine affects cognitive strategies used to perform the memory task. Furthermore, the lack of enhancement of activation after nicotine administration in smokers likely reflects tolerance.

Reducing the time before consulting with symptoms of lung cancer:a randomised controlled trial in primary care

Background: Most individuals with lung cancer have symptoms for several months before presenting to their GP. Earlier consulting may improve survival. Aim: To evaluate whether a theory-based primary care intervention increased timely consulting of individuals with symptoms of lung cancer. Design and setting: Open randomised controlled trial comparing intervention with usual care in two general practices in north-east Scotland. Method: Smokers and ex-smokers aged ≥55 years were randomised to receive a behavioural intervention or usual care. The intervention comprised a single nurse consultation at participants' general practice and a self-help manual. The main outcomes were consultations within target times for individuals with new chest symptoms (≤3 days haemoptysis, ≤3 weeks other symptoms) in the year after the intervention commenced, and intentions about consulting with chest symptoms at 1 and 6 months. Results: Two hundred and twelve participants were randomised and 206 completed the trial. The consultation rate for new chest symptoms in the intervention group was 1.19 (95% confidence interval [CI] = 0.92 to 1.53; P = 0.18) times higher than in the usual-care group and the proportion of consultations within the target time was 1.11 (95% CI = 0.41 to 3.03; P = 0.83) times higher. One month after the intervention commenced, the intervention group reported intending to consult with chest symptoms 31 days (95% CI = 7 to 54; P = 0.012) earlier than the usual care group, and at 6 months this was 25 days (95% CI = 1.5 to 48; P = 0.037) earlier. Conclusion: Behavioural intervention in primary care shortened the time individuals at high risk of lung disease intended to take before consulting with new chest symptoms (the secondary outcome of the study), but increases in consultation rates and the proportions of consultations within target times were not statistically significant. © British Journal of General Practice.

An Analytical Workflow for Metagenomic Data and its Application to the Study of Chronic Obstructive Pulmonary Disease (COPD)

Metagenomics is the culture-independent study of genetic material obtained directly from environmental samples. It has become a realistic approach to understanding microbial communities thanks to advances in high-throughput DNA sequencing technologies over the past decade. Current research has shown that different sites of the human body house varied bacterial communities. There is a strong correlation between an individual’s microbial community profile at a given site and disease. Metagenomics is being applied more often as a means of comparing microbial profiles in biomedical studies. The analysis of the data collected using metagenomics can be quite challenging and there exist a plethora of tools for interpreting the results. An automatic analytical workflow for metagenomic analyses has been implemented and tested using synthetic datasets of varying quality. It is able to accurately classify bacteria by taxa and correctly estimate the richness and diversity of each set. The workflow was then applied to the study of the airways microbiome in Chronic Obstructive Pulmonary Disease (COPD). COPD is a progressive lung disease resulting in narrowing of the airways and restricted airflow. Despite being the third leading cause of death in the United States, little is known about the differences in the lung microbial community profiles of healthy individuals and COPD patients. Bronchoalveolar lavage (BAL) samples were collected from COPD patients, active or ex-smokers, and never smokers and sequenced by 454 pyrosequencing. A total of 56 individuals were recruited for the study. Substantial colonization of the lungs was found in all subjects and differentially abundant genera in each group were identified. These discoveries are promising and may further our understanding of how the structure of the lung microbiome is modified as COPD progresses. It is also anticipated that the results will eventually lead to improved treatments for COPD.

Assessment of vitamin A status in chronic obstructive pulmonary disease patients and healthy smokers

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Ex vivo investigation of novel wound healing therapies and development of a 3-D human skin equivalent wound model

It has previously been found that complexes comprised of vitronectin and growth factors (VN:GF) enhance keratinocyte protein synthesis and migration. More specifically, these complexes have been shown to significantly enhance the migration of dermal keratinocytes derived from human skin. In view of this, it was thought that these complexes may hold potential as a novel therapy for healing chronic wounds. However, there was no evidence indicating that the VN:GF complexes would retain their effect on keratinocytes in the presence of chronic wound fluid. The studies in this thesis demonstrate for the first time that the VN:GF complexes not only stimulate proliferation and migration of keratinocytes, but also these effects are maintained in the presence of chronic wound fluid in a 2-dimensional (2-D) cell culture model. Whilst the 2-D culture system provided insights into how the cells might respond to the VN:GF complexes, this investigative approach is not ideal as skin is a 3-dimensional (3-D) tissue. In view of this, a 3-D human skin equivalent (HSE) model, which reflects more closely the in vivo environment, was used to test the VN:GF complexes on epidermopoiesis. These studies revealed that the VN:GF complexes enable keratinocytes to migrate, proliferate and differentiate on a de-epidermalised dermis (DED), ultimately forming a fully stratified epidermis. In addition, fibroblasts were seeded on DED and shown to migrate into the DED in the presence of the VN:GF complexes and hyaluronic acid, another important biological factor in the wound healing cascade. This HSE model was then further developed to enable studies examining the potential of the VN:GF complexes in epidermal wound healing. Specifically, a reproducible partial-thickness HSE wound model was created in fully-defined media and monitored as it healed. In this situation, the VN:GF complexes were shown to significantly enhance keratinocyte migration and proliferation, as well as differentiation. This model was also subsequently utilized to assess the wound healing potential of a synthetic fibrin-like gel that had previously been demonstrated to bind growth factors. Of note, keratinocyte re-epitheliasation was shown to be markedly improved in the presence of this 3-D matrix, highlighting its future potential for use as a delivery vehicle for the VN:GF complexes. Furthermore, this synthetic fibrin-like gel was injected into a 4 mm diameter full-thickness wound created in the HSE, both keratinocytes and fibroblasts were shown to migrate into this gel, as revealed by immunofluorescence. Interestingly, keratinocyte migration into this matrix was found to be dependent upon the presence of the fibroblasts. Taken together, these data indicate that reproducible wounds, as created in the HSEs, provide a relevant ex vivo tool to assess potential wound healing therapies. Moreover, the models will decrease our reliance on animals for scientific experimentation. Additionally, it is clear that these models will significantly assist in the development of novel treatments, such as the VN:GF complexes and the synthetic fibrin-like gel described herein, ultimately facilitating their clinical trial in the treatment of chronic wounds.

Looking through the haze of discontent : smokers as a data source

In the case of industrial relations research, particularly that which sets out to examine practices within workplaces, the best way to study this real-life context is to work for the organisation. Studies conducted by researchers working within the organisation comprise some of the (broad) field’s classic research (cf. Roy, 1954; Burawoy, 1979). Participant and non-participant ethnographic research provides an opportunity to investigate workplace behaviour beyond the scope of questionnaires and interviews. However, we suggest that the data collected outside a workplace can be just as important as the data collected inside the organisation’s walls. In recent years the introduction of anti-smoking legislation in Australia has meant that people who smoke cigarettes are no longer allowed to do so inside buildings. Not only are smokers forced outside to engage in their habit, but they have to smoke prescribed distances from doorways, or in some workplaces outside the property line. This chapter considers the importance of cigarette-smoking employees in ethnographic research. Through data collected across three separate research projects, the chapter argues that smokers, as social outcasts in the workplace, can provide a wealth of important research data. We suggest that smokers also appear more likely to provide stories that contradict the ‘management’ or ‘organisational’ position. Thus, within the haze of smoke, researchers can uncover a level of discontent with the ‘corporate line’ presented inside the workplace. There are several aspects to the increased propensity of smokers to provide a contradictory or discontented story. It may be that the researcher is better able to establish a rapport with smokers, as there is a removal of the artificial wall a researcher presents as an outsider. It may also be that a research location physically outside the boundaries of the organisation provides workers with the freedom to express their discontent. The authors offer no definitive answers; rather, this chapter is intended to extend our knowledge of workplace research through highlighting the methodological value in using smokers as research subjects. We present the experience of three separate case studies where interactions with cigarette smokers have provided either important organisational data or alternatively a means of entering what Cunnison (1966) referred to as the ‘gossip circle’. The final section of the chapter draws on the evidence to demonstrate how the community of smokers, as social outcasts, are valuable in investigating workplace issues. For researchers and practitioners, these social outcasts may very well prove to be an important barometer of employee attitudes; attitudes that perhaps cannot be measured through traditional staff surveys.

Practice as method : the ex/centric fixations project

In the past decade, scholars have proposed a range of terms to describe the relationship between practice and research in the creative arts, including increasingly nuanced definitions of practice-based research, practice-led research and practice-as-research. In this paper, I consider the efficacy of creative practice as method. I use the example of The Ex/Centric Fixations Project – a project in which I have embedded creative practice in a research project, rather than embedding research in a creative project. The Ex/Centric Fixations project investigates the way spectators interpret human experiences – especially human experiences of difference, marginalisation or discrimination – depicted onstage. In particular, it investigates the way postmodern performance writing strategies, and the presence of performing bodied to which the experience depicted can be attached, impacts on interpretations. It is part of a broader research project which examines the performativity of spectatorship, and intervenes in emergent debates about performance, ethics and spectatorship in the context of debate about whether live performance is a privileged site for the emergence of an ethical face-to-face encounter with the Other. Using the metaphor of the Mobius strip, I examines the way practice – as a method, rather than an output – has informed, influenced and problematised the broader research project.