Lack of protective effect of tiotropium vs induced dynamic hyperinflation in moderate COPD

SummaryStudy objectiveNovel evaluation of protective effect of tiotropium against induced dynamic hyperinflation (DH) during metronome paced hyperventilation (MPH) in moderate COPD.MethodsProspective, randomized, double-blind, placebo control, crossover study. Lung function measured pre/post MPH at 30 breaths/min for 20 s in 29 (18M) COPD patients (GOLD Stage 2) age 70 ± 9 yr (mean ± SD) before and after 30 days of 18 μg tiotropium bromide vs placebo. Lung CT scored for emphysema (ES).ResultsAt baseline post 180 μg aerosolized albuterol sulfate, FEV1: 1.8 ± 0.6 L (69 ± 6%pred) and ≥60% predicted in all, and 14 of 29 had FEV1 (L) ≥70% predicted with FEV1/FVC 58 ± 8%. After 29 days + 23 h post tiotropium (trough) there was significant decrease only in FRC/TLC% (p = 0.04); after 30 days + 2 h post tiotropium (peak) significant increase only in FEV1 (L) (p = 0.03) compared to placebo. Results post MPH induced DH at baseline and after 30 days and 2 h post placebo or tiotropium were similar with decrease in IC 0.44 ± 0.06 L (p < 0.001). Correlation between ES and increased FEV1 (L) at peak tiotropium: r = 0.19, p = 0.96 and decreased FRC/TLC% at trough tiotropium: r = −0.26, p = 0.36.ConclusionIn moderate COPD, tiotropium did not reduce MPH induced DH and reduction in IC. However, at peak tiotropium, there was significant bronchodilation in FEV1 (L) and at trough a decrease in FRC/TLC% compared to placebo despite varying emphysema

Mounier-Kuhn syndrome: A rare cause of severe bronchial dilatation with normal pulmonary function test: A case report

SummaryTracheobronchomegaly (TBM) (Mounier-Kuhn syndrome) is dilatation of the trachea and major bronchi because of atrophy or absence of elastic fibers and smooth muscle cells. We present a case of TBM with normal pulmonary function test (PFT).The patient was a 37-year-old man with increasing productive cough and without fever, wheezes, chest pain, weight loss or any respiratory disease. Chest helical computed tomography (CT) scan showed tracheomegaly with transversal diameters of the trachea of 44mm. CT scan showed collapse of the trachea. Few large diverticular out-pouching and openings in the trachea was seen in bronchoscopy. PFT results were normal.PFT in large airway disorders may be normal while abnormalities may indicate underlying small airway disorder. An underlying small airway disorders is responsible for abnormal reports in PFT of these patients. We may need to re-evaluate the role of PFT within follow-up of patients with large airway disorder

The effect of montelukast on exhaled nitric oxide of alveolar and bronchial origin in inhaled corticosteroid-treated asthma

SummaryBackgroundInhaled corticosteroid therapy suppresses nitric oxide levels (NO) of airway origin but not necessarily NO of alveolar or small airway origin. Systemic therapy with an oral anti-leukotriene agent may suppress NO production in distal airways and alveoli not reached by inhaled therapy.MethodsAdult patients with mild asthma were treated for 3 weeks with inhaled fluticasone 250μg twice daily then with inhaled fluticasone plus oral montelukast 10mg daily for 3 additional weeks. We monitored exhaled NO (eNO), spirometry, lung volumes, and asthma symptoms scores at baseline and at the end of each treatment period. In a subset of patients, we continued with montelukast monotherapy and repeated these measurements.ResultsIn the 18 patients studied, pulmonary function parameters and asthma symptom scores were not altered significantly from baseline by any therapy. The total eNO at baseline was 55±35.3ppb, dropping to 28.1±15.3ppb (p=0.005) after 3 weeks of fluticasone and to 23.5±14ppb (p=0.001 vs. baseline) after the addition of montelukast. The trend towards reduced total eNO with the combination therapy vs. monotherapy was not statistically significant. Alveolar eNO dropped from 4.2±2.4 at baseline to 3.0±1.5 (p=0.1) after fluticasone and then to 2.2±0.9 (p=0.08 vs. baseline) after fluticasone plus montelukast, increasing then to 3.8±1.8 after montelukast alone (p=0.6 vs. baseline).ConclusionsLeukotriene receptor antagonists administered systemically might decrease small airway/alveolar sites of inflammation when combined to inhaled corticosteroid therapy

Glutamate and Synaptic Plasticity Systems and Smoking Behavior: Results from a Genetic Association Study

Smoking behavior is a multifactorial phenotype with significant heritability. Identifying the specific loci that influence smoking behavior could provide important etiological insights and facilitate the development of treatments to further reduce smoking related mortality. Although several studies pointed to different candidate genes for smoking, there is still a need for replication especially in samples from different countries. In the present study, we investigated whether 21 positive signals for smoking behavior from these studies are replicated in a sample of 531 blood donors from the Brazilian population. The polymorphisms were chosen based on their representativeness of different candidate biologic systems, strength of previous evidence, location and allele frequencies. By genotyping with the Sequenom MassARRAY iPLEX platform and subsequent statistical analysis using Plink software, we show that two of the SNPs studied, in the SLC1A2 (rs1083658) and ACTN1 (rs2268983) genes, were associated with smoking behavior in our study population. These genes are involved in crucial aspects of nicotine dependence, glutamate system and synaptic plasticity, and as such, are biologically plausible candidates that merit further molecular analyses so as to clarify their potential role in smoking behavior

Las Provincias : diario de Valencia: Año LIV Número 16466 - 1919 Diciembre 07

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In Search of the Genes of Asthma on the Island of Tristan da Cunha

Asthma, like several common diseases such as diabetes and atherosclerosis, occurs in families and thus probably has a complex polygenic basis, in which environmental factors also play a role. In trying to elucidate the genetic mechanism, studies of communities characterized by a high level of interbreeding and a high prevalence of asthma should be helpful. One such community has been described in the medical literature, the island of Tristan da Cunha. The University of Toronto Genetics of Asthma Project decided to study this community. It sent a team to the island to construct a geneology, obtain a history of respiratory and allergy symptoms by questionnaire, perform allergy skin testing and methocholine challenge, and obtain blood for white cell genetic studies. The initial results of this study are presented here, together with a historical perspective on the people of Tristan da Cunha

Variation at DENND1B and Asthma on the Island of Tristan da Cunha

A high prevalence of asthma has been documented among the inhabitants of Tristan da Cunha, an isolated island in the South Atlantic. The population derives from just 28 founders. We performed lung function testing, including methacholine inhalation challenge, allergen skin prick testing, and collected DNA from essentially all of the current island population (269 individuals), and genotyped a panel of 43 single-nucleotide polymorphisms (SNPs) reported as associated with asthma and atopy. We carried out a mixed-model association analysis using the known pedigree. There were 96 individuals diagnosed as asthmatic (36%), and heritability estimates were similar to those from nonisolated population samples (multifactorial threshold model, h2 = 48%). The first component from a genetic principal components analysis using the entire SNP panel was nonlinearly associated with asthma, with the maximum risk to those intermediate to reference (Human Genome Diversity Project) European and African samples means. The single most strongly associated SNP was rs2786098 (p = 5.5 × 10-5), known to regulate the gene DENND1B. This explained approximately one-third of the trait heritability, with an allelic odds ratio for the A allele of 2.6. Among A/A carriers, 10 out of 12 individuals were asthmatic. The rs2786098*A variant was initially reported to decrease the risk of childhood (atopic) asthma in European but slightly increase the risk in African-descended populations, and does significantly alter Th2 cell function. Despite an absence of overall association with this variant in recent asthma genome wide association studies meta-analyses, an effect may exist on the particular genetic background of the Tristan da Cunha population

Effect of Fluticasone 250 μg/salmeterol 50 μg and Montelukast on Exhaled Nitric Oxide in Asthmatic Patients

BACKGROUND: Monitoring noninvasive biomarkers of inflammation is an important adjunct in asthma therapy.OBJECTIVE: The goal of the present study was to identify airway and alveolar site(s) of inflammation using exhaled nitric oxide (NO) as a marker in asthmatic patients, and to evaluate the NO response to maintenance fluticasone 250 μg/salmeterol 50 μg (F/S) and add-on montelukast 10 mg (M).METHODS: Thirty (24 women) nonsmoking, mild to moderate asthmatic patients were studied, mean age (± SD) 43±9 years, treated with F/S for more than one year. All were clinically stable for longer than eight weeks and had not taken oral corticosteroids and/or leukotriene antagonists for eight weeks before the present study. Spirometry, Juniper asthma symptom score, fractional exhaled NO (FENO) 100 mL/s, bronchial NO and alveolar NO concentration (CANO) were measured in a single-blind, nonrandomized crossover study.PROTOCOL: Visit 1: baseline F/S; visit 2: after four weeks of F/S plus M; visit 3: after four weeks of S plus M; and visit 4: after four weeks of S only. Values in asthmatic patients were also compared with 34 nonsmoking age-matched healthy controls with normal lung function.RESULTS: After 180 μg aerosolized metered dose inhaler albuterol, the forced expiratory volume in 1 s at baseline was 2.6±0.8 L (86%±16% of the predicted value) and the forced expiratory volume in 1 s over the forced vital capacity was 77%±9% (mean ± SD), and was similar at visits 2 to 4. Juniper scores were mildly abnormal at visits 1 to 3, but significantly worse (P=0.03) at visit 4 versus visits 1 to 3. FENO values at visits 1 to 3 were similar but significantly increased (P=0.007) at visit 4. Bronchial NO was higher (P=0.03) at visit 4, versus visits 1 and 2, and was no different at visit 3. Compared with the healthy subjects, FENO and bronchial NO values were abnormal (greater than the normal mean plus 2 SD) in 33% of asthmatic patients at visits 1 to 3. CANO was similar for visits 1 to 4. CANO was abnormal (greater than the normal mean + 2 SD) in 20% of asthmatic patients.CONCLUSION: In clinically stable asthmatic patients, despite controller treatment including moderate-dose inhaled corticosteroids and add-on M, 33% of mild to moderate asthmatic patients have ongoing nonsuppressed bronchial sites of increased NO production, compared with healthy control subjects. These controllers have no effect on CANO, which was abnormal in 20% of the asthmatic patients studied. The addition of add-on M to baseline moderate-dose inhaled corticosteroid did not further reduce total exhaled, bronchial and/or alveolar NO production.Peer Reviewe