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.

The relationship between omega-3 and smoking habit: a cross-sectional study.

BACKGROUND: Omega3 polyunsaturated fatty acids (PUFAs) are related to several diseases, including smoking. The aim of this study was to evaluate the relationship between omega-3 intake and tobacco smoking, taking into account the qualitative differences in dietary intake between smokers and non-smokers, the amount of the ingested PUFA and their red blood (RBC) contents. We also looked for an association between omega-3 RBC content and smoking, and also between omega3 intake and the level of nicotine dependence. METHODS: Using a cross-sectional study, we included 50 current smokers (group I) and 50 lifetime non-smokers (group II), aged 18-75 years. We screened them at the Toronto Western Hospital and the Centre for Addiction and Mental Health (Toronto, Canada). The subjects completed a questionnaire with demographic data, lifestyle habits and details of food intake. The PUFAs measured in the RBC membranes were alphalinolenic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid and docosahexaenoic acid (DHA). In order to perform an adjusted comparison between smokers and non-smokers we used the ANCOVA model. RESULTS: After adjusting for confounding factors, non-smokers showed higher consumption of PUFAs, especially salmon: 800 g (0-7.740) than smokers 430 g (0-2.150) P < 0.001. They also had higher DHA levels compared to smokers: 4.81% (2.79-10.21) and 4.13% (2.33-7.73), respectively, p < 0.05. The other PUFAs showed no significant differences between the two groups. CONCLUSIONS: Smokers ate less fish rich in omega3 fatty acids than non-smokers, showing and inverse and significant relationship between omega3 intake and smoking. Smokers had lower levels of DHA and EPA, a not previously reported finding. Considering that PUFAs probably interfere in smoking habit, the increase in omega-3 consumption may become a perspective in prevention or treatment of smoking. However, this inference must be evaluated through specific studies.

Tiotropium induced bronchodilation and protection from dynamic hyperinflation is independent of extent of emphysema in COPD.

BACKGROUND: The magnitude of tiotropium (1) induced bronchodilation and (2) protection against dynamic hyperinflation in COPD phenotypes has not been studied. METHODS: We studied moderate to severe COPD patients with varying extent of emphysema as evaluated by high-resolution thin-section lung CT. Spirometry including inspiratory capacity (IC) was measured before and immediately after metronome paced hyperventilation (MPH) at 2 times resting respiratory rate for 20s to induce dynamic hyperinflation. Spirometry was obtained at baseline and pre- and 1.5h post-18 microg tiotropium via HandiHaler after 30 day tiotropium treatment period in a single blind, open label intervention. RESULTS: In 29 COPD patients (15M), age 70+/-9 years (mean+/-SD) with smoking history of 53+/-37 pack years, baseline forced expiratory volume in 1s (FEV(1)) post-180 microg albuterol MDI was 1.6+/-0.4 L (61+/-8% predicted) and FEV(1)/FVC 59+/-6%. Lung CT emphysema score (LCTES) was 23+/-20 (mean+/-SD) on a scale of 0-100 (none to most severe emphysema). After 30-day tiotropium, FEV(1) increased 101+/-124 mL (mean+/-SD) (p<0.001) and Spearman correlation (r)=-0.04, p=0.8 with LCTES; IC increased 163+/-232 mL (p<0.001), and r=-0.2, p=0.3 with LCTES. Results following MPH induced DH before and after 30-day tiotropium were significant (p<0.001) and similar: IC decreased 340+/-280 mL before and 337+/-270 mL after tiotropium, and r=-0.3, p=0.9 with LCTES. CONCLUSION: Tiotropium significantly increased FEV(1) (L) and inspiratory capacity in moderate-severe COPD, independent of extent of lung CT emphysema score. Despite bronchodilation and lower resting lung volume, tiotropium did not abbreviate induced dynamic hyperinflation, which was also independent of underlying emphysema.

Effect of fluticasone 250 microg/salmeterol 50 microg 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 microg/salmeterol 50 microg (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 microg 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.

One-year outcomes and health care utilization in survivors of severe acute respiratory syndrome.

BACKGROUND: Severe Acute Respiratory Syndrome (SARS) became a global epidemic in 2003. Comprehensive information on 1-year outcomes and health care utilization is lacking. Research conducted during the SARS outbreak may help inform research planning for future public health emergencies. The objective of this study was to evaluate the 1-year outcomes in survivors of SARS and their family caregivers. METHOD: The study was prospective and observational. We evaluated 117 SARS survivors from Toronto, Ontario. Patients were interviewed and underwent physical examination, pulmonary function testing, chest radiography, a 6-minute-walk test, quality-of-life measures, and self-report of health care utilization. At 1 year, informal caregivers were identified for a survey on caregiver burden. RESULTS: The enrolled survivors of SARS were young (median age, 42 years), and most were women (67%) and health care workers (65%). At 1 year after hospital discharge, pulmonary function measures were in the normal range, but 18% of patients had a significant reduction in distance walked in 6 minutes. The Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) domains were 0.3 to 1.0 SD below normal at 1 year. Of the patients, 17% had not returned to work by 1 year. Fifty-one patients required 668 visits to psychiatry or psychology practitioners. During the SARS epidemic, informal caregivers reported a decline of 1.6 SD below normal on the mental component score of the SF-36. CONCLUSIONS: Most SARS survivors had good physical recovery from their illness, but some patients and their caregivers reported a significant reduction in mental health 1 year later. Strategies to ameliorate the psychological burden of an epidemic on the patient and family caregiver should be considered as part of future pandemic planning.

Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial.

BACKGROUND: Treatment of moderate or severe chronic obstructive pulmonary disease (COPD) with combinations of inhaled corticosteroids, long-acting beta-agonists, and long-acting anticholinergic bronchodilators is common but unstudied. OBJECTIVE: To determine whether combining tiotropium with salmeterol or fluticasone-salmeterol improves clinical outcomes in adults with moderate to severe COPD compared with tiotropium alone. DESIGN: Randomized, double-blind, placebo-controlled trial conducted from October 2003 to January 2006. SETTING: 27 academic and community medical centers in Canada. PATIENTS: 449 patients with moderate or severe COPD. INTERVENTION: 1 year of treatment with tiotropium plus placebo, tiotropium plus salmeterol, or tiotropium plus fluticasone-salmeterol. MEASUREMENTS: The primary end point was the proportion of patients who experienced an exacerbation of COPD that required treatment with systemic steroids or antibiotics. RESULTS: The proportion of patients in the tiotropium plus placebo group who experienced an exacerbation (62.8%) did not differ from that in the tiotropium plus salmeterol group (64.8%; difference, -2.0 percentage points [95% CI, -12.8 to 8.8 percentage points]) or in the tiotropium plus fluticasone-salmeterol group (60.0%; difference, 2.8 percentage points [CI, -8.2 to 13.8 percentage points]). In sensitivity analyses, the point estimates and 95% confidence bounds shifted in the direction favoring tiotropium plus salmeterol and tiotropium plus fluticasone-salmeterol. Tiotropium plus fluticasone-salmeterol improved lung function (P = 0.049) and disease-specific quality of life (P = 0.01) and reduced the number of hospitalizations for COPD exacerbation (incidence rate ratio, 0.53 [CI, 0.33 to 0.86]) and all-cause hospitalizations (incidence rate ratio, 0.67 [CI, 0.45 to 0.99]) compared with tiotropium plus placebo. In contrast, tiotropium plus salmeterol did not statistically improve lung function or hospitalization rates compared with tiotropium plus placebo. LIMITATIONS: More than 40% of patients who received tiotropium plus placebo and tiotropium plus salmeterol discontinued therapy prematurely, and many crossed over to treatment with open-label inhaled steroids or long-acting beta-agonists. CONCLUSIONS: Addition of fluticasone-salmeterol to tiotropium therapy did not statistically influence rates of COPD exacerbation but did improve lung function, quality of life, and hospitalization rates in patients with moderate to severe COPD. International Standard Randomised Controlled Trial registration number: ISRCTN29870041.

Tiotropium and simplified detection of dynamic hyperinflation.

STUDY OBJECTIVE: To detect dynamic hyperinflation (DH) by evaluating reduction in inspiratory capacity (IC) during metronome-paced hyperventilation (MPH) in patients with moderate-to-severe COPD, studied before and after treatment with tiotropium. METHODS: IC and FEV(1) were measured before and immediately after MPH at two times resting the respiratory rate for 20 s in 60 COPD patients (28 men; mean age, 66 +/- 10 years [+/- SD]) before and after 30 days of treatment with tiotropium bromide, 18 mug. Patients were encouraged to maintain a constant tidal volume during MPH. RESULTS: At baseline, mean FEV(1) was 1.5 +/- 0.1 L (+/- SE) [57 +/- 1.6% of predicted], mean FVC was 2.6 +/- 0.1L (77 +/- 1.8% of predicted), and mean FEV(1)/FVC was 56 +/- 1%. After 180 mug of aerosolized albuterol sulfate, mean FEV(1) was 1.7 +/- 0.1 L (63 +/- 1.5% of predicted) [p < 0.001] and mean FEV(1)/FVC was 58 +/- 1%. Compared to baseline, after 30 days and 1.5 h after tiotropium there was an increase in IC of 0.18 +/- 0.04L (p < 0.0001); FEV(1) of 0.13 +/- 0.03 L (5.6 +/- 0.8% of predicted; p = 0.0002); FVC of 0.22 +/- 0.05 L (6.5 +/- 1.3% of predicted; p < 0.001); and decrease in end-expiratory lung volume (EELV)/total lung capacity (TLC) of - 3.1 +/- 0.6% (p = 0.0001); a decrease in end-inspiratory lung volume (EILV)/TLC of - 2.9 +/- 1.3% (p = 0.03); and no change in TLC (- 0.06 +/- 0.05 L). Results following MPH-induced DH at baseline and after 30 days of tiotropium were similar, with decreases in IC (- 0.35 +/- 0.03 L; p < 0.001); FEV(1) (- 0.05 +/- 0.04 L; p = 0.2); and FVC (- 0.22 +/- 0.03 L; p < 0.0001); no change in TLC; and increases in EELV/TLC (11.8 +/- 1.0% of predicted; p < 0.0001) and EILV/TLC (4.0 +/- 1.3% of predicted, p < 0.003). CONCLUSION: In patients with moderate-to-severe COPD, tiotropium did not reduce MPH-induced DH and reduction in IC, compared to baseline. However, because tiotropium induced bronchodilation and increased baseline IC, lower operational lung volumes may blunt the effect of MPH-induced DH. The noninvasive simplicity of MPH-induced DH provides a clinically useful screening surrogate to monitor changes in IC following treatment with tiotropium.

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

Tracheobronchomegaly (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.

Role of spirometry and exhaled nitric oxide to predict exacerbations in treated asthmatics.

OBJECTIVE: To evaluate the complementary roles of exhaled nitric oxide (NO) and spirometry to predict asthma exacerbations requiring one or more tapering courses of systemic corticosteroids. METHODS: We prospectively studied 44 nonsmoking asthmatics (24 women) aged 51 +/- 21 years (mean +/- SD) who were clinically stable for 6 weeks and receiving 250 mug of fluticasone/50 mug of salmeterol or equivalent for 3 years. Total exhaled NO (FENO), small airway/alveolar NO (CANO), large airway NO flux (J'awNO), and spirometry were measured. RESULTS: Baseline FEV(1) was 2.1 +/- 0.7 L, 70 +/- 20% of predicted after 180 mug of albuterol. Twenty-two of 44 asthmatics had one or more exacerbations over 18 months, 16 of 22 asthmatics had two exacerbations, and 6 of 22 asthmatics were hospitalized, including 1 asthmatic with near-fatal asthma. When baseline FEV(1) was 76% of predicted, exacerbations occurred only in 2 of 13 asthmatics (15%) [p = 0.003, chi(2)]. Using a receiver operating characteristic (ROC) curve for first exacerbation, the area under the curve was 0.67 with cutoff FEV(1) of 76% of predicted (sensitivity, 0.91; specificity, 0.50; positive predictive value, 0.65; negative predictive value, 0.85; positive likelihood ratio [LR(+)], 1.8; negative likelihood ratio [LR(-)], 0.18). When baseline FENO was >/= 28 parts per billion (ppb), exacerbations occurred in 13 of 17 asthmatics (76%); if baseline FENO was < 28 ppb, exacerbations occurred in only 9 of 27 asthmatics (33%) [p = 0.005, chi(2)]. Using the ROC curve for first exacerbation, the area under the curve was 0.71 with FENO cutoff point of 28 ppb (sensitivity, 0.59; specificity, 0.82; positive predictive value, 0.77; negative predictive value, 0.87; LR(+), 3.3; LR(-), 0.5). Independent of baseline FEV(1), FENO >/= 28 ppb increased the relative risk (RR) for exacerbation by 3.4 (95% confidence interval [CI], 1.3 to 9.1; Mantel-Haenszel, p = 0.007). An abnormal increase in CANO increased RR by 3.0 (95% CI, 0.9 to 9.9; p = 0.04), and abnormal J'awNO increased RR by 2.4 (95% CI, 1.0 to 5.6; p = 0.04). Independent of baseline FENO, FEV(1) /= 28 ppb and FEV(1) 76% of predicted had a 0% probability of exacerbation. CONCLUSION: Combining FENO and FEV(1) percentage of predicted can stratify risk for asthma exacerbation.

A cysteinyl leukotriene 2 receptor variant is associated with atopy in the population of Tristan da Cunha.

The clinical heterogeneity of asthma suggests that the contribution of genetic variability in candidate gene loci to well-defined phenotypes, such as atopy, may be examined to identify appropriate genetic risk factors for asthma. The gene encoding the cysteinyl leukotriene 2 (CysLT2) receptor has been implicated in atopy since it is localized to a region of chromosome 13q14 that has been linked to atopy in several populations and the cysteinyl leukotrienes are known to activate eosinophils and mast cells in atopy. Accordingly, we analysed the contribution of CysLT2 receptor gene variation to atopy in the inhabitants of Tristan da Cunha, a population characterized by both a founder effect and a 47% prevalence of atopy. Single-stranded conformational polymorphism analysis revealed four variants. Among these, the M201V [corrected] variant was activated with four-fold less potency by leukotriene D4 (LTD4) in a calcium flux assay. The CysLT2 receptor partial agonist, BAY u9773, also showed four-fold lower potency on the M201V [corrected] variant. The M201V [corrected] mutation is located within the extracellular region of the fifth transmembrane spanning domain of CysLT2 receptor, a position that may alter ligand binding and effector signalling. The novel M201V [corrected] CysLT2 receptor variant was associated with atopy (21%) on Tristan da Cunha compared with those who were non-atopic (7%) (Fisher's exact test, P=0.0016) in a manner that was independent of asthma (two-way ANOVA, P=0.0015). This represents the first association of a coding mutation in the CysLT2 receptor gene, located on chromosome 13q14, with the atopic phenotype found in the Tristan da Cunha population.

Unsuspected loss of lung elastic recoil in chronic persistent asthma.

STUDY OBJECTIVES: To investigate the progression and mechanism(s) for fixed maximum expiratory airflow (max) limitation in patients with chronic persistent asthma. METHODS: When optimally treated and in clinically stable condition, we studied 21 asthmatic patients and classified them into three groups based on the severity of expiratory airflow limitation: (1) group A included 5 asthmatic patients (four women; mean +/- SD age, 51 +/- 17 years) with mild persistent asthma (FEV(1) > 80% predicted) with serial FEV(1) measurements obtained prior to the present study for 16 +/- 4 years; (2) group B included 11 asthmatic patients (three women; mean age, 64 +/- 11 years) with moderate persistent asthma (FEV(1) of 60 to 80% predicted) with serial FEV(1) measurements for 12 +/- 4 years; and (3) group C included 5 asthmatic patients (three women; mean age, 55 +/- 16 years) with severe persistent asthma (FEV(1) < 60% predicted) with serial FEV(1) measurements for 11 plus minus 5 years. RESULTS: Lung CT indicated no or trivial emphysema, and diffusion was normal in all asthmatics. There was a marked loss of lung elastic recoil at total lung capacity (TLC) in all asthmatic patients in group B (16 +/- 4 cm H(2)O) and group C (15 +/- 5 cm H(2)O), but none or minimal in group A (22 +/- 1 cm H(2)O) [p < 0.01], and loss of elastic recoil accounted for 34% and 50% of decreased maximal expiratory airflow (max) at 80% and 70% TLC, respectively. Comparison with previous longitudinal data indicated individual asthmatics when in clinically stable condition remained predominantly in the same FEV(1) percent predicted classification group as in the current study. CONCLUSION: Patients with chronic moderate and severe persistent asthma, despite optimal therapy, have reduced max for many years in part due to (early?) loss of lung elastic recoil from unknown mechanism(s). This challenges current concept of airway remodeling.

Simplified detection of dynamic hyperinflation.

STUDY OBJECTIVE: To detect dynamic hyperinflation by comparing reduction in inspiratory capacity (IC) during both paced hyperventilation and cycle ergometry in patients with moderate-to-severe COPD, studied before and after acute bronchodilation. METHODS: IC and FEV(1) were measured before and after metronome-paced hyperventilation at twice the resting respiratory rate for 20 s in 16 patients with COPD before and after 54 microg aerosolized ipratropium bromide (IB). We also studied the same 16 patients before and after administration of 54 microg aerosolized IB during symptom-limited incremental cycle ergometry when the final respiratory rate was also twice the resting rate. RESULTS: Resting IC was 2.23 +/- 0.53 L (mean +/- SD), and the mean decrease in IC from baseline was 0.36 +/- 0.25 L after exercise (p < 0.001), and not significantly different (p = 0.64) from mean decrease in IC of 0.40 +/- 0.29 L following hyperventilation. Results following hyperventilation and exercise were similar after bronchodilator. The mean difference for decrease of IC between hyperventilation and exercise was 0.138 L (95% confidence interval, - 0.347 to 0.622; r = 0.66, p = 0.006). The decrease in FEV(1) was 0.01 +/- 0.13 L after exercise and 0.06 +/- 0.18 L after hyperventilation. Separately, baseline and peak end-expiratory and end-inspiratory lung volumes were similar with hyperventilation vs exercise both before and after bronchodilator. CONCLUSION: Both metronome-paced hyperventilation and incremental cycle ergometry, when resting respiratory rate was doubled, provoked similar significant decrease in IC, even after administration of 54 microg aerosolized IB. The noninvasive simplicity of hyperventilation for 20 s provides a clinically useful screening surrogate to monitor changes in IC following exercise.

Effect of montelukast on exhaled nitric oxide and nonvolatile markers of inflammation in mild asthma.

STUDY OBJECTIVES: Leukotriene receptor antagonists appear to exert anti-inflammatory activity in asthma. We undertook the present study to evaluate the effect of montelukast on levels of exhaled nitric oxide (ENO) and two inflammatory markers, hydrogen peroxide (H(2)O(2)), and cysteinyl leukotrienes (cys-LTs), in the exhaled breath condensate of subjects with mild asthma. PATIENTS: Twenty stable subjects with mild asthma (15 women and 5 men; mean [+/- SD] age, 34.8 +/- 12.6 years) were included in the study. INTERVENTION: A 1-week run-in period was followed by 2 weeks of treatment (with montelukast or placebo) that was administered in randomized, double-blind, crossover fashion. One week of washout followed each treatment arm. RESULTS: Montelukast significantly reduced the levels of ENO from baseline (median, 52.5 parts per billion [ppb]; 25th to 75th percentile, 37.8 to 101.8 ppb) during the entire treatment period (ie, day 1 to day 14), with the effect measurable as early as day 1 (median, 45.9 ppb; 25th to 75th percentile, 29.3 to 92.5 ppb) and with the maximal effect being observed on day 7 (median, 35.7 ppb; 25th to 75th percentile, 27.6 to 66.6 ppb). The levels of ENO did not change significantly with placebo therapy. Montelukast improved symptom score and reduced peak expiratory flow (PEF) variability. Changes in PEF variability correlated positively with changes in ENO (r = 0.46; p = 0.04). No significant changes in FEV(1) or concentration of H(2)O(2) in the exhaled breath condensate were observed. Levels of cys-LTs were undetectable in the exhaled breath condensate. CONCLUSIONS: We concluded that montelukast reduces the levels of ENO in patients with mild asthma, a finding that is compatible with an anti-inflammatory effect of montelukast, and that ENO appears to be more sensitive in detecting this effect than FEV(1) and H(2)O(2) levels in the exhaled breath condensate.

Risk factors for near-fatal asthma.

BACKGROUND: There is a paucity of lung function data in patients, both before and after episodes of near-fatal asthma (NFA), requiring transient endotracheal intubation and mechanical ventilation. METHODS: Lung function was initially measured in 43 asthmatic patients (age range, 16 to 49 years), who were observed and treated in a tertiary referral asthma clinic and were clinically stable at the time of study. Subsequently, clinical and physiologic follow-up studies were obtained over > 5 years. The primary outcomes were to determine (1) the integrity of lung elastic recoil and (2) the severity of expiratory airflow limitation, and (3) to correlate these outcomes with adverse clinical complications. RESULTS: Fourteen of 26 asthmatic patients (54%) [age range, 30 to 49 years] had significantly reduced lung elastic recoil pressures at all lung volumes compared to 3 of 17 asthmatic patients (18%); p = 0.02 [chi(2) test and Fisher exact test] [age range, 16 to 26 years]. In asthmatic patients between the ages of 30 and 49 years, significant loss of lung elastic recoil was noted in 4 of 10 patients with mild reduction in FEV(1) (FEV(1), > 79% predicted), 6 of 12 patients with moderate reduction in FEV(1) (FEV(1), 61 to 79% predicted), and all 4 patients with severe reduction in FEV(1) (FEV(1), < 61% predicted). In asthmatic patients between the ages of 16 and 26 years, significant loss of lung elastic recoil was noted in 0 of 11 patients with mild reduction in FEV(1), 2 of 5 patients with moderate reduction in FEV(1), and 1 of 1 patient with severe reduction in FEV(1). A subgroup of 10 asthmatic patients (7 men) [mean (+/- SD) age, 37 +/- 11 years] were studied when clinically stable, both before and after an episode of NFA in 8 cases and only after an episode of NFA in 2 additional cases. In 1 of 10 cases, the FEV(1) was mildly reduced, in 4 cases it was moderately reduced, and in 5 cases it was severely reduced, both before and after an episode of NFA. The sensitivity was 90%, the specificity was 61%, the positive predictive value was 41%, and the negative predictive value was 95% for NFA with an FEV(1) < or = 79% predicted or FEV(1)/FVC ratio of < 75%. Prior to an episode of NFA, all 8 asthmatic patients had significant loss of lung elastic recoil pressure, and afterward all 10 had significant loss of lung elastic recoil pressure (ie, less than the predicted normal mean minus 1.64 SD at a total lung capacity [TLC] of 100 to 70% predicted). The sensitivity was 100%, the specificity was 79%, the positive predictive value was 59%, and the negative predictive value was 100% for NFA with the loss of lung elastic recoil. The mean TLC measured with a plethysmograph in 10 patients with NFA was 7.2 +/- 1.41 (124 +/- 16% predicted). The sensitivity for TLC of > 115% predicted was 70%, the specificity was 70%, the positive predictive value was 88%, and the negative predictive value was 41% for NFA. CONCLUSION: A persistent reduction in FEV(1) of < or = 79% predicted or an FEV(1)/FVC ratio of < 75%, and, especially, the loss of lung elastic recoil and hyperinflation at TLC are risk factors for NFA. The loss of lung elastic recoil in asthmatic patients was associated with increased age, duration of disease, and progressive expiratory airflow limitation.

Reference values of pulmonary function tests for Canadian Caucasians.

A multicentre, cross-sectional study was carried out in six centres across Canada to establish a national standard for pulmonary function tests using healthy, lifetime nonsmokers, with each centre aiming to test 10 men and 10 women from each decade from 20 to 80 years of age. Data from each centre were used to derive prediction equations for each centre, and pooled data from all centres (total: 327 women and 300 men) were used to derive Canadian predicted equations. The predictive models were compared with three widely used published models for selected tests. It was found that, in general, the equations modelled for each centre could be replaced by the models obtained when pooling all data (Canadian model). Comparisons with the published references showed good agreement and similar slopes for most tests. The results suggest that pulmonary function test results obtained from different centres in Canada were comparable and that standards currently used remain valid for Canadian Caucasians.

Review of exhaled nitric oxide in chronic obstructive pulmonary disease.

The up-regulation of nitric oxide (NO) by inflammatory cytokines and mediators in central and peripheral airway sites can be easily monitored in exhaled air (F(E)NO). It is now possible to estimate the predominant airway site of increased F(E)NO i.e. large versus peripheral airway/alveoli, and its potential pathologic and physiologic role in obstructive lung disease. In asthma, six double-blind, randomized, controlled algorithm trials have reported only equivocal benefits of add-on measurements of F(E)NO to usual clinical guideline management including spirometry. Significant design issues, as emphasized by Gibson, may exist. However, meta-analysis of these six studies (Petsky et al 2012 Thorax 67 199-208) concluded that routine serial measurements of F(E)NO for clinical asthma management does not appear warranted. In COPD including chronic bronchitis and emphysema, despite significant expiratory airflow limitation, when clinically stable as well as during exacerbation, F(E)NO, j'(awNO) and C(ANO) may all be normal or increased. Furthermore, the role of add-on monitoring of exhaled NO to GOLD management guidelines is less clear because of the absence of conclusive doubleblind, randomized, control trial studies concerning potential clinical benefits in the management of COPD.

Profile of eicosanoids in breath condensate in asthma and COPD.

The collection of exhaled breath condensates (EBC) is a noninvasive method for obtaining samples from the lungs. Eicosanoids are lipid mediators implicated in the asthmatic inflammatory response. The objective of our study was to investigate whether the profile of eicosanoid lipid mediators in EBC can characterize the inflammation in asthma and chronic obstructive pulmonary disease (COPD). EBC samples were collected from 22 healthy controls (C), 25 mild intermittent asthmatics (MIA), 20 with moderate to severe asthma (MSA) and 20 with moderate to severe COPD. EBC samples were analyzed by unique tandem mass spectrometry that allows the quantification of up to 25 eicosanoid mediators simultaneously. No differences were found between MIA and C. Subjects with MSA and COPD had higher levels of 6-keto, PGE2, LTB4, 11-12 EET and AA, while lower levels of LXA4, 11DHyTxB2, 11HETE and 8,9EET, when compared to MSA and C (p < 0.05). Our study shows that the analysis of EBC through mass spectrometry is mixed and has a similar response in MSA and COPD when compared to MIA and controls.

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.

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

STUDY OBJECTIVE: Novel evaluation of protective effect of tiotropium against induced dynamic hyperinflation (DH) during metronome paced hyperventilation (MPH) in moderate COPD. METHODS: Prospective, randomized, double-blind, placebo control, crossover study. Lung function measured pre/post MPH at 30 breaths/min for 20 s in 29 (18 M) 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). RESULTS: At baseline post 180 µg aerosolized albuterol sulfate, FEV(1): 1.8±0.6 L (69±6% pred) and ≥60% predicted in all, and 14 of 29 had FEV(1) (L) ≥70% predicted with FEV(1)/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 FEV(1) (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 FEV(1) (L) at peak tiotropium: r=0.19, p=0.96 and decreased FRC/TLC% at trough tiotropium: r=-0.26, p=0.36. CONCLUSION: In moderate COPD, tiotropium did not reduce MPH induced DH and reduction in IC. However, at peak tiotropium, there was significant bronchodilation in FEV(1) (L) and at trough a decrease in FRC/TLC% compared to placebo despite varying emphysema.