Matrix metalloproteinase-9 increases in the sputum from allergic occupational asthma patients after specific inhalation challenge.

BACKGROUND: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play a role in the pathogenesis of asthma. MMP-9 increases in the sputum of asthmatic patients after bronchial challenge with common allergens. We sought to assess whether a high-molecular-weight occupational allergen was able to induce changes in MMP-9 as well as in other MMPs and TIMPs in subjects with occupational asthma. METHODS: Ten patients underwent specific inhalation challenge (SIC) on 2 consecutive days. We monitored changes in lung function by measuring FEV(1) for 7 h. Induced sputum test was performed at 6 h after sham and flour challenge. The total and differential cell counts were analyzed. Levels of MMPs (specifically MMP-2, MMP-7, MMP-9 and MMP-13) were measured using Fluorokine® MultiAnalyte Profiling kits and a Luminex® Bioanalyzer, while levels of TIMP-1 and TIMP-2 were measured by ELISA. RESULTS: Flour challenge increased the percentage of eosinophils in sputum samples. Asthmatic reactions induced by flour were associated with a significant increase in the sputum level of MMP-9 (p = 0.05), but not in the levels of MMP-2, MMP-7, MMP-13, TIMP-1 and TIMP-2. Sputum levels of MMP-9 measured after flour challenge were nearly significantly correlated (r = 0.67; p = 0.06) with the maximal fall in FEV(1) observed during the asthmatic reaction, but they did not correlate with the number of neutrophils (r = 0.18; p = 0.7) and eosinophils (r = 0.55; p = 0.2). CONCLUSIONS: This study showed that MMP-9 increases in sputum samples from sensitized occupational asthma patients after SIC with flour.

Matrix metalloproteinases and tissue inhibitors of metalloproteinases in nasal lavage after an inhalation challenge with flour.

OBJECTIVES/HYPOTHESIS: The existence of nasal mucosa remodeling in allergic rhinitis is controversial. Few data are available on the dynamics of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in nasal fluid after an allergen challenge. We examined whether an immediate allergic reaction that induces nasal congestion and inflammation is able to also induce changes in remodeling parameters in nasal fluid. STUDY DESIGN: Controlled experimental study. METHODS: Ten patients with allergic occupational rhinitis due to flour underwent a control and active inhalation challenge with serial monitoring of nasal congestion and nasal symptoms with acoustic rhinometry and a visual analogue scale. Levels of remodeling markers (MMP-2, MMP-7, MMP-9, MMP-13, TIMP-1, TIMP-2) and inflammatory cells in nasal fluid were measured before the challenge and at 30 minutes, 6 hours, and 24 hours following the challenge. RESULTS: In contrast to the control challenge, the flour challenge induced nasal symptoms and significant decreases in nasal volume in all subjects. After the flour challenge, a significant increase in nasal levels of TIMP-2 and a nonsignificant increase in TIMP-1 levels were observed, whereas no significant changes in nasal levels of MMPs were documented. CONCLUSIONS: This study showed that after an inhalation challenge with an occupational allergen, the nasal mucosa displayed an imbalance in favor of TIMPs enzymes activity as compared to MMPs enzymes activity, represented in an increase in nasal levels of TIMP-2 during the course of the early reaction following the allergen challenge.

Identification of clinically significant psychological distress and psychiatric morbidity by examining quality of life in subjects with occupational asthma.

BACKGROUND: The Juniper Asthma Specific Quality of Life Questionnaire (AQLQ(S)) is a questionnaire that allows measurement of disease specific quality of life. We wanted to examine correlations between the (AQLQ(S)) general and different subscale scores and both psychiatric morbidity and levels of psychological distress in individuals with occupational asthma (OA) and to determine if results in the emotional function subscale allow identification of individuals with clinically significant psychological distress or current psychiatric disorders. METHODS: This was a cross-sectional study of individuals with OA who were assessed during a re-evaluation for permanent disability, after they were no longer exposed to the sensitizing agent. Patients underwent a general sociodemographic and medical history evaluation, a brief psychiatric interview (Primary Care Evaluation of Mental Disorders, PRIME-MD) and completed a battery of questionnaires including the AQLQ(S), the St-Georges Respiratory Questionnaire (SGRQ), and the Psychiatric Symptom Index (PSI). RESULTS: There was good internal consistency (Cronbach alpha = 0.936 for the AQLQ(S) total score) and construct validity for the AQLQ(S) (Spearman rho = -0.693 for the SGRQ symptom score and rho = -0.650 for the asthma severity score). There were medium to large correlations between the total score of the AQLQ(S) and the SGRQ symptom score (r = -.693), and PSI total (r = -.619) and subscale scores (including depression, r = -.419; anxiety, r = -.664; anger, r = -.367; cognitive disturbances, r = -.419). A cut-off of 5.1 on the AQLQ(S) emotional function subscale (where 0 = high impairment and 7 = no impairment) had the best discriminative value to distinguish individuals with or without clinically significant psychiatric distress according to the PSI, and a cut-off of 4.7 best distinguished individuals with or without a current psychiatric disorder according to the PRIME-MD. CONCLUSIONS: Impaired quality of life is associated with psychological distress and psychiatric disorders in individuals with OA. Findings suggest that the AQLQ(S) questionnaire may be used to identify patients with potentially clinically significant levels of psychological distress.

Direct costs of occupational asthma due to sensitization in Quebec (1988 to 2002): revisited.

BACKGROUND: In a previous study, the authors assessed direct costs for occupational asthma (OA) in a random sample of eight to 10 accepted claims per year for OA between 1988 and 2002. Compensation for loss of income (CLI) was found to be significantly higher for men and for OA caused by low-molecular-weight agents. OBJECTIVES AND METHODS: To identify sociodemographic factors that modulate CLI, the dossier of each claimant in the previous study was re-examined. RESULTS: Higher CLI costs were directly related to the duration of CLI (over which loss of income was reimbursed) (r=0.65). Costs of CLI were higher in patients 30 years of age or older at diagnosis, married subjects and individuals who were offered early retirement or were enrolled in an active interventional rehabilitation program. Higher CLI costs in men, but not in women, were associated with the following sociodemographic factors: older age, different rehabilitation program (early retirement and active program versus no specific program) and married status. Older age was found to be significant in the multivariate analysis performed for men. The cost of CLI was higher in workers with OA caused by low-molecular-weight agents. Although proportionally fewer men and younger workers were affected with OA caused by low-molecular-weight agents, the longer duration of CLI for this category of agent could explain the higher costs. CONCLUSION: Higher costs for CLI were associated in men (but not women) with older age, married status and type of rehabilitation program (early retirement and active rehabilitation). Higher costs of CLI for OA caused by low-molecular-weight agents were associated with a longer duration of CLI per se, and not with sociodemographic factors.

Quality-of-life, psychological, and cost outcomes 2 years after diagnosis of occupational asthma.

OBJECTIVE: To examine the association between clinical and socioeconomic variables and their influence on psychological and cost outcomes in patients with occupational asthma (OA). METHODS: Longitudinal study of 60 subjects who claimed compensation for OA in Quebec. Besides clinical markers of asthma, quality of life (QOL), psychological distress (PD) measures, and an instrument to diagnose mental disorders were used. RESULTS: The QOL and PD parameters had moderate correlations with clinical markers of OA. Asthma severity, employment, marital status, income, and the length of employment with the employer showed the strongest associations with QOL and PD. More-impaired QOL was associated with higher direct costs for compensation. CONCLUSION: Impaired QOL and PD are frequent among subjects with OA receiving compensation and are associated with clinical markers of OA and socioeconomic factors.

Does the methacholine test reproduce symptoms?

BACKGROUND: The interpretation of methacholine test results do not usually consider the symptoms for which the subject was referred and those that occur during the test. OBJECTIVE: To assess the association between methacholine test results and symptoms, and to examine variables that may affect this association. METHODS A total of 400 prospectively chosen subjects who underwent methacholine testing for possible asthma were investigated. The subjects answered a short questionnaire regarding the symptoms for which they had been referred and those that were encountered during the methacholine test. RESULTS: The positive predictive value for the reproduction of symptoms during the test compared with symptoms for which subjects had been referred were 84% for dyspnea, 87% for cough, 81% for wheezing and 72% for chest tightness. The positive predictive value among the values obtained by measuring the provocative concentration of methacholine causing a 20% fall (PC20) in forced expiratory volume in 1 s on the one hand, and specific symptoms on the other, varied by up to approximately 50%; negative predictive values were higher. Forty-eight per cent of subjects with a PC20 of 16 mg/mL or lower reported that the test had globally reproduced their symptoms. This association was significantly stronger in women, young subjects and those taking inhaled steroids. CONCLUSIONS: The methacholine test generally reproduced the symptoms for which the subjects were referred. The absence of a specific symptom (eg, dyspnea, cough, wheezing or chest tightness), either in daily life or at the time of methacholine testing, was more generally associated with a negative test than the reverse. The global impression that the test had reproduced what the patient had experienced in daily life was significantly associated with a positive test (ie, a PC20 of 16 mg/mL or lower), with the association being stronger in young subjects and women.

Factors discriminating spontaneous pursed-lips breathing use in patients with COPD.

Pursed-lips breathing (PLB) is often spontaneously performed by chronic obstructive pulmonary disease (COPD) patients. The aim of this study was to evaluate spontaneous PLB prevalence and to identify factors discriminating its use. Fifty-seven patients with COPD (FEV(1) = 44.3 +/- 17.4%pred) underwent pulmonary function testing and two incremental bicycle exercise tests. Peak workload (Wpeak), oxygen uptake (VO(2)peak), breathing pattern, and dyspnea (Borg scale) were measured in the first exercise test and spontaneous PLB performance in the second. Six patients spontaneously performed pursed-lips breathing during rest (PLBrest), exercise and recovery, 18 during exercise and recovery (PLBex), 7 during recovery only (PLBrec), 20 not at all (PLBno), and 6 performed other expiratory resistive maneuvers. PLBrest and PLBex patients exhibited a lower Wpeak, O(2) uptake, and minute ventilation (V(E)), greater expiratory flow limitation and higher slopes relating dyspnea to V(E) or W (%predicted). PLBrest patients were more hypercapnic, had a lower exercise tolerance and diffusion capacity, and greater flow limitation and hyperinflation. PLBrec and PLBno patients were indistinguishable with regard to pulmonary function, dyspnea, and exercise performance. The most significant independent predictors of spontaneous PLB use during exercise were FEV(1)/FVC and the slope relating dyspnea to V(E). Spontaneous PLB is most often performed by COPD subjects when ventilation is stimulated by exercise, and during recovery from exercise. Severity of airflow obstruction and the dyspnea experienced during exercise play an important role in determining whether or not PLB is spontaneously performed by COPD patients.

Sites of allergic airway smooth muscle remodeling and hyperresponsiveness are not associated in the rat.

The cause-and-effect relationship between airway smooth muscle (ASM) remodeling and airway hyperresponsiveness (AHR) following allergen challenge is not well established. Using a rat model of allergen-induced ASM remodeling we explored the relationship between the site of ASM remodeling and AHR. Brown Norway rats, sensitized and challenged (3 times at 5-day intervals) with ovalbumin, were intranasally administered 0.1 mg/kg budesonide 24 and 1 h before challenge. Airway responses to aerosolized methacholine were assessed 48 h or 1 wk after three challenges. Airways were stained and analyzed for total airway wall area, area of smooth muscle-specific α-actin, and goblet cell hyperplasia, and the constant-phase model was used to resolve the changes in respiratory system mechanics into large airway and peripheral lung responses. After three ovalbumin challenges, there was a significant increase in ASM area and in the total wall area in all sized airways as well as an increase in goblet cells in the central airways. Budesonide inhibited ASM growth and central airway goblet cell hyperplasia following ovalbumin challenges. Budesonide also inhibited small but not large airway total wall area. AHR was attributable to excessive responses of the small airways, whereas responsiveness of the large airways was unchanged. Budesonide did not inhibit AHR after repeated challenge. We conclude that ASM remodeling induced by repeated allergen challenges involves the entire bronchial tree, whereas AHR reflects alterations in the lung periphery. Prevention of ASM remodeling by corticosteroid does not abrogate AHR.

Airway remodeling in subjects with severe asthma with or without chronic persistent airflow obstruction.

BACKGROUND: The patterns of airway remodeling and the biomarkers that distinguish different subtypes of severe asthma are unknown. OBJECTIVES: We sought to characterize subjects with severe asthma with and without chronic persistent airflow obstruction with respect to airway wall remodeling (histopathologic and radiologic) and specific sputum biomarkers. METHODS: Subjects with severe asthma with chronic persistent (n = 16) or intermittent (n = 18) obstruction were studied. Endobronchial biopsy specimens were analyzed for airway smooth muscle area, epithelial detachment, basement membrane thickness, and submucosal fibrosis. Levels of eosinophil cationic protein, myeloperoxidase, matrix metalloproteinase 9, tissue inhibitor of matrix metalloproteinase 1 (ELISA), and 27 cytokines (multiplex assay) and differential cell counts were measured in induced sputum. Airway thickness was measured by means of high-resolution computed tomographic scanning. RESULTS: Chronic persistent obstruction was associated with earlier age of onset, longer disease duration, more inflammatory cells in the sputum, and greater smooth muscle area (15.65% +/- 2.69% [n = 10] vs 8.96% +/- 1.99% [n = 14], P = .0325). No differences between groups were found for any of the biomarker molecules measured in sputum individually. However, principal component analysis revealed that the dominant variables in the chronic persistent obstruction group were IL-12, IL-13, and IFN-gamma, whereas IL-9, IL-17, monocyte chemotactic protein 1, and RANTES were dominant in the other group. Airway imaging revealed no differences between groups. CONCLUSION: Subjects with severe asthma with chronic persistent obstruction have increased airway smooth muscle with ongoing T(H)1 and T(H)2 inflammatory responses. Neither airway measurements on high-resolution computed tomographic scans nor sputum analysis seem able to identify such patients.

Long-term outcomes of acute irritant-induced asthma.

RATIONALE: The long-term outcomes of acute irritant-induced asthma (IIA) are mostly unknown. OBJECTIVES: To study the long-term outcomes of IIA. METHODS: We reassessed 35 subjects who experienced IIA at a mean interval of 13.6 +/- 5.2 years. MEASUREMENTS AND MAIN RESULTS: The causal agent was chlorine in 20 cases (57%). At diagnosis, the mean +/- SD FEV(1) was 74.5 +/- 19.5% predicted, and all subjects showed bronchial hyperresponsiveness. At reassessment, all subjects reported respiratory symptoms, and 24 (68%) were on inhaled steroids. There were no significant improvements in FEV(1) and FEV(1)/FVC values. Twenty-three subjects had a methacholine test, and only six subjects had normal levels of responsiveness. Of the remaining 12 subjects, six had improvement in FEV(1) after bronchodilator >or=10%. In samples of induced sputum obtained from 27 subjects, six had eosinophils >or=2%. Levels of inflammatory and remodeling mediators were higher than in control subjects but were no different from subjects with occupational asthma due to sensitization. Quality of life score was 4.4 +/- 1.5 on a 0 (worst) to 7 (best) scale. Twelve subjects had an abnormal depression score. CONCLUSIONS: This study provides the first evidence of significant long-term impact of acute IIA on various outcomes.

The Dutch diagnostic model for laboratory animal allergen sensitization was generalizable in Canadian apprentices.

OBJECTIVE: To assess the transportability of an existing diagnostic questionnaire model for the sensitization to laboratory animal (LA) allergens. STUDY DESIGN AND SETTING: The model was externally validated in 414 Canadian animal health apprentices. Several approaches were used: (1) no adjustment; (2) recalibration of the intercept of the model; (3) re-estimation of the intercept and the regression coefficients of predictors; and (4) model revision, by excluding the existing predictor(s) and/or including new predictor(s). The bootstrapping procedure was done following the third and fourth methods. The calibration was assessed graphically and with the Hosmer-Lemeshow (HL) test. Discriminative properties were determined by the area under the receiver operating characteristic curve (ROC area). RESULTS: When applied without adjustment, the model's discriminative ability was adequate (ROC area was 0.74 vs. the original ROC area of 0.76); the calibration was poor (HL test P<0.001). The other methods yielded models with good calibration (P>0.10) and reasonable discrimination (ROC area ranged between 0.73 and 0.75). The refitted and revised model showed a good internal validity (correction factor from the bootstrapping procedure was more than 0.90). CONCLUSION: Once updated, the diagnostic model is valid and can be applied with reasonable performance in an animal health apprentice setting.

Direct costs of occupational asthma in Quebec between 1988 and 2002.

BACKGROUND: Forty to 70 cases of occupational asthma due to sensitization to an agent present in the workplace are accepted each year by the Commission de la santé et de la sécurité du travail, the Quebec medicolegal agency. OBJECTIVES AND METHODS: In a random sample of eight to 10 accepted claims per year from 1988 to 2002, the direct costs of compensation for loss of income (CLI) and compensation for functional impairment (CFI), as well as the associations of these costs with selected variables, were assessed. RESULTS: Mean costs (presented as Canadian dollars x10(3)) of CLI, CFI and total were 72.5, 11.7 and 92.8, respectively, while the median costs were 40.7, 7.6 and 61.3 for CLI, CFI and total, respectively. Median CLI costs were significantly higher in men than women (69.9 versus 13.1), workers aged 40 years or older versus those younger than 40 years (90.1 versus 27.4), workers with occupational asthma due to workplace exposure to low versus high molecular weight agents (51.2 versus 38.6), and workers taking inhaled steroids at diagnosis (92 versus 52) and reassessment (81 versus 35). Median CFI costs were also higher in those requiring retraining (10.4) and taking early retirement (61.8) than workers who stayed with the same employer but in a different job (5.4). Median CFI costs were significantly higher for individuals being treated with inhaled steroids at the time of diagnosis (14.0 versus 5.2) and reassessment (13 versus 6), and for those left with bronchial hyperresponsiveness (9.5 versus 0.8) related to forced expiratory volume in 1 s and forced expiratory volume in 1 s/forced vital capacity. CONCLUSION: Age, sex, nature of occupational agent, treatment with inhaled steroids and type of rehabilitation all affect CLI, whereas lung function status at baseline and reassessment is related to CFI.

Reproducibility of nasal lavage in the context of the inhalation challenge investigation of occupational rhinitis.

BACKGROUND: The nasal lavage (NAL) method is increasingly used to assess changes in upper airways inflammation in the investigation of occupational rhinitis (OR). A good reproducibility of the method is fundamental to accurately assess changes in markers of inflammation in nasal secretions before and after inhalation challenges. The main objective of this study was to assess the short-term reproducibility of cells and cellular markers of inflammation in NAL in the setting of specific inhalation challenge (SIC) investigating OR. An ancillary objective was to assess the reproducibility of NAL in the context of two different SIC methodologies. METHODS: Twenty-five subjects attended the laboratory for 2 separate days of NAL performed within the same week. On the first visit subjects underwent NAL before a SIC sham session and on the second visit before a SIC with the active agent. These prechallenge NAL measurements obtained on both days were used to analyze the reproducibility of the NAL method. RESULTS: The reproducibility for cell differential counts was satisfactory for neutrophils (intraclass correlation coefficient [ICC] = 0.68), for eosinophils (ICC = 0.95), for macrophages (ICC = 0.77), and for epithelial cells (ICC = 0.73). The reproducibility of total cell counting was poor (ICC = 0.12). The reproducibility of ECP concentrations was satisfactory (ICC = 0.67). Eosinophil counts were reproducible in the context of two different challenge methodologies. CONCLUSION: The NAL method was shown to be sufficiently reproducible to be considered useful for the monitoring of upper airways inflammation during the investigation of OR by SIC.

Long-term outcomes in a prospective cohort of apprentices exposed to high-molecular-weight agents.

RATIONALE: We conducted a long-term (8-yr) follow-up of 408 apprentices entering programs involving exposure to high-molecular-weight allergens. OBJECTIVES: The objectives were to assess the frequency of new and persisting sensitization, symptoms, and bronchial hyperresponsiveness in relation with job history after ending apprenticeship and to examine characteristics significantly associated with the incidence and remission of these occupational outcomes. METHODS: A respiratory symptom questionnaire, skin prick tests with work-related allergens (laboratory animals, flour, and latex), spirometry, and methacholine challenge were administered. The association between incidence or remission of these outcomes and individual characteristics at baseline and end of apprenticeship was examined. MEASUREMENTS AND MAIN RESULTS: In subjects who at any time during follow-up held a job related to their training (78%), the incidence of sensitization, rhinoconjunctival and chest symptoms, and bronchial hyperresponsiveness at follow-up was 1.3, 1.7, 0.7, and 2.0 per 100 person-years, respectively. The remission of these outcomes acquired during apprenticeship was 18.5, 9.6, 9.6, and 12.4 per 100 person-years, respectively, in subjects no longer in a job related to training. Several clinical, immunological, and functional characteristics at baseline and acquired during apprenticeship were found to be significantly associated with the incidence and remission of the outcomes. CONCLUSIONS: The incidence of sensitization, symptoms, and bronchial hyperresponsiveness was lower while at work than during the apprenticeship period. A high proportion of subjects in a job not related to training experienced remission of symptoms acquired during apprenticeship.

Reproducibility of acoustic rhinometry in the investigation of occupational rhinitis.

BACKGROUND: To diagnose occupational rhinitis, it is mandatory to conduct an objective assessment of changes in nasal patency during specific inhalation challenge (SIC). The reproducibility of acoustic rhinometry measurements in the setting of occupational challenges has never been examined. This study assessed the reproducibility of acoustic rhinometry during SIC investigation of occupational rhinitis. METHODS: Twenty-four subjects underwent acoustic rhinometry measurements during SIC investigation of occupational rhinitis. Subjects attended 3-6 days of SIC within a week by means of a realistic or closed-circuit apparatus methodology RESULTS: All of the within-day intraclass correlation coefficients (ICCs) for nasal volume (2-5 cm) and minimum cross-sectional area (MCA) based on a different number of measurements (2-7) were above 0.85; all of the coefficients of variation (CVs)for the same parameters were low (below 10%). The between-day CVs based on different numbers of SIC sessions ranged from 8.0 to 8.8% and from 6.8 to 8.8%for nasal volume and MCA, respectively. The between-day ICCs ranged from 0.80 to 0.88 and from 0.83 to 0.94 for nasal volume and MCA, respectively. CONCLUSION: Acoustic rhinometry showed good within- and between-day reproducibility and can be recommended for the objective monitoring of nasal patency during SIC investigating occupational rhinitis.

Orthopnea and tidal expiratory flow limitation in chronic heart failure.

BACKGROUND: Tidal expiratory flow limitation (FL) is common in patients with acute left heart failure and contributes significantly to orthopnea. Whether tidal FL exists in patients with chronic heart failure (CHF) remains to be determined. PURPOSES: To measure tidal FL and respiratory function in CHF patients and their relationships to orthopnea. METHODS: In 20 CHF patients (mean [+/- SD] ejection fraction, 23 +/- 8%; mean systolic pulmonary artery pressure [sPAP], 46 +/- 18 mm Hg; mean age, 59 +/- 11 years) and 20 control subjects who were matched for age and gender, we assessed FL, Borg score, spirometry, maximal inspiratory pressure (Pimax), mouth occlusion pressure 100 ms after the onset of inspiratory effort (P(0.1)), and breathing pattern in both the sitting and supine positions. The Medical Research Council score and orthopnea score were also determined. RESULTS: In the sitting position, tidal FL was absent in all patients and healthy subjects. In CHF patients, Pimax was reduced, and ventilation and P(0.1)/Pimax ratio was increased relative to those of control subjects. In the supine position, 12 CHF patients had FL and 18 CHF patients claimed orthopnea with a mean Borg score increasing from 0.5 +/- 0.7 in the sitting position to 2.7 +/- 1.5 in the supine position in CHF patients. In contrast, orthopnea was absent in all control subjects. The FL patients were older than the non-FL patients (mean age, 63 +/- 8 vs 53 +/- 12 years, respectively; p < 0.03). In shifting from the seated to the supine position, the P(0.1)/Pimax ratio and the effective inspiratory impedance increased more in CHF patients than in control subjects. The best predictors of orthopnea in CHF patients were sPAP, supine Pimax, and the percentage change in inspiratory capacity (IC) from the seated to the supine position (r(2) = 0.64; p < 0.001). CONCLUSIONS: In sitting CHF patients, tidal FL is absent but is common supine. Supine FL, together with increased respiratory impedance and decreased inspiratory muscle force, can elicit orthopnea, whom independent indicators are sPAP, supine Pimax and change in IC percentage.

Childhood predictors of smoking in adolescence: a follow-up study of Montreal schoolchildren.

BACKGROUND: The factors that cause children to become smokers in adolescence remain unclear. Although parental smoking and peer pressure may play a role, physiological factors such as lung volume have also been identified. METHODS: To investigate these and other possible childhood predictors of teenage smoking, we gathered follow-up data on 191 Montréal schoolchildren, aged 5-12 years (average 9.2 yr) when first examined. At an average age of 13.0 years, they answered further questions on their health and smoking behaviour and provided a second set of spirometric measurements. RESULTS: At the second survey, 80% of the children had entered high school and 44% had become smokers. Reaching puberty between the surveys was the most significant determinant of becoming a smoker: 56.4% of the 124 children postpubertal at the second survey had taken up smoking, versus 17.9% of the 67 who were still prepubertal (p = 0.001). We found salivary cotinine level, a measure of uptake of environmental tobacco smoke, to be an independent predictor of becoming a teenage smoker; even after adjustment for sex, socioeconomic status of parents, a crowding index, and the numbers at home of siblings, adult smokers and cigarettes smoked, it remained significant for both groups: postpubertal (odds ratio [OR] 1.2, 95% confidence interval [CI] 1.2-3.0) and prepubertal (OR 2.1, 95% CI 1.0- 4.5). The influence of forced vital capacity was marginally significant only in the postpubertal group (OR 5.0, 95% CI 0.88-28.3). INTERPRETATION: The proportion of nicotine absorbed from that available in environmental tobacco smoke during childhood is associated with subsequent smoking in adolescence. The more efficient absorption of nicotine seen in some children may be related to physiological factors such as lung capacity.

The development of emphysema in cigarette smoke-exposed mice is strain dependent.

Only 20% of smokers develop chronic obstructive pulmonary disease. An important determinant of susceptibility is genomic variation. We undertook this study to define strains of mice with different susceptibilities for the development of smoking-induced emphysema because they could help identify genetic factors of susceptibility. NZWLac/J, C57BL6/J, A/J, SJ/L, and AKR/J strains were exposed to cigarette smoke for 6 months. Elastance (Htis), the extent of emphysema (mean linear intercept [Lm]), and the inflammatory cell and cytokine response were measured. NZWLac/J had no change in Lm or Htis (resistant). C57BL6/J, A/J, and SJ/L increased Lm, but not Htis (mildly susceptible). AKR/J increased Lm and Htis (super-susceptible). Only AKR/J had significant inflammation comprising macrophages, neutrophils, and T cells. The AKR/J showed an upregulation of Th1 cytokines whereas in the C57BL/6/J and NZWlac/J, cytokines did not change or were downregulated. We conclude that Lm, elastance, and inflammation are features that are needed to phenotype emphysema in mice. The inflammatory cell and cytokine profile may be an important determinant of the phenotype in response to cigarette smoke exposure. The identification of resistant and susceptible strains for the development of emphysema could be useful for genomic studies of emphysema susceptibility in mice and eventually in humans.

Recovery of methacholine responsiveness after end of exposure in occupational asthma.

Recent data suggest that responsiveness to methacholine continues to improve 2 and more years after cessation of exposure to agents causing occupational asthma (OA). The goal of this study was to characterize further the curve of improvement to methacholine responsiveness in subjects with OA. Eighty subjects with confirmed OA who had at least two assessments of a provocative concentration of histamine causing a 20% drop in FEV(1) (PC(20)) and were seen for at least 2 years after cessation of exposure. The shape of recovery of PC(20) was assessed by CARMA (James K. Lindsey, Liège, Belgium) analysis. Slopes of recovery were compared in the first 2.5 years in 55 subjects and from 2.5 years until the end of observation in 56 subjects. Recovery curves showed progressive improvements in PC(20) significantly influenced by time lapse since end of exposure, sex, baseline PC(20), and FEV(1). The slopes of recovery were significantly different from zero both for the first 2.5 years after cessation of exposure (0.27 +/- 0.05 SEM natural logarithm of PC(20) per year) and later (0.09 +/- 0.008 SEM natural logarithm of PC(20) per year), with the slope significantly steeper for the first 2.5 years. This study shows that improvement in responsiveness to methacholine continues for years after cessation of exposure but that the improvement is more rapid in the first 2.5 years.