Päivi Piirilä

N-acetyltransferase genotypes as modifiers of diisocyanate exposure-associated asthma risk

We observed previously that polymorphisms in glutathione S-transferase (GST) genes modified allergic responses to diisocyanate exposure. Here, we extended the study to examine the possible role of N-acetyltransferase (NAT) genotypes in the development of diisocyanate-induced ill effects, both separately and in combination with the previously examined GSTM1, GSTM3, GSTP1 and GSTT1 genotypes. The study population comprised 182 diisocyanate-exposed workers, 109 of whom were diagnosed with diisocyanate-induced asthma and 73 of whom had no symptoms of asthma. The diisocyanates to which the workers had been exposed to were diphenylmethane diisocyanate (MDI), hexamethylene diisocyanate (HDI) and toluene diisocyanate (TDI). The NAT2 genotype did not have any significant effect on the risk of developing asthma, but the putative slow acetylator NAT1 genotypes posed a 2.54-fold risk of diisocyanate-induced asthma (95% confidence interval [CI] 1.32 to 4.91). The effect of the NAT1 genotype was especially marked for workers exposed to TDI, among whom the NAT1 slow acetylator genotypes posed a 7.77-fold risk of asthma (95% CI 1.18 to 51.6). Statistically significant increases in asthma risk were also observed among the whole study population for the concurrent presence of the GSTM1 null genotype and either NAT1 (odds ratio [OR] 4.53, 95% CI 1.76 to 11.6) or NAT2 (OR 3.12, 95% CI 1.11 to 8.78) slow acetylator genotypes, and of NAT1 and NAT2 slow acetylator genotypes (OR 4.20, 95% CI 1.51 to 11.6). The results suggest for the first time that in addition to GSTs, the NATs play an important role in inception of asthmatic reactions related to occupational exposure to diisocyanates.

Acquired obesity and poor physical fitness impair expression of genes of mitochondrial oxidative phosphorylation in monozygotic twins discordant for obesity

Defects in expression of genes of oxidative phosphorylation in mitochondria have been suggested to be a key pathophysiological feature in familial insulin resistance. We examined whether such defects can arise from lifestyle-related factors alone. Fourteen obesity-discordant (BMI difference 5.2 +/- 1.8 kg/m(2)) and 10 concordant (1.0 +/- 0.7 kg/m(2)) monozygotic (MZ) twin pairs aged 24-27 yr were identified among 658 MZ pairs in the population-based FinnTwin16 study. Whole body insulin sensitivity was measured using the euglycemic hyperinsulinemic clamp technique. Transcript profiles of mitochondrial genes were compared using microarray data of fat biopsies from discordant twins. Body composition of twins was determined using DEXA and maximal oxygen uptake (Vo(2max)) and working capacity (W(max)) using a bicycle ergometer exercise test with gas exchange analysis. The obese cotwins had lower insulin sensitivity than their nonobese counterparts (M value 6.1 +/- 2.0 vs. 9.2 +/- 3.2 mg x kg LBM(-1) x min(-1), P < 0.01). Transcript levels of genes involved in the oxidative phosphorylation pathway (GO:0006119) in adipose tissue were lower (P < 0.05) in the obese compared with the nonobese cotwins. The obese cotwins were also less fit, as measured by Vo(2max) (50.6 +/- 6.5 vs. 54.2 +/- 6.4 ml x kg LBM(-1) x min(-1), for obese vs. nonobese, P < 0.05), W(max) (3.9 +/- 0.5 vs. 4.4 +/- 0.7 W/kg LBM, P < 0.01) and also less active, by the Baecke leisure time physical activity index (2.8 +/- 0.5 vs. 3.3 +/- 0.6, P < 0.01). This implies that acquired poor physical fitness is associated with defective expression of the oxidative pathway components in adipose tissue mitochondria.

Validated method for automatic detection of lung sound crackles

Crackling lung sounds are associated with many pulmonary diseases. Their occurrence reflects the quality and the severity of the disease. An automatic method for crackle detection is developed, based on analysing the spectral stationarity of the lung sound. The method is validated by studying the crackles of 20 adult patients; 10 with fibrosing alveolitis (FA) and 10 with bronchiectasis (BE). The number of crackles detected by the automatic method in inspiratory cycles is compared to the number of crackles counted from time-expanded waveforms by two expert observers. The total number of inspiratory cycles studied is 117 and that of crackles 1064. The method has a sensitivity of 89 per cent and a positive predictivity of 88 per cent for patients with FA and 80 per cent and 83 per cent respectively, for patients with BE. The linear correlation coefficients between the numbers of crackles counted by the automatic method and by the observers is 0·86 (p<0·001) for the patients with FA and 0·93 (p<0·001) for the patients with BE. The values refer to whole inspiratory cycles. The new automatic method seems reliable enough for clinical and scientific purposes. In enables a rapid and objective analysis of large materials with crackling lung sounds.

Inflammation and functional outcome in diisocyanate-induced asthma after cessation of exposure

Background:  The clinical outcome of diisocyanate‐induced asthma has been found to be poor despite cessation of exposure. Our aim was to study the outcome of diisocyanate‐induced asthma after initiation of inhaled steroid treatment at a mean period of 7 months (range 2–60 months) after cessation of exposure by following up lung function and bronchial inflammation.

Decreased cytokine and chemokine mRNA expression in bronchoalveolar lavage in asymptomatic smoking subjects.

Background: Smoking alters the inflammatory cell balance in the airways, often leading to repeated respiratory infections and, eventually, chronic obstructive pulmonary disease (COPD) in susceptible individuals. Objective: It was the aim of this study to evaluate alterations in the airway inflammatory balance caused by chronic cigarette smoke exposure. Methods: We compared results of biopsy and bronchoalveolar lavage (BAL) samples from non-smoking (n = 8) and smoking (n = 5; pack years 25.06 ± 11.75, range 7.13–36.8) subjects without COPD. Results: In BAL samples, we found a significantly higher number of total cells (353 ± 96 million vs. 114 ± 52 million; p = 0.003) and macrophages (331 ± 100 million vs. 84 ± 36 million; p = 0.002) in asymptomatic smoking subjects in comparison with never-smokers. Macrophages correlated negatively with the forced expiratory volume in 1 s as percent of the predicted value (ρ = –0.75, p = 0.003). Of 23 mediators examined, mRNA expression of cytokines interleukin (IL)-6, interferon-γ, tumor necrosis factor-β, IL-13 and chemokines CCL5, CCL3, CCL4 and CCL20 was significantly lowered in BAL cells of smokers compared with never-smokers and was negatively correlated with macrophages and positively correlated with the forced expiratory volume in 1 s as percent of the predicted value. Differential cell counts were similar between smokers and never-smokers in the bronchial biopsies. Conclusion: We conclude that in a susceptible population, smoking suppresses inflammatory defense by inhibiting expression of inflammatory mediators in the airways on a large scale.

Work, Unemployment and Life Satisfaction among Patients with Diisocyanate Induced Asthma-A Prospective Study

Work, Unemployment and Life Satisfaction among Patients with Diisocyanate Induced Asthma—A Prospective Study: Päivi L Piirilä, et al. Department of Occupational Medicin of the Finnish Institute of Occupational Health, Finland—Occupational asthma has been found to be associated with lowered socio‐economic outcomes, an increased unemployment rate and a decreased quality of life. The compensation of occupational diseases is comparatively favourable in Finland. Our aim was to follow‐up the working status and life satisfaction of patients with diisocyanate‐induced asthma in 245 cases diagnosed during 1976–1992. A questionnaire was sent out on average 10 (3–19) yr after the diagnosis to the surviving 235 patients. The questionnaire was validated by re‐examining 91 of them clinically, and with spirometry, histamine challenge test and peak flow surveillance. Of the 213 responding patients, 14% were unemployed, and for 50% of them unemployment was caused by asthma. Unemployment was associated with nocturnal asthma symptoms (OR 10.93; CI 2.69– 44.452), increased PEF variability (OR 8.46; CI 1.52– 46.97) and with the use of short‐acting βsympathomimetic medication (p=0.045). Satisfaction with life was associated with present working (OR 3.50; CI 1.73–7.06) and with good condition of asthma as assessed by the use of asthma medication (OR 0.49; CI 0.27–0.89) and objective measurements of the asthma condition, e.g. PEF variability (OR 0.21; CI 0.08–0.59). As a conclusion, unemployment was remarkably low as compared with earlier reports and related to the period of simultaneous economic recession. Unemployment, as well as dissatisfaction with life were associated with poor conditions of asthma. Unemployment was associated with improper asthma care favouring the use of short‐acting βsympathomimetic medication. Proper follow‐up of asthma is essential for minimizing the social complaints of occupational asthma, as well as for enhancing life satisfaction.

Associations between sports participation, cardiorespiratory fitness, and adiposity in young adult twins

Exercise behavior, cardiorespiratory fitness, and obesity are strongly influenced by genetic factors. By studying young adult twins, we examined to what extent these interrelated traits have shared genetic and environmental etiologies. We studied 304 twin individuals selected from the population-based FinnTwin16 study. Physical activity was assessed with the Baecke questionnaire, yielding three indexes: sport index, leisure-time index, and work index. In this study, we focused on sport index, which describes sports participation. Body composition was determined using dual-energy X-ray absorptiometry and cardiorespiratory fitness using a bicycle ergometer exercise test with gas exchange analysis. The Baecke sport index was associated with high maximal oxygen uptake adjusted for lean body mass (Vo(2max)[adj]) (r = 0.40), with low body fat percentage (BF%) (r = -0.44) and low waist circumference (WC) (r = -0.29). Heritability estimates for the key traits were as follows: 56% for sport index, 71% for Vo(2max)[adj], 77% for body mass index, 66% for WC, and 68% for BF%. The association between sport index and Vo(2max) was mostly explained by genetic factors (70%), as were both the association between sport index and BF% (71%) and that between sport index and WC (59%). Our results suggest that genetic factors explain a considerable part of the associations between sports participation, cardiorespiratory fitness, and obesity.

Increase in prevalence of physician-diagnosed asthma in Helsinki during the Finnish Asthma Programme: improved recognition of asthma in primary care? A cross-sectional cohort study

Background: The continuing rise in asthma prevalence has been questioned, with recent reports suggesting a plateau. Aims: To assess a 10-year trend in the age-adjusted prevalence of physician-diagnosed asthma, respiratory and allergic symptoms, and use of asthma medication in the adult population of Helsinki during the Finnish Asthma Programme from 1994 to 2004. Methods: Two cross-sectional postal surveys were conducted among random Finnish National Population Registry samples 10 years apart using the same protocol. A total of 6,062 subjects (75.9%) and 2,449 subjects (61.9%) participated in 1996 and 2006, respectively. Results: The prevalence of physician-diagnosed asthma increased from 6.5% in 1996 to 10.0% in 2006 (p<0.001). This was evident in both genders aged <60 years, but particularly in women aged <40 years, paralleling an increased use of asthma medication. Concurrently, the prevalence of allergic rhinoconjunctivitis increased from 37.2% to 44.4% (p<0.001). The prevalence of physician-diagnosed chronic obstructive pulmonary disease remained unchanged (3.7%), while current smoking abated. Subjects with a smoking history had more respiratory symptoms (p<0.001). Among subjects without physician-diagnosed asthma, those reporting allergic rhinoconjunctivitis had a higher prevalence of lower respiratory tract symptoms. Conclusions: The prevalence of allergic rhinoconjunctivitis and physician-diagnosed asthma has increased in Helsinki during 10 years in adults, especially in women aged <40 years. Concomitantly, the use of asthma medication increased and subjects with physiciandiagnosed asthma were less symptomatic. The increase in the prevalence of physician-diagnosed asthma may partly be due to improved diagnostic recognition of asthma in primary care during the Finnish Asthma Programme, but the concurrent rise in allergic rhinoconjunctivitis may reflect a true rise in prevalence.

Atopic sensitization to common allergens without symptoms or signs of airway disorders does not increase exhaled nitric oxide

Background:  Elevated fractional exhaled nitric oxide (FENO) associates positively with symptomatic atopy among asthmatics and in the general population. It is, however, unclear whether sensitization to common allergens per se– as verified with positive skin prick tests – affects FENO in healthy individuals.

Cardiovascular autonomic responsiveness in postmenopausal women with and without hot flushes

OBJECTIVES During menopausal transition autonomic balance is known to shift towards sympathetic dominance, but the role of vasomotor hot flushes in this phenomenon is not understood. We compared cardiovascular autonomic responsiveness between women with and without hot flushes. STUDY DESIGN AND MAIN OUTCOME MEASURES One hundred fifty recently postmenopausal healthy women with varying degree of hot flushes (none, mild, moderate, severe) underwent comprehensive cardiovascular autonomic nervous testing (controlled and deep breathing, active orthostatic test, Valsalva manoeuvre and handgrip test) assessing both sympathetic and parasympathetic activity. The responses of heart rate, heart rate variability and blood pressure in these tests were evaluated. RESULTS Responses in heart rate showed differences between the study groups only in the Valsalva manoeuvre where the tachycardia ratio in all symptomatic women was lower (p=0.041) than in women without hot flushes. Neither change in the heart rate variability analyses nor the blood pressure responses were affected by hot flush status. However, there was a non-significantly higher maximum systolic (140 (112-182)mmHg vs. 135 (102-208)mmHg) and diastolic blood pressure (94 (72-112)mmHg vs. 90 (66-122)mmHg) following the handgrip test in women without hot flushes vs. all the symptomatic women. CONCLUSIONS Menopausal hot flushes seem to be associated with a possibly increased sympathetic preponderance without an effect on parasympathetic activity in cardiovascular autonomic responses. This may imply a potentially negative impact on cardiovascular health in women experiencing hot flushes.