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Clinical testing of bronchial hyperreactivity (BHR) provides valuable information in asthma diagnostics. Nevertheless, the test results depend to a great extent on the testing procedure: test substance, apparatus and protocol. In Nordic countries, three protocols predominate in the testing field: Per Malmberg, Nieminen and Sovijarvi methods. However, knowledge of their equivalence is limited. We aimed to find equivalent provocative doses (PD) to obtain similar bronchoconstrictive responses for the three protocols. We recruited 31 patients with suspected asthma and health care workers and performed BHR testing with methacholine according to Malmberg and Nieminen methods, and with histamine according to Sovijarvi. We obtained the individual response-dose slopes for each method and predicted equivalent PD values. Applying a mixed-model, we found significant differences in the mean (standard error of mean) response-dose (forced expiratory volume in one second (FEV1)%/mg): Sovijarvi 7.2 (1.5), Nieminen 13.8 (4.2) and Malmberg 26 (7.3). We found that the earlier reported cut-point values for moderate BHR and marked BHR between the Sovijarvi (PD15) and Nieminen (PD20) methods were similar, but with the Malmberg method a significant bronchoconstrictive reaction was measured with lower PD20 values. We obtained a relationship between slope values and PD (mg) between different methods, useful in epidemiological research and clinical practice.

BACKGROUND: Child-onset asthma is known to remit with high probability, but remission in adult-onset asthma is seem-ingly less frequent. Reports of the association between remission and asthma age of onset up to late adulthood are scarce. OBJECTIVE: To evaluate the association between asthma remission, age at diagnosis and gender, and assess risk factors of nonremission. METHODS: In 2016, a random sample of 16,000 subjects aged 20 to 69 years from Helsinki and Western Finland were sent a FinEsS questionnaire. Physician-diagnosed asthma was catego-rized by age at diagnosis to early-(0-11 years), intermediate-(12-39 years), and late-diagnosed (40-69 years) asthma. Asthma remission was defined by not having had asthma symptoms and not having used asthma medication in the past 12 months. RESULTS: Totally, 8199 (51.5%) responded, and 879 reported physician-diagnosed asthma. Remission was most common in early-diagnosed (30.2%), followed by intermediate-diagnosed (17.9%), and least common in late-diagnosed asthma (5.0%) (P < .001), and the median times from diagnosis were 27, 18.5, and 10 years, respectively. In males, the corresponding remission rates were 36.7%, 20.0%, and 3.4%, and in females, 20.4%, 16.6%, and 5.9% (gender difference P < .001). In multivariable binary logistic regression analysis, signifi-cant risk factors of asthma nonremission were intermediate (odds ratio [OR] = 2.15, 95% confidence interval: 1.373.36) and late diagnosis (OR = 11.06, 4.82-25.37) compared with early diagnosis, chronic obstructive pulmonary disease (COPD) (OR = 5.56, 1.26-24.49), allergic rhinitis (OR = 2.28, 1.50-3.46), and family history of asthma (OR = 1.86, 1.22-2.85). Results were similar after excluding COPD. CONCLUSION: Remission was rare in adults diagnosed with asthma after age 40 years in both genders. Late-diagnosed asthma was the most significant independent risk factor for nonremission. (C) 2020 American Academy of Allergy, Asthma & Immunology

Objective: To investigate the current prevalence of physician-diagnosed obstructive airway diseases by respiratory symptoms and by sex in Sweden and Finland. Method: In 2016, a postal questionnaire was answered by 34,072 randomly selected adults in four study areas: Västra Götaland and Norrbotten in Sweden, and Seinäjoki-Vaasa and Helsinki in Finland. Results: The prevalence of asthma symptoms was higher in Norrbotten (13.2%), Seinäjoki-Vaasa (14.8%) and Helsinki (14.4%) than in Västra Götaland (10.7%), and physician-diagnosed asthma was highest in Norrbotten (13.0%) and least in Västra Götaland (10.1%). Chronic productive cough was most common in the Finnish areas (7.7–8.2% versus 6.3–6.7%) while the prevalence of physician-diagnosed chronic bronchitis (CB) or chronic obstructive pulmonary disease (COPD) varied between 1.7 and 2.7% in the four areas. Among individuals with respiratory symptoms, the prevalence of asthma was most common in Norrbotten, while a diagnosis of COPD or CB was most common in Västra Götaland and Seinäjoki-Vaasa. More women than men with respiratory symptoms reported a diagnosis of asthma in Sweden and Seinäjoki-Vaasa but there were no sex differences in Helsinki. In Sweden, more women than men with symptoms of cough or phlegm reported a diagnosis of CB or COPD, while in Finland the opposite was found. Conclusion: The prevalence of respiratory symptoms and corresponding diagnoses varied between and within the countries. The proportion reporting a diagnosis of obstructive airway disease among individuals with respiratory symptoms varied, indicating differences in diagnostic patterns both between areas and by sex. Accepted author version posted online: 30 May 2020Published online: 13 Jun 2020

Vertaisarvioitu. Epästabiilissa sepelvaltimotaudissa lepo-EKG:n muutos voi olla kivuttomalla potilaalla ainoa viite uhkaavasta sydäntapahtumasta. Kuvaamme tapauksen, jossa hyvävointisen potilaan EKG-löydös oli ratkaiseva vihje uhkaavasta sydäninfarktista.

Background: Genetic alterations occurring in lung cancer are the basis for defining molecular subtypes and essential for targeted therapies. Exhaled breath condensate (EBC) is a form of non-invasive sample that, amongst components, contains DNA from pulmonary tissue. Nextgeneration sequencing (NGS) was herein used to analyze mutations in EBC from patients with lung cancer. Materials and Methods: EBC was collected from 26 patients with cancer and 20 healthy controls. Amplicon-based sequencing using Ion Ampliseq Colon and Lung Cancer gene panel v2 was applied. Results: The sequencing was successful in 17 patients and 20 controls. EBC from patients revealed 39 hotspot mutations occurring in: adenomatous polyposis coli (APC), v-raf murine sarcoma viral oncogene homolog B (BRAE), discoidin domain receptor tyrosine kinase 2 (DDR2), epidermal growth factor receptor (EGFR), erb-b2 receptor tyrosine kinase 4 (ERBB4), F-box and WD repeat domain containing 7 (FBXW7), fibroblast growth factor receptor 1 (FGER1), FGFR3 (fibroblast growth factor receptor 3), Kirsten rat sarcoma viral oncogene homolog (KRAS), mitogen-activated protein kinase kinase 1 (MAP2K1), met proto-oncogene (MET), neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphatase and tensin homolog (PTEN), ret proto-oncogene (RET), SMAD family member 4 (SMAD4), serine/threonine kinase 11 (STK11), and tumorprotein p53 (TP53) genes. EBC from controls revealed 35 hotspot mutations. The average mutant allele fraction was higher in patients than controls. Conclusion: NGS can identify mutations in EBCs from patients with lung cancer. This could provide a promising non-invasive method for the assessment of gene mutations in lung cancer.

Purpose This study aims to investigate 1) how monozygotic (MZ) twin pairs who are discordant for body mass index (BMI) differ for objectively and subjectively measured physical activity (PA) and cardiorespiratory fitness (VO2max), and 2) associations of PA and VO2max with adiposity and measures of metabolic health, in individual twins and independent of genetic and shared environmental effects within twin pairs. Methods We examined 27 BMI-discordant and 14 BMI-concordant MZ twin pairs. Fat and fat free mass (ffm) were measured by dual energy x-ray absorptiometry and VO2max by spiroergometry. PA was measured objectively by accelerometers using ActiGraph GT1M for daytime activity and Actiwatch AW7 for 24h/day. Self-reported PA was obtained through the Baecke and IPAQ long-form questionnaires. Results Objectively measured moderate to vigorous PA (MVPA, min/day), steps/day and VO2max/kg were significantly lower, by 30%, 21% and 14% respectively in the heavy compared with the lean co-twins of the BMI-discordant twin pairs. There were no significant differences in self-reported PA or VO2max/ffm. As expected, PA and VO2max/ffm were similar in the BMI-concordant co-twins. Furthermore, the 24-h recording of activity suggested that the heavier co-twins had more restless sleep during the night, whereas the leaner co-twins were more active during the day. Within all twin pairs, higher MVPA and steps per day were associated with lower fat percentage and improved metabolic health measures. Conclusion Objectively, but not subjectively measured PA is associated with lower adiposity and better metabolic health, independent of genetic and shared environmental factors. This article is protected by copyright. All rights reserved.

Background Onset of allergic asthma has a strong association with childhood but only a few studies have analyzed incidence of asthma from childhood to late adulthood in relation to allergy. The purpose of the study was to assess age-specific incidence of allergic and non-allergic asthma. Methods Questionnaires were sent to 8000 randomly selected recipients aged 20–69 years in Finland in 2016. The response rate was 52.3% (n = 4173). The questionnaire included questions on e.g. atopic status, asthma and age at asthma diagnosis. Asthma was classified allergic if also a physician-diagnosed allergic rhinitis was reported. Results The prevalence of physician-diagnosed asthma and allergic rhinitis were 11.2 and 17.8%, respectively. Of the 445 responders with physician-diagnosed asthma, 52% were classified as allergic and 48% as non-allergic. Median ages at diagnosis of allergic and non-allergic asthma were 19 and 35 years, respectively. Among subjects with asthma diagnosis at ages 0–9, 10–19, 20–29, 30–39, 40–49, 50–59 and 60–69 years, 70, 62, 58, 53, 38, 19 and 33%, respectively, were allergic. For non-allergic asthma, the incidence rate was lowest in children and young adults (0.7/1000/year). It increased after middle age and was highest in older age groups (2.4/1000/year in 50–59 years old). Conclusions The incidence of allergic asthma is highest in early childhood and steadily decreases with advancing age, while the incidence of non-allergic asthma is low until it peaks in late adulthood. After approximately 40 years of age, most of the new cases of asthma are non-allergic.

Background Mulibrey nanism (MUL) is a rare growth restriction disorder with multiple organ manifestations caused by genetic defects affecting the TRIM37 protein. A perimyocardial heart disease is the most serious manifestation. Many MUL children appear to suffer from airway obstruction related to infection or exercise, prompting use of inhaled therapies. Asthma medication is continued up to adolescence or even to adulthood due to persisting of symptoms. The pulmonary pathophysiology has previously not been evaluated in any MUL cohort. Methods Thirty three finnish MUL patients (median age 20 years) were investigated with several lung function tests: spirometry with bronchodilatation test, single-breath diffusing capacity for carbon monoxide, single-breath lung volume measurements with helium dilution, and thoracic gas volume, airway resistance and specific conductance measurements with a body plethysmograph. As MUL typically affects body proportions, all variables were compared with reference values and with predicted values calculated from sitting height. Results Total lung capacity and forced vital capacity were markedly reduced (total lung capacity [TLC] and forced vital capacity [FVC], P = 12% and >= 200 mL) was found only in one patient. Conclusion MUL patients typically have volume restriction of the lungs, but function of the pulmonary tissue remains intact. Evidence of asthma in lung function testing at adult age is rare.

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Background Mortality and hospitalization due to asthma have decreased in many European countries, but asthma symptoms still cause a lot of morbidity and costs. Objectives We evaluated prevalence trends of asthma, asthma symptoms and allergic rhinoconjunctivitis in adults aged 20–69 years during a 20-year period from 1996 to 2016 in the city of Helsinki, the capital of Finland. Methods Three cross-sectional postal surveys were conducted in random population samples 10 years apart. In 1996, 2006 and 2016, a total of 6062 (response rate 75.9%), 2449 (61.9%) and 4026 subjects (50.3%) took part, respectively. Results In all responders, the prevalence of physician-diagnosed asthma was 6.6% in 1996, 10% in 2006 and 10.9% in 2016. The prevalence increased from 1996 to 2006, but stabilized from 2006 to 2016, both in men and women and in smokers and non-smokers. The prevalence of current asthma (8.5% in 2006 and 8.8% in 2016) and of asthma with rhinoconjunctivitis (7.6% in 2006 and 7.5% in 2016) remained also at the same level. Allergic rhinoconjunctivitis decreased significantly from 2006 (42.7%) to 2016 (39.0%, p = 0.004). Those with physician diagnosed asthma reported significantly less symptoms in 2016 compared to 2006 and 1996, although there was no change in smoking habits or medication use. Young asthmatics (20–29 years) without rhinoconjunctivitis reported least symptoms. Conclusion Previously observed increase of physician-diagnosed asthma prevalence in adults seems to be levelling off in Helsinki, and patients have fewer symptoms than 20 years ago. In addition, allergic rhinoconjunctivitis is less frequent than 10 years earlier. (247 words).

Multiple studies have shown that in approximately half of individuals with pulmonary embolism (PE), the deep venous thrombosis (DVT) is not evident at the moment of PE diagnosis. The underlying factors and the origin of PE in these patients are not completely understood: missed DVT, embolization of DVT in its entirety, or de-novo PE being possible explanations. The aim of this study was to evaluate the differences in PE patient with or without co-existing DVT. Sixty-three consecutive PE patients were included. Whole leg bilateral Doppler compression ultrasound was performed to all patients. The PE location and extension, C-reactive protein, platelet count, hemostatic markers FV, FVIII, FXIIIa, Fibrinogen, von Willebrand factor antigen, thrombomodulin were assessed. Thorough clinical assessment including echocardiography and pulmonary function tests were performed upon arrival and seven months later. The mean age of the patients was 57 years (SD 17.3) and 33 (52%) were women. Thirty-one patients (49.2%) had coexisting DVT. The presence of DVT was associated with the proximal location of the PE (100%), whereas none of the patients (n = 10) with exclusively peripheral PE had coexisting DVT. The PE extension, the measured hemostatic and inflammatory markers or the patient characteristics did not statistically differ between patients with isolated PE and PE with co-existing DVT. In roughly half of the PE patients no DVT could be detected. The location of the PE was associated with the presence of co-existing DVT. There were no differences in the PE extension, hemostatic markers or in the patient characteristic between patients with isolated PE or PE with coexisting DVT. Copyright (C) 2019 Wolters Kluwer Health, Inc. All rights reserved.

// Omar Youssef 1 , Aija Knuuttila 2 , Paivi Piirila 3 , Tom Bohling 4 , Virinder Sarhadi 1, * , Sakari Knuutila 1, * 1 Faculty of Medicine, Department of Pathology, University of Helsinki, Helsinki, Finland 2 Department of Pulmonary Medicine, University of Helsinki and Helsinki University Hospital, Heart and Lung Center, Helsinki, Finland 3 Unit of Clinical Physiology, HUS-Medical Imaging Center, Helsinki University Hospital and Helsinki University, Helsinki, Finland 4 Department of Pathology, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland * These authors have contributed equally to this work Correspondence to: Sakari Knuutila, email: sakari.knuutila@helsinki.fi Keywords: exhaled breath condensate, mutations, healthy individuals, next generation sequencing Received: December 10, 2016 Accepted: January 16, 2017 Published: February 09, 2017 ABSTRACT Exhaled breath condensate (EBC) is a non-invasive source that can be used for studying different genetic alterations occurring in lung tissue. However, the low yield of DNA available from EBC has hampered the more detailed mutation analysis by conventional methods. We applied the more sensitive amplicon-based next generation sequencing (NGS) to identify cancer related mutations in DNA isolated from EBC. In order to apply any method for the purpose of mutation screening in cancer patients, it is important to clarify the incidence of these mutations in healthy individuals. Therefore, we studied mutations in hotspot regions of 22 cancer genes of 20 healthy, mainly non-smoker individuals, using AmpliSeq colon and lung cancer panel and sequenced on Ion PGM. In 15 individuals, we detected 35 missense mutations in TP53, KRAS, NRAS, SMAD4, MET, CTNNB1, PTEN, BRAF, DDR2, EGFR, PIK3CA, NOTCH1, FBXW7, FGFR3, and ERBB2: these have been earlier reported in different tumor tissues. Additionally, 106 novel mutations not reported previously were also detected. One healthy non-smoker subject had a KRAS G12D mutation in EBC DNA. Our results demonstrate that DNA from EBC of healthy subjects can reveal mutations that could represent very early neoplastic changes or alternatively a normal process of apoptosis eliminating damaged cells with mutations or altered genetic material. Further assessment is needed to determine if NGS analysis of EBC could be a screening method for high risk individuals such as smokers, where it could be applied in the early diagnosis of lung cancer and monitoring treatment efficacy.

Background: Asthma is currently divided into different phenotypes, with age at onset as a relevant differentiating factor. In addition, asthma with onset in adulthood seems to have a poorer prognosis, but studies investigating age-specific incidence of asthma with a wide age span are scarce. Objective: To evaluate incidence of asthma diagnosis at different ages and differences between child- and adult-diagnosed asthma in a large population-based study, with gender-specific analyzes included. Methods: In 2016, a respiratory questionnaire was sent to 8000 randomly selected subjects aged 20-69 years in western Finland. After two reminders, 4173 (52.3%) subjects responded. Incidence rate of asthma was retrospectively estimated based on the reported age of asthma onset. Adult-diagnosed asthma was defined as a physician-diagnosis of asthma made at >= 18 years of age. Results: Among those with physician-diagnosed asthma, altogether, 63.7% of subjects, 58.4% of men and 67.8% of women, reported adult-diagnosed asthma. Incidence of asthma diagnosis was calculated in 10-year age groups and it peaked in young boys (0-9 years) and middle-aged women (40-49 years) and the average incidence rate during the examined period between 1946 and 2015 was 2.2/1000/year. Adult-diagnosed asthma became the dominant phenotype among those with physician-diagnosed asthma by age of 50 years and 38 years in men and women, respectively. Conclusions: Asthma is mainly diagnosed during adulthood and the incidence of asthma diagnosis peaks in middle-aged women. Asthma diagnosed in adulthood should be considered more in clinical practice and management guidelines.

Fractional exhaled nitric oxide (F

Previous reports link differential DNA methylation (DNAme) to environmental exposures that are associated with lung function. Direct evidence on lung function DNAme is, however, limited. We undertook an agnostic epigenome-wide association study (EWAS) on pre-bronchodilation lung function and its change in adults.In a discovery–replication EWAS design, DNAme in blood and spirometry were measured twice, 6–15 years apart, in the same participants of three adult population-based discovery cohorts (n=2043). Associated DNAme markers (p−7) were tested in seven replication cohorts (adult: n=3327; childhood: n=420). Technical bias-adjusted residuals of a regression of the normalised absolute β-values on control probe-derived principle components were regressed on level and change of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and their ratio (FEV1/FVC) in the covariate-adjusted discovery EWAS. Inverse-variance-weighted meta-analyses were performed on results from discovery and replication samples in all participants and never-smokers.EWAS signals were enriched for smoking-related DNAme. We replicated 57 lung function DNAme markers in adult, but not childhood samples, all previously associated with smoking. Markers not previously associated with smoking failed replication. cg05575921 (AHRR (aryl hydrocarbon receptor repressor)) showed the statistically most significant association with cross-sectional lung function (FEV1/FVC: pdiscovery=3.96×10−21 and pcombined=7.22×10−50). A score combining 10 DNAme markers previously reported to mediate the effect of smoking on lung function was associated with lung function (FEV1/FVC: p=2.65×10−20).Our results reveal that lung function-associated methylation signals in adults are predominantly smoking related, and possibly of clinical utility in identifying poor lung function and accelerated decline. Larger studies with more repeat time-points are needed to identify lung function DNAme in never-smokers and in children.

Fractional exhaled nitric oxide (F

The objective of this study was to evaluate associations between the breathing sound spectra and glottal dimensions in exercise-induced vocal cord dysfunction (EIVCD) during a bicycle ergometry test. Nineteen subjects (mean age 21.8 years and range 13–39 years) with suspected EIVCD were studied. Vocal folds were continuously imaged with videolaryngoscopy and breathing sounds were recorded during the bicycle exercise test. Twelve subjects showed paradoxical movement of the vocal folds during inspiration by the end of the exercise. In seven subjects, no abnormal reactions in vocal folds were found; they served as control subjects. The glottal quotient (interarytenoid distance divided by the anteroposterior glottal distance) was calculated. From the same time period, the tracheal–vocal tract resonance peaks of the breathing sound spectra were analyzed, and stridor sounds were detected and measured. Subjects with EIVCD showed significantly higher resonance peaks during the inspiratory phase compared to the expiratory phase (p

Multiple acyl-CoA dehydrogenation deficiency is genetically heterogenous metabolic disease with mutations in genes involved in electron transfer to the mitochondrial respiratory chain. Disease symptoms vary from severe neonatal form to late-onset presentation with metabolic acidosis, lethargy, vomiting, muscle pain and weakness. Riboflavin therapy has been shown to ameliorate diseases symptoms in some of these patients. Recently, mutations in FAD synthase have been described to cause multiple acyl-CoA dehydrogenation deficiency. We describe here the effect of riboflavin supplementation therapy in a previously reported adult patient with multiple acyl-CoA dehydrogenation deficiency having compound heterozygous gene variations in FLAD1 (MIM: 610595) encoding FAD synthase. We present thorough clinical history including laboratory investigations, muscle MRI, muscle biopsy and spiroergometric analyses comprising of a follow-up of 20 years. Our data suggest that patients with adult-onset multiple acyl-CoA dehydrogenation deficiency with FLAD1 gene mutations also benefit from long-term riboflavin therapy. (C) 2017 Elsevier B.V. All rights reserved.

Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function. Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in is (FEV1), forced vital capacity (PVC) and FEV1/FVC) of 12 595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status. We observed negative associations between telomere length and asthma (beta= -0.0452, p= 0.024) as well as COPD (beta= -0.0982, p=0.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p=1.07 x 10(-7)), FVC (p=2.07 x 10(-5)), and FEV1/FVC (p =5.27 x 10(-3)). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients. Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases.

Objectives To determine whether genetic polymorphisms in several candidate genes related to innate immunity and protease–antiprotease balance modify individual susceptibility to develop asbestos-related fibrotic pleuropulmonary changes. Methods Sixteen polymorphisms from nine genes (NLRP3, CARD8, TNF, TGFB1, GC, MMP1, MMP9, MMP12 and TIMP2) were genotyped from 951 Finnish asbestos-exposed workers. The genotype/haplotype data were compared to signs of fibrosis and pleural thickenings using linear and logistic regression analysis adjusted for potential confounders. Results A functional polymorphism (Q705K; rs35829419) in the NLRP3 gene was associated with interstitial lung fibrosis (p=0.013), and the TGFB1 rs2241718 SNP with visceral pleural fibrosis (VPF) (p=0.044). In stratified analysis, the carriage of at least one NLRP3 variant allele conferred a 2.5-fold increased risk for pathological interstitial lung fibrosis (OR 2.44, 95% CI 0.97 to 6.14). Conversely, the carriage of at least one TGFB1 rs2241718 variant allele protected against VPF (OR 0.62, 95% CI 0.39 to 0.98). The TIMP2 rs2277698 SNP and a haplotype consisting of the TGFB1 rs1800469 and rs1800470 SNPs were associated with the degree of pleural thickening calcification (p=0.037 and p=0.035), and the CARD8 rs2043211 SNP with the greatest thickness of pleural plaques (p=0.015). Conclusions Our results support the hypothesis that the NLRP3 inflammasome is important in the development of fibrotic lung disease by associating the NLRP3 rs35829419 variant allele with increased risk of asbestos-related interstitial lung fibrosis, and the TGFB1 rs2241718 variant allele with decreased risk of asbestos-related VPF. Polymorphisms in CARD8 and TIMP2 are proposed to modify the development and/or calcification of pleural thickenings.

Objective To compare in controlled cardiovascular autonomic function tests the effects of hormone therapy (HT) on heart rate variability (HRV) responses in postmenopausal women with and without pretreatment hot flushes. Design A randomized placebo-controlled trial. Setting Finland, Helsinki University Central Hospital. Population A total of 150 recently postmenopausal and healthy women with prospectively evaluated hot flushes. Methods Women (72 with and 78 without hot flushes) were randomized to receive estradiol alone or in combination with medroxyprogesterone acetate or placebo for 6 months. Time and frequency domain measures of HRV were assessed at baseline and after HT with short-term recordings during paced quiet and deep breathing and with active orthostatic tests, both under carefully controlled laboratory conditions to avoid confounding factors present in long-term ambulatory HRV measurements. Main outcome measures Responses of time and frequency domain measures of HRV to HT. Results At baseline HRV was similar in women with and without hot flushes. Pretreatment hot flushes did not associate with changes in time domain parameters of HRV during controlled quiet or deep breathing or active orthostatic tests after different types of HT. However, HT reduced HRV in very low frequency power in women with pretreatment hot flushes (from 371 ± 40 to 258 ± 28 ms2, p = 0.018). HT did not have an effect on other frequency domain measures during quiet breathing or active orthostatic tests. Conclusions Hormone therapy did not significantly modify the HRV responses in women with or without hot flushes under controlled short-term measurements of the cardiovascular autonomic nervous system.

Introduction: Bronchial hyperresponsiveness (BHR) elevates the risk for development of respiratory symptoms and accelerates the decline in forced expiratory volume in the first second (FEV1). We thus aimed to assess the prevalence, determinants and quantity of BHR in Helsinki. Objectives: This study involved 292 randomly selected subjects age 26–66 years, women comprising 58%. Methods: Following a structured interview, a spirometry, a bronchodilation test, and a skin-prick test, we assessed a bronchial challenge test with inhaled histamine using a dosimetric tidal breathing method. Results included the provocative dose inducing a decrease in FEV1 by 15% (PD15FEV1) and the dose-response slope. For statistical risk factor-analyses, the severity of BHR was considered; PD15 values ≤1.6 mg (BHR) and ≤0.4 mg [moderate or severe BHR (BHRms)] served as cut-off levels. Results: BHR presented in 21.2% and BHRms in 6.2% of the subjects. FEV1

Background Anoctaminopathies are muscle diseases caused by recessive mutations in the ANO5 gene. The effects of anoctaminopathy on oxidative capacity have not previously been studied in a controlled setting. Objective To characterize oxidative capacity in a clinically and genetically well-defined series of patients with anoctaminopathy. Methods We sequenced the ANO5 gene in 111 Finnish patients with suspected LGMD2. Patients with positive findings underwent close clinical examination, including electromyography, muscle MRI, and, in selected cases, muscle biopsy. Oxidative capacity was analyzed using spiroergometry and compared to age-matched healthy controls. Results We characterized 12 newly identified and 2 previously identified patients with ANO5 mutations from 11 families. Our material was genetically homogeneous with most patients homozygous for the Finnish founder variant c.2272C>T (p.Arg758Cys). In one family, we found a novel p.Met470Arg variant compound heterozygous with p.Arg758Cys. Lower limb muscle MRI revealed progressive fatty degeneration of specific posterior compartment muscles. Patients' spiroergometric profiles showed that anoctaminopathy significantly impaired oxidative capacity with increasing ventilation. Conclusions Our findings support earlier reports that anoctaminopathy progresses slowly and demonstrate that the disease impairs the capacity for aerobic exercise.

Context: The joint effects of cardiorespiratory fitness (CRF) and body composition on metabolic health are not well known. Objective: To examine the associations of CRF, fat-free mass index (FFMI), and fat mass index (FMI) with metabolic health in individual twins and controlling for genetic and shared environmental effects by studying monozygotic intrapair differences. Design, Setting, and Participants: Two cross-sectional samples of healthy adult monozygotic and dizygotic twins were drawn from population-based Danish and Finnish national twin registries (n = 996 and n = 309). Main Measures: CRF was defined as VO2max divided by fat-free mass. Insulin sensitivity and acute insulin response indices were derived from an oral glucose tolerance test. A continuous metabolic syndrome score was calculated. Visceral and liver fat were measured in the Finnish sample. Associations were analyzed separately in both cohorts with multivariate linear regression and aggregated with meta-analytic methods. Results: Insulin sensitivity, acute insulin response, metabolic syndrome score, visceral, and liver fat amount had strong and statistically significant associations with FMI (|β| 0.53 to 0.79), whereas their associations with CRF and FFMI were at most weak (|β| 0.02 to 0.15). The results of the monozygotic intrapair differences analysis showed the same pattern. Conclusions: Although FMI is strongly associated with worsening of metabolic health traits, even after controlling for genetic and shared environmental factors, there was little evidence for the effects of CRF or FFMI on metabolic health. This suggests that changing FMI rather than CRF or FFMI may affect metabolic health irrespective of genetic or early environmental determinants.

To assess the predictive value of lung function impairment on mortality among asbestos-exposed workers. A total of 590 workers originally screened for occupational lung disease including spirometry and pulmonary diffusing capacity measurements were followed up for mortality data (ICD-10 classification). The mean follow-up time was 10.5 years. Associations of different lung function parameters with mortality from all causes and from cardiovascular (I00-I99) and non-malignant respiratory diseases (J00-J99) were analysed. Factor analysis was used to create obstructive and restrictive factors. A total of 191 deaths were found altogether. Most measured lung function variables were associated with increased mortality when studied separately. Both decreased forced expiratory flow in one second (hazard ratio/measurement unit = 0.977, 95 % CI 0.969–0.988, p

Although fractional exhaled nitric oxide (FENO) measurement is a widely used method to assess eosinophilic bronchial inflammation, knowledge on extrabronchial factors affecting measurement results is still limited. Our aim was to study the eventual modifying effect of mouth wash on FENO values and their variability.A total of 16 healthy Caucasian women performed FENO measurements with a chemiluminescence analyzer according to ATS guidelines (2005), with an exhalation flow rate of 50 ml/s against a flow resistor. On the first day three successive FENO measurements were performed: first after mouth wash with water containing sodium and potassium bicarbonates, and thereafter twice without mouth wash. On the second day, the FENO measurement was first performed without mouth wash, then with preceding mouth wash twice, and finally without preceding mouth wash. Each FENO measurement consisted of three measurements with the average reported and the time interval between the FENO measurements was 10 minutes on both days.The FENO level increased significantly in the subsequent measurements performed without mouth wash (p0.01), when the baseline measurement was performed with mouth wash. On the second day, the FENO level decreased significantly in measurements performed with preceding mouth wash, compared with the first measurement without preceding mouth wash (p0.01).The results indicate a slight but statistically significant decreasing effect of mouth wash on the FENO. The findings suggest that mouth wash prior to FENO measurement could standardize the measurement procedure, by decreasing the effect of NO produced in the mouth on the measurement result.

Pulmonary emphysema is a smoking-induced condition of the lung. Genetically determined differences in the activities of enzymes that metabolize oxidative agents are suspected to modify individual susceptibility to emphysema, as well as other smoking-related pulmonary disorders. We investigated whether polymorphisms in selected xenobiotic-metabolizing enzyme genes predispose to emphysematous changes and airflow limitation among Finnish Caucasian construction workers. PCR-based methods were used to analyze nine common polymorphisms in EPHX1, GSTM1, GSTM3, GSTP1, GSTT1, and NAT2 genes among 988 Finnish construction workers. The genotype data were compared with different emphysematous signs confirmed with high-resolution computed tomography and with forced vital capacity and forced expiratory volume in 1 s. For this, linear and logistic regression analyses, adjusted for the potential confounders, were used. The EPHX1 Tyr113His polymorphism was associated with emphysematous changes (P=0.007), including paraceptal (P=0.039), panlobular (P=0.013), and bullae (P=0.003) type changes. The GSTM3 promoter polymorphism was associated with forced expiratory volume in 1 s/forced vital capacity ratio (P=0.010), and the GSTT1 genotype with emphysematous signs (P=0.008), including paraceptal (P=0.015), panlobular (P=0.031), and bullae-type (P=0.045) changes. In further analysis, the GSTT1 deletion was found to pose a two-fold overall risk for having emphysematous changes (odds ratio: 2.01; 95% confidence interval: 1.33-3.03), and almost a four-fold risk for having severe emphysematous changes (odds ratio: 3.70; 95% confidence interval: 2.15-6.36). The results indicate a significant modifying role for GSTT1 gene polymorphism in the individual risk and severity of emphysematous changes. This study was financially supported by the Finnish Work Environment Fund (Grant 105091) and ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility), a network of excellence operating within the European Union 6th Framework Program, Priority 5: ‘Food Quality and Safety’ (Contract No 513943).

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.

The assessment of the presence of eosinophilic airway inflammation may help in predicting the steroid response in subjects with respiratory symptoms. Unlike patients with asthma, only a subset of patients with chronic obstructive pulmonary disease (COPD) benefits from steroid treatment. Fractional exhaled nitric oxide (FENO) is a useful surrogate marker for eosinophilic airway inflammation, but data on the repeatability of FENO measurements in COPD needed for the assessment of significant change are insufficient. The aim of this study was to assess the short-term repeatability of FENO measurement in subjects with moderate to very severe chronic airway obstruction compared to that in healthy subjects. We studied 20 patients with stable COPD and 20 healthy subjects, and determined FENO (flow rate 50 ml s(-1) ) three times: at baseline, 10 min and 24 h after baseline. Spirometry was performed on the first study day after the FENO measurements. The median FENO concentration in patients with COPD was 15·6 ppb, and in healthy subjects, 15·2 ppb. The coefficient of variation (CoV) for 24-h measurements was 12·4% in COPD patients, and 15·9% in healthy subjects. Among COPD patients with global initiative for chronic obstructive lung disease stage 2 disease, the CoV was 13·7%, and among those with stage 3-4 disease, 10·5%. The findings indicate that the short-term repeatability of FENO measurement in patients with moderate to very severe COPD is equally good as in healthy subjects. A change in FENO exceeding 24% is likely to reflect a minimum measurable change in COPD.

The objective of this study was to determine whether genetic polymorphisms in enzymes that metabolise oxidative agents modify the individual susceptibility to developing asbestos and smoking-related pleuropulmonary changes. Nine polymorphisms of six genes (EPHX1, GSTM1, GSTM3, GSTP1, GSTT1 and NAT2) were genotyped from 1,008 Finnish asbestos-exposed workers. The genotype data were compared to signs of lung fibrosis and pleural thickenings, as well as with total lung capacity, single-breath diffusing capacity of the lung for carbon monoxide (D(L,CO)) and specific diffusing capacity (expressed as D(L,CO) per unit of alveolar volume (V(A))). The GSTT1 deletion polymorphism was associated with fibrotic changes (p=0.003), and decreased D(L,CO) (p=0.02) and D(L,CO)/V(A) (p=0.002), and the GSTM1 deletion polymorphism was associated with the greatest thickness of pleural plaques (p=0.009). On further analysis, the GSTT1 null genotype was found to pose over a three-fold risk for severe fibrotic changes (OR 3.12, 95% CI 1.51-6.43), and around two-fold risks for decreased D(L,CO) (OR 1.77, 95% CI 1.06-2.95) and D(L,CO)/V(A) (OR 2.37, 95% CI 1.33-4.23). In addition, the GSTM1 null genotype showed an elevated risk (OR 1.36, 95% CI 1.03-1.80) for thicker pleural plaques. Our data suggest that inherited detoxification capacity may affect the development and severity of asbestos and smoking-related nonmalignant pulmonary changes.

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. Methods: Bronchoscopy was performed on 17 patients 2 days after a positive inhalation challenge test, after which budesonide 1600 μg a day was started. Bronchoscopy, spirometry, and histamine challenge tests were repeated at 6 months and on average 3 years. The results were also compared with those obtained from 15 healthy control subjects. Results: Nonspecific bronchial hyperreactivity diminished significantly (P = 0.006); however, forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) values decreased, with a median yearly reduction of FEV1 of 79 ml. The count of mast cells in bronchial mucosa decreased (P = 0.012) and that of macrophages increased (P = 0.001). Interleukin-4 level in mucosa was during the first year significantly higher than in controls but its level decreased in the follow-up. Interleukin-6, interleukin-15, and tumour necrosis factor alpha messenger-RNA levels were significantly higher in hyperreactive patients than in nonhyperreactive patients at the end of the follow-up. Conclusion: Our results indicate that inflammation may persist in diisocyanate-induced asthma despite inhaled steroid medication. However, TH2-type inflammation diminished. Persistent nonspecific bronchial hyperreactivity was associated with proinflammatory acting cytokines produced mainly by macrophages. Considering the poor prognosis of the disease the findings could be utilized to develop the follow-up and treatment of diisocyanate-induced asthma.

Objective: The aim was to study the causes of respiratory hypersensitivity in dental personnel based on the statistics of the Finnish Register of Occupational Diseases (FROD; 1975–1998) and the patient material of the Finnish Institute of Occupational Health (FIOH; 1990–1998). Methods: Details about the cases of respiratory hypersensitivity were compiled from the FROD. The occupational rhinitis diagnoses studied at the FIOH were based on work-related symptoms and a change in the status of the nasal mucosa during challenge testing; and the diagnosis of occupational asthma based on reactions in challenge testing, or on IgE positivity and peak flow monitoring at work and during days off. Results: A total of 64 cases of occupational respiratory diseases (ORDs) was diagnosed in dental personnel during 1975 to1998 according to the FROD; two cases in 1975 to 1989, and 62 in 1990 to 1998. Twenty-eight cases were of occupational asthma (18 caused by methacrylates), 28 occupational rhinitis (six caused by methacrylates), seven allergic alveolitis and one organic dust toxic syndrome (ODTS). The non-acrylate-material diagnosed in 1990–1998 at the FIOH comprised three cases of asthma and one of rhinitis caused by chloramine-T (sodium-N-chlorine-p-toluene sulphonamide); as well as one case of asthma, seven cases of rhinitis, and two cases of combined rhinitis and conjunctivitis caused by natural rubber latex (NRL). Furthermore, one case of occupational rhinitis caused by Nobetec containing colophony was diagnosed. The incidence rate (IR) of ORD increased from 0 in 1988 to a peak of 105.1 new cases per100,000 working years in 1995. During the last observation year, i.e. 1998, the IR was 55 new cases per 100,000 workers. The IR in dental personnel was lower than in the whole working population in Finland up until 1992, but since then has been greater than in the whole population, peaking in 1995 when the IR of dental personnel was 2.55 times greater than in the whole population. Conclusion: The present study shows the increasing frequency of respiratory hypersensitivity among dental personnel. Besides methacrylates, important causes of respiratory hypersensitivity are NRL and chloramine-T.

Occupational exposure to 4,4'-methylenediphenyl diisocyanate (MDI) was measured during moulding of rigid polyurethane foam. The aim of the study was to find out whether an MDI-derived urinary amine metabolite could be detected in the urine of workers exposed to apparently low levels of MDI. Airborne MDI was sampled on 1-(2-methoxyphenyl)-piperazine (2MP)-impregnated glass fibre filters and determined by high-performance liquid chromatography (HPLC) using ultraviolet (UV) and electrochemical (EC) detection. The limit of detection of MDI was 3 ng ml-1 for a 20 microliters injection. The precision of sample preparation, expressed as relative standard deviation (RSD), was 1.3% with UV detection and 2.1% with EC detection at a concentration of 70 ng MDI ml-1 (n = 6). The 2MP-MDI derivative was stable at +4 degrees C up to eight weeks. The accuracy of the method was validated in an international quality control programme. Workers (n = 57) from three different factories participated in the study. Urinary 4,4'-methylenedianiline (MDA) metabolite was determined after acid hydrolysis as heptafluorobutyric anhydride derivatives by gas chromatography-mass spectrometry using chemical ionisation and monitoring negative ions. The limit of detection in urine was 0.2 nmol l-1. The precision of six analyses for a urine sample spiked to a concentration of 1 nmol l-1 was 29% (RSD). The MDI concentrations were below the limit of detection in most (64%) of the air samples collected in the worker's breathing zone. Still, detectable amounts of MDA were found in 97% of the urine samples. Monitoring of urinary MDA appears to be an appropriate method of assessing MDI exposure in work environments with low or undetectable MDI concentrations in the workplace air.

In 1976-1992 245 new cases of asthma induced by diisocyanates were diagnosed, caused by hexamethylene diisocyanate (HDI) in 39%, diphenylmethane diisocyanate (MDI) in 39%, and toluene diisocyanate (TDI) in 17% of the cases. Our aim was to study the clinical outcome of diisocyanate-induced asthma. A questionnaire was sent to the 235 patients alive in 1995, and validated by reexamining clinically 91 of them. The study was carried out on average 10 () yr after the diagnosis. Of the patients 82% experienced symptoms of asthma, 34% used no medication, and 35% were on regular medication. The patients having displayed immunoglobulin E (IgE) antibodies to isocyanates used less medication (OR 0.273; CI 0.098, 0.758) and had fewer symptoms of asthma (OR 0.329; CI 0.124, 0.875) than the IgE-negative ones. They also had a significantly shorter duration of symptoms (p = 0.0025), latency period (p = 0.0249), and duration of exposure (p = 0.0008) than the IgE-negative patients. This did not, however, entirely explain the more favourable outcome of the IgE-positive patients. Patients with HDI-induced asthma used less medication (OR 0.412; CI 0.229, 0.739) than patients with MDI- and TDI-induced asthma. The results confirm the generally rather poor medical outcome of diisocyanate-induced asthma; the persistence of symptoms and unspecific bronchial reactivity were pronounced in TDI-induced asthma. A more favourable outcome was associated with IgE mediation and HDI inducement.

To assess risk factors related to the development of chronic obstructive pulmonary disease (COPD) including smoking and occupational exposure (OE) to dusts, gases or fumes, we performed a longitudinal 11-year follow-up postal survey. The original study population was a random population sample of 8000 inhabitants of Helsinki aged 20 to 69 years in 1996. Participants of the first postal questionnaire were invited to this follow-up survey in 2007 with 4302 (78%) answers obtained. Cumulative incidence of COPD in 11 years was 3.43% corresponding to an incidence rate of 3.17/1000/year after exclusion of those with self-reported physician-diagnosed COPD and ever COPD in 1996. Smoking and age, but not gender, were associated with incident COPD. Reported family history of COPD increased the cumulative incidence to 8.55% vs 3.04% among those without a family history (p0.001). In multivariate analysis, significant independent risk factors for incident COPD were: current smoking in 1996 (OR 4.40 [95% CI 2.89-6.71]), age over 50 (OR 3.42 [95% CI 2.22-5.26]), family history of COPD (OR 2.08 [1.27-3.43]), ever asthma (OR 2.28 [1.35-3.86]), and self-reported OE (OR 2.14 [1.50-3.05]). Occupational exposure to dusts, gases or fumes, assessed both based on self-reported exposure and a job exposure matrix using reported professions, was an independent risk factor for incident COPD. Smoking and OE together yielded an additive effect on incidence of COPD.

Background: Dynamic gas compression during forced expiration has an influence on conventional flow-volume spirometry results. The extent of gas compression in different pulmonary disorders remains obscure. Utilizing a flow plethysmograph we determined the difference between thoracic and mouth flows during forced expiration as an indication of thoracic gas compression in subjects with different pulmonary diseases characterized by limitations in pulmonary mechanics. Methods: Patients with emphysema (N = 16), interstitial lung disease (ILD) (N = 15), obesity (N = 15) and healthy controls (N = 16) were included. Compressed expiratory flow-volume curves (at mouth) and corresponding compression-free curves (thoracic) were recorded. Peak flow (PEF) and maximal flows at 75%, 50% and 25% of remaining forced vital capacity (MEF75, MEF50 and MEF25) were derived from both recordings. Their respective difference was assessed as an indicator of gas compression. Results: In all groups, significant differences between thoracic and mouth flows were found at MEF50 (p < 0.01). In controls, a significant difference was also measured at MEF75 (p

Air-flow standardized breath sounds were recorded at the chest and at the trachea during histamine challenge test and after subsequent bronchodilation in 12 asthmatics and 6 healthy controls for spectral analysis, to be compared with simultaneous changes in spirometric variables. Of all the lung sound variables measured, the changes in median frequency of the power spectrum (F50) of tracheal expiratory sounds were found to correlate best (r = 0.853, p0.0001) with changes in FEV1. The increase of F50 during histamine challenge was significantly larger in asthmatics than in healthy control subjects (p0.005). The provocative dose of histamine inducing a decrease of 15 percent in FEV1 (PD15FEV1) and the provocative dose causing an increase of 30 percent in tracheal expiratory F50 (PD30F50) were significantly related (r = 0.754, p = 0.012). In asthmatics, the breath sound frequency distribution in terms of median frequency reflected acute changes in airways obstruction with high sensitivity and specificity. The present method for breath sound analysis can be applied for patients with limited cooperation during bronchial challenge tests.

Objectives To compare the responses of heart rate and blood pressure to various autonomic tests in women with and without pre-treatment hot flushes during estradiol and estradiol + medroxyprogesterone acetate (MPA) use. Study design and main outcome measures Hundred and fifty recently postmenopausal women (72 with and 78 without hot flushes) were randomized to receive transdermal estradiol (1 mg/day), oral estradiol (2 mg/day) alone or in combination with MPA (5 mg/day), or placebo for six months. Cardiovascular responsiveness was comprehensively assessed with controlled and deep breathing, active orthostatic test, Valsalva maneuver and handgrip test. Results Hot flushes were accompanied with a significant reduction (−2.2 ± 0.7 vs. 1.3 ± 1.1 beats/min, p = 0.03) in resting heart rate during estradiol-only treatment; the route of estradiol administration was no factor in this regard. This effect was attenuated by the addition of MPA to oral estradiol. Hot flushes were also associated with reduced maximal heart rate in response to handgrip during the use of estradiol-only therapy (−2.2 ± 1.3 vs. 2.8 ± 1.5 beats/min, p = 0.038); again, the MPA addition eliminated this effect. Hot flushes were accompanied with lowered resting but augmented blood pressure responses to handgrip test during all hormone regimens, whereas in women without hot flushes estradiol-only regimen tended to elevate diastolic resting blood pressure. Conclusions Hot flushes appear as determinants for cardiovascular responses to hormone therapy. Estradiol-only therapy causes beneficial changes in cardiovascular regulation in flushing women, and these are blunted, in part, by the addition of MPA.

Background Asthma leads to structural changes in the airways, including the modification of extracellular matrix proteins such as tenascin-C. The role of tenascin-C is unclear, but it might act as an early initiator of airway wall remodelling, as its expression is increased in the mouse and human airways during allergic inflammation. In this study, we examined whether Th1 or Th2 cells are important regulators of tenascin-C in experimental allergic asthma utilizing mice with impaired Th1 (STAT4-/-) or Th2 (STAT6-/-) immunity. Methods Balb/c wildtype (WT), STAT4-/- and STAT6-/- mice were sensitized with intraperitoneally injected ovalbumin (OVA) followed by OVA or PBS airway challenge. Airway hyperreactivity (AHR) was measured and samples were collected. Real time PCR and immunohistochemistry were used to study cytokines and differences in the expression of tenascin-C. Tenascin-C expression was measured in human fibroblasts after treatment with TNF-α and IFN-γ in vitro. Results OVA-challenged WT mice showed allergic inflammation and AHR in the airways along with increased expression of TNF-α, IFN-γ, IL-4 and tenascin-C in the lungs. OVA-challenged STAT4-/- mice exhibited elevated AHR and pulmonary eosinophilia. The mRNA expression of TNF-α and IFN-γ was low, but the expression of IL-4 was significantly elevated in these mice. OVA-challenged STAT6-/- mice had neither AHR nor pulmonary eosinophilia, but had increased expression of mRNA for TNF-α, IFN-γ and IL-4. The expression of tenascin-C in the lungs of OVA-challenged STAT4-/- mice was weaker than in those of OVA-challenged WT and STAT6-/- mice suggesting that TNF-α and IFN-γ may regulate tenascin-C expression in vivo. The stimulation of human fibroblasts with TNF-α and IFN-γ induced the expression of tenascin-C confirming our in vivo findings. Conclusions Expression of tenascin-C is significantly attenuated in the airways of STAT4-/- mice, which may be due to the impaired secretion of TNF-α and IFN-γ in these mice.

Background SERPINE2 (serpin peptidase inhibitor, clade E, member 2) has previously been identified as a positional candidate gene for chronic obstructive pulmonary disease (COPD) and has subsequently been associated to COPD and emphysema in several populations. We aimed to further examine the role of SERPINE2 polymorphisms in the development of pulmonary emphysema and different emphysema subtypes. Methods Four single nucleotide polymorphisms (SNPs) in SERPINE2 were analyzed from 951 clinically and radiologically examined Finnish construction workers. The genotype and haplotype data was compared to different emphysematous signs confirmed with high-resolution computed tomography (HRCT), forced vital capacity (FVC), forced expiratory volume in one second (FEV1), diffusing capacity (DLCO), and specific diffusing capacity (DLCO/VA). Results Three of the studied SERPINE2 SNPs (rs729631, rs975278, and rs6748795) were found to be in tight linkage disequilibrium. Therefore, only one of these SNPs (rs729631) was included in the subsequent analyses, in addition to the rs840088 SNP which was in moderate linkage with the other three studied SNPs. The rs729631 SNP showed a significant association with panlobular emphysema (p = 0.003). In further analysis, the variant allele of the rs729631 SNP was found to pose over two-fold risk (OR 2.22, 95% CI 1.05-4.72) for overall panlobular changes and over four-fold risk (OR 4.37, 95% CI 1.61-11.86) for pathological panlobular changes. A haplotype consisting of variant alleles of both rs729631 and rs840088 SNPs was found to pose an almost four-fold risk for overall panlobular (OR 3.72, 95% CI 1.56-8.90) and subnormal (OR 3.98, 95% CI 1.55-10.20) emphysema. Conclusions Our results support the previously found association between SERPINE2 polymorphisms and pulmonary emphysema. As a novel finding, our study suggests that the SERPINE2 gene may in particular be involved in the development of panlobular changes, i.e., the same type of changes that are involved in alpha-1-antitrypsin (AAT) -deficiency.

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 (V̇o2max[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 V̇o2max[adj], 77% for body mass index, 66% for WC, and 68% for BF%. The association between sport index and V̇o2max 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.

Acute pulmonary embolism (PE) often decreases pulmonary diffusing capacity for carbon monoxide (DL,CO), but data on the mechanisms involved are inconsistent. We wanted to investigate whether reduction in diffusing capacity of alveolo-capillary membrane (DM) and pulmonary capillary blood volume (Vc) is associated with the extent of PE or the presence and severity of right ventricular dysfunction (RVD) induced by PE and how the possible changes are corrected after 7-month follow-up. Forty-seven patients with acute non-massive PE in spiral computed tomography (CT) were included. The extent of PE was assessed by scoring mass of embolism. DL,CO, Vc, DM and alveolar volume (VA) were measured by using a single breath method with carbon monoxide and oxygen both at the acute phase and 7 months later. RVD was evaluated with transthoracic echocardiography and electrocardiogram. Fifteen healthy subjects were included as controls. DL,CO, DL, CO/VA, DM, vital capacity (VC) and VA were significantly lower in the patients with acute PE than in healthy controls (P

Recorded crackling lung sounds of 11 patients with pneumonia were studied with phonopneumography, FFT spectrography and time-expanded waveform display. The sounds were recorded on average six days after the onset of pneumonia and the recording was repeated two to four days later. In the first recording the crackles were coarse and midinspiratory. The patients with unilateral pneumonia had a significant difference in the upper frequency limit of inspiratory sound of the FFT spectrum between the healthy and diseased lung (p less than 0.01). In the second recording, the beginning of crackling had shifted later (p less than 0.01) and the end point of crackling also became later (p less than 0.05). The largest deflection width of the individual crackles became shorter (p less than 0.05). The results indicate that the pneumonic crackles vary markedly during the clinical course of pneumonia. The duration of the individual crackles became shorter and the timing of the crackles shifted toward the end of inspiration.

We have studied the crackling lung sounds of ten patients with cryptogenic fibrosing alveolitis, ten with bronchiectasis, ten with chronic obstructive pulmonary disease, and ten with heart failure by analyzing frequency, waveform, and timing of crackles. The upper frequency limit of inspiratory sounds was higher in CFA than in COPD or in HF. The period of crackling was shorter in COPD than in CFA or BE. Inspiratory crackling terminated significantly earlier in COPD than in CFA, BE, or HF. The initial deflection width and the two-cycle duration of the expanded waveforms of crackles were smaller in CFA than in BE, COPD, or HF. The largest deflection width was smaller in CFA than in BE, HF, or COPD and smaller in BE than in HF. The results indicate that crackling lung sounds in different diseases have distinctive features and that their analysis can be of diagnostic value. (Chest 1991; 99:1076-83)

The objective of our study was to determine the repeatability of successive measurements of exhaled nitric oxide (NO) with a portable device (NIOX MINO). We assembled a sample of 332 pairs of repeated NO measurements acquired in the same session. The mean of the two successive measurements varied from 4.0 to 279.5 parts per billion (ppb). The mean coefficient of repeatability (CoR) of the entire study sample was 2.4 ppb. The difference between paired measurements increased slightly with increasing fractional exhaled nitric oxide (FENO); for the mean FENO of 24.0 ppb the calculated CoR was 2.2 and for the FENO of 54 ppb it was 3.2 ppb. The difference between paired observations for FENO values50 ppb was significantly lower than that for values50 ppb (p0.001). The demonstrated repeatability of successive measurements with the device supports the view that, when the exhalation manoeuvre is technically valid and FENO is within normal limits, repeated determinations of FENO are generally not necessary for screening. In other cases, the mean value of two successive measurements would represent a more reliable measurement result.

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/m2) and 10 concordant (1.0 ± 0.7 kg/m2) 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 (V̇o2max) and working capacity (Wmax) 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·kg LBM−1·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 V̇o2max (50.6 ± 6.5 vs. 54.2 ± 6.4 ml·kg LBM−1·min−1, for obese vs. nonobese, P < 0.05), Wmax (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.

Microarray studies have shown that matrilysin or matrix metalloproteinase (MMP)-7 is highly upregulated in the lungs of patients with idiopathic pulmonary fibrosis (IPF), but MMP-7 protein expression has not been systematically compared between IPF and other interstitial lung diseases. MMP-7 levels in bronchoalveolar lavage fluid (BALF) were compared to corresponding samples from nonspecific interstitial pneumonia (NSIP), sarcoidosis, and healthy controls. MMP-7 levels in the BALF were determined by ELISA and localization of MMP-7 in the lung tissue by immunohistochemistry. MMP-7 was similarly elevated in the BALF of all these disorders compared to healthy controls (p=0.007). Even control subjects with prolonged cough displayed a tendency towards elevated MMP-7 expression. There was a negative correlation between BALF MMP-7 levels and forced expiratory vital capacity (r=-0.348, p=0.02, n=42). In IPF lung, MMP-7 immunoreactivity appeared predominantly in the fibrotic parenchyma and arterial wall. In sarcoidosis and NSIP, prominent MMP-7 immunoreactivity was found in areas of inflammation. These results demonstrate that elevated BALF MMP-7 is not restricted to IPF alone but is also observed in other interstitial lung diseases and cannot be used as a differential diagnostic marker for IPF.

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.

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 beta-sympathomimetic 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 beta-sympathomimetic medication. Proper follow-up of asthma is essential for minimizing the social complaints of occupational asthma, as well as for enhancing life satisfaction.