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To understand the determinants of inhaled aerosol particle distribution and targeting in the lung, knowledge of regional deposition, lung morphology and regional ventilation, is crucial. No single imaging modality allows the acquisition of all such data together. Here we assessed the feasibility of dual-energy synchrotron radiation imaging to this end in anesthetized rabbits; both in normal lung (n = 6) and following methacholine (MCH)-induced bronchoconstriction (n = 6), a model of asthma. We used K-edge subtraction CT (KES) imaging to quantitatively map the regional deposition of iodine-containing aerosol particles. Morphological and regional ventilation images were obtained, followed by quantitative regional iodine deposition maps, after 5 and 10 minutes of aerosol administration. Iodine deposition was markedly inhomogeneous both in normal lung and after induced bronchoconstrition. Deposition was significantly reduced in the MCH group at both time points, with a strong dependency on inspiratory flow in both conditions (R2 = 0.71; p < 0.0001). We demonstrate for the first time, the feasibility of KES CT for quantitative imaging of lung deposition of aerosol particles, regional ventilation and morphology. Since these are among the main factors determining lung aerosol deposition, we expect this imaging approach to bring new contributions to the understanding of lung aerosol delivery, targeting, and ultimately biological efficacy.

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BACKGROUND: Diagnostic assessment of lung function necessitates up-to-date reference values. The aim of this study was to estimate reference values for spirometry for the Finnish population between 18 and 80 years and to compare them with the existing Finnish, European and the recently published global GLI2012 reference values. METHODS: Spirometry was performed for 1380 adults in the population-based FinEsS studies and for 662 healthy non-smoking volunteer adults. Detailed predefined questionnaire screening of diseases and symptoms, and quality control of spirometry yielded a sample of 1000 native Finns (387 men) healthy non-smokers aged 18-83 years. Sex-specific reference values, which are estimated using the GAMLSS method and adjusted for age and height, are provided. RESULTS: The predicted values for lung volumes are larger than those obtained by GLI2012 prediction for the Caucasian subgroup for forced vital capacity (FVC) by an average 6·2% and 5·1% and forced expiratory volume in 1 s (FEV1) by an average 4·2% and 3·0% in men and women, respectively. GLI2012 slightly overestimated the ratio FEV1/FVC with an age-dependent trend. Most reference equations from other European countries, with the exception of the Swiss SAPALDIA study, showed an underestimation of FVC and FEV1 to varying degrees, and a slight overestimation of FEV1/FVC. CONCLUSION: This study offers up-to-date reference values of spirometry for native Finns with a wide age range. The GLI2012 predictions seem not to be suitable for clinical use for native Finns due to underestimation of lung volumes.

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K-edge subtraction computed tomography (KES-CT) allows simultaneous imaging of both structural features and regional distribution of contrast elements inside an organ. Using this technique, regional lung ventilation and blood volume distributions can be measured experimentally in vivo. In order for this imaging technology to be applicable in humans, it is crucial to minimize exposure to ionizing radiation with little compromise in image quality. The goal of this study was to assess the changes in signal-to-noise ratio (SNR) of KES-CT lung images as a function of radiation dose. The experiments were performed in anesthetized and ventilated rabbits using inhaled xenon gas in O2 at two concentrations: 20% and 70%. Radiation dose, defined as air kerma (Ka), was measured free-in-air and in a 16 cm polymethyl methacrylate phantom with a cylindrical ionization chamber. The dose free-in-air was varied from 2.7 mGy to 8.0 Gy. SNR in the images of xenon in air spaces was above the Rose criterion (SNR > 5) when Ka was over 400 mGy with 20% xenon, and over 40 mGy with 70% xenon. Although in human thorax attenuation is higher, based on these findings it is estimated that, by optimizing the imaging sequence and reconstruction algorithms, the radiation dose could be further reduced to clinically acceptable levels.

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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.

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In K-edge subtraction (KES) imaging with synchrotron radiation computed tomography (SRCT), two images are taken simultaneously using energies above and below the K-absorption edge of a contrast agent. A logarithmic difference image reveals the contrast agent concentration with good accuracy. Similarly, in temporal subtraction imaging (TSI) the reference image is taken before the introduction of the contrast agent. Quantitative comparisons of in vivo images of rabbit lung indicated that similar results for concentrations of iodine in blood vessels and xenon in airways are obtained by KES and TSI, but the level of noise and artifacts was higher in the latter. A linear fit showed that in the lung parenchyma rho(TSI) = (0.97 +/- 0.03)rho(KES) + (0.00 +/- 0.05) for xenon and rho(TSI) = (1.21 +/- 0.15)rho(KES) + (0.0 +/- 0.1) for iodine. For xenon the calculation of time constant of ventilation gave compatible values for both of the methods. The two methods are combined for the simultaneous determination of the xenon concentration (by KES) and the iodine concentration (by TSI) in lung imaging, which will allow simultaneous in vivo determination of ventilation and perfusion.

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The Finnish National Prevention and Treatment Programme for Chronic Bronchitis and COPD, launched in 1998, has, to date, been running for 6 years (2003). The goals of this action programme were to reduce the incidence of COPD and the number of moderate and severe cases of the disease, and to reduce both the number of days of hospitalisation and treatment costs. A prevalent implementation of over 250 information and training events started. Health centres and pharmacies appointed a person in charge of COPD patients. In order to improve the cooperation between primary and specialised care, two thirds of hospital districts created local COPD treatment chains. The early diagnosis of COPD by spirometric examination was activated during the programme. Number of health centres with available spirometric services increased to 95%. Before the start of the programme, approximately 5-9% of the adult population had COPD. During the whole programme, the proportion of male and female smokers decreased from 30% to 26% and from 20% to 19%, respectively. The total number of hospitalisation periods and days due to COPD decreased by 15% and 18%, respectively. Both the number of pensioners and daily sickness days due to COPD also decreased by 18%. Registered COPD induced deaths remained at their previous levels during the monitoring period, i.e. around 1000 deaths out of 5.2 millions annually. The measures recommended by the programme have been widely introduced but they need to be still more effective.

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BACKGROUND: We aimed to assess the prevalence of allergic sensitization and multiple sensitization, risk factors, and the clinical impact of being sensitized in the adult population of Helsinki, Finland. METHODS: As a part of the FinEsS study, a population-based random sample of 498 adults aged 26-60 years were tested for 15 common aeroallergens with skin prick tests (SPTs) and interviewed on respiratory symptoms and diseases, including respiratory irritants and childhood environment. RESULTS: The prevalence of at least one positive prick test was 46.9%. A large difference by age was found: 56.8% were sensitized among those aged 26-39 years, 49.2% in the age group 40-49 years, and 35.6% in the age group 50-60 years (P<0.001). Sensitization to multiple allergens was common among young subjects with 42% of the sensitized responding to at least four allergens, while this proportion was only 16% of the sensitized among those aged 50-60 years. The prevalence of physician-diagnosed asthma, allergic rhinitis (AR) or conjunctivitis, and wheeze increased significantly with increasing number of positive responses to SPTs. Having a family history of AR or conjunctivitis was a significant risk factor for allergic sensitization and for sensitization to any of the pollens. Further, urban living in childhood yielded an increased risk for pollen sensitization. CONCLUSIONS: The prevalence of allergic sensitization was high in the urban adult population of Helsinki. More than half of those aged 26-39 years was sensitized and 24% was sensitized to at least four allergens. Sensitization to multiple allergens was associated with a high prevalence of asthma, AR or conjunctivitis, and wheeze.

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This study was conducted to evaluate how bronchial responsiveness to direct and indirect stimuli relate to nitric oxide producing airway inflammation, and whether the relationship differs between atopic and nonatopic patients with various degrees of bronchial hyperresponsiveness and airway inflammation in a group of otherwise homogenous young men. We studied 181 consecutive non-smoking steroid-naive young male conscripts referred to military hospital because of respiratory symptoms suggesting asthma. Skin prick tests, spirometry, measurement of exhaled nitric oxide (FENO), and standardized airway challenges with histamine and exercise were performed. 128 patients were atopic. FENO was significantly higher in the atopic group, median 21.2 ppb, compared to 10.2 ppb in the nonatopic group. Still, 36% of all nonatopic patients had elevated FENO. Bronchial responsiveness to histamine (HIB) was similar in the two groups, but exercise-induced bronchoconstriction (EIB) was stronger in atopics (P < 0.01). FENO associated significantly with atopy (P < 0.001), severity of EIB (P < 0.001) and HIB (P = 0.006) in multiple linear regression model. In separate regression models for atopic and nonatopic patients FENO associated with severity of EIB and HIB in atopic patients only. The results were similar when patients with confirmed diagnosis of asthma were analyzed separately. Our results indicate that FENO significantly associates with EIB and HIB in atopic, but not in nonatopic steroid-naïve patients with asthmatic symptoms. The finding suggests that in such atopic patients degree of airway hyperresponsiveness may reflect severity of airway inflammation. However, in nonatopic patients with similar symptoms other mechanisms of airway hyperresponsiveness may be more important.

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A respiration-gated synchrotron radiation computed tomography (SRCT) technique, which allows visualization and direct quantification of inhaled stable xenon gas, was used to study the effect of tidal volume (Vt) on regional lung ventilation. High-resolution maps (pixel size 0.35 x 0.35 mm) of local washin time constants (tau) and regional specific ventilation were obtained in five anesthetized, paralyzed, and mechanically ventilated rabbits in upright body position at the fourth, sixth, and eighth dorsal vertebral levels with a Vt from 4.9 +/- 0.3 to 7.9 +/- 0.4 ml/kg (means +/- SE). Increasing Vt without an increase in minute ventilation resulted in a proportional increase of mean specific ventilation up to 65% in all studied lung levels and reduced the scattering of washin tau values. The tau values had log-normal distributions. The results indicate that an increase in Vt decreases nonuniformity of intraregional ventilatory gas exchange. The findings suggest that (SRCT) provides a new quantitative tool with high spatial discrimination ability for assessment of changes in peripheral pulmonary gas distribution during mechanical ventilation.

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BACKGROUND: Bronchial hyperresponsiveness (BHR) is characteristic of asthmatic airways, is induced by airway inflammation, and is reduced by inhaled corticosteroids (ICS). The time course for the onset and cessation of the effect of ICS on BHR is unclear. The effect of inhaled fluticasone propionate (FP) on BHR in patients with mild persistent asthma was assessed using time intervals of hours, days and weeks. METHODS: Twenty six asthmatic patients aged 21-59 years were selected for this randomised, double blind, parallel group study. The effect of 250 micro g inhaled FP (MDI) administered twice daily was compared with that of placebo on BHR assessed using a dosimetric histamine challenge method. The dose of histamine inducing a decrease in forced expiratory volume in 1 second (FEV(1)) by 15% (PD(15)FEV(1)) was measured before and 6, 12, 24 and 72 hours, and 2, 4 and 6 weeks after starting treatment, and 48 hours, 1 week and 2 weeks after cessation of treatment. Doubling doses of changes in PD(15)FEV(1) were calculated and area under the curve (AUC) statistics were used to summarise the information from individual response curves. RESULTS: The increase in PD(15)FEV(1) from baseline was greater in the FP group than in the placebo group; the difference achieved significance within 72 hours and remained significant until the end of treatment. In the FP group PD(15)FEV(1) was 1.85-2.07 doubling doses above baseline between 72 hours and 6 weeks after starting treatment. BHR increased significantly within 2 weeks after cessation of FP treatment. CONCLUSIONS: A sustained reduction in BHR to histamine in patients with mild asthma was achieved within 3 days of starting treatment with FP at a daily dose of 500 micro g. The effect tapered within 2 weeks of cessation of treatment.

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BACKGROUND: Exhaled nitric oxide (NOexp) is an indicator of eosinophilic airways inflammation. This study evaluated short-term variability of NOexp in 13 healthy subjects (19-41 years, eight males) and in 31 patients with asthmatic respiratory symptoms (19-21 years, all male) to obtain data for assessment of short-term changes of NOexp in clinical situations. METHODS: Mild asthma was confirmed in 10 patients (Group = asthma). Twenty-one patients with asthmatic respiratory symptoms did not fulfill the functional criteria of asthma (Group = respiratory symptoms). The procedure to determine NOexp followed the European Respiratory Society (ERS) guidelines; the mean expiratory flow used during sampling was 0.09-0.12 l/s. NOexp for each subject was determined as the mean of at least three successive measurements at the baseline, followed by determinations at 10 min, 6 h and 24 h after the baseline. RESULTS: At the baseline, the mean (SD) value of NOexp was 6.6 (2.3) parts per billion (ppb) in the healthy controls, and significantly higher both in patients with respiratory symptoms (14.6 (11) ppb, P = 0.0076) and in those with asthma (34.2 (43) ppb, P < 0.001). Intraclass correlation coefficient of NOexp measured at baseline and after an interval of 10 min was 0.959 in healthy subjects, 0.986 in patients with respiratory symptoms and 0.936 in asthma patients, respectively. Short-term variability in terms of coefficient of variation (CoV) of repeated measurements of NOexp at 10 min, 6 hand 24 h was 5.1, 10.8 and 11.7% in healthy subjects, 71, 16.4 and 22.2% in patients with respiratory symptoms and 13.5, 19.4 and 26.4% in asthma patients, respectively. CONCLUSIONS: Reproducibility of NOexp using standardized methods was good both in healthy subjects and in asthmatic patients. However, in asthmatics the short-term variation of NOexp was over two times as high as in healthy subjects. The level of NOexp was elevated, except in asthma, also in patients with asthmatic respiratory symptoms who did not fulfill the functional criteria of asthma.

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Variable extra thoracic obstruction has been found in spirometric studies in subjects with unilateral vocal fold paralysis. The aim of the study was to further evaluate airflow dynamics in these subjects with body plethysmography and tracheal sound analysis. Ten patients with unilateral vocal fold paralysis without a history of chronic pulmonary diseases and 10 healthy control subjects were studied. Flow-volume spirometry, body plethysmography and tracheal sound analysis were performed within 1 day. The study shows that peak inspiratory flow (PIF) and specific airway conductance (SG(aw)) expressed as percentage of Finnish reference values were significantly lower and airway resistance (R(aw)) was higher among the patients than among the controls (P=0.004, P=0.026 and P=0.004, respectively). The patients had higher sound amplitude of both inspiratory and expiratory tracheal sounds than the controls [root mean square (RMS) values of the power spectra were 31.5 and 25 dB, P=0.006 in inspiration and 31.5 and 26 dB, P=0.013 in expiration, respectively]. Quartile frequencies (F25 and F50) and RMS of expiratory tracheal sounds had significant negative correlation with PIF (P=0.02, P<0.001, P=0.02, respectively) and forced inspiratory volume in 1 s (FIV(1)) (P=0.01, P<0.001, P=0.01, respectively). There was also an association between F50 and peak expiratory flow (PEF) (P=0.02). According to the present study, both quiet breathing and forced inspiration are disturbed in subjects with unilateral vocal fold paralysis. A close relationship between tracheal sounds and respiratory function tests exists.

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The aim of this study was to investigate the changes in tracheal sounds and airflow dynamics in patients who underwent surgical medialization of a unilaterally paralysed vocal fold. Ten adults with unilateral vocal fold paralysis but no history of pulmonary diseases were included. Vocal fold medialization was performed by an injection of autologous fascia into the paralysed vocal fold. Recording of tracheal sounds, flow-volume spirometry and body plethysmography were carried out before and 4-14 months after the operation. The mean number of inspiratory wheezes per respiratory cycle increased from 0.02 (range 0-0.10) to 0.42 (range 0-0.86) and the mean number of expiratory wheezes per respiratory cycle from 0.03 (range 0-0.20) to 0.36 (range 0-0.89). The increment was statistically significant (P=0.03 and P=0.04, respectively). The mean expiratory sound amplitude, in terms of root mean square (RMS), increased from 31.5 dB (range 24.0-38.0) to 34.9 dB (range 25-42) (P=0.03) and the average peak inspiratory flow (PIF) decreased from 4.63 l s-1 (range 2.84-7.51) to 4.03 l s-1 (range 2.27-6.68) (P=0.01). The results indicate that when the paralysed vocal fold is brought into midline by a surgical procedure, the prevalence of inspiratory and expiratory wheezes increases and sound intensity rises. According to this preliminary data tracheal sound analysis gives additional information for the assessment of the subtle changes in the larynx.

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OBJECTIVE: Color flow duplex scanning is currently the best method available for vein graft surveillance. However, it puts a considerable strain on the workload of a vascular unit and requires a highly trained operator. The aim of this study was to develop and validate a new, noninvasive tool for graft surveillance. The utility of transfer function index (TFI) of pulse volume recordings is tested for this purpose. METHODS: The design of the study was a blind comparative study that involved 70 testing procedures that were performed on 58 different infrainguinal vein bypass grafts. The TFI was measured with a portable vascular laboratory multi-cuff unit. Ankle/brachial indexes were obtained with the same device. Color flow duplex scanning was used as a diagnostic standard. A graft was defined as at risk, according to duplex scanning, if a local stenosis with a V2/V1 more than 2 was found or if peak systolic velocity remained less than 45 cm/s throughout the graft. The repeatability of the method was tested on 30 grafts. RESULTS: A total of 63 tests were available for analysis. Seven tests were excluded. Four were excluded because they had unreliable TFI measurement due to cardiac arrhythmias, and in three tests, the whole graft could not be visualized in the duplex scan. Forty normal and 22 at-risk grafts were found. One graft was occluded. The TFI was significantly lower for at-risk grafts (0.89) versus normal grafts (1.09; P =.005). A TFI of 1.02 or less correctly detected 21 of 22 at-risk grafts. The sensitivity, specificity, and accuracy were 96%, 65%, and 76%, respectively. The ability of the ankle/brachial index to detect the at-risk grafts was clearly inferior to the TFI. The repeatability of the method at proximal thigh, distal thigh, and proximal calf was +/- 0.21, +/- 0.07, and +/- 0.14, respectively. CONCLUSION: The TFI is a sensitive and reliable method to detect an at-risk graft. The examination is noninvasive, simple, quick to perform, and well tolerated by the patients. We suggest that the TFI could be the first-line screening method in vein graft surveillance.

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BACKGROUND: According to previous studies, the prevalence of asthma has been lower in Finland than in other Nordic countries. In the present study, we assessed the prevalence of asthma and respiratory symptoms in northern Finland and calculated risk factors for these conditions. METHODS: In November 1995, 7937 randomly selected subjects, 20-69 years of age, in northern Finland were invited to participate in a postal questionnaire survey. Complete answers were received from 6633 subjects (83.6%). RESULTS: Asthma diagnosed by a physician was reported by 6.0%, while 6.3% were using asthma medicines. Asthma was most common in young adults and the elderly. The prevalence of wheezing during the previous 12 months was reported by 19.7%, while wheezing with shortness of breath apart form colds during the previous 12 months was reported by 7.1%. Only small differences between the sexes were found in prevalence of asthma and respiratory symptoms. All symptoms were strongly smoking-dependent. Sixty-three percent of men and 42% of women were current or ex-smokers. Family history of obstructive airway disease was the strongest risk factor for asthma (OR 2.9), while increasing age, smoking, and family history of obstructive airway disease were the most important risk factors for frequent wheeze. CONCLUSIONS: The results indicate that the prevalence of asthma and symptoms associated with asthma in adults in northern Finland is now similar to that observed in Sweden and the other Nordic countries.

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Small airways play a key role in the distribution of ventilation and in the matching of ventilation to perfusion. The purpose of this study was to introduce an imaging method that allows measurement of regional lung ventilation and evaluation of the function of airways with a small diameter. The experiments were performed at the Medical Beamline of the European Synchrotron Radiation Facility. Monochromatic synchrotron radiation beams were used to obtain quantitative respiration-gated images of lungs and airways in two anaesthetized and mechanically ventilated rabbits using inhaled stable xenon (Xe) gas as a contrast agent. Two simultaneous images were acquired at two different energies, above and below the K-edge of Xe. Logarithmic subtraction of the two images yields absolute Xe concentrations. This technique is known as K-edge subtraction (KES) radiography. Two-dimensional planar and CT images were obtained showing spatial distribution of Xe concentrations within the airspaces, as well as the dynamics of filling with Xe. Bronchi down to 1 mm in diameter were visible both in the subtraction radiographs and in tomographic images. Absolute concentrations of Xe gas were calculated within the tube carrying the inhaled gas mixture, small and large bronchi, and lung tissue. Local time constants of ventilation with Xe were obtained by following the evolution of gas concentration in sequential computed tomography images. The results of this first animal study indicate that KES imaging of lungs with Xe gas as a contrast agent has great potential in studies of the distribution of ventilation within the lungs and of airway function, including airways with a small diameter.

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BACKGROUND AND AIM: In epidemiological questionnaire studies results can be influenced by non-responder bias. However, in respiratory epidemiology this has been analysed in very few recently published papers. The aim of our paper is to assess if the results found in our previous postal questionnaire study in an adult population in Northern Finland were biased by non-response. METHODS: A random sample of 385 persons from the 1,284 non-responders in a previous postal questionnaire study was examined. The same questionnaire as in the original study was again mailed to these persons, and those still not answering were contacted by phone. RESULTS: Totally 183 complete answers (48%) were collected. Lack of interest (56%) and forgetting to mail the response letter (22%) were the most common reasons to non-response. Typical non-responders were young men and current smokers who less frequently reported respiratory symptoms in exercise and asthma than the responders in the original study. Answers collected by phone gave for some questions higher prevalence rates than postal answers. CONCLUSION: Firstly, in this population the response rate (83.6%) in the original study was high enough to provide reliable results for respiratory symptoms and diseases, only the prevalence of current smoking was biased by non-response. Secondly, the methods used for collecting responses in a non-response study may influence the results.

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Exhaled nitric oxide (NOexp) is an indicator of inflammation in the airways. Reference values obtained from healthy adults or information on long-term variation of NOexp are not yet available. The aims of this pilot study were to collect values of NOexp from a selected group of healthy adults and to assess their long-term variation. We studied 26 healthy subjects (age 21-48, 16 male, 10 female) with normal findings in flow-volume spirometry, pulmonary diffusing capacity, relative amount of blood eosinophils, chest X-ray and ECG at rest. NOexp was determined according to the European Respiratory Society guidelines during slow expiration against an airflow resistance. The measurements were repeated after 7 (n = 13) and 23 days (n = 17). The mean value of NOexp (n = 26) was 6.9 ng g-1 (95% confidence interval, 6.0-7.9 ng g-1). The upper limit of intra-individual variation (+2 SD) was 11.9 ng g-1 and the lower limit (-2 SD) 1.9 ng g-1, respectively. The mean (SD) value of NO production (NO output) was 39.1 pmol s-1 (20 pmol s-1). We found no correlation between NOexp and age (r = -0.06, P = 0.78) and no association of NOexp with the gender (male vs. female, P = 0.40). The intraindividual coefficient of variation (CoV) was 15.8% of NOexp and 20.7% of NO output within the interval of 7 days. CoV was 16.8% of NOexp and 18% of NO output within the interval 23 days. The results suggest that NOexp values over 12 ng g-1 are abnormally high in healthy subjects. According to the results the change of NOexp by 30-35% or more within the interval of 1-3 weeks would be abnormal.

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