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A Phase IV, 4-week, open, randomized multicenter parallel group trial compared correct use and acceptability of Diskus, Turbuhaler, and Easyhaler powder inhalers among 326 inhaler naive asthmatics/symptomatics. The subjects were asked to read the instruction leaflet before taking one dose at the first visit. The correct use was evaluated when the subject took the dose. After that, the subjects were instructed in correct use. The use of the devices was also videotaped at every visit, and independent referees judged correct use. Acceptability was evaluated by a questionnaire. At the first visit, the proportions of subjects who used the devices correctly were as follows: Easyhaler, 45%; Diskus, 43%; and Turbuhaler, 51%. The corresponding figures at the last visit were 84%, 89%, and 81%. The differences at any visit were not statistically significant. Acceptability was greater for Easyhaler and Diskus for three of eight items throughout the study, all pertaining to receiving the powder from the device and control of the inhalation of the powder. Patient education in the use of devices is important, because only half of the subjects used the devices correctly, and still after 4 weeks 10-20% could not use the devices satisfactorily, regardless of which device.

Previous studies have shown both similar and distinct inflammatory changes in atopic and nonatopic asthma. This study was set to investigate the bronchial inflammatory cell infiltrate and subepithelial basement membrane (BM) tenascin deposition in subjects with newly diagnosed asthma and bronchial hyperresponsiveness (BHR). Seventy-nine asthmatic subjects (age 18–60 years) were recruited and 58 were atopic according to skin prick testing. The patients recorded asthma symptoms and peak flow measurements for 14 days. Lung function and BHR were measured by spirometry and histamine challenge. Serum eosinophil cationic protein (ECP) and blood eosinophils were assessed. Fiberoptic bronchoscopy was performed to obtain bronchial biopsies. Serum ECP was higher in the atopic group but eosinophil counts did not differ. There were no differences in inflammatory cells studied (activated eosinophils, T-lymphocytes, mast cells or macrophages) between nonatopic and atopic subjects. BM tenascin layer was significantly thicker in atopic compared with nonatopic subjects (7.6 vs 6.3μm, P=0.007). The thickness of tenascin correlated with eosinophil, T-lymphocyte, and macrophage counts, as well as with IL-4-positive cell counts and the correlation was seen only in atopic asthmatics. These findings suggest that inflammatory cells may have a regulatory role in tenascin expression in atopic asthma.

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 μg 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 μg. The effect tapered within 2 weeks of cessation of treatment.

The present study was performed to measure the vasoregulatory reactions to dynamic changes in local skin temperature during open bed phototherapy. Periodic thermal stimulation using warm and cool air currents was applied to the skin of ten term infants with physiological jaundice, before and during open bed phototherapy. The reactivity of skin blood flow (SBF) and heart rate was measured using laser Doppler flowmetry and power spectral analysis. The baseline SBF increased significantly by 70% (P = 0.008) during phototherapy without any significant change in skin or rectal temperature. Before phototherapy, the rhythmic (0.08 Hz) thermal skin stimulation increased the oscillations of SBF (from 89 ± 26 au to 213 ± 37 au, P = 0.02) at the stimulation frequency band. This response was further increased (P = 0.03) during phototherapy (from 198 ± 54 au to 658 ± 115 au, P = 0.004). Phototherapy increased SBF in icteric otherwise healthy neonates. The cutaneous vasodilatation augments the cardiovascular responsiveness to thermal stimulation. Conclusions These results suggest that open bed phototherapy does not inhibit the cardiovascular responsiveness to local thermal skin stimulation in healthy term infants.

The relationship between oesophageal pressure variation and amplitude variation in the static-charge-sensitive bed (SCSB) ballistocardiogram suggests that changes in intrathoracic pressure can be detected using the SCSB method. We investigated whether amplitude variation in the static-charge-sensitive bed ballistocardiogram (SAV) is related to severity of airway obstruction in patients with asthma and chronic obstructive pulmonary disease. The ability of SAV to detect an increase in airway obstruction induced by histamine challenge was also tested. Twenty-six patients suffering from asthma and 12 patients with chronic obstructive pulmonary disease (COPD) were enrolled in the study. SAV, amplitude from the SCSB ballistocardiogram, respiratory amplitude from the SCSB respiratory wave form and heart rate from the electrocardiogram (ECG) were computed using analysing software (Biorec, Helsinki, Finland) during a 7-min supine rest. SAV was related to forced expiratory volume in one second (FEV1) immediately after signal recording. Asthma patients participated in a standardized histamine challenge test to reveal the effect of acute bronchoconstriction on SAV. An inverse relationship existed between baseline FEV1 and SAV in asthma and COPD. In the histamine inhalation test, FEV1 fell by 0.7 +/- 0.3 l or 26% +/- 11% (P < 0.0001) and SAV increased by 12% +/- 5% (P < 0.0001) in 12 asthma patients. The fall in FEV1 induced by histamine followed regularly and correlated significantly with the rise in SAV (n = 24, r = -0.58, P = 0.002). Changes in respiratory amplitude or heart rate did not explain changes in SAV. SAV may not separate the upper airway obstruction from the bronchial obstruction but it is related to severity of airway obstruction. The clinically significant increase in airway obstruction induced by histamine inhalation increases amplitude variation in SCSB.

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.

Objectives: Chronic obstructive pulmonary disease (COPD) is globally a major, but often undiagnosed, cause of morbidity and mortality. The aims of this study were to assess the prevalence of COPD in Helsinki, Finland, with international diagnostic criteria and to analyse risk factors including socioeconomic status, and disease severity. Methods: A general population sample of 628 adults (368 women) completed flow-volume spirometry with bronchodilation test and a structured interview. Post-bronchodilation spirometry was assessed both using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria and relative to the fifth percentile of the reference value (lower limit of normal, LLN). Results: According to GOLD criteria, 37 (5.9%), and by using the LLN criteria, 43 subjects (6.8%) had airway obstruction consistent with COPD. Using the GOLD criteria, four subjects or 0.6% of the population had severe, 3.0% moderate, and 2.2% mild COPD. Of those with post-bronchodilator obstruction, 49% had no previous diagnosis of obstructive airways disease and did not use medication for any respiratory disease. The prevalence of undiagnosed COPD defined by GOLD was 2.9% (LLN 3.3%). In addition to age, smoking history, and prior history of asthma, socioeconomic status based on occupation was significantly related to COPD in the population. Manual workers in industry (GOLD 10.0%, LLN 11.7%) and non-manual assistant employees (10.2%, 10.2%) had a significantly higher prevalence of COPD than professionals (2.8%, 2.3%). Conclusions: Although smoking is the main modifiable risk factor for COPD, the disease was significantly related to manual workers and non-manual assistant employees, i.e. socioeconomic groups reflecting occupation.

Background: Chronic obstructive pulmonary disease (COPD) is associated with increased mortality and poor health-related quality of life (HRQoL) compared with the general population. The objective of this study was to identify clinical characteristics which predict mortality and very poor HRQoL among the COPD population and to develop a Bayesian prediction model. Methods: The data consisted of 738 patients with COPD who had visited the Pulmonary Clinic of the Helsinki and Turku University Hospitals during 1995-2006. The data set contained 49 potential predictor variables and two outcome variables: survival (dead/alive) and HRQoL measured with a 15D instrument (very poor HRQoL = 0.70). In the first phase of model validation we randomly divided the material into a training set (n = 538), and a test set (n = 200). This procedure was repeated ten times in random fashion to obtain independently created training sets and corresponding test sets. Modeling was performed by using the training set, and each model was tested by using the corresponding test set, repeated in each training set. In the second phase the final model was created by using the total material and eighteen most predictive variables. The performance of six logistic regressions approaches were shown for comparison purposes. Results: In the final model, the following variables were associated with mortality or very poor HRQoL: age at onset, cerebrovascular disease, diabetes, alcohol abuse, cancer, psychiatric disease, body mass index, Forced Expiratory Volume (FEV1) % of predicted, atrial fibrillation, and prolonged QT time in ECG. The prediction accuracy of the model was 77%, sensitivity 0.30, specificity 0.95, positive predictive value 0.68, negative predictive value 0.78, and area under the ROC curve 0.69. While the sensitivity of the model reminded limited, good specificity, moderate accuracy, comparable or better performance in classification and better performance in variable selection and data usage in comparison to the logistic regression approaches, and positive and negative predictive values indicate that the model has potential in predicting mortality and very poor HRQoL in COPD patients. Conclusion: We developed a Bayesian prediction model which is potentially useful in predicting mortality and very poor HRQoL in patients with COPD.

Effect of continuous ( n = 30) and periodic ( n = 5) breathing on forehead skin blood flow (SBF) oscillations was studied in healthy 3-day-old preterm and term infants. Femoral SBF was measured in 10 of the term infants during continuous breathing. Respiratory and SBF signals were analysed by power spectrum during the control period. The signal analysis was repeated during rhythmic thermal stimulation which was applied to the skin of each infant in order to synchronise spontaneous SBF oscillations. During the control period, the forehead and femoral SBF of all the studied infants oscillated at frequencies corresponding to the frequency of regular continuous breathing. External thermal stimulation decreased these high-frequency oscillations of forehead SBF in both preterm and term infants. Oscillations in femoral SBF of term infants remained unchanged. During periodic breathing, the spontaneous forehead SBF oscillation was synchronised to the frequency of respiratory amplitude variation. Despite periodic breathing, thermal stimulation was able to resynchronise the SBF oscillation to the stimulation frequency in 4 5 infants. Forehead SBF oscillates at the frequency of both continuous and periodic breathing in preterm as well as in term infants on postnatal day 3. Rhythmic thermal stimulation synchronises SBF and affects SBF more effectively than continuous or periodic breathing. These results suggest functional neural control of cutaneous vasculature at birth.

Milla Katajisto,1 Henna Kupiainen,1 Piritta Rantanen,1 Ari Lindqvist,1 Maritta Kilpeläinen,2 Heikki Tikkanen,3 Tarja Laitinen21Clinical Research Unit for Pulmonary Diseases and Division of Pulmonology, Helsinki University Central Hospital, Helsinki, Finland; 2Department of Pulmonary Diseases and Clinical Allergology, Turku University Hospital and University of Turku, Turku, Finland; 3Department of Sports and Exercise Medicine, Institute of Clinical Medicine, Helsinki University and Foundation of Sports and Exercise Medicine, Helsinki, FinlandObjective: To study patients’ levels of exercise activity and the clinical characteristics that relate to physical activity and inactivity among patients with chronic obstructive pulmonary disease (COPD).Methods: A postal questionnaire was administered to 719 patients with COPD in 2010; patients were recruited from the Helsinki and Turku University Central Hospitals in Finland and have been followed since 2005. The questionnaire asked participants about their exercise routines and other daily activities, potential restrictions to exercise, health-related quality of life, and subjective sensations of dyspnea upon exertion.Results: A total of 50% of the participants reported exercising > 2 times a week throughout the year. The proportion of the exercise inactive patients increased in parallel with disease progression, but the participants exhibited great variation in the degree of activity as well as in sport choices. Year-round activity was better maintained among patients who exercised both indoors and outdoors. Training activity was significantly correlated with patients’ reported subjective dyspnea (r = 0.32, P < 0.001), health-related quality of life (r = 0.25, P < 0.001), mobility score (r = 0.37, P < 0.001), and bronchial obstruction (r = 0.18, P < 0.001). Active patients did not differ from inactive patients in terms of sex, age, smoking status, somatic comorbidities, or body mass index. Irrespective of the level of severity of patients’ COPD, the most significant barrier to exercising was the subjective sensation of dyspnea.Conclusion: When a patient with COPD suffers from dyspnea and does not have regular exercise routines, the patient will most likely benefit from an exercise program tailored to his or her physical capabilities.Keywords: COPD, physical fitness, exercise training, physical activity, pulmonary rehabilitation

Smoking cessation is the cornerstone of COPD management, but difficult to achieve in clinical practice. The effect of comorbidities on smoking cessation and risk factors for mortality were studied in a cohort of 739 COPD patients recruited in two Finnish University Hospitals. The diagnosis of COPD was done for the first time on average 5.5 years prior to the enrollment. Data from the medical records and followup questionnaires (years 0, 1, 2, and 4) have been analyzed. The patients’ lung function varied greatly; mean FEV158% of predicted. A total of 60.2% of men and 55.6% of women had been able to quit smoking. Alcohol abuse (OR 2.1, 95% CI 1.4–3.3) and psychiatric conditions (OR 1.8, 95% CI 1.2–2.7) were strongly related to low success rates of quitting. Among current smokers high nicotine dependency was again explained by alcohol abuse and psychiatric conditions. Non-quitters were younger than quitters, but their mortality rates remained significantly higher even when the model was adjusted for impairment of lung functions and comorbidities. In conclusion, co-existing addiction and psychiatric diseases significantly decreased the success rates in smoking cessation and increased mortality among the patients.

Background There is a pressing need for new forms of treatment for COPD. Based on the known pathophysiology of COPD, inhibition of matrix metalloproteinases is a theoretically promising approach. This Phase IIa study evaluated the effects of AZD1236, a selective MMP-9 and MMP-12 inhibitor, on the biomarkers of inflammation and emphysematous lung tissue degradation in patients with moderate-to-severe COPD. Methods This was a multinational, randomized, double-blind, placebo-controlled signal-searching study conducted in men and women aged ≥40 years with stable moderate-to-severe COPD. After a 2–6-week period to eliminate any remaining effects of previous medication, 55 patients received oral AZD1236 75 mg or matching placebo twice daily for 6 weeks. Differential cell count and TNF-α levels in induced sputum and 24-h urinary desmosine excretion were the main study variables, but a range of exploratory biomarkers was also assessed in induced sputum, blood and urine. Secondary variables included lung function and patient-recorded Clinical COPD Questionnaire (CCQ) responses and diary records of symptoms, adverse events, use of rescue medication and AZD1236 plasma concentrations. Results The majority of variables showed little change compared to placebo although there was a possible, but not statistically significant reduction in urinary desmosine excretion and reductions in the number and percentage of lymphocytes in sputum and blood with AZD1236. No effect was seen on clinical parameters after 6 weeks of treatment. The proportion of patients experiencing adverse events was similar in both treatment groups. Conclusions AZD1236 dosed orally at 75 mg twice daily was generally well tolerated over 6 weeks in patients with moderate-to-severe COPD. No clinical efficacy of AZD1236 was demonstrated in this short-term signal-searching study, although possible evidence of an impact on desmosine may suggest the potential value of selective inhibitors of MMPs in the treatment of COPD in longer term trials.

Twenty-four pilots (age 20-32 years) were monitored with a Holter monitor during 26 hours including a high-Gz flight in order to evaluate heart rate (HR) and cardiac rhythm. Flight experience did not predict the mean in-flight HR (range 69-121 beats/minute), which decreased with increasing age and correlated to the maximum HR during sleep. We recorded maximally 27 ventricular and 97 supraventricular ectopic beats, 10 junctional rhythms, 5 gray-out, 1 vestibular symptom, and 1 instance of numbness of the feet during the flight. No causal relationship between HR, cardiac arrhythmia, or symptoms was found. Adaptation to in-flight +Gz stress takes place without significant arrhythmia and at a submaximal age-related HR.

The tolerability of 57 non-smoking asthma patients inhaling salbutamol as needed (ATS, 18--60 years, 60% < or = FEV1 < or =100%, PD15FEV1

Background Given that the assessment of health-related quality of life (HRQoL) is an essential outcome measure to optimize chronic obstructive pulmonary disease (COPD) patient management, there is a need for a short and fast, reliable and valid instrument for routine use in clinical practice. The objective of this study was to analyse the relationship between the disease-specific Airways questionnaire (AQ20) and the generic 15D health-related quality of life (HRQoL) instrument simultaneously in a large cohort of patients with COPD. We also compare the HRQoL of COPD patients with that of the general population. Methods The AQ20 and 15D were administered to 739 COPD patients representing an unselected hospital-based COPD population. The completion rates and validity of, and correlations among the questions and dimension scores were examined. A factor analysis with varimax rotation was performed in order to find subsets of highly correlating items of the questionnaires. Results The summary scores of AQ20 and 15D were highly correlated (r = - 0.71, p < 0.01). In AQ20 over 50% of patients reported frequent cough, breathlessness during domestic work, and chest problem limiting their full enjoyment of life. 15D results showed a noteworthy decrease of HRQoL in breathing, mobility, sleeping, usual activities, discomfort and symptoms, vitality, and sexual activity (scores ≤ 0.75). Compared to the age- and gender-standardized Finnish general population, the COPD patients were statistically significantly worse off on 13 of 15 dimensions. Conclusions The AQ20 and 15D summary scores are comparable in terms of measuring HRQoL in COPD patients. The data support the validity of 15D to measure the quality of life in COPD. COPD compromises the HRQoL broadly, as reflected by the generic instrument. Both questionnaires are simple and short, and could easily be used in clinical practice with high completion rates.

This study aims to compare diagnostic and clinical outcomes of Chronic Obstructive Pulmonary Disease (COPD) from the gender perspective using retrospective health care data and patient reported outcomes in a real-world setting. An electronic database was constructed from complete medical records of 844 COPD patients who were recruited in Helsinki and Turku University Central Hospitals during the years 2005-07. The patients were identified from the hospital discharge registries by ICD10 code J44.8 in the age group of 18-75 years of age. The medical history was obtained from all healthcare providers who had treated these patients during the previous 5-10 years; the study intends to continue their follow-up annually for the next 10 years. Thirty-six percent (N = 266) of the participants were women. The COPD diagnosis had been made at the same age for both genders. Women, however, reported significantly less pack-years than men. Compared to the men, the women displayed less advanced airway obstruction, but more severe gas transfer impairment. Parenchymal damage when evaluated by diffusion capacity correlated significantly stronger with FEV(1) (% of predicted) in women than men. The BMI index of the women was lower than that of the men. Cardiovascular diseases, diabetes and alcoholism were significantly more common in men, but women suffered more psychiatric conditions, especially depression. This cohort showed several significant gender dependent differences in the clinical presentation that need to taken under consideration in the assessment of COPD progression and the disease management.

Background The assessment of bronchodilator-induced change in forced vital capacity (FVC) is dependent on forced expiratory time (FET) in subjects with airflow limitation. Limited information is available on the concurrent responses of FVC, forced expiratory volume in six seconds (FEV6), and FET in the bronchodilation test among patients with obstructive airways disease or in the general population. The aim of this study was to assess the changes in FEV6, FVC, and FET, and their relationships in a standardized bronchodilation test in the general population. Methods We studied bronchodilation response in a general adult population sample of 628 individuals (260 men, 368 women) with flow-volume spirometry. The largest FVC, the corresponding FET and the largest FEV6 both at the baseline and after 0.4 mg of inhaled salbutamol were selected for analysis. Results After administration of salbutamol FEV6 decreased on average -13.4 (95% CI -22.3 to -4.5) ml or -0.2% (-0.4% to 0.0%) from the baseline. The 95th percentile of change in FEV6 was 169.1 ml and 5.0%. FVC decreased on average -42.8 (-52.4 to -33.3) ml or -1.0% (-1.2% to -0.7%). Concurrently FET changed on average -0.2 (-0.4 to 0.0) seconds or 0.4% (-1.4% to 2.3%). There were four subjects with an increase of FVC over 12% and only one of these was associated with prolonged FET after salbutamol. Changes in FEV6 and FVC were more frequently positive in subjects with reduced FEV1/FVC in baseline spirometry. Conclusion In general adult population, both FEV6 and FVC tended to decrease, but FET remained almost unchanged, in the bronchodilation test. However, those subjects with signs of airflow limitation at the baseline showed frequently some increase of FEV6 and FVC in the bronchodilation test without change in FET. We suggest that FEV6 could be used in assessment of bronchodilation response in lieu of FVC removing the need for regulation of FET during bronchodilation testing.

Study objective — The study assessed the physiological validity of an automatic thermal stimulation method to induce synchronised oscillations in the neural cardiovascular control system. Design — Automatic alternating rhythmic warm and cool immersion of different skin areas of 18 males was done at different frequencies and water temperatures. The neurally mediated responses to the periodic thermal stimulation were measured from skin blood flow and heart rate and compared to those of a sham stimulation. Respiration was monitored for control purposes. The reproducibility of the stimulation and responses was examined. Subjects — 18 young males volunteered for the study. Measurements and main results — The water bath method produced reproducible thermal stimulation and responses of skin blood flow and heart rate. Rhythmic thermal stimulation at 0.013-0.096 Hz synchronised the oscillations of the forearm skin blood flow when the thermal stimulus amplitude exceeded 10°C. The increase in the stimulus amplitude or enlargement of the stimulus area did not further increase the oscillatory response of skin blood flow. Sham stimulation or mean temperature of the periodic thermal stimulation in the range 23-33°C did not influence the oscillations of skin blood flow. Local cooling of the stimulated lower legs attenuated the response of skin blood flow. Both thermal stimulation and sham stimulation affected heart rate, but no stable synchronisation of the periodic heart rate variability was found at supine rest. Thermal stimulation of the sitting subjects' forearm instead of legs increased the synchronisation of the periodic heart rate variability. Conclusions — The response of skin blood flow agreed with the theory of the thermal entrainment. In a supine man, both thermal stimulation and non-specific central nervous influences induced significant and reproducible interactions with periodic heart rate variability and respiration.

Summary Background: The recent American Thoracic Society/European Respiratory Society spirometry guidelines harmonized quality criteria and included assessment of forced expiratory time (FET) in bronchodilation testing when an isolated significant forced vital capacity (FVC) bronchodilation effect is observed. No consensus exists on the criteria of accepted variability of FET. Forced expiratory volume in 6 s (FEV6) has been suggested to replace FVC, especially in primary care. We examined the variability of FET and FEV6 and its determinants in the general population. Methods: We studied the results of acceptable flow-volume measurements from a general population sample of 603 subjects aged 25–74 years. Intra-class correlation coefficients (ICC), coefficients of variation (CoV), absolute and relative differences of FET, forced expiratory volume in 1 s (FEV1), FEV6 and FVC from the three acceptable curves were calculated. Results: FET had a mean CoV of 11·3% and ICC of 0·873. The average CoV and ICC for FEV1, FVC and FEV6 were 1·4% and 0·996, respectively. The 95th percentile of FET difference was 2·7 s. Older age was associated with slightly higher variability. Reproducibility of FET (CoV 10·6%) was better, that of both FEV6 (1·5%) and FVC (1·7%) slightly worse, in subjects with airflow limitation (FEV1/FVC

Forced expiratory time (FET) has gained new interest in the joint recommendation of the American Thoracic Society (ATS) and the European Respiratory Society (ERS) for the assessment of spirometry. Interpretation of FET is, however, difficult as limited information is available on spirometric and anthropometric determinants of FET in populations.We studied a non-selected population sample including healthy non-smokers with a structured interview and flow-volume spirometry. Regular medication, if any, was continued. Spirometry of 603 individuals (248 men, 355 women) fulfilled predefined quality criteria based on modified ATS recommendations. FET from the flow-volume curve with the largest sum of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) was used in analyses.The mean FET in the population sample was 10.7 (95% CI 10.4-11.1) s and in healthy non-smokers 9.8 (9.2-10.4) s. Men had on average longer FET (11.3 s versus 10.3 s), but the gender difference was not significant when FEV1/FVC was used as a covariate. FEV1/FVC (r = -0.613, P0.01) and maximal mid-expiratory flow (MMEF) correlated negatively and age (r = 0.279, P0.01), body mass index (BMI) and smoking pack-years positively with FET.The findings indicate that mean FET is around 11 s in a non-selected adult population and around 10 s in healthy non-smokers. FET increases slightly with age and BMI, suggesting age- and weight-related changes in pulmonary mechanics. The negative correlation of FET with FEV1/FVC and MMEF even in healthy non-smokers indicates that airflow limitation, either pathological or physiological, tends to prolong FET.

Study objective – The aim of the study was to investigate the effect of posture on thermally stimulated cardiovascular oscillations. Design – The effect of increased gravitational stress (rising from sitting to standing position) on the thermally stimulated cardiovascular oscillations was measured in young male volunteers. Extensive cardiovascular function data were obtained using a cardiovascular investigation protocol. Subjects – The volunteers were five fit young men, aged 20-21 years. Experiments and main results – Cardiovascular changes from sitting to standing indicated increased sympathetic and decreased parasympathetic influence on heart and skin blood vessels; mean heart rate increased, beat to beat heart rate variability diminished, high frequency periodic heart rate variability decreased, low frequency heart rate oscillations and ratio of low frequency to high frequency heart rate variability increased, mean skin blood flow and oscillations of skin blood flow decreased (all p

Background We have shown that inhalation of leukotriene (LT) E 4 contributes to specific recruitment of eosinophils to the airway mucosa in patients with asthma at the time of maximal decrease in airway-specific conductance. Objective We examined the ability of the cysteinyl LT 1 receptor antagonist, zafirlukast, to improve or prevent LT-mediated eosinophilia and airway obstruction in asthma. Methods Bronchial biopsies were taken and pulmonary function was measured before and 4 to 6 hours after the dose of inhaled LTE 4 causing a ≥15% fall in FEV 1 at baseline both at week 0 and after 6-week randomly assigned treatment with a high dose of zafirlukast, 80 mg twice daily. Results Leukotriene E 4 inhalation at week 0 doubled the number of eosinophils in the airway mucosa in 21 of 25 patients with mild asthma, increased the numbers of neutrophils and lymphocytes, and decreased FEV 1 (−17%). Zafirlukast reduced both airway eosinophilia and obstruction in FEV 1 , whereas with a double-blind placebo treatment, the effect of LTE 4 on both parameters persisted for 6 weeks. On repeat LTE 4 inhalation challenge after 6 weeks, zafirlukast treatment prevented further airway eosinophilia and decrease in FEV 1 seen in the placebo group. Conclusion Persistent LTE 4 -induced airway eosinophilia may form the basis of an amplification mechanism for further eosinophil recruitment. Zafirlukast prevents LTE 4 -induced eosinophilic airway inflammation in mild asthma.

Salmeterol (SLM) is a long-acting beta(2)-receptor agonist that produces bronchodilatation for 12 hours in asthmatic subjects. The effects of the regular use of long-acting beta(2)-agonists on airway inflammation are largely unknown.We examined the effects of 16 weeks of treatment with 50 microg SLM bid, 250 microg fluticasone propionate (FP) bid,5 mg disodium cromoglycate (DSCG) qid, or placebo on airway inflammation in bronchial mucosa.Airway inflammation was assessed in bronchial biopsy specimens before and after treatments and bronchial hyperresponsiveness (BHR) in 80 patients with newly diagnosed asthma. Inflammatory cells and tenascin in the basement membrane were studied with immunohistochemical methods. Peak expiratory flow rate (PEF), symptoms, and need for rescue medication were recorded.SLM, FP, and DSCG reduced symptoms and need for rescue medication (P.04). Both SLM and FP improved PEF and increased PD15FEV(1) to histamine by 2.8 and 5.2 doubling dose units, respectively. Both compounds reduced BHR more than placebo (P.05). Both SLM and placebo had no effect on any inflammatory cell type. In both FP-treated and DSCG-treated patients, the number of EG2-positive eosinophils in the airway mucosa decreased (P =.002 and P.05, respectively).SLM showed no anti-eosinophil properties in this study, but it provided good symptom control. FP provided the best anti-eosinophil properties and symptom relief of the studied compounds.

Background To examine risk factors for asthma patients’ emergency room (ER) visits in a well organized asthma care setting. Methods A random sample of 344 asthma patients from a Pulmonary Clinic of a University Hospital were followed through medical records from 1995 to 2006. All the ER visits due to dyspnea, respiratory infections, chest pain, and discomfort were evaluated. Results The mean age of the study population was 56 years (SD 13 years), 72% being women. 117 (34%) of the patients had had at least one ER visit during the follow-up (mean 0.5 emergency visits per patient year, range 0–7). Asthma exacerbation, lower and upper respiratory infections accounted for the 71% of the ER visits and 77% of the hospitalizations. The patients with ER visits were older, had suffered longer from asthma and more frequently from chronic sinusitis, were more often ex- or current smokers, and had lower lung function parameters compared to the patients without emergency visits. Previous (HR 1.9, CI 1.3-3.1) and current smoking (HR 3.6, CI 1.6-8.2), poor self-reported health related quality of life (HRQoL) (HR 2.5, CI 1.5-4), and poor lung function (FEV1

The aim of the present study was to evaluate the safety of sputum induction in patients with varying severity of chronic obstructive pulmonary disease. The subjects were 28 smokers with baseline forced expiratory volume in one second (FEV1) of (mean and range) 1.8 (0.8-2.9) L that is 53 (28-69)% of the predicted and reversibility of 2.5 (-7.4-9.9)%. Sputum was induced after premedication with 200 microg salbutamol at increasing concentrations (0.9, 3, 4, and 5%) of hypertonic saline nebulized by an ultrasonic nebulizer. The procedure was well tolerated, and none of the patients reported major side-effects. However, the mean change from prebronchodilator FEV1 during induction was -8.5 (-23-11)%, p=0.001, and from postbronchodilator FEV1 -10.7 (-25-5)%, p0.0001. Three (11%) of the patients had a fall in FEV1 from the prebronchodilator baseline of20%, and a further 10 (36%) had a fall of 10-20%. Patients with greater reversibility in airway obstruction seemed to get the best benefit from the bronchodilator pretreatment, since there was an inverse relationship between reversibility in FEV1 and fall in FEV1 during induction (r=-0.4, p=0.03). It is concluded that sputum induction by hypertonic saline inhalation can cause meaningful bronchoconstriction in patients with chronic obstructive pulmonary disease, despite pretreatment with an inhaled beta2-agonist. The results highlight the importance of monitoring spirometry during sputum induction to detect bronchoconstriction.

The clinical efficacy, tolerability and acceptability of a new multidose powder inhaler (MDPI) containing beclomethasone dipropionate (BDP) were compared with those of a BDP aerosol administered with a large volume spacer (MDI-spacer) among adult asthmatics currently receiving from 500 to 1,000 microgram/day of an inhaled corticosteroid. During the study, the dosage of BDP from both devices was 400 microgram twice daily. Ninety-one patients were randomized to the MDPI group and 42 to the MDI-spacer group. The trial was performed as an open, randomized, parallel group multicenter study. The duration of the treatment period was 12 weeks, and the study was preceded by a 2-week run-in period. During the run-in period, the mean morning peak expiratory flow (PEF) was 487 and 466 1/min in the MDPI and MDI-spacer groups, respectively. After the 12-week treatment, the morning PEF was 491 1/min in the MDPI group and 463 1/min in the MDI-spacer group. The evening values were 500 and 479 1/min during the run-in period and 496 and 476 1/min after the 12-week treatment, respectively. Asthma symptom scores and the use of rescue medication were low in both groups, indicating good efficacy of the preparations tested. The median dose of histamine required to decrease forced expiratory volume in 1 s by 15% increased during the study from 800 to 1,098 microgram in the MDPI group and from 795 to 960 microgram in the MDI-spacer group. The most frequent adverse events in both groups were hoarseness and sore throat. There were no statistically significant differences between the treatment groups in serum cortisol values or in the number of patients with thrush. Seventy-two percent of the patients regarded the MDPI easier to use while 95% considered it more portable. Over 80% of the patients felt that the MDPI was also easier to clean and as easy or easier to learn to use than the MDI-spacer. To conclude, the novel powder inhaler is well tolerated and at least equally effective as the conventional MDI-spacer combination in the treatment of asthma with BDP. However, in everyday use, patients clearly favored the powder inhaler.

BACKGROUND: Co-morbidities are common in chronic obstructive pulmonary disease (COPD). We assessed the contribution of common co-morbidities on health related quality of life (HRQoL) among COPD patients.METHODS: Using both generic (15D) and respiratory-specific (AQ20) instruments, HRQoL was assessed in a hospital based COPD population (N = 739, 64% males, mean age 64 years, SD 7 years) in this observational study with inferential analysis. The prevalence of their co-morbidities was compared with those of 5000 population controls. The patients represented all severity stages of COPD and the patterns of common concomitant disorders differed between patients.RESULTS: Co-morbidities such as psychiatric conditions, alcohol abuse, cardiovascular diseases, and diabetes were more common among COPD patients than in age and gender matched controls. Psychiatric conditions and alcohol abuse were the strongest determinants of HRQoL in COPD and could be detected by both 15D (Odds Ratio 4.7 and 2.3 respectively) and AQ20 (OR 2.0 and 3.0) instruments. Compared to respiratory specific AQ20, generic 15D was more sensitive to the effects of comorbidities while AQ20 was slightly more sensitive for the low FEV1. FEV1 was a strong determinant of HRQoL only at more severe stages of disease (FEV1 CONCLUSIONS: The results suggest that co-morbidities may impair HRQoL at an early stage of the disease, while bronchial obstruction becomes a significant determinant of HRQoL only in severe COPD.

Oscillations of skin blood flow and heart rate can be synchronised using external rhythmic thermal stimulation in healthy adults and infants. We examined the effect of thermal stimulation on the cutaneous circulation and heart rate of an anencephalic neonate using cutaneous laser Doppler flowmetry and ECG monitoring. The results suggest that synchronisation of SBF and HR to thermal stimulation can also be induced in an anencephalic newborn.

The reactivity of skin blood flow and heart rate to periodic thermal stimulation was studied in 10 term small-for-gestational age (SGA) infants, in 9 preterm and 8 term normal-sized infants during the first two postnatal months. During the first postnatal days, the increase in thermally stimulated skin blood flow oscillations was absent in SGA infants but was clearly present in both preterm ( p < 0.01) and term ( p < 0.01) normal-sized infants. The responsiveness of SGA infants improved during the follow-up (p < 0.05). The response of the periodic heart rate variability of SGA and preterm infants was inferior to term normal-sized infants until the age of 2 months. The cardiovascular responsiveness of growth-retarded infants seems abnormal during the first days of life, and may impair their ability to meet stress, e.g. changes of ambient temperature. Heart rate variability, laser Doppler, neonate, skin blood flow, spectral analysis

Cardiovascular functional stability was studied in 17 young men (20-year-old conscripts) with the symptoms of primary fibromyalgia (PF). They were compared to 20 medical students of the same age. The subjects underwent an orthostatic test, deep breathing test, Valsalva maneuver, and a handgrip test. They were evaluated by an autoanamnestic questionnaire on vegetative symptoms and laboratory tests on blood chemistry. The heart rate of the PF group after 8 min of active standing was 32 +/- 15 beats/min greater than at supine rest. The corresponding figure for the controls was 23 +/- 7 beats/min (p = 0.001). Twelve conscripts with PF (71%) presented sympathicotonic cardiovascular reaction on the orthostatic test (p < 0.001). Four of these sympathicotonic conscripts and two other conscripts (total 35%) had an abnormal high index of dystonic symptoms (p = 0.01). The results suggest that young men with symptoms of PF have not only cardiovascular dystonic symptoms but also increased sympathetic nervous reactivity of the cardiovascular system.

Six healthy volunteers received 15 mg midazolam, 50 mg ephedrine, or placebo orally before a 50-minute aerobic treadmill exercise and in a control session. Plasma drug concentrations for pharmacokinetic calculations were estimated from samples drawn up to 24 hours after drug intake. Heart rate, blood pressure, critical flicker fusion test, Maddox wing test, and visual analog scales relating to mood and feelings of tiredness were included in the sessions as pharmacodynamic measures. These tests were made at 35, 55, and 75 minutes and at 2, 2 1/2, 3 1/2, and 5 hours after drug intake. Exercise impaired the absorption of midazolam and counteracted the midazolam-induced decrement in flicker fusion threshold. Whether the effect on flicker fusion was caused mainly by the pharmacokinetic changes or by a general alerting effect of exercise cannot be verified by this experiment. The kinetics of ephedrine was not affected by exercise, but exercise enhanced the tachycardic response to ephedrine and abolished its pressor effect.

Polyvalent killed influenza virus vaccine or saline was administered subcutaneously to 27 asthmatics to investigate the effect of influenza vaccine on respiratory function and on airway responsiveness to inhaled histamine. The patients were adults with mild to moderate asthma. Airway resistance (Raw) and intrathoracic gas volume (ITGV) were measured immediately before and 2, 3 and 21 days after vaccine or saline injection. Raw and ITGV values were used to calculate specific airway conductance (SGaw). Bronchial reactivity was expressed as the provocative dose of histamine diphosphate producing a decrease of 40% in SGaw (PD40). Fourteen (87%) of 16 asthmatics who received killed virus vaccine displayed a significant rise in serum antibody level as measured by single radial haemolysis in gel test. No significant alterations in mean Raw, ITGV and SGaw values were observed after viral vaccination. The median PD40 values for histamine also remained unchanged. However, an increased bronchial reactivity was observed in some patients after administration of virus vaccine or saline. Subclinical natural infection or allergen exposure cannot be excluded as possible causes of the increased airway reactivity in these patients. The side-effects of vaccination were minimal and no more harmful than those produced by saline injection. We conclude that the killed influenza virus vaccine used is effective in boosting serum antibody levels and is suitable for adult asthmatics when prophylactic immunisation is indicated.

Udgivelsesdato: 2008-Oct BACKGROUND: The control of daytime and nighttime symptoms is an important measure of effectiveness of asthma therapy, especially, when administered once-daily. OBJECTIVE: To evaluate the efficacy of evening and morning administrations of mometasone furoate administered via a dry powder inhaler (MF-DPI) 400 microg once-daily (QD) to show equivalence. METHODS: Open-label, randomized, parallel-group study in adult patients with mild to moderate asthma with a > or = 3-month history of ICS use. Patients received MF-DPI 400 microg QD either in the morning (AM) or evening (PM) for 12 weeks. The primary measure was the change in asthma symptoms from baseline to week 12. Secondary outcomes included response to treatment, adherence, inhaler device evaluation, use of rescue medication, urinary cortisol levels, and differential white blood cell count. RESULTS: A total of 1537 patients were randomized; the efficacy population comprised 543 and 479 patients in the MF-DPI QD morning and evening groups, respectively. Mean improvements from baseline in daytime symptom scores at week 12 with morning and evening administration of MF-DPI 400 microg were -0.11+/-0.59 and -0.12+/-0.68, respectively (95% CI, -0.095 to 0.061) and the corresponding improvements in nighttime symptom scores were -0.08+/-0.59 and -0.07+/-0.50, respectively (95% CI, -0.067 to 0.068). Use of rescue medication was the same in both groups (1 puff/day). MF-DPI QD was well tolerated regardless of time of administration. CONCLUSIONS: This open-label study did not identify differences between morning and evening dosing of MF-DPI 400 microg QD. A better effect of evening dosing compared to morning dosing found in previous double-blind placebo-controlled studies could not be confirmed.

Viozan ™ (sibenadet HCl, AR-C68397AA) is a novel dual D 2 dopamine receptor, β 2 -adrenoceptor agonist, developed specifically to treat the key symptoms of chronic obstructive pulmonary disease (COPD), breathlessness, cough and sputum. The dual sensory nerve modulation and bronchodilator effects of sibenadet have been demonstrated in initial dose-ranging studies of patients with COPD and large-scale clinical evaluation has now been completed. Sibenadet efficacy was determined by assessing symptomatic changes, as defined by the novel assessment tool, the Breathlessness, Cough and Sputum Scale (BCSS © ). The findings of two placebo-controlled studies are reported. These multicentre, double-blind, placebo-controlled studies recruited over 2000 patients with stable COPD, randomized to receive sibenadet (500 μg) or placebo, pressurized metered-dose inhaler (pMDI) (three times daily) for a period of 12 or 26 weeks. Diary cards were completed daily by patients throughout the study to record BCSS scores, peak expiratory flow (PEF), study drug and rescue bronchodilator usage, changes in concomitant medication and adverse events. The primary endpoints were defined as change from baseline to the final 4 weeks of the treatment period in mean BCSS total score, and forced expiratory volume in one second (FEV 1 ) measured 1 hour after administration of the final dose of study drug and expressed as a percentage of the predicted FEV 1 . In addition, clinic assessments were made to determine changes in pulmonary function, health-related quality of life, perception of treatment efficacy and adverse events. Despite initial improvements in mean daily BCSS total scores in patients receiving sibenadet, the difference in the change from baseline to the final 4 weeks of the treatment period between the two treatment groups was neither statistically significant, nor considered to be of clinical importance. Although marked bronchodilator activity was seen early on with sibenadet treatment, the duration of effect diminished as the studies progressed. Sibenadet use was not associated with any safety concerns. These studies, utilizing the novel BCSS, have clearly illustrated that, despite initial symptomatic improvement with sibenadet therapy, this clinical benefit was not sustained over the course of the study.

Adherence to maintenance therapy is often poor in patients with asthma. Simplifying dosing regimens has the potential to improve both adherence and asthma-related morbidity. In this 12-week, randomized, double-blind, double-dummy, parallel-group study, 617 patients with mild to moderate persistent asthma (mean forced expiratory volume in 1s [FEV1] 78.5% predicted) who were not optimally controlled on inhaled corticosteroids (200-500 microg/day) were randomized to once-daily budesonide/formoterol (80/4.5 microg, 2 inhalations in the evening), twice-daily budesonide/formoterol (80/4.5 microg, 1 inhalation), or a corresponding dose of budesonide once-daily (200 microg, 1 inhalation in the evening). All patients received budesonide (100 microg twice daily) during a 2-week run-in. Changes in mean morning peak expiratory flow (PEF) were similar for od budesonide/formoterol (23.4 l/min) and twice-daily budesonide/formoterol (24.1 l/min), and both were greater than with budesonide (5.5 l/min; both P0.001). Evening PEF, symptom-free days, reliever-free days, and asthma control days were improved with budesonide/formoterol therapy vs. budesonide (P0.05 vs. budesonide for all variables). All treatments were well tolerated. Budesonide/formoterol administered once daily in the evening is a convenient treatment regimen that is as effective in improving asthma control as twice-daily dosing in patients with mild to moderate persistent asthma.