Altered microRNA expression of nasal mucosa in long-term asthma and allergic rhinitis.

BACKGROUND: Asthma and allergic rhinitis (AR) commonly coexist and can be taken as manifestations of one syndrome. Evidence exists that microRNAs (miRNAs) are important in controlling inflammatory processes and they are considered promising biomarkers. However, little is known about the differences in miRNA expression in patients with chronic allergic airway disease. This study evaluated the inflammatory and miRNA profiles of the nasal mucosa of patients with long-term asthma with and without AR. METHODS: We analyzed inflammatory cells, cytokines, and miRNAs in nasal biopsies and measured exhaled and nasal nitric oxide levels during the nonpollen season in 117 middle-aged men who had suffered mainly from allergic asthma for approximately 20 years and also in 33 healthy controls. RESULTS: The differences in the number of nasal eosinophils and cytokine expression levels were modest in nasal biopsies taken from asthmatics. Downregulation of miR-18a, miR-126, let-7e, miR-155, and miR-224 and upregulation of miR-498, miR-187, miR-874, miR-143, and miR-886-3p were observed in asthmatic patients in comparison to controls. The differences in miRNA expression were mainly similar in asthmatics with and without AR. With regard to asthma severity, a trend of increased miRNA expression in persistent asthma was seen, whereas the downregulation of certain miRNAs was most distinct in nonpersistent-asthma patients. CONCLUSIONS: Differences in miRNA expression in the nasal mucosa of subjects with long-term asthma and AR can be seen also when no markers of Th2-type inflammation are detected. Asthma severity had only a minor impact on miRNA expression.

Positive exercise test and obstructive spirometry in young male conscripts associated with persistent asthma 20 years later.

BACKGROUND: Asthma often begins in childhood or early adulthood and is a common disease among conscripts. The identification of long-term predictive factors for persistent asthma may lead to improved treatment opportunities and better disease control. OBJECTIVE: Our aim was to study the prognostic factors of the severity of asthma among 40-year-old male conscripts whose asthma began in youth. METHODS: We studied 119 conscripts who were referred to the Central Military Hospital during 1987-1990 due to asthma and who attended a follow-up visit approximately 20 years later. Asthma severity was evaluated during military service according to the medical records, and 20 years later during a follow-up visit using Global Initiative for Asthma guidelines. We used the results of lung function and allergy tests at baseline as predictors of current persistent asthma. RESULTS: Compared with baseline, asthma was less severe at follow-up: 11.8% of subjects were in remission, 42.0% had intermittent asthma, 10.9% had mild persistent asthma, and 35.3% had moderate/severe persistent asthma (p < .001). In multivariate models, a positive exercise test at baseline yielded an odds ratio (OR) of 3.2 (95% CI 1.0-9.8, p = .046), a decreased FEV1/FVC % predicted an OR of 4.0 (95% CI 1.7-9.3, p = .002), and a decreased FEF50% % predicted an OR of 2.8 (95% CI 1.3-6.4, p = .012) for current persistent asthma. CONCLUSIONS: About half of the men had persistent asthma at the 20-year follow-up. Positive exercise tests and obstructive spirometry results were related to the persistence of asthma and may be useful long-term prognostic factors for asthma severity.

Smoking attenuates increase in exhaled nitric oxide in atopic but not in nonatopic young adults with asthma.

BACKGROUND: Measurement of fractional exhaled nitric oxide (FENO) is useful in assessing eosinophilic airway inflammation. Smoking may modify airway inflammation and reduce FENO levels, compromising the diagnostic value of FENO in smokers. How smoking influences FENO in atopic versus nonatopic asthmatics is unknown. The aim of the present study was to compare FENO in atopic and nonatopic steroid-naive young asthmatic adults and in healthy subjects in terms of smoking. METHODS: Forty-six (30 atopic) smoking and 70 (54 atopic) nonsmoking steroid-naive army conscripts (mean age 20 years) with current symptomatic asthma underwent FENO measurement, skin prick tests, spirometry with a bronchodilation test, bronchial histamine challenge, and a standardized exercise test. Ten healthy smokers and 9 healthy nonsmokers underwent FENO measurement, spirometry and bronchial histamine challenge. RESULTS: Smokers with asthma showed significantly higher FENO than did healthy smokers and nonsmokers (p = 0.001, both comparisons). Among atopic asthmatics, FENO was lower in smokers than in nonsmokers (p = 0.002) whereas among nonatopic asthmatics no such difference was detectable (p = 0.89). However, even among nonatopic asthmatic smokers FENO was significantly higher than among healthy controls (p = 0.01). CONCLUSION: Smoking seems to attenuate the increase in FENO in atopic but not in nonatopic asthmatics. This finding suggests differences in biochemical mechanisms of NO formation in atopic and nonatopic asthma. However, FENO was significantly higher both in atopic and nonatopic asthmatic smokers than in healthy controls. This suggests that FENO can be applied for diagnostic purposes also in young adult smokers.

Genetic influences on resting electrocardiographic variables in older women: a twin study.

BACKGROUND: Previous studies in young and middle-aged men and women have shown that resting electrocardiographic (ECG) variables are influenced by genetic factors. However, the extent to which resting ECG variables are influenced by genetic factors in older women is unknown. Thus, the aim of this study was to estimate the relative contribution of genetic and environmental influences to individual differences in resting ECG variables among older female twins without overt cardiac diseases. METHODS: Resting ECG recordings were obtained from 186 monozygotic and 203 dizygotic twin individuals, aged 63-76 years. Quantitative genetic modeling was used to decompose the phenotypic variance in each resting ECG variable into additive genetic, dominance genetic, shared environmental, and unique environmental influences. RESULTS: The results showed that individual differences in the majority of the resting ECG variables were moderately to highly explained by additive genetic influences, ranging from 32% for T axis to 72% for TV(5). The results also suggested dominance genetic influences on QRS duration, TV(1), and Sokolow-Lyon voltage (36%, 53%, and 57%, respectively). Unique environmental influences were important for each resting ECG variable, whereas shared environmental influences were detected only for QT interval and QTc. CONCLUSION: In older women without overt cardiac diseases, genetic influences explain a moderate to high proportion of individual differences in the majority of the resting ECG variables. Genetic influences are especially strong for T-wave amplitudes, left ventricular mass, and hypertrophy indices, whereas other variables, including heart rate, intervals, and axes, are more affected by environmental influences.

Electrocardiographic indices of left ventricular hypertrophy and repolarization phase share the same genetic influences: a twin study.

BACKGROUND: Both left ventricular hypertrophy (LVH) and repolarization phase (RP) are known to be attributable to genetic influences, but less is known whether they share same genetic influences. The aim of this study was to investigate to what extent individual differences in electrocardiographic (ECG) LVH and RP are explained by genetic and environmental influences and whether these influences are shared between these two traits. METHODS: Resting ECG recordings were obtained from 186 monozygotic and 203 dizygotic female twin individuals, aged 63 to 76 years. Latent factors, called LVH and RP, were formed to condense the information obtained from LVH indices (Cornell voltage and Cornell product) and T-wave amplitudes (leads V(5) and II), respectively. Multivariate quantitative genetic modeling was used both to decompose the phenotypic variances into additive genetic, common environmental, and unique environmental influences, and for the calculation of genetic and environmental correlations between LVH and RP. RESULTS: Additive genetic influences explained 16% of individual differences in LVH and 74% in RP. The remaining individual differences were explained by both common and unique environmental influences. The genetic correlation and unique environmental correlation between LVH and RP were -0.93 and -0.05, respectively. CONCLUSIONS: In older women without overt cardiac diseases, RP is under stronger genetic control than LVH. The majority of genetic influences are shared between LVH and RP whereas environmental influences are mainly specific to each.

Effects of long-term physical activity on cardiac structure and function: a twin study.

Previous studies have shown that athletic training or other physical activity causes structural and functional adaptations in the heart, but less is known how long-term physical activity affects heart when genetic liability and childhood environment are taken into account. The aim of this study was to investigate the effects of long-term physical activity vs. inactivity on cardiac structure and function in twin pairs discordant for physical activity for 32 years. Twelve same-sex twin pairs (five monozygotic and seven dizygotic, 50-67 years) were studied as a part of the TWINACTIVE study. Discordance in physical activity was initially determined in 1975 and it remained significant throughout the follow-up. At the end of the follow-up in 2007, resting echocardiographic and electrocardiographic measurements were performed. During the follow-up period, the active co-twins were on average 8.2 (SD 4.0) MET hours/day more active than their inactive co-twins (p < 0.001). At the end of the follow-up, resting heart rate was lower in the active than inactive co-twins [59 (SD 5) vs. 68 (SD 10) bpm, p=0.03]. The heart rate-corrected QT interval was similar between the co-twins. Also, there was a tendency for left ventricular mass per body weight to be greater and T wave amplitude in lead II to be higher in the active co-twins (18% and 15%, respectively, p=0.08 for both). Similar trends were found for both monozygotic and dizygotic twin pairs. In conclusion, the main adaptation to long- term physical activity is lowered resting heart rate, even after partially or fully controlling for genetic liability and childhood environment. Key pointsThe main adaptation to long-term physical activity is lowering of resting heart rate, even after controlling for genetic liability.VO2peak is increased in the active co-twins compared with their inactive co-twins and accordingly, also submaximal heart rates during the clinical exercise test are lower in physically active co-twins.There is a tendency for increased LVM per body weight and heightened T wave amplitude in the active co-twins.

Muscle fiber-type distribution predicts weight gain and unfavorable left ventricular geometry: a 19 year follow-up study.

BACKGROUND: Skeletal muscle consists of type-I (slow-twitch) and type-II (fast-twitch) fibers, with proportions highly variable between individuals and mostly determined by genetic factors. Cross-sectional studies have associated low percentage of type-I fibers (type-I%) with many cardiovascular risk factors. METHODS: We investigated whether baseline type-I% predicts left ventricular (LV) structure and function at 19-year follow-up, and if so, which are the strongest mediating factors. At baseline in 1984 muscle fiber-type distribution (by actomyosin ATPase staining) was studied in 63 healthy men (aged 32-58 years). The follow-up in 2003 included echocardiography, measurement of obesity related variables, physical activity and blood pressure. RESULTS: In the 40 men not using cardiovascular drugs at follow-up, low type-I% predicted higher heart rate, blood pressure, and LV fractional shortening suggesting increased sympathetic tone. Low type-I% predicted smaller LV chamber diameters (P < or = 0.009) and greater relative wall thickness (P = 0.034) without increase in LV mass (concentric remodeling). This was explained by the association of type-I% with obesity related variables. Type-I% was an independent predictor of follow-up body fat percentage, waist/hip ratio, weight gain in adulthood, and physical activity (in all P < or = 0.001). After including these risk factors in the regression models, weight gain was the strongest predictor of LV geometry explaining 64% of the variation in LV end-diastolic diameter, 72% in end-systolic diameter, and 53% in relative wall thickness. CONCLUSION: Low type-I% predicts obesity and weight gain especially in the mid-abdomen, and consequently unfavourable LV geometry indicating increased cardiovascular risk.

Recurrent pericarditis in children and adolescents: report of 15 cases.

OBJECTIVES: The aim of this study was to analyze the clinical findings, course, and treatment of recurrent pericarditis (RP) in patients with onset in childhood and adolescence. BACKGROUND: Recurrent pericarditis is a chronic condition that has presented problems in management. Knowledge about this disease is based on observations in adults, and no series of children has previously been published. METHODS: Fifteen children (nine males, six females) in whom pericarditis had recurred at least twice were encountered in the period 1985 to 1998. Their age at onset was 6.5 to 16.8 years (mean 11.6 years), and the follow-up was 4.0 to 16.2 years (mean 8.0 years). RESULTS: Recurrent pericarditis was preceded by open-heart surgery by 1 month to 5 years earlier in 7 of 15 patients. The six children with an atrial septal defect (ASD) had an operation at an older age (mean 9.9 years) than usual (mean 4.8 years). The risk of RP in children operated on for ASD at the age of six years or later was 5%. An initial attack of pericarditis was associated with pleuritis and/or pneumonia in 10 of 15 patients and with colitis in 2 of 15 patients During follow-up, the patients had 2 to 30 recurrences (mean 9.9). Later attacks tended to be milder. At the end of follow-up, 7 patients had been without attacks for >or=4 years, whereas after 4 to 16 years, the remaining patients still had active disease. No instance of constriction was found. Altogether, 11 of 15 patients were treated with corticosteroids. However, corticosteroids, whether alone or with methotrexate (n = 5), azathioprine (n = 1), cyclosporine (n = 1), or colchicine (n = 4) did not prevent recurrences. CONCLUSIONS: The most frequent background for RP in children was the closure of ASD after the age of six years. Its course was unpredictable and often chronic, irrespective of the underlying cause or the therapy given. Colchicine did not prevent relapses.

Middle-aged men with asthma since youth: the impact of work on asthma.

OBJECTIVES: To evaluate current occupational exposure and its associations with asthma control, exacerbations, and severity in middle-aged men with asthma from youth. METHODS: We used the Finnish Defence Force registers, 1986 to 1990, to select conscripts with asthma to represent mild or moderate asthmatic group (asthma group 1; N = 505), men who were exempted from military service to represent relatively severe asthmatic group (asthma group 2; N = 393), and a control group without asthma (N = 1500). A questionnaire was sent out in 2009. RESULTS: The current self-reported or expert-evaluated exposure to asthma-aggravating factors differed only slightly between the asthmatic groups and the controls. In asthma group 2, being a manual worker or self-employed (odds ratio, 4.5; 95% confidence interval, 1.2 to 16.3) significantly associated with asthma exacerbations. CONCLUSIONS: Current work may associate with the asthma outcome of middle-aged men with relatively severe asthma in their youth.

Repeatability of exhaled nitric oxide measurements in patients with COPD.

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.

Reduced work ability in middle-aged men with asthma from youth--a 20-year follow-up.

We studied, whether asthma diagnosed in childhood or early adulthood affects work ability 20 years later. We used Finnish Defence Force registers, 1986-1990, to select: (1) conscripts with asthma to represent a mild/moderate asthma group (n=485), (2) asthmatics who were exempted from military service to represent a relatively severe asthma group (n=393) and (3) a control group (n 1500) without asthma. A questionnaire consisting of validated questions on asthma and work ability was sent out in 2009. A total of 54% of the men in the first study group, 44% of those in the second study group and 44% of the controls answered. The mean age of the participants was 41 (range 37-51). Self-assessed current work ability compared with lifetime best had decreased in 28.9% of the first asthma group, in 31.1% of the second asthma group, and in 19.7% of the controls (p = 0.0007). Current smoking (OR 2.5), only basic education (OR 2.6), being a manual worker (OR 2.7) and current severe asthma (OR 3.8) associated most strongly with decreased work ability among the asthmatics. Both mild and more severe asthma at the age of around 20 seems to be associated with reduced work ability in 40-year-old males.

Electrocardiographic and other clinical correlates of walking ability in older women.

The purpose of this study was to examine how resting electrocardiographic (ECG) and other clinical variables, which can be included in a routine clinical examination, predict walking ability in older women. Three hundred and twenty women (63-75 years) without overt cardiac diseases and apparent mobility limitations were studied. Measurements performed were clinical examination (standard 12-lead resting ECG, assessment of physical activity level, presence of chronic diseases, use of beta-blockers, body mass index (BMI), ability to squat, resting blood pressure) and six-minute walking test. Participants walked 533+/-75 m in the six-minute walking test. The best electrocardiographic predictors of long walking distance were high TV(5) and TII, but their explanation rates were small (4.5% and 3.8%, respectively). In hypertensive participants (systolic blood pressure=SBP> or =160 mmHg), the respective values were 9.3% and 5.8%. The best predictors of long walking distance were ability to squat without limitations and low BMI (15.5% and 13.6%, respectively). Altogether the studied variables explained 36% of the variation in walking distance. The data gathered in clinical examination give useful information for the assessment of walking ability in relatively healthy older women. Resting ECG does not give clinically significant additional information for the assessment in subjects without overt cardiac disease.

Equally elevated concentrations of exhaled nitric oxide in nonatopic and low-sensitized atopic asthmatics.

BACKGROUND: Some studies show concentrations of exhaled nitric oxide (FENO) in nonatopic asthma and in healthy subjects to be similar, but include asthmatics on inhaled steroids, which is likely to interfere with the results. AIM: Comparison of FENO between nonatopic asthmatics, low-sensitized and high-sensitized atopic asthmatics, and healthy controls. METHODS: We studied 85 non-smoking, steroid-naive young men with recently diagnosed symptomatic asthma and 10 healthy controls. FENO was measured according to European Respiratory Society Guidelines. In skin prick tests of 13 common aeroallergens, subjects with a total sum of prick wheals 3-10mm were regarded as low-sensitized and those with >10mm, as high-sensitized. Flow-volume spirometry, standardized histamine challenge, and an exercise test were also carried out. RESULTS: Prick tests revealed 14 subjects to be nonatopic and 71 atopic. In high-sensitized subjects with atopic asthma, the FENO median (25-75 quartiles) was significantly higher, 34.9 (21.3-53.8) parts per billion (ppb), than in subjects with nonatopic asthma, 15.2 (9.7-24.7)ppb (p<0.001), both being significantly higher than in healthy controls, 6.6 (5.2-8.5)ppb (p<0.001). FENO levels were similar in nonatopic and in low-sensitized atopic asthmatics, with no difference between them in bronchial responsiveness to histamine and exercise. CONCLUSION: Among steroid-naive young male asthmatics, FENO was equally elevated in nonatopic asthma and in low-sensitized atopic asthma but lower than in those with high-sensitized atopic asthma. These differences in FENO between asthma groups parallel the differences in airway function disturbance in terms of responsiveness to histamine or exercise.

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

BACKGROUND: Elevated fractional exhaled nitric oxide (FENO) associates positively with symptomatic atopy among asthmatics and in the general population. It is, however, unclear whether sensitization to common allergens per se- as verified with positive skin prick tests--affects FENO in healthy individuals. OBJECTIVE: The aim of this study was to examine the association between FENO and sensitization to common allergens in healthy nonsmoking adults with no signs or symptoms of airway disorders. METHODS: FENO measurements (flow rate: 50 mL/s), skin prick tests to common inhalant allergens, structured interviews, spirometry, bronchodilatation tests and bronchial histamine challenges were performed on a randomly selected population of 248 subjects. Seventy-three of them (29%) were nonsmoking asymptomatic adults with no history of asthma, persistent or recurrent upper or lower airway symptoms and no signs of airway disorders in the tests listed above. RESULTS: FENO concentrations were similar in skin prick test positive (n = 32) and negative (n = 41) healthy subjects, with median values of 13.2 and 15.5 ppb, respectively (P = 0.304). No correlation appeared between FENO and the number of positive reactions (r = -0.138; P = 0.244), or the total sum of wheal diameters (r = -0.135; P = 0.254). The nonparametric one-tailed 95% upper limits of FENO among skin prick positive and negative healthy nonsmoking subjects were 29 and 31 ppb, respectively. CONCLUSIONS: Atopic constitution defined as positive skin prick test results does not increase FENO in healthy nonsmoking adults with no signs or symptoms of airway disorders. This suggests that same reference ranges for FENO can be applied to both skin prick test positive and negative subjects.

Effects of beta-blocker therapy on ventricular repolarization documented by 24-h electrocardiography in patients with type 1 long-QT syndrome.

OBJECTIVES: We tested the hypothesis that in long-QT syndrome (LQT) type 1 (LQT1), beta-blocker therapy may decrease both the diurnal maximal T-wave peak to T-wave end interval (TPE) and the maximal ratio between late and early T-wave peak amplitude (T2/T1 ratio), which are electrocardiographic counterparts of transmural dispersion of repolarization (TDR) and early afterdepolarizations (EA), respectively. BACKGROUND: Ventricular repolarization duration and increased TDR and EAs are the three electrophysiological components generating the high risk of ventricular arrhythmias and sudden death in the inherited LQT. In the most prevalent LQT1 form of LQT, treatment with beta-blockers reduces serious arrhythmia events dramatically without a known influence on QT interval duration. In experimental LQT1 models, beta-blockers decrease TDR and prevent EAs. METHODS: We reviewed 24-h electrocardiographic recordings obtained before and during the treatment with beta-blockers from 24 genotyped LQT1 patients to record maximal TPE intervals and T2/T1 ratios as well as maximal and rate-adapted QT intervals using a computer-assisted program. RESULTS: Treatment with beta-blockers decreased the maximal diurnal T2/T1 amplitude ratio from 3.0+/- 1.0 to 2.2 +/- 0.6 (p = 0.002). Beta-blockers also decreased both maximal TPE intervals and abrupt maximal QT intervals at heart rates higher than 85 beats/min, whereas QT intervals measured at steady-state conditions remained unchanged. CONCLUSIONS: Prevention of abrupt increases of electrocardiographic TDR, EA, and ventricular repolarization duration at elevated heart rates may explain the favorable clinical effects of beta-blockers in LQT1.

Muscle fiber-type distribution as a predictor of blood pressure: a 19-year follow-up study.

The known association between physical activity and low blood pressure may be influenced by inherited characteristics. Skeletal muscle consists of type I (slow-twitch) and type II (fast-twitch) muscle fibers, with proportions highly variable between individuals and mostly determined by genetic factors. A high percentage of type I fibers (type I%) has been associated with low blood pressure in cross-sectional studies. We investigated whether type I percentage predicts future blood pressure levels and explains part of the association between physical activity and blood pressure. At baseline, in 1984, muscle fiber-type distribution, physical activity, and body mass index (BMI) were determined in 64 healthy men (age, 32 to 58 years). At follow-up, in 2003, blood pressure, physical activity, and BMI were determined in these men. In subjects without antihypertensive medication (n=43), type I percentage accounted for 5%/18% of the variation in systolic/diastolic blood pressure. A high type I percentage predicted, independent of both baseline (in 1984) and follow-up (in 2003), physical activity, BMI, and low systolic and diastolic blood pressure. Adjusted for all baseline covariates, a 20-unit higher type I percentage predicted a 11.6-mm Hg lower systolic blood pressure (P=0.018) and a 5.0-mm Hg lower diastolic blood pressure (P=0.018). High levels of physical activity in 1984 predicted low diastolic blood pressure, but this association was lost when type I percentage was included into the model. A high proportion of type I fibers in skeletal muscle is an independent predictor of low blood pressure and explains part of the known association between high levels of physical activity and low blood pressure.