Physical activity, cardiorespiratory fitness, and metabolic outcomes in monozygotic twin pairs discordant for body mass index.

This study aims to investigate (i) how monozygotic (MZ) twin pairs who are discordant for body mass index (BMI) differ for objectively and subjectively measured physical activity (PA) and cardiorespiratory fitness (VO2 max) and (ii) associations of PA and VO2 max with adiposity and measures of metabolic health, in individual twins and independent of genetic and shared environmental effects within twin pairs. We examined 27 BMI-discordant and 14 BMI-concordant MZ twin pairs. Fat and fat-free mass (ffm) were measured by dual-energy X-ray absorptiometry and VO2 max by spiroergometry. PA was measured objectively by accelerometers using ActiGraph GT1M for daytime activity and Actiwatch AW7 for 24 h/d. Self-reported PA was obtained through the Baecke and IPAQ long-form questionnaires. Objectively measured moderate-to-vigorous PA (MVPA, min/d), steps/d, and VO2 max/kg were significantly lower, by 30%, 21%, and 14%, respectively, in the heavier compared with the leaner co-twins of the BMI-discordant twin pairs. There were no significant differences in self-reported PA or VO2 max/ffm. As expected, PA and VO2 max/ffm were similar in the BMI-concordant co-twins. Furthermore, the 24-h recording of activity suggested that the heavier co-twins had more restless sleep during the night, whereas the leaner co-twins were more active during the day. Within all twin pairs, higher MVPA and steps per day were associated with lower fat percentage and improved metabolic health measures. Objectively, but not subjectively measured PA is associated with lower fat percentage and better metabolic health, independent of genetic and shared environmental factors.

Association of breathing sound spectra with glottal dimensions in exercise-induced vocal cord dysfunction.

The objective of this study was to evaluate associations between the breathing sound spectra and glottal dimensions in exercise-induced vocal cord dysfunction (EIVCD) during a bicycle ergometry test. Nineteen subjects (mean age 21.8 years and range 13-39 years) with suspected EIVCD were studied. Vocal folds were continuously imaged with videolaryngoscopy and breathing sounds were recorded during the bicycle exercise test. Twelve subjects showed paradoxical movement of the vocal folds during inspiration by the end of the exercise. In seven subjects, no abnormal reactions in vocal folds were found; they served as control subjects. The glottal quotient (interarytenoid distance divided by the anteroposterior glottal distance) was calculated. From the same time period, the tracheal-vocal tract resonance peaks of the breathing sound spectra were analyzed, and stridor sounds were detected and measured. Subjects with EIVCD showed significantly higher resonance peaks during the inspiratory phase compared to the expiratory phase (p < 0.014). The glottal quotient decreased significantly in the EIVCD group (p < 0.001), but not in the control group. 8 out of 12 EIVCD patients (67%) showed stridor sounds, while none of the controls did. There was a significant inverse correlation between the frequencies of the breathing sound resonance peaks and the glottal quotient. The findings indicate that the typical EIVCD reaction of a paradoxical approximation of the vocal folds during inspiration, measured here as a decrease in the glottal quotient, is significantly associated with an increase in inspiratory resonance peaks. The findings are applicable in the documentation of EIVCD findings using videolaryngoscopy, in addition to giving clinicians tools for EIVCD recognition. However, the study is limited by the small number of subjects.

Genetic susceptibility to asbestos-related fibrotic pleuropulmonary changes.

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

Matrix metalloproteinases-7, -8, -9 and TIMP-1 in the follow-up of diisocyanate-induced asthma.

BACKGROUND: Diisocyanate-induced asthma (DIA) is known to be associated with poor prognosis. We wished to clarify if matrix metalloproteinases (MMP)-7, -8 or -9 or tissue inhibitor of matrix metalloproteinases (TIMP-1) are associated with the functional or inflammatory outcome in DIA patients. METHODS: This is a longitudinal study where 17 patients with DIA diagnosed by a specific challenge test to diisocyanates were monitored. Exposure to diisocyanates was terminated seven (mean) months before the challenge test. The studies included spirometry, histamine challenge test and bronchoscopy. MMP-7, MMP-8, TIMP-1 [Enzyme-linked immunosorbent assay (ELISA)- and immunofluorometric assay-methods], MMP-9 (ELISA and zymography), interferon-gamma, tumour necrosis factor-alpha, interleukin-6, -8, -15, -17, CXCL-5/ENA-78, monocyte chemoattractant protein-1 and macrophage inhibitory factor (MIF) (ELISA) were assayed from bronchoalveolar lavage (BAL) fluid. Inhaled steroid therapy was initiated after the examinations, which were repeated at 6 months and at 3 years during the treatment. The results were compared with those of 15 healthy controls. RESULTS: Inhaled steroid medication increased BAL levels of MMP-9 and MMP-9/TIMP-1 and decreased MMP-7 and MMP-7/TIMP-1. The increase in MMP-9 levels was associated with a decline in the TH-2 type inflammation. CONCLUSIONS: Our data suggest that reduced TH-2 type inflammation in DIA after inhaled steroid medication is reflected as elevated MMP-9 and MMP-9/TIMP-1 levels in BAL. MIF may be the inducer of MMP-9. This might point to some protective role for MMP-9 in DIA.

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

BACKGROUND: The clinical outcome of diisocyanate-induced asthma has been found to be poor despite cessation of exposure. Our aim was to study the outcome of diisocyanate-induced asthma after initiation of inhaled steroid treatment at a mean period of 7 months (range 2-60 months) after cessation of exposure by following up lung function and bronchial inflammation. METHODS: Bronchoscopy was performed on 17 patients 2 days after a positive inhalation challenge test, after which budesonide 1600 mug a day was started. Bronchoscopy, spirometry, and histamine challenge tests were repeated at 6 months and on average 3 years. The results were also compared with those obtained from 15 healthy control subjects. RESULTS: Nonspecific bronchial hyperreactivity diminished significantly (P = 0.006); however, forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) values decreased, with a median yearly reduction of FEV1 of 79 ml. The count of mast cells in bronchial mucosa decreased (P = 0.012) and that of macrophages increased (P = 0.001). Interleukin-4 level in mucosa was during the first year significantly higher than in controls but its level decreased in the follow-up. Interleukin-6, interleukin-15, and tumour necrosis factor alpha messenger-RNA levels were significantly higher in hyperreactive patients than in nonhyperreactive patients at the end of the follow-up. CONCLUSION: Our results indicate that inflammation may persist in diisocyanate-induced asthma despite inhaled steroid medication. However, TH2-type inflammation diminished. Persistent nonspecific bronchial hyperreactivity was associated with proinflammatory acting cytokines produced mainly by macrophages. Considering the poor prognosis of the disease the findings could be utilized to develop the follow-up and treatment of diisocyanate-induced asthma.

Upper abdominal symptoms in patients with Type 1 diabetes: unrelated to impairment in gastric emptying caused by autonomic neuropathy.

AIMS: Diabetic gastroparesis is a common condition occurring in some 30-50% of patients with long-term diabetes. Some studies have found a relationship between autonomic neuropathy and diabetic gastroparesis. In addition to autonomic neuropathy, acute changes in plasma glucose concentration can also affect gastric emptying. The objective was to examine the relationship between autonomic nerve function, glucose concentration, gastric emptying, and upper abdominal symptoms in Type 1 diabetic patients. METHODS: Gastric emptying of solids and liquids was measured with scintigraphy in 27 patients with longstanding Type 1 diabetes with upper abdominal symptoms. Autonomic nerve function was examined by standardized cardiovascular tests, and plasma glucose concentrations were measured during scintigraphy. Severity of abdominal symptoms and quality of life were explored by validated questionnaires. RESULTS: Seven patients (26%) had delayed gastric emptying of solids and three (11%) of liquids. Mean gastric half-emptying time of solids was 128 +/- 116 min and of liquids 42 +/- 30 min. Of the 26 patients undergoing tests, 16 (62%) had autonomic nerve dysfunction. Autonomic neuropathy score (1.6 +/- 1.7) correlated positively with the gastric emptying rate of solids (P = 0.006), a rate unrelated to symptom scores or plasma glucose concentrations during scintigraphy. Quality of life in patients with abdominal symptoms was lower than in the normal Finnish population. CONCLUSIONS: Impaired gastric emptying of solids in patients with Type 1 diabetes is related to autonomic neuropathy, but not to actual glycaemic control. The upper abdominal symptoms observed in these patients cannot be explained, however, by impaired gastric emptying.

Patient with multiple acyl-CoA dehydrogenation deficiency disease and FLAD1 mutations benefits from riboflavin therapy.

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

Glutathione S-transferase genotypes and allergic responses to diisocyanate exposure.

Diisocyanates are the most common low molecular weight chemicals to cause occupational asthma. However, only some 5-10% of exposed workers develop asthma, which suggests an underlying genetic susceptibility. Diisocyanates and their metabolites may be conjugated with glutathione by glutathione S-transferases (GSTs). We examined whether polymorphisms in the GSTM1, GSTM3, GSTP1 and GSTT1 genes modify allergic responses to diisocyanate exposure. The study population consisted of 182 diisocyanate exposed workers, 109 diagnosed with diisocyanate-induced asthma and 73 without asthma. Lack of the GSTM1 gene (null genotype) was associated with a 1.89-fold risk of diisocyanate-induced asthma [95% confidence interval (CI) 1.01-3.52]. Moreover, among the asthma patients, the GSTM1 null genotype was associated with lack of diisocyanate-specific immunoglobulin (Ig)E antibodies [odds ratio (OR) 0.18, 95% CI 0.05-0.61] and with late reaction in the specific bronchial provocation test (OR 2.82, 95% CI 1.15-6.88). Similarly, GSTM3 AA genotype was related to late reaction in the specific bronchial provocation test (OR 3.75, 95% CI 1.26-11.2). The GSTP1 Val/Val genotype, on the other hand, was related to high total IgE levels (OR 5.46, 95% CI 1.15-26.0). The most remarkable effect was seen for the combination of GSTM1 null and the GSTM3 AA genotype which was strongly associated with lack of diisocyanate-specific IgE antibodies (OR 0.09, 95% CI 0.01-0.73) and with late reaction in the bronchial provocation test (OR 11.0, 95% CI 2.19-55.3). The results suggest, for the first time, that the polymorphic GSTs, especially the mu class GSTs, play an important role in inception of ill effects related to occupational exposure to diisocyanates.

Changes in crackle characteristics during the clinical course of pneumonia.

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

Differences in acoustic and dynamic characteristics of spontaneous cough in pulmonary diseases.

The aim of this study was to determine whether the flow dynamics and sound spectra of spontaneous cough show characteristic differences in asthma, acute and chronic bronchitis, TBCS and FPD. During the cough, the air flow from the mouth and the sound from the sternal manubrium were simultaneously recorded. The cough sounds were analyzed spectrographically. Peak expiratory flow during cough was significantly lower in asthma than in TBCS, acute bronchitis or FPD. Duration of the first cough sound was longer in asthma than in FPD, TBCS or chronic bronchitis. The number of additional cough sounds was smaller in asthma than in the other conditions. The highest frequency components of cough sound were lower in asthma than in chronic bronchitis or TBCS. The results indicate that pulmonary diseases differ with respect to acoustic and dynamic characteristics of spontaneous cough. This finding may prove useful in the diagnosis of cough.

Long-term recording and automatic analysis of cough using filtered acoustic signals and movements on static charge sensitive bed.

Reliable long-term assessment of cough is necessary in many clinical and scientific settings. A new method for long-term recording and automatic analysis of cough is presented. The method is based on simultaneous recording of two independent signals: high-pass filtered cough sounds and cough-induced fast movements of the body. The acoustic signals are recorded with a dynamic microphone in the acoustic focus of a glass fiber paraboloid mirror. Body movements are recorded with a static charge-sensitive bed located under an ordinary plastic foam mattress. The patient can be studied lying or sitting with no transducers or electrodes attached. A microcomputer is used for sampling of signals, detection of cough, statistical analyses, and on-line printing of results. The method was validated in seven adult patients with a total of 809 spontaneous cough events, using clinical observation as a reference. The sensitivity of the method to detect cough was 99.0 percent, and the positive predictivity was 98.1 percent. The system ignored speaking and snoring. The method provides a convenient means of reliable long-term follow-up of cough in clinical work and research.

Averaged and time-gated spectral analysis of respiratory sounds. Repeatability of spectral parameters in healthy men and in patients with fibrosing alveolitis.

STUDY OBJECTIVE: To obtain a basis for assessment of changes in breath sound spectra in patients with pulmonary diseases, short-term and day-to-day repeatability of spectral parameters was studied. DESIGN: Breath sounds were recorded simultaneously from the trachea and from the chest twice at an interval of 15 min (short-term repeatability) and of 1 to 3 days (day-to-day repeatability). During recordings, air flow at the mouth was controlled, the target inspiratory and expiratory peak flow being 1.25 L/s. Inspiratory and expiratory breath sound spectra were averaged over 7 to 10 successive respiratory cycles. The repeatability of sound intensity (RMS), frequency of maximum intensity (Fmax), and median frequency (F50) was analyzed with analysis of variance. PARTICIPANTS: Short-term repeatability was studied in 10 healthy nonsmoking men (age 25 to 44 years), and day-to-day repeatability was studied in 10 healthy nonsmoking men (age 23 to 41 years) and in 12 patients with clinically stable fibrosing alveolitis (age 35 to 82 years). RESULTS: Short-term coefficient of variation (CoV) of Fmax and F50 was 2.6 to 6.7% when recorded from the chest, and 6.2 to 8.7% when recorded from the trachea. Day-to-day CoV of Fmax and F50 in healthy subjects was 4.7 to 8.5% and 5.0 to 8.7% recorded from the chest or from the trachea, respectively. Inspiratory day-to-day variation in those parameters was higher in patients with fibrosing alveolitis. CoV of RMS was high, ranging from 18 to 47% in different subject groups and sampling situations. CONCLUSIONS: Repeatability of F50 of averaged flow-controlled lung sound spectra is good both in healthy subjects and in patients with fibrosing alveolitis. Thus, F50 of respiratory sound spectra may be useful in monitoring of changes induced by respiratory diseases and interventions. These results emphasize the importance of standardization of recording conditions and of analyzing techniques.

Changes in frequency spectra of breath sounds during histamine challenge test in adult asthmatics and healthy control subjects.

Air-flow standardized breath sounds were recorded at the chest and at the trachea during histamine challenge test and after subsequent bronchodilation in 12 asthmatics and 6 healthy controls for spectral analysis, to be compared with simultaneous changes in spirometric variables. Of all the lung sound variables measured, the changes in median frequency of the power spectrum (F50) of tracheal expiratory sounds were found to correlate best (r = 0.853, p < 0.0001) with changes in FEV1. The increase of F50 during histamine challenge was significantly larger in asthmatics than in healthy control subjects (p < 0.005). The provocative dose of histamine inducing a decrease of 15 percent in FEV1 (PD15FEV1) and the provocative dose causing an increase of 30 percent in tracheal expiratory F50 (PD30F50) were significantly related (r = 0.754, p = 0.012). In asthmatics, the breath sound frequency distribution in terms of median frequency reflected acute changes in airways obstruction with high sensitivity and specificity. The present method for breath sound analysis can be applied for patients with limited cooperation during bronchial challenge tests.

Crackles in patients with fibrosing alveolitis, bronchiectasis, COPD, and heart failure.

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

Original waveform of lung sound crackles: a case study of the effect of high-pass filtration.

In lung sound research, low-frequency noise usually disturbs the sound signal being recorded. Some researchers therefore use high-pass filtration before the final analysis. In this study, the effect of digital and analog high-pass filtration on the morphology of the lung sound crackles is evaluated. The original nonprefiltered crackle waveform is presented, and the effect of the high-pass filtration on the crackle waveform characteristics is elucidated in one patient with silicoasbestosis.

A thirteen-year follow-up of respiratory effects of acute exposure to sulfur dioxide.

OBJECTIVES: In 1977, nine men were accidentally exposed to sulfur dioxide in an explosion in a pyrite mine. The lung function of seven men was followed after the accident. A four-year follow-up has been published previously. The greatest decrease in forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1.0), and maximal midexpiratory flow (MMEF) was observed one week after the accident, after which all these parameters improved without reaching the preaccident level. Reversible bronchial obstruction was still present in three patients, and a positive reaction in the histamine challenge test was found for four. In the present paper, the lung function follow-up 13 years after the accident is reported for six men. METHODS: The patients' clinical condition, chest X-ray, spirometry, and histamine challenge test were studied 13 years after the incident. RESULTS: Spirometry was normal in one worker, two displayed obstruction, and three had a combined obstructive and restrictive, mainly obstructive, ventilatory impairment. In the histamine challenge test, four patients showed bronchial hyperreactivity, one with a nearly significant reaction. Because of bronchial obstruction one patient could not perform the challenge test. CONCLUSIONS: This 13-year follow-up showed that acute inflammatory obstruction caused by exposure to sulfur dioxide left, as sequelae, obstructive impairment of ventilatory function and permanent bronchial hyperreactivity. The clinical picture displayed by these patients was named the "reactive airways dysfunction syndrome" (RADS) in 1985. Four of the patients also showed symptoms of chronic bronchitis.

Validated method for automatic detection of lung sound crackles.

Crackling lung sounds are associated with many pulmonary diseases. Their occurrence reflects the quality and the severity of the disease. An automatic method for crackle detection is developed, based on analysing the spectral stationarity of the lung sound. The method is validated by studying the crackles of 20 adult patients; 10 with fibrosing alveolitis (FA) and 10 with bronchiectasis (BE). The number of crackles detected by the automatic method in inspiratory cycles is compared to the number of crackles counted from time-expanded waveforms by two expert observers. The total number of inspiratory cycles studied is 117 and that of crackles 1064. The method has a sensitivity of 89 per cent and a positive predictivity of 88 per cent for patients with FA, and 80 per cent and 83 per cent respectively, for patients with BE. The linear correlation coefficients between the numbers of crackles counted by the automatic method and by the observers is 0.86 (p less than 0.001) for the patients with FA and 0.93 (p less than 0.001) for the patients with BE. The values refer to whole inspiratory cycles. The new automatic method seems reliable enough for clinical and scientific purposes. It enables a rapid and objective analysis of large materials with crackling lung sounds.

Distribution of crackles on the flow-volume plane in different pulmonary diseases.

A new method to represent and evaluate crackles on the flow-volume plane is described. Characteristic crackle patterns were found in patients with pneumonia, bronchiectasis, chronic obstructive pulmonary disease, heart failure and cryptogenic fibrosing alveolitis. In addition to visual assessment, simple statistical parameters were used to describe the observed pathological phenomena.

A new versatile PC-based lung sound analyzer with automatic crackle analysis (HeLSA); repeatability of spectral parameters and sound amplitude in healthy subjects.

A versatile PC-based lung sound analyzer has been developed for short-term recording and analysis of respiratory sounds in research and clinical applications. The system consists of two sound sensors, a flow sensor, a filtering signal amplifier and a PC with a data acquisition card and software for measurement and analysis of the sounds. The analyses include phonopneumography, time expanded waveform analysis, spectral analysis with time averaged Fast Fourier Transform, frequency analysis in time domain (sonogram), and automatic detection and waveform analysis of crackles. Short-term repeatability of spectral parameters of tracheal and lung sounds was studied in 10 healthy subjects. The coefficients of variation (CoV) of the averaged quartile frequencies (F25, F50 and F75) of lung sounds during flow-controlled tidal breathing were 3.7, 4.0 and 8.9% in expiration and 2.7, 3.5 and 4.5% in inspiration, respectively. CoVs of the averaged F25, F50 and F75 of expiratory tracheal sounds were 6.9, 3.0 and 2.4%, and those of inspiratory tracheal sounds 6.3, 2.6 and 3.3%, respectively. Examples of lung sound analysis of samples containing adventitious sounds such as crackles and wheezes are presented. The results indicate that the median frequency has the best repeatability of quartile frequencies of breath sounds and they suggest that the variations of those parameters are low enough for diagnostic purposes. The results also suggest that the analyzer can be a useful new tool for pulmonary research in the fields of physiological and clinical short-term studies of respiratory sounds.