Kazuo Chin

Effects of nasal continuous positive airway pressure on soluble cell adhesion molecules in patients with obstructive sleep apnea syndrome.

PURPOSE Obstructive sleep apnea syndrome is common in middle-aged men and may be associated with an increased risk of cardiovascular disease. We investigated the effect of nasal continuous positive airway pressure (CPAP) treatment on levels of soluble cell adhesion molecules-which have been shown to be associated with the development of atherosclerosis-in these patients. SUBJECTS AND METHODS We studied 23 patients with obstructive sleep apnea syndrome diagnosed by polysomnography who were treated with nasal CPAP. Serum soluble intercellular adhesion molecule-1, E-selectin, and vascular cell adhesion molecule-1 levels were measured before nasal CPAP was started, and after 3 or 4 days (n = 19), 1 month (n = 23), or 6 months (n = 11) of treatment. RESULTS After 3 to 4 days of nasal CPAP therapy, the mean (+/- SD) soluble E-selectin level had decreased from 89 +/- 44 ng/mL to 69 +/- 28 ng/mL (P = 0.002). After 1 month, the soluble intercellular adhesion molecule-1 level had decreased from 311 +/- 116 ng/mL to 249 +/- 74 ng/mL (P = 0.02). After 6 months, soluble vascular cell adhesion molecule-1 levels had not changed significantly, while the mean soluble intercellular adhesion molecule-1 level (212 +/- 59 ng/mL) had decreased further (P = 0.02). Before treatment, soluble intercellular adhesion molecule-1 levels and the apnea and hypopnea index were correlated (r = 0.43, P = 0.04). CONCLUSIONS Obstructive sleep apnea and hypopnea have a significant adverse effect on serum soluble cell adhesion molecule-1 levels that may be reduced by nasal CPAP treatment.

High sensitivity C-reactive protein in asthma

Asthma is characterised by chronic inflammation of the airways, but the relevance of high-sensitivity assays for C-reactive protein (hs-CRP), which are known to be a sensitive marker of low-grade systemic inflammation, has not been fully studied in asthma. The objective was to examine serum hs-CRP levels in patients with asthma and their relationship to clinical characteristics and degree of airway inflammation. Serum hs-CRP levels were cross-sectionally examined in steroid-naive (n = 22) and steroid-inhaling (n = 23) adult patients with asthma and healthy controls (n = 14). All were nonsmokers. Serum hs-CRP levels were significantly increased in steroid-naive patients (mean±sd 1.33±1.48 mg·L−1) compared with controls (0.21±0.30 mg·L−1), but not in patients on inhaled corticosteroid. Among steroid-naive patients, serum hs-CRP levels significantly negatively correlated with indices of pulmonary function (forced expiratory volume in one second/forced vital capacity and forced mid-expiratory flow) and positively with sputum eosinophil count. Among patients on inhaled corticosteroid, hs-CRP levels did not correlate with any indices. In conclusion, an increase in serum C-reactive protein levels measured by high-sensitivity assays may be associated with airflow obstruction and airway inflammation, and may serve as a surrogate marker of airway inflammation in asthma.

CT Scan Findings of Emphysema Predict Mortality in COPD

BACKGROUND Emphysematous change as assessed by CT imaging has been reported to correlate with COPD prognostic factors such as FEV(1) and diffusing capacity of the lung for carbon monoxide (Dlco). However, few studies have assessed the relationship between CT scan assessment and COPD mortality from mild to severe stages of the disease. In this study, we analyzed this relationship in patients with various stages of COPD. METHODS Two hundred and fifty-one outpatients with stable COPD were included in the study. CT scan and pulmonary function tests were performed at study entry in a single institution. The percentage of low attenuation area was measured to quantitatively evaluate emphysematous change with a custom-made software. Prognostic data also were collected, and the median follow-up time was 8 years. RESULTS Of the 251 patients, 79 died, with 40 classified as respiratory deaths not involving lung cancer. Univariate Cox analysis revealed that emphysematous change as assessed by CT scan, lung function, age, or BMI were significantly correlated with mortality. Multivariate analysis revealed that emphysematous change as assessed by CT scan had the best association with mortality. CONCLUSIONS Emphysematous change as assessed by CT scan predicts respiratory mortality in outpatients with various stages of COPD.

Development of a Japanese version of the Epworth Sleepiness Scale (JESS) based on Item Response Theory

BACKGROUND Various Japanese versions of the Epworth Sleepiness Scale (ESS) have been used, but none was developed via standard procedures. Here we report on the construction and testing of the developer-authorized Japanese version of the ESS (JESS). METHODS Developing the JESS involved translations, back translations, a pilot study, and psychometric testing. We identified questions in the ESS that were difficult to answer or were inappropriate in Japan, proposed possible replacements for those questions, and tested them with analyses based on item response theory (IRT) and classical test theory. The subjects were healthy people and patients with narcolepsy, idiopathic hypersomnia, or obstructive sleep apnea syndrome. RESULTS We identified two of our proposed questions as appropriate replacements for two problematic questions in the ESS. The JESS had very few missing data. Internal consistency reliability and test-retest reliability were high. The patients had significantly higher JESS scores than did the healthy people, and higher JESS scores were associated with worse daytime function, as measured with the Pittsburgh Sleep Quality Index. CONCLUSIONS In Japan, the JESS provides reliable and valid information on daytime sleepiness. Researchers who use the ESS with other populations should combine their knowledge of local conditions with the results of psychometric tests.

Prostaglandin F 2α receptor signaling facilitates bleomycin-induced pulmonary fibrosis independently of transforming growth factor-β

Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix (ECM) proteins, which lead to distorted lung architecture and function. Given that anti-inflammatory or immunosuppressive therapy currently used for IPF does not improve disease progression therapies targeted to blocking the mechanisms of fibrogenesis are needed. Although transforming growth factor-β (TGF-β) functions are crucial in fibrosis, antagonizing this pathway in bleomycin-induced pulmonary fibrosis, an animal model of IPF, does not prevent fibrosis completely, indicating an additional pathway also has a key role in fibrogenesis. Given that the loss of cytosolic phospholipase A2 (cPLA2) suppresses bleomycin-induced pulmonary fibrosis, we examined the roles of prostaglandins using mice lacking each prostoaglandin receptor. Here we show that loss of prostaglandin F (PGF) receptor (FP) selectively attenuates pulmonary fibrosis while maintaining similar levels of alveolar inflammation and TGF-β stimulation as compared to wild-type (WT) mice, and that FP deficiency and inhibition of TGF-β signaling additively decrease fibrosis. Furthermore, PGF2α is abundant in bronchoalveolar lavage fluid (BALF) of subjects with IPF and stimulates proliferation and collagen production of lung fibroblasts via FP, independently of TGF-β. These findings show that PGF2α-FP signaling facilitates pulmonary fibrosis independently of TGF-β and suggests this signaling pathway as a therapeutic target for IPF.

Relationship Between Pulmonary Emphysema and Osteoporosis Assessed by CT in Patients With COPD

BACKGROUND Osteoporosis is one of the important systemic features of COPD. Although COPD itself is regarded as one risk factor for osteoporosis, the relationship between the extent of emphysema and reduced bone density is still unclear. Our first aim was therefore to measure vertebral bone density and the percentage of low-attenuation area (LAA%) in the lungs using chest CT scans in COPD patients. Our second aim was to investigate the relationships among CT scan measurements, anthropometric parameters, and pulmonary function. METHODS Chest CT scans and pulmonary function tests were performed in 65 male patients with COPD. Using CT images, the CT scan density of the thoracic and lumbar vertebrae (T4, T7, T10, and L1) and the LAA% were measured quantitatively, and their correlations were analyzed. RESULTS Linear regression analyses revealed that LAA% had a significant negative correlation with bone mineral density (BMD) [r = -0.522]. In addition, multiple regression analysis showed that only LAA% and body mass index (BMI) were predictive of BMD among age, BMI, smoking index, FEV(1), arterial blood gas, and LAA%. CONCLUSIONS The extent of pulmonary emphysema significantly correlated with reduced bone density. Our study suggested that COPD itself could be a risk factor for osteoporosis and that chest CT scanning is useful for the management of COPD as a systemic disease.

Effects of obstructive sleep apnea syndrome on serum aminotransferase levels in obese patients

PURPOSE Obesity has been associated with obstructive sleep apnea and hepatic steatosis. We investigated the effects of obstructive sleep apnea and treatment with nasal continuous positive airway pressure (CPAP) on serum aminotransferase levels in obese patients. METHODS We studied 40 obese men with obstructive sleep apnea syndrome. None had hepatitis B antigen or C antibody, autoimmune disease, or an excessive intake of alcohol. Serum levels of aspartate aminotransferase, alanine aminotransferase, triglyceride, glucose, insulin, and leptin were determined in the afternoon and in the morning immediately after sleep, before and after nasal CPAP treatment. RESULTS Aminotransferase levels were abnormal in 35% (n = 14) of patients. Before treatment, mean (+/- SD) aspartate aminotransferase levels were higher in the morning than in the previous afternoon (presleep, 34 +/- 20 IU/L; postsleep, 39 +/- 28 IU/L; P = 0.006). The overnight mean increases in aminotransferase levels were less marked after the first night of nasal CPAP treatment (aspartate aminotransferase: from 6 +/- 11 IU/L to 2 +/- 6 IU/L, P = 0.0003; alanine aminotransferase: from 5 +/- 9 IU/L to 2 +/- 6 IU/L, P = 0.006). Leptin levels (n = 23) decreased significantly after treatment (P = 0.0002), whereas insulin resistance (calculated by the homeostasis model assessment method) and triglyceride levels were unchanged. Improvements in aspartate and alanine aminotransferase levels were maintained after 1 and 6 months of nasal CPAP treatment. CONCLUSION Nasal CPAP therapy may have beneficial effects on serum aminotransferase abnormalities in obese patients who have obstructive sleep apnea.

The nocturnal secretion of cardiac natriuretic peptides during obstructive sleep apnoea and its response to therapy with nasal continuous positive airway pressure

The nocturnal secretion profile of the newly identified natriuretic peptide (NP), brain natriuretic peptide (BNP), was studied in 14 patients with obstructive sleep apnoea syndrome (OSAS) (apnoea hypopnoea index: 60.5±3.4, mean±SE) during two separate nights before and during nasal continuous positive airway pressure (NCPAP) therapy. Plasma levels of NPs (atrial natriuretic peptides; ANP and BNP) were measured at 2‐h intervals during sleep. Simultaneously, blood pressure was measured by a non‐invasive method (Finapres®, Ohmeda, Englewood, CO, USA) and urine was collected for determing volume and catecholamine levels. Urinary and serum sodium concentration were determined before and after the study. Eight non‐snoring subjects were also studied for the investigation of normal nocturnal profiles of BNP levels. To understand the discrete secretion profiles of the two NPs during sleep, blood was sampled from an additional seven patients every 5 min over a 30‐min period around 00.00 and 04.00 hours before NCPAP. In patients with OSAS, plasma BNP levels increased from the beginning of sleep (22:00 h) to the morning (06:00 h) before NCPAP therapy (P< 0.01, anova). Baseline BNP levels were not significantly correlated with patients clinical and poly‐ somnographic parameters. However, in the latter half of the sleep period (02:00–06:00 h), increases in BNP levels during the night before NCPAP therapy were significantly correlated with blood pressure elevations (systolic: r=0.784 P< 0.01, diastolic: r=0.587 P< 0.01) and with apnoea duration (r=0.582 P< 0.01). In normal subjects BP and BNP levels were not changed significantly during sleep. Plasma BNP levels were well correlated with concomitant ANP levels (P< 0.001). NCPAP therapy reduced ANP and BNP levels during sleep and in the morning (P< 0.01). Plasma levels of BNP at 5 min intervals before NCPAP therapy revealed few variations. On the other hand, ANP levels fluctuated over the 30‐min period. Changes in BNP levels during sleep in the patients with OSAS may be related to blood pressure variations, but may be too small to play a significant physiological role in regulating diuresis in OSAS. Further work is required to determine the precise role of dual natriuretic system in cardiovascular load and natriuresis in OSAS.

Body mass index in male patients with COPD: correlation with low attenuation areas on CT

Background: Chronic obstructive pulmonary disease (COPD) is characterised by the presence of airflow limitation caused by loss of lung elasticity and/or airway narrowing. The pathological hallmark of loss of lung elasticity is emphysema, and airway wall remodelling contributes to the airway narrowing. Using CT, these lesions can be assessed by measuring low attenuation areas (LAA) and airway wall thickness/luminal area, respectively. As previously reported, COPD can be divided into airway dominant, emphysema dominant and mixed phenotypes using CT. In this study, it is postulated that a patient’s physique may be associated with the relative contribution of these lesions to airflow obstruction. Methods: CT was used to evaluate emphysema and airway dimensions in 201 patients with COPD. Emphysema was evaluated using percentage of LAA voxels (LAA%) and airway lesion was estimated by percentage wall area (WA%). Patients were divided into four phenotypes using LAA% and WA%. Results: Body mass index (BMI) was significantly lower in the higher LAA% phenotype (ie, emphysema dominant and mixed phenotypes). BMI correlated with LAA% (ρ = −0.557, p<0.0001) but not with WA%. BMI was significantly lower in the emphysema dominant phenotype than in the airway dominant phenotype, while there was no difference in forced expiratory volume in 1 s %predicted between the two. Conclusion: A low BMI is associated with the presence of emphysema, but not with airway wall thickening, in male smokers who have COPD. These results support the concept of different COPD phenotypes and suggest that there may be different systemic manifestations of these phenotypes.

Relationship of airway wall thickening to an imbalance between matrix metalloproteinase-9 and its inhibitor in asthma

Background: The balance between matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) may be critical in extracellular matrix remodelling, a characteristic of asthmatic airways. An excess of TIMP-1 over MMP-9 has been associated with chronic airflow obstruction but the mechanisms underlying this association remain unknown. Recent computed tomographic (CT) studies indicate that airway wall thickening is associated with chronic airflow obstruction. Methods: Sputum levels of MMP-9, TIMP-1, and their molar ratio were examined in 26 patients with stable asthma and their relationship with pulmonary function and airway wall thickness, assessed by a validated CT technique which measured wall area corrected by body surface area (WA/BSA), the ratio of WA to outer wall area (WA%), and the absolute wall thickness corrected by √BSA of a segmental bronchus (T/√BSA), was examined. Results: Sputum MMP-9 levels were inversely correlated with WA% and TIMP-1 levels were positively correlated with WA/BSA and T/√BSA. The MMP-9/TIMP-1 molar ratio was inversely correlated with WA% and T/√BSA and positively correlated with post-bronchodilator values of mid-forced expiratory flow and maximum expiratory flow at the quartile of lung volume. Conclusion: Excess TIMP-1 may have a pathogenetic role in airway wall thickening in asthmatic patients which may result in chronic airflow obstruction.