Usefulness of a 4-Grade Novel Mouthpiece Device for Increased Mouth Pressure Reproducing Artificial Difficulty in Breathing.

OBJECTIVE: The use of a novel 4-grade mouthpiece device to reproduce difficulty in breathing was assessed in healthy individuals. METHODS: A double-blind, randomized, crossover-controlled trial was conducted to investigate the efficacy and safety of the device with increasing mouth pressure. The modified Borg (mBorg) scale values, respiratory system resistance at 5 Hz (R5), and forced expiratory volume in one second (FEV1) were assessed while using the device. MATERIALS: The four grades of breathing difficulty device were tested in 32 healthy participants. RESULTS: The 4-grade device linearly worsened the mBorg scale with increasing mouth pressure. The mean R5 (± standard deviation [SD]) with grade I, II, III, and IV devices were 5.6 ± 0.1, 10.3 ± 0.3, 21.5 ± 0.7, and 54.8 ± 2.0 kPa/L/s, respectively. The mean %FEV1 predicted (± SD) were 83.6 ± 15.9% with grade I, 55.3 ± 11.8% with grade II, 32.0 ± 6.1% with grade III, and 15.3 ± 3.2% with the grade IV device. The mBorg scale was positively correlated with R5 (r = 0.79, p < 0.0001) and negatively with %FEV1 predicted (r = -0.81, p < 0.0001). No severe adverse events were reported during the trial. CONCLUSION: We demonstrated that the novel device could effectively reproduce the semi-quantitative artificial difficulty in breathing safely and easily in healthy individuals. These devices could be helpful to understand the mechanisms of difficulty in breathing.

The Efficacy and Safety of First-Line Single-Inhaler Triple versus Dual Therapy in Controller-Naïve and Symptomatic Adults with Asthma: A Preliminary Retrospective Cohort Study.

Purpose: The efficacy and safety of first-line triple and dual therapy remain unclear because the stepwise strategy is a worldwide standard in controller-naïve asthma. A preliminary retrospective cohort study was conducted to investigate the efficacy and safety of first-line triple and dual therapy for managing controller-naïve and symptomatic adult patients with asthma. Patients and Methods: Patients with asthma who received first-line single-inhaler triple therapy (SITT) or dual therapy (SIDT) for at least 8 weeks were selected between December 1, 2020, and May 31, 2021, in Fujiki Medical and Surgical Clinic, Miyazaki, Japan. Data on daytime and nighttime visual analog scale (VAS) scores, lung function tests, fractional exhaled nitrogen oxide (FENO), and adverse events were compared between SITT and SIDT pre- and post-treatment. Results: The SITT significantly improved the nighttime, but not daytime, VAS scores better than the SIDT 2 weeks post-treatment (P = 0.0026), whereas SITT and SIDT significantly improved daytime and nighttime VAS scores after treatment compared to baseline. Both therapies also significantly improved lung functions and FENO post-treatment. The proportion of patients achieving complete control in the nighttime VAS scores after SITT was significantly higher than that four (P = 0.0186) and 8 weeks (P = 0.0061) after SIDT. Only patients with SITT experienced dry mouth. Conclusion: Our study demonstrated that first-line SITT and SIDT were effective, and SITT improved disease control faster than SIDT in controller-naïve and symptomatic adult patients with asthma. The first-line SITT may contribute to faster and better control levels in symptomatic patients with asthma.

Daytime and Nighttime Visual Analog Scales May Be Useful in Assessing Asthma Control Levels Before and After Treatment.

Purpose: Few questionnaires evaluate daytime and nighttime symptoms separately, although these assessments could contribute to the improvement of disease control levels and prevention of future risks in asthma. The purpose of this retrospective study was to investigate whether daytime and nighttime visual analog scales (VAS) are useful in measuring the perception of symptoms, assessing disease control levels, and evaluating the treatment effects in asthma. Patients and Methods: Self-reporting asthma control tests (ACT) before and after treatment are standardized tests used to determine disease control levels. A multiple regression analysis was performed to determine the correlation between daytime and nighttime VAS and the characteristics of patients before treatment, as well as the changes in VAS and lung functions and fractional exhaled nitrogen oxide after treatment in 55 treatment-naïve symptomatic adult patients with asthma. Results: Both daytime (r = -0.57, P < 0.0001) and nighttime (r = -0.46, P < 0.0001) VAS correlated well with ACT scores, and there was a correlation between daytime and nighttime VAS (r = 0.33, P = 0.0148) before treatment. In addition, the changes in daytime (r = -0.65, P < 0.0001) and nighttime (r = -0.44, P < 0.0001) VAS were significantly associated with changes in the ACT scores. The multiple regression analysis (ß [95% confidence interval]) revealed that improvements in the daytime (-2.33 [-4.55 to -0.11], P = 0.0405) and nighttime (-3.09 [-6.25 to 0.07], P = 0.0505) VAS were associated with an increased forced vital capacity after treatment, although there was no correlation between the VAS and characteristics before treatment. Conclusion: Our study demonstrated that daytime and nighttime VAS were useful in assessing disease control levels and evaluating the treatment effects in asthma.

Poor Asthma Control in Schoolchildren May Lead to Lower Lung Function Trajectory from Childhood to Early Adulthood: A Japanese Cohort Study.

Purpose: Although childhood asthma is a risk factor for adult lung function disorders, the correlation between childhood asthma control level and lung function growth remains unclear in Japan. The correlation between childhood asthma control and early adulthood lung function growth was investigated in this study. Patients and Methods: We included 505 children with asthma from the Omuta City Air Pollution-Related Health Damage Cohort Program. The characteristics and lung function of girls and boys aged 6-11 years and 12-17 years were compared between poor and good asthma control groups. Results: Among the 505 children, 214 (42.4%) showed poor asthma control. The mean percentage forced expiratory volume in 1 second predicted for girls and boys aged 6-11 years (80.2% and 79.2%, respectively) and 12-17 years (80.0% and 81.1%, respectively) in the poor control group was significantly lower than those of girls and boys aged 6-11 years (87.9% and 87.3%, respectively) and 12-17 years (88.1% and 87.8%, respectively) in the good control group. However, a linear regression model did not reveal between-group differences in the slopes of lung function growth for both sexes. Girls (24.6%, P < 0.0001) and boys (24.4%, P = 0.0026) in the poor control group had a significantly higher proportion of young adults with obstructive ventilatory patterns than girls (1.4%) and boys (8.1%) in the good control group. Conclusion: Our findings revealed that poor childhood asthma control leaded to lung function disorders, which suggest the importance of early asthma control in school children.

Overweight improves long-term survival in Japanese patients with asthma.

BACKGROUND: Obesity is a risk factor for severe and difficult-to-treat asthma. However, the impact of different physiques on long-term outcomes is poorly understood. We aimed to investigate the correlation between obesity and asthma-associated long-term mortality in Japanese adults. METHODS: From the data on 3146 individuals with air pollution-related respiratory diseases in the Omuta City Air Pollution-Related Health Damage Cohort Program, 697 adult patients with asthma were analyzed. Hazard ratios for long-term all-cause and respiratory disease -related mortality were compared in patients with different physiques using the Cox proportional hazard models. The classification of physiques was based on the WHO obesity criteria. RESULTS: Of the 697 patients, 439 died during the median observation period of 26.3 years. The number (% of total) of underweight, normal-weight, pre-obese, and obese class I-III individuals were 75 (10.8%), 459 (65.9%), 140 (20.1%), and 23 (3.3%), respectively. The Cox proportional hazard model (adjusted hazard ratio [95% confidence interval], P value) showed that pre-obese group had a significantly reduced risk for all-cause (0.65 [0.51 to 0.83], P < 0.05) and respiratory disease (0.55 [0.37 to 0.81], P < 0.05)-related mortality related to normal-weight group. CONCLUSIONS: Our cohort program demonstrated that being slightly overweight may reduce the risk of long-term mortality in patients with asthma. However, the influence of obesity on long-term outcomes remains unclear in asthma, because of the small number of obese patients included in our study. Our findings suggest that interventions, including nutrition and exercises, should be provided to Japanese patients with asthma.

Role of Regulatory T cells in Airway Inflammation in Asthma.

Asthma is an allergic disease characterized by chronic airway inflammation, airway hyperresponsiveness (AHR), reversibility and remodeling. Inhaled corticosteroids (ICS) are effective in many patients with asthma. However, ICS are a controlling, but not but curative treatment, and there are still many patients with refractory and difficult-to-treat asthma. The evaluation of airway inflammation by induced sputum, non-specific AHR by methacholine, and asthmatic reactions by specific allergen challenge techniques are useful not only to investigate the pathogenesis of asthma but also to help develop new drugs for asthma management. Interactions between inflammation and regulation, such as between regulatory T cells (Tregs), and AHR were investigated using these techniques. The phenotypes are Tregs characterized by expression of the forkhead box P3 (Foxp3) and cytotoxic T-lymphocyte antigen 4 (CTLA4), which are potent mediators of dominant self-tolerance. Foxp3 and CTLA4 interact with each other. In patients with mild asthma, airway Tregs were decreased and airway eosinophilic inflammation was activated with accelerated AHR. Human asthmatic attack models by allergen challenge demonstrated that airway Tregs were decreased from the baseline with late asthmatic response (LAR) in patients with dual-responder asthma, and there was a significant correlation between change in airway Tregs and LAR. Airway Tregs were increased with escalation of interleukin-10 by ICS. The investigation of Tregs may lead to new strategies for management of asthma and other allergic diseases.

High Detection Rates of Urine Mycobacterium tuberculosis in Patients with Suspected Miliary Tuberculosis.

Objective The utility of detecting Mycobacterium tuberculosis in urine samples from patients with pulmonary tuberculous with diffuse small nodular shadows (suspected miliary tuberculosis (MTB)) is still unclear in Japan. A retrospective cross-sectional study was conducted to investigate the detection rates of M. tuberculosis in urine of patients with suspected MTB. Methods Among 687 hospitalized patients with tuberculosis, 45 with culture-confirmed suspected MTB and the data of culture and polymerase chain reaction (PCR) for M. tuberculosis in urine and sputum samples were investigated. The detection rates of M. tuberculosis in urine using cultures and PCR were calculated. The detection rate of urine was then compared with that of bone marrow aspiration. Results Fourteen patients with suspected MTB were ultimately analyzed. A diagnosis of miliary tuberculosis was suspected in all patients before anti-tuberculosis chemotherapy. Positive results by PCR (11 [78.6%] cases) and culture (8 [57.1%]) were obtained from urine samples. In patients with suspected MTB, there was no significant difference in the detection rates between M. tuberculosis in urine using a combination of PCR and culture (85.6% [12/14 cases]) and bone marrow aspiration (66.7% [8/12 cases]) (p>0.05). Conclusion Using PCR and culture, we demonstrated high detection rates of M. tuberculosis in the urine of patients with suspected MTB. A combination of PCR and culture compared favorably with the detection rates achieved with bone marrow aspiration. We believe that detection of M. tuberculosis from urine and sputum samples may be easy and safe for patients with disseminated tuberculosis infections such as definitive MTB.

Responsiveness of blood and sputum inflammatory cells in Japanese COPD patients, non-COPD smoking controls, and non-COPD nonsmoking controls.

PURPOSE: To compare pulmonary and systemic inflammatory mediator release, pre- and poststimulation, ex vivo, in cells from Japanese patients with chronic obstructive pulmonary disease (COPD), non-COPD smoking controls, and non-COPD nonsmoking controls (NSC). PATIENTS AND METHODS: This was a nontreatment study with ten subjects per group. Inflammatory biomarker release, including interleukin (IL)-6 and -8, matrix metalloproteinase-9, and tumor necrosis factor (TNF)-α, was measured in peripheral blood mononuclear cells (PBMC) and sputum cells with and without lipopolysaccharide or TNF-α stimulation. RESULTS: In PBMC, basal TNF-α release (mean ± standard deviation) was significantly different between COPD (81.6±111.4 pg/mL) and nonsmoking controls (9.5±5.2 pg/mL) (P<0.05). No other significant differences were observed. Poststimulation biomarker release tended to increase, with the greatest changes in the COPD group. The greatest mean increases were seen in the lipopolysaccharide-induced release of matrix metalloproteinase-9, TNF-α, and IL-6 from PBMC. Pre- and poststimulation data from sputum samples were more variable and less conclusive than from PBMC. In the COPD group, induced sputum neutrophil levels were higher and macrophage levels were lower than in either control group. Significant correlations were seen between the number of sputum cells (macrophages and neutrophils) and biomarker levels (IL-8, IL-6, and TNF-α). CONCLUSION: This was the first study to compare cellular inflammatory mediator release before and after stimulation among Japanese COPD, smoking controls, and nonsmoking controls populations. Poststimulation levels tended to be higher in patients with COPD. The results suggest that PBMC are already preactivated in the circulation in COPD patients. This provides further evidence that COPD is a multicomponent disease, involving both airway and systemic inflammation.

"Frequent exacerbator" is a phenotype of poor prognosis in Japanese patients with chronic obstructive pulmonary disease.

BACKGROUND: The prognosis of Japanese patients with COPD who suffer repeated exacerbations is unclear, although Westerners with such episodes have a poor prognosis. MATERIALS AND METHODS: We conducted a 1-year prospective observational trial involving 90 Japanese patients with COPD: 58 nonexacerbators, 12 infrequent exacerbators, and 20 frequent exacerbators classified on the basis of exacerbation frequency (zero, one, and two or more exacerbations/year), respectively, during the previous year were observed prospectively for 1 year. The characteristics of frequent exacerbators, the frequency of exacerbation, and the period until the first event were then compared among the groups. RESULTS: A total of 78 patients completed the study. Frequent exacerbators had a significantly higher risk of frequent exacerbation in the following year than the case for nonexacerbators (odds ratio [95% confidence interval] 2.94 [1.21-7.17], P=0.0340), but not in comparison with infrequent exacerbators (1.51 [0.49-4.63], P>0.05). The mean annual frequency of exacerbations in the following year was significantly (P=0.0020) higher in the frequent exacerbators (1.4 exacerbations/year) than in the nonexacerbators (0.4), but not in the infrequent exacerbators (0.9, P>0.05). The mean period until the first exacerbation was significantly shorter in the frequent exacerbators than in the infrequent or nonexacerbators (P=0.0012). Independent risk factors for future frequent exacerbation included the presence of gastroesophageal reflux disease, more severe airflow obstruction, and use of inhaled corticosteroids. CONCLUSION: Our present results indicate that Japanese COPD patients suffering frequent exacerbation have a poor prognosis. The characteristics of Japanese and Western COPD patients suffering frequent exacerbation are similar.

Evaluation of the Modified Medical Research Council Dyspnea Scale for Predicting Hospitalization and Exacerbation in Japanese Patients with Chronic Obstructive Pulmonary Disease.

OBJECTIVE: The modified Medical Research Council (mMRC) scale is recommended for conducting assessments of dyspnea and disability and functions as an indicator of exacerbation. The aim of this study was to investigate whether the mMRC scale can be used to predict hospitalization and exacerbation in Japanese patients with chronic obstructive pulmonary disease (COPD). METHODS: In a previous 52-week prospective study, 123 patients with COPD were classified into five groups (grades 0 to 4) according to the mMRC scale and four groups (stages I to IV) according to the spirometric Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification. The frequency and period until the first event of hospitalization and exacerbation were compared among the groups. RESULTS: The population of patients who experienced hospitalization and exacerbation during the 52-week study period, with an mMRC scale grade of 4, 3, 2, 1 and 0 was 50.0 and 100, 55.6 and 88.9, 21.1 and 73.7, 2.6 and 48.7, and 4.0 and 22.0%, respectively. A multivariate analysis adjusted for the GOLD stage and age showed that the patients with an mMRC scale grade of ≥3 had higher frequencies of hospitalization and exacerbation than those with lower grades. Meanwhile, the patients with an mMRC scale grade of ≥2 showed a significantly earlier time until the first exacerbation, but not hospitalization, in comparison with those with grade 0. CONCLUSION: The present results indicate that, among Japanese patients with COPD, those with an mMRC scale grade of ≥3 have a significantly poorer prognosis and that the mMRC scale can be used to predict hospitalization and exacerbation.

Paired maximum inspiratory and expiratory plain chest radiographs for assessment of airflow limitation in chronic obstructive pulmonary disease.

BACKGROUND: The usefulness of paired maximum inspiratory and expiratory (I/E) plain chest radiography (pCR) for diagnosis of chronic obstructive pulmonary disease (COPD) is still unclear. OBJECTIVES: We examined whether measurement of the I/E ratio using paired I/E pCR could be used for detection of airflow limitation in patients with COPD. METHODS: Eighty patients with COPD (GOLD stage I=23, stage II=32, stage III=15, stage IV=10) and 34 control subjects were enrolled. The I/E ratios of frontal and lateral lung areas, and lung distance between the apex and base on pCR views were analyzed quantitatively. Pulmonary function parameters were measured at the same time. RESULTS: The I/E ratios for the frontal lung area (1.25±0.01), the lateral lung area (1.29±0.01), and the lung distance (1.18±0.01) were significantly (p<0.05) reduced in COPD patients compared with controls (1.31±0.02 and 1.38±0.02, and 1.22±0.01, respectively). The I/E ratios in frontal and lateral areas, and lung distance were significantly (p<0.05) reduced in severe (GOLD stage III) and very severe (GOLD stage IV) COPD as compared to control subjects, although the I/E ratios did not differ significantly between severe and very severe COPD. Moreover, the I/E ratios were significantly correlated with pulmonary function parameters. CONCLUSIONS: Measurement of I/E ratios on paired I/E pCR is simple and reproducible, and can detect airflow limitation in patients with severe and very severe COPD.

COPD assessment tests scores are associated with exacerbated chronic obstructive pulmonary disease in Japanese patients.

BACKGROUND: Guidelines recommend chronic obstructive pulmonary disease (COPD) assessment tests (CATs) for evaluation of symptoms and management risks. To investigate whether CAT can predict moderate or severe exacerbations in Japanese COPD patients, a single-blinded prospective study was performed. METHODS: A 123 Japanese COPD patients were classified into high-CAT (n=64) and low-CAT (n=59) groups. The frequencies and periods of moderate or severe exacerbation and hospitalization were compared between the two groups. Multivariate logistic regression analysis was performed to investigate whether CAT could predict exacerbations. A receiver operating characteristic (ROC) curve analysis was employed to find an appropriate CAT score for exacerbation. RESULTS: The high-CAT group was significantly older, had a lower body mass index, and had a lower airflow obstruction as compared to the low CAT group. The frequency of moderate or severe exacerbation (1.3±1.3 events per patient per year, p<0.0001) and hospitalizations (0.2±0.4, p=0.0202) in the high-CAT group was significantly higher than in the low-CAT group (0.4±0.7 and 0.0±0.1, respectively). Multivariate logistic regression analysis showed that both high CAT score and low airflow obstruction were independently predictive of frequent moderate or severe COPD exacerbation. ROC analysis showed that the best cut-off CAT score for moderate or severe COPD exacerbation was 8 points. CONCLUSION: Our present results indicate that COPD Japanese patients showing high CAT scores have a poor prognosis, and that the CAT score is able to predict exacerbation in Japanese COPD.

Positive association between the plasma levels of 5-hydroxyindoleacetic acid and the severity of depression in patients with chronic obstructive pulmonary disease.

BACKGROUND: The role of plasma monoamines in patients with chronic obstructive pulmonary disease (COPD) with depression is unclear. To investigate monoamines in 20 depressed patients with COPD, the plasma concentrations of serotonin, 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid, and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured and compared with those in 50 non-depressed COPD patients, and also with 23 age- and gender-matched non-smokers and 13 smokers as non-depressed healthy controls. METHODS: Diagnosis of depression was assessed using the Centre for Epidemiologic Studies Depression Scale. Plasma concentrations of monoamines were measured by high-performance liquid chromatography. RESULTS: None of the depressed COPD patients had suicidal ideation. The plasma 5-HIAA level [median, (25% and 75% quartiles)] in depressed COPD patients [6.8 ng/mL, (4.9 and 13.1)] was significantly higher than in non-depressed COPD patients [5.4, (4.2 and 7.5)] (p=0.022) and non-smokers [5.1 (3.8 and 7.2)] (p=0.041), but not smokers [4.7, (4.0 and 6.7)] (p>0.05). The plasma 5-HIAA level (r=0.24, p=0.049) was significantly associated with the severity of depression in patients with COPD. The plasma MHPG level was significantly higher in depressed COPD patients (p=0.043) than in smokers, but was not higher than that in non-depressed COPD patients or non-smokers, although the level of MHPG was not associated with the severity of depression. CONCLUSION: The plasma 5-HIAA level is increased in depressed COPD patients. Plasma monoamines may be a good biomarker for detection of depression in patients with COPD.

Decreased CTLA4(+) and Foxp3(+) CD25(high)CD4(+) cells in induced sputum from patients with mild atopic asthma.

BACKGROUND: Details of the comparisons between airway and peripheral blood regulatory T cells (Tregs) in patients with atopic asthma are still unclear. The objective of this study is to investigate the profiles of both airway and circulating Tregs in atopic asthma. METHODS: We measured the numbers of Tregs and eosinophils in induced sputum and peripheral blood in 28 patients with mild atopic asthma and compared these with numbers in 18 healthy controls. The frequency (%) of Tregs (surface CTLA4+, intracellular Foxp3+, and CTLA4+Foxp3+ on CD25highCD4+ T cells) in sputum and blood was determined by intracellular 5-color flow cytometry. We also correlated the numbers with the level of airway hyperresponsiveness (AHR) in asthmatics. RESULTS: The mean frequencies of cells expressing CTLA4+ (19.4 ± 2.1%, p = 0.075), Foxp3+ (16.4 ± 3.3%, p = 0.001), and CTLA4+Foxp3+ (7.0 ± 1.1%, p = 0.008) in induced sputum from asthmatics were significantly lower than controls (27.2 ± 3.7%, 37.4 ± 4.7%, and 18.2 ± 3.6%, respectively), whereas in peripheral blood, there was no inter-group difference in the frequencies of cells expressing CTLA4+ (7.1 ± 1.5% vs 5.7 ± 1.7%, p > 0.05), Foxp3+ (35.7 ± 3.2% vs 21.1 ± 3.9%, p > 0.05), and CTLA4+Foxp3+ (6.6 ± 1.5% vs 4.2 ± 1.0%, p > 0.05). Moreover, the frequency of CD25highCD4+ cells expressing CTLA4+, but not Foxp3+, in induced sputum was associated with AHR (r = 0.60, p = 0.009) and airway eosinophilic inflammation (r = -0.60, p = 0.008) in asthmatics. CONCLUSIONS: Airway, but not circulating, Tregs are decreased in mild atopic asthmatics, and are negatively correlated to an increase of airway eosinophilic inflammation and AHR.

Depression, but not sleep disorder, is an independent factor affecting exacerbations and hospitalization in patients with chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVE: Patients with chronic obstructive pulmonary disease (COPD) may experience depression and sleep disorders, which can adversely affect their health-related quality of life (HRQOL). The aim of this study was to investigate depression and sleep disorders among 85 COPD patients and 46 control subjects, aged 40 years and over. METHODS: Patients underwent spirometry and arterial blood gas analysis, self-completed St. George's respiratory questionnaire and were assessed on the center for epidemiologic studies depression (CES-D) and the Pittsburgh sleep quality index (PSQI). The frequency of exacerbations among COPD patients was prospectively monitored for 12 months. RESULTS: The prevalence of depression and sleep disorders was significantly higher among COPD patients than control subjects. The relative risks (95% confidence interval) of depression and sleep disorders were 7.58 (1.03 to 55.8) and 1.82 (1.03 to 3.22), respectively, in COPD patients compared with control subjects. Among COPD patients, there was a correlation between CES-D and PSQI. Lower body mass index, more severe dyspnoea, poorer HRQOL, lower partial pressure of arterial oxygen and higher partial pressure of arterial carbon dioxide were significantly associated with the incidence of depression and sleep disorders. Exacerbations and hospitalizations were more frequent among COPD patients with depression than those with sleep disorders alone or those without depression or sleep disorders. CONCLUSIONS: Depression and sleep disorders are very common co-morbidities among COPD patients and significantly reduce activities and HRQOL among these patients. Depression, but not sleep disorder, is an independent risk factor for exacerbations and hospitalization among COPD patients.

Overexpression of chitinase 3-like 1/YKL-40 in lung-specific IL-18-transgenic mice, smokers and COPD.

We analyzed the lung mRNA expression profiles of a murine model of COPD developed using a lung-specific IL-18-transgenic mouse. In this transgenic mouse, the expression of 608 genes was found to vary more than 2-fold in comparison with control WT mice, and was clustered into 4 groups. The expression of 140 genes was constitutively increased at all ages, 215 genes increased gradually with aging, 171 genes decreased gradually with aging, and 82 genes decreased temporarily at 9 weeks of age. Interestingly, the levels of mRNA for the chitinase-related genes chitinase 3-like 1 (Chi3l1), Chi3l3, and acidic mammalian chitinase (AMCase) were significantly higher in the lungs of transgenic mice than in control mice. The level of Chi3l1 protein increased significantly with aging in the lungs and sera of IL-18 transgenic, but not WT mice. Previous studies have suggested Chi3l3 and AMCase are IL-13-driven chitinase-like proteins. However, IL-13 gene deletion did not reduce the level of Chi3l1 protein in the lungs of IL-18 transgenic mice. Based on our murine model gene expression data, we analyzed the protein level of YKL-40, the human homolog of Chi3l1, in sera of smokers and COPD patients. Sixteen COPD patients had undergone high resolution computed tomography (HRCT) examination. Emphysema was assessed by using a density mask with a cutoff of -950 Hounsfield units to calculate the low-attenuation area percentage (LAA%). We observed significantly higher serum levels in samples from 28 smokers and 45 COPD patients compared to 30 non-smokers. In COPD patients, there was a significant negative correlation between serum level of YKL-40 and %FEV(1). Moreover, there was a significant positive correlation between the serum levels of YKL-40 and LAA% in COPD patients. Thus our results suggest that chitinase-related genes may play an important role in establishing pulmonary inflammation and emphysematous changes in smokers and COPD patients.

Soluble interleukin-18 receptor complex is a novel biomarker in rheumatoid arthritis.

INTRODUCTION: There has been no report in the literature of a soluble form of interleukin (IL)-18 receptor α (IL-18Rα). In this study, we evaluated the levels and characteristics of soluble IL-18Rα (sIL-18Rα) in the sera of patients with rheumatoid arthritis (RA) and compared these results to control populations. METHODS: The sIL-18Rα complex was isolated from pooled human blood serum using an anti-IL-18Rα monoclonal antibody affinity column. The purified sIL-18Rα was then examined using Western blot analysis and used in experiments to evaluate the effects on an IL-18-responsive natural killer (NK) human cell line, NK0. An enzyme-linked immunosorbent assay was developed, and sera from 145 patients with RA, 6 patients with adult-onset Still's disease, 31 patients with osteoarthritis (OA), 39 patients with systemic lupus erythematosus (SLE) and 67 controls were tested, along with levels of immunoglobulin M, rheumatoid factor, anticyclic citrullinated peptide antibody, IL-18, IL-13 and interferon (IFN)-γ. Area under the receiver operating characteristic curve (ROC-AUC) analysis was used to evaluate the diagnostic utility of the sIL-18Rα complex. RESULTS: The isolated sIL-18Rα complex can be associated with IL-18 and the soluble form of the IL-18Rß chain. The sIL-18Rα complex bound to the surface to the NK0 cell line, antagonized the stimulatory effects of IL-18 and IL-2 on the NK0 cell line and inhibited IFN-γ production by the cells. The serum levels of sIL-18Rα complex in RA (186.0 ± 33.5 ng/mL, n = 145) and adult-onset Still's disease (98.2 ± 8.9 ng/mL, n = 6) were significantly (P < 0.001) higher than those in the healthy controls (52.3 ± 8.5 ng/mL, n = 67), OA (38.6 ± 5.4 ng/mL, n = 31), SLE (44.6 ± 3.2 ng/mL, n = 39). The serum level of sIL-18Rα complex was not significantly different between RA and adult-onset Still's disease patients. The serum levels of IL-18, IL-13 and IFN-γ in the RA patients were significantly (P < 0.01) higher than in OA and SLE patients as well as healthy controls. ROC-AUC analysis of the serum concentration of sIL-18Rα indicated that it was significantly diagnostic of RA. Moreover, a tumor necrosis factor inhibitor, etanercept, significantly (P < 0.0001) decreased levels of sIL-18Rα in the sera of 29 RA patients 6 months after treatment. CONCLUSIONS: The sIL-18Rα complex could be a potentially useful biomarker for the diagnosis of RA.

Elevated levels of thioredoxin 1 in the lungs and sera of idiopathic pulmonary fibrosis, non-specific interstitial pneumonia and cryptogenic organizing pneumonia.

OBJECTIVE: Oxidant stress is thought to be involved in the establishment of idiopathic interstitial pneumonia (IIP). Thioredoxin 1 (TRX1) plays a role as a strong antioxidant in vivo, suggesting that TRX1 may be involved in the pathogenesis of IIPs. However, there is no report on TRX1 levels in the sera of IIPs. In addition, TRX1 expression in the lungs of non-specific interstitial pneumonia (NSIP) and cryptogenic organizing pneumonia (COP) patients also has not been reported. Here, we investigated whether or not TRX1 levels are altered in the lungs and sera of patients with idiopathic pulmonary fibrosis (IPF), NSIP, and COP. METHODS: Immunohistochemical analysis was performed to examine the expression of TRX1. TRX1 levels in sera were measured using an ELISA kit. RESULTS: TRX1 was expressed in the bronchiole-alveolar epithelium, especially with regenerative or metaplastic feature, and in alveolar macrophages in usual interstitial pneumonia (UIP) and fibrotic NSIP. TRX1 was weakly expressed in the lungs of cellular NSIP and COP. TRX1 producing cells in UIP (n=16), fibrotic NSIP (n=15), cellular NSIP (n=4), and COP (n=5) were significantly increased when compared to nonsmokers (n=7). TRX1 producing cells in UIP and fibrotic NSIP were significantly increased when compared to cellular NSIP and COP. TRX1 levels in the sera of the patients with IPF (n=32; 74.2 ± 7.5 ng/mL), fibrotic NSIP (n=7; 82.5 ± 18.4 ng/mL), cellular NSIP (n=3; 62.2 ± 3.2 ng/mL) and COP (n=17; 88.8 ± 19.7 ng/mL) were significantly higher than those of control subjects (n=74; 35.3 ± 2.7 ng/mL). Furthermore, TRX1 levels in the sera of IPF patients who later showed acute exacerbation (n=7; 106.6 ± 16.3 ng/mL) were significantly higher than those of IPF patients without acute exacerbation (n=25; 65.1 ± 7.6 ng/mL). CONCLUSION: Overproduction of TRX1 in the lungs and sera may play an important role in the pathogenesis of IIPs.

[The relation between nutritional state of tuberculous patients admitted in tuberculous ward and their outcome at the time of discharge].

OBJECTIVES: To investigate the relation between nutritional state of tuberculous patients admitted in tuberculous ward and their outcome at the time of discharge. PATIENTS AND METHODS: We retrospectively investigated BMI, peripheral blood lymphocyte count, serum albumin concentration, and induration size of PPD skin test at the time of admission from their clinical charts of all 174 tuberculous patients newly admitted in NHO Omuta National Hospital during the period from 2000 to 2002, and based on these indices, the nutritional state of tuberculous patients was divided into severely impaired, moderately impaired, and mildly impaired or normal. The relation between nutritional state on admission and the outcome at the time of discharge was examined. RESULTS: The worse the nutritional state on admission, the higher the rate of death from all causes and tuberculosis, and the higher the average age and the duration of hospitalization. CONCLUSIONS: The assessment method of nutritional state reported in our study is easily applicable to every tuberculous patients admitted in tuberculous ward, and the outcome of tuberculous patients at the time of discharge could be expected, based on the nutritional state assessed with this method. Prospective study is needed to ascertain the validity of results obtained in the present study.

[A case of Streptomyces pneumonia].

A 85-year-old man who had a past history of gastrectomy but no subsequent chemotherapy was suffering fever and fatigue. The infiltrative shadow with cavitation on his chest X-ray film did not improve despite treatment with several antibiotics after admission. Transcutaneous needle aspiration performed for diagnosis of the cavitated lung lesion yielded Streptomyces. A definitive diagnosis of streptomyces lung infection was established. We believed that this is the first case of streptomyces infection of the lung reported in Japan. The current case was also rare because he did not have any immunosuppressive status, while almost all cases previously reported.