Low-dose salbutamol suppresses airway responsiveness to histamine but not methacholine in subjects with asthma.

BACKGROUND: Airway hyperresponsiveness is a cardinal feature of asthma. Although the modulation of cholinergic neuroeffector transmission may play a role in airway responsiveness, in vivo evidence remains scarce. It is well known that histamine causes bronchoconstriction partly via vagal reflex, whereas methacholine does not. To investigate the significance of modulating neuroeffector transmission, we compared the effect of low-dose salbutamol-a ß2-adrenoceptor agonist-on airway responsiveness to histamine with that to methacholine. METHODS: We enrolled 12 subjects with stable asthma. After screening confirmed that inhalation of low-dose salbutamol (1µg) did not change their basic pulmonary function, subjects underwent measurement of airway responsiveness to inhaled histamine and methacholine with or without pretreatment with low-dose salbutamol, in a randomized, crossover fashion. Airway responsiveness was measured by an astograph by which respiratory conductance (Grs) was assessed by the forced oscillation method during continuous inhalation of histamine or methacholine in stepwise incremental concentrations. Airway responsiveness was calculated as the cumulative dose of bronchoconstrictors that induced a decrease of 35% in Grs. RESULTS: Inhalation of 1µg of salbutamol significantly attenuated airway responsiveness to histamine but not methacholine. This selective attenuation was observed irrespective of disease severity or phenotype, namely atopy or non-atopy. CONCLUSION: Low-dose salbutamol suppresses airway responsiveness to histamine but not methacholine in subjects with asthma. The present study may provide a novel insight into the bronchoprotective mechanism of ß2-adorenoceptor agonist in clinical settings.

Development of the Japanese version of the COPD Assessment Test.

BACKGROUND: We aimed to develop the Japanese version of the COPD Assessment Test (TM) (CAT), which was recently developed in overseas countries, to measure the health status of patients with chronic obstructive pulmonary disease (COPD) and to validate its psychometric properties. METHODS: The original CAT was translated to Japanese through linguistic validation. Then, an Internet-based survey was conducted by including 301 Japanese patients with COPD who were over 40 years of age and had a history of smoking, to assess the reliability and validity of the translated CAT. RESULTS: The Japanese CAT was shown to have high internal consistency (Cronbach's α coefficient: 0.891). The assessment using the Japanese CAT was highly correlated with assessment using the COPD-specific St. George's Respiratory Questionnaire (r = 0.820). The assessment also showed correlation between the Japanese CAT and a generic health-related quality of life (QOL) questionnaire (SF-12v2). CONCLUSION: The Japanese version of the CAT has high reliability and validity, and can be expected to serve as a short and simple questionnaire for precise assessment of the health status of Japanese patients with COPD.

Periostin, a matricellular protein, plays a role in the induction of chemokines in pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal form of interstitial lung disease (ILD). The precise molecular mechanisms of IPF remain poorly understood. However, analyses of mice receiving bleomycin (BLM) as a model of IPF established the importance of preceding inflammation for the formation of fibrosis. Periostin is a recently characterized matricellular protein involved in modulating cell functions. We recently found that periostin is highly expressed in the lung tissue of patients with IPF, suggesting that it may play a role in the process of pulmonary fibrosis. To explore this possibility, we administered BLM to periostin-deficient mice, and they subsequently showed a reduction of pulmonary fibrosis. We next determined whether this result was caused by a decrease in the preceding recruitment of neutrophils and macrophages in the lungs because of the lower production of chemokines and proinflammatory cytokines. We performed an in vitro analysis of chemokine production in lung fibroblasts, which indicated that periostin-deficient fibroblasts produced few or no chemokines in response to TNF-α compared with control samples, at least partly explaining the lack of inflammatory response and, therefore, fibrosis after BLM administration to periostin-deficient mice. In addition, we confirmed that periostin is highly expressed in the lung tissue of chemotherapeutic-agent-induced ILD as well as of patients with IPF. Taking these results together, we conclude that periostin plays a unique role as an inducer of chemokines to recruit neutrophils and macrophages important in the process of pulmonary fibrosis in BLM-administered model mice. Our results suggest a therapeutic potential for periostin in IPF and drug-induced ILD.

Anhedonia in Japanese patients with Parkinson's disease: analysis using the Snaith-Hamilton Pleasure Scale.

BACKGROUND: Anhedonia, a lowered ability to experience physical or social pleasure, has recently been recognized as a non-motor symptom of Parkinson's disease. OBJECTIVE: To identify the frequency of anhedonia and the factors influencing hedonic tone in Japanese patients with Parkinson's disease. PATIENTS AND METHODS: We recruited 86 consecutive outpatients with a clinical diagnosis of PD attending two Japanese hospitals (one university hospital and one community hospital) in February 2010. We used the self-rating Snaith-Hamilton Pleasure Scale (SHAPS) translated into Japanese language from the original English version to assess and quantify hedonic tone as a subjectively experienced phenomenon. We studied the association of anhedonia with the variables age, age at onset, gender, disease duration, disease severity and antiparkinsonian drugs. RESULTS: Thirty-nine patients (45%) were male and 47 (55%) were female. Mean age was 72.01±9.07 (49-89) years, with mean age at onset of 64.93±11.42 (31-88) years. Mean disease duration was 7.20±5.54 (1-23) years. The mean Hoehn and Yahr scale was 2.76±0.78. The mean SHAPS score of the total sample was 1.19±1.86. The SHAPS score of 14 patients (16.3%) was 3 or more, indicating anhedonia. The mean SHAPS score was lower in patients taking pramipexole (0.58±0.97) than in patients not taking pramipexole (1.57±2.16). Multiple linear regression analysis identified pramipexole as a significant negative influencing factor on the SHAPS score, while disease severity and entacapone treatment were identified as positive influencing factors. The age, onset age, gender, disease duration, and use of pergolide, amantadine, zonisamide, selegiline, anticholinergic agents and droxidopa did not significantly affect the SHAPS score. CONCLUSION: Anhedonia is not rare non-motor symptom in Japanese patients with Parkinson's disease. This study suggests an anti-anhedonic property of pramipexole.

C-reactive protein levels, airflow obstruction, and chronic kidney disease.

OBJECTIVES: There is some evidence that chronic obstructive pulmonary disease and chronic kidney disease (CKD) may be related, perhaps through systemic inflammation, which is common to both. However, this relationship has not yet been clearly demonstrated. The aim of this study was to investigate the association between airflow obstruction, CKD, and C-reactive protein (CRP) levels in Japanese men. METHODS: The study included 11,587 men, aged 40-88 years, who underwent a health check-up. Airflow obstruction was defined as a forced expiratory volume in 1 s/forced vital capacity of <70%, and its severity was based on the Global Initiative for Chronic Obstructive Lung Disease guidelines (GOLD). CKD was defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m(2). RESULTS: Airflow obstruction was present in 7.9% of the participants, and 10.6% of the participants had CKD. The average CRP levels were 0.11 ± 0.36, 0.13 ± 0.41, and 0.18 ± 0.41 mg/L for subjects with normal lung function, GOLD stage I, and GOLD stage II-IV, respectively. With regard to CKD, the average CRP levels were 0.11 ± 0.32 and 0.18 ± 0.6 mg/L for subjects without and with CKD, respectively. Analysis of covariance showed no significant differences between the CRP level and lung function status or CKD after age was adjusted for. Logistic regression analysis showed no association among subjects with the three different lung function statuses after age, body mass index, hypertension, diabetes, hyper-low-density-lipoprotein-cholesterolemia, smoking, physical activity, and alcohol intake were controlled for. CONCLUSIONS: Based on the results of this study, we conclude that there is no interrelationship between CRP level, airflow obstruction, and CKD.

Efficacy and safety of inhaled formoterol 4.5 and 9 µg twice daily in Japanese and European COPD patients: phase III study results.

BACKGROUND: This study evaluated the efficacy and safety of the long-acting ß2-agonist formoterol in patients with moderate-to-severe COPD. METHODS: This double-blind, placebo-controlled, parallel-group, multinational phase III study randomized patients ≥ 40 years of age with moderate-to-severe COPD to inhaled formoterol 4.5 or 9 µg twice daily (bid) via Turbuhaler or placebo for 12 weeks. Salbutamol 100 µg/actuation via pMDI was permitted as reliever medication. The primary outcome variable was change (ratio) from baseline to treatment period in FEV1 60-min post-dose. RESULTS: 613 patients received treatment (formoterol 4.5 µg n = 206; 9 µg n = 199; placebo n = 208); 539 (87.9%) male; 324 (52.9%) Japanese and 289 (47.1%) European. End of study increases in FEV1 60-min post-dose were significantly greater (p < 0.001 for both) with formoterol 4.5 and 9 µg bid (113% of baseline for both) than with placebo, as were all secondary outcome measures. The proportion of patients with an improvement in St George's Respiratory Questionnaire score of ≥ 4 was 50.2% for formoterol 4.5 µg (p = 0.0682 vs. placebo), 59.2% (p = 0.0004) for 9 µg, and 41.3% for placebo. Reduction in reliever medication use was significantly greater with formoterol vs. placebo (9 µg: -0.548, p < 0.001; 4.5 µg: -0.274, p = 0.027), with 9 µg being significantly superior to 4.5 µg (-0.274, p = 0.029). Formoterol was well tolerated with the incidence and type of adverse events not being different for the three groups. CONCLUSIONS: Formoterol 4.5 µg and 9 µg bid was effective and well tolerated in patients with COPD; there was no difference between formoterol doses for the primary endpoint; however, an added value of formoterol 9 µg over 4.5 µg bid was observed for some secondary endpoints. TRIAL REGISTRATION: NCT00628862 (ClinicalTrials.gov); D5122C00001 (AstraZeneca Study code).

[A case of myocarditis associated with polymyositis preceded by interstitial pneumonia].

A 33-year old man was admitted to our hospital because of an abnormal shadow on the chest radiograph, dry cough, and exertional dyspnea. Chest radiograph and high-resolution computed tomography (HRCT) on admission showed ground-glass opacities and bronchiectasis with volume loss in the bilateral dorsal areas. Thoracoscopic lung biopsy specimens showed mainly a pattern of NSIP (nonspecific interstitial pneumonia). We considered this case as hypersensitivity pneumonia or interstitial pneumonia (IP) associated with collagen disease. Oral prednisolone (PSL) was initiated at 55 mg/day (1 mg/kg). However he complained of proximal muscle weakness and pain and difficulty of breathing. He had heart failure due to the myocarditis. We established a diagnosis of IP associated with polymyositis and it was confirmed by his symptoms, muscle biopsy findings and elevation of serum CPK. We considered this case as the myocarditis due to polymyositis.

Comparison of leukotriene receptor antagonists and anti-histamines as an add-on therapy in patients with asthma complicated by allergic rhinitis.

Patients with asthma are often complicated by allergic rhinitis, and the intimate pathophysiological association between allergic rhinitis and asthma often imposes a significant morbidity on affected individuals. The present study was conducted to assess the clinical efficacies of leukotriene receptor antagonists (LTRAs) and anti-histamines on asthma as an add-on therapy in patients with asthma complicated by allergic rhinitis. Consecutive patients with asthma were recruited to fill in systematic self-administered questionnaires concerning symptoms and conditions related to asthma and allergic rhinitis. The questionnaire was conducted twice, one month apart, and the attending physicians gave detailed information on disease control and medications on both occasions. In the study 3,140 patients with asthma participated, and 634 had concomitant allergic rhinitis (mean age: 53.1, 389 female). The second survey disclosed that treatment with LTRAs or anti-histamines had been added in 26 patients and 19 patients, respectively, without any changes in other medications. There were no significant differences in age, gender, severity of disease, or baseline treatments. The initial survey indicated that the patients who were treated with LTRAs had significantly more severe asthma-related symptoms (i.e. wheeze, cough and sleep disturbance) and experienced greater dissatisfaction with the treatment than did those who were treated with anti-histamines. The second survey disclosed significant reductions in sneezing (p=0.03), rhinorrhea (p=0.01), dyspnea (p=0.046), sleep disturbance (p=0.02), over-all asthma symptoms (p=0.013), and an improvement in satisfaction with treatment (p=0.019) in patients to whom LTRAs were added-on, whereas the patients receiving anti-histamines reported no significant changes in these symptoms. These results suggest that LTRAs are more effective than anti-histamines as an add-on therapy in symptomatic patients with asthma complicated by allergic rhinitis.

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.

Twelve-year cumulative incidence of airflow obstruction among Japanese males.

BACKGROUND: To date, there is very limited longitudinal data on COPD and incidence estimates in Japan. The aim of this study was to investigate the 12-year cumulative incidence of airflow obstruction (COPD) in Japanese males. METHODS: This study included 913 male subjects, aged 30-76 years, who underwent lung function tests at a medical check-up in 1994 (baseline), 1999, and 2006. The study group consisted of 263 persistent never smokers, 296 early quitters, 117 late quitters, and 237 persistent smokers without airflow obstruction at baseline. The 12-year cumulative incidence of airflow obstruction was estimated. The spirometric criteria for diagnosis of airflow obstruction were forced expiratory volume in 1 second (FEV(1))/forced vital capacity (FVC) of <0.7 and 5th percentile lower limit of normal (FEV(1)/FVC

[A case of pulmonary multicentric Castleman disease which appeared as a very large lesion].

A 31-year-old man visited our hospital with a persistent cough. Computed tomography (CT) scans of his chest showed a very large mass and multiple nodular lesions in the right lung field, mediastinal and hilar lymph node enlargement and splenomegaly. Laboratory analysis showed polyclonal hyperimmunoglobulinemia and increased levels of serum C-reactive protein (14.05 mg/dl) and interleukin-6 (44.2 pg/ml). The pathological findings of lung specimens obtained using video-assisted thoracoscopy revealed hyperplasia of the lymphoid follicles with germinal centers, plasma cell infiltration which stained positively with either anti-kappa chain or anti-lambda chain antibodies, and fibrosis in the alveolar septum. We made a diagnosis of multicentric Castleman disease based on high levels of serum IL-6, multiple lymph node enlargement and splenomegaly, although this case had histological findings in common not only with Castleman disease but also with inflammatory myofibroblastic tumor. His abnormal chest radiography findings and laboratory data significantly improved 6 months after his first visit, without any treatment. Multicentric Castleman disease showing a very large mass is extremely rare.

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.

[A case of pulmonary Langerhans cell histiocytosis with panhypopituitarism].

A 34-year-old woman developed polydipsia, polyuria, amenorrhea and loss of pubic hair in 2001, but did not seek medical advice. On September 7th, 2009, she was admitted to our hospital complaining of acute exacerbation of dyspnea on exertion. Chest computed tomography (CT) showed multiple cystic lesions, predominantly in bilateral lower lung fields. Non-segmental, diffuse ground-glass attenuated areas and thickened bronchovascular bundles were also seen in bilateral lung fields. Pathological findings of lung specimens from a surgical lung biopsy (right S6 and S8) 14 years previously showed infiltration of S100 protein-positive histiocytoid cells in the bronchiolar wall. As a result, pulmonary Langerhans cell histiocytosis (PLCH) was diagnosed. Moreover, panhypopituitarism due to LCH was identified on endocrine testing. Dyspnea on exertion, reduction of carbon-monoxide diffusing capacity (D(LCO)) and ground-glass attenuation areas on CT were improved by smoking cessation alone, and she was discharged. However, similar acute deterioration of PLCH recurred 4 months after first admission. Her dyspnea on exertion, reduction of D(LCO) and ground-glass attenuation areas on CT were improved again by 500 mg/day methylprednisolone pulse therapy for 3 days. This case was a unique combination of panhypopituitarism and the appearance and disappearance of ground-glass attenuation areas on CT, paralleling PLCH disease activity.

Partial SPAST and DPY30 deletions in a Japanese spastic paraplegia type 4 family.

Spastic paraplegia type 4 (SPG4) is the most common autosomal dominant hereditary SPG caused by mutations in the SPAST gene. We studied the four-generation pedigree of a Japanese family with autosomal dominant hereditary SPG both clinically and genetically. Twelve available family members (ten affected; two unaffected) and two spouses were enrolled in the study. The clinical features were hyperreflexia in all four limbs, spasticity of the lower extremities, impaired vibration sense, mild cognitive impairment confirmed by the Wechsler Adult Intelligence Scale-Third Edition, and peripheral neuropathy confirmed by neurophysiological examinations. All four female patients experienced miscarriages. The cerebrospinal fluid tau levels were mildly increased in two of three patients examined. Linkage analyses revealed the highest logarithm of odds score of 2.64 at 2p23-p21 where the SPAST gene is located. Mutation scanning of the entire exonic regions of the SPAST gene by direct sequencing revealed no mutations. Exonic copy number analysis by real-time quantitative polymerase chain reaction revealed heterozygous deletion of exons 1 to 4 of the SPAST gene. Breakpoint analysis showed that the centromeric breakpoint was located within intron 4 of SPAST while the telomeric breakpoint was located within intron 3 of the neighboring DPY30 gene, causing a deletion of approximately 70 kb ranging from exons 1 to 3 of DPY30 to exons 1 to 4 of SPAST. To our knowledge, this is the first report of SPG4 associated with partial deletions of both the SPAST and DPY30 genes. The partial heterozygous deletion of DPY30 could modify the phenotypic expression of SPG4 patients with this pedigree.

Prognostic value of SUVmax measurements obtained by FDG-PET in patients with non-small cell lung cancer receiving chemotherapy.

[(18)F]Fluorodeoxyglucose (FDG) uptake has been shown to correlate well with tumor proliferation rates. In patients with non-small cell lung cancer (NSCLC) receiving chemotherapy, we analyzed the relationships between the maximum standardized uptake value (SUVmax) obtained by FDG positron emission tomography (FDG-PET) and other clinical factors, and examined whether or not SUVmax could predict progression-free survival (PFS) and/or overall survival (OS). This retrospective study involved 62 consecutive NSCLC patients (35 male and 27 female: median age, 65 years). All patients underwent FDG-PET examination before treatment. As the first-line treatment, the patients received chemotherapy with (n=15) or without (n=47) radiotherapy. Survival curves were obtained by the Kaplan-Meier method, and differences in survival between subgroups were analyzed by the log-rank test and the Cox proportional hazards model. Significant correlations were observed between SUVmax and gender (P=0.006), histology (P<0.001), smoking status (P=0.049), stage (P=0.015), and treatment modality (P=0.008), but not other factors, including age (P=0.402) and performance status (P=0.421). The median SUVmax was 5.1 (25-75th percentile: 3.45-7.0) in patients with adenocarcinoma and 8.3 (25-75th percentile: 6.9-9.9) in those with other types of NSCLC. Adenocarcinomas showed significantly lower SUVmax than the other tumor types (P<0.001). Cox analysis adjusting for possible confounding factors, including gender, smoking status, histology and stage, demonstrated that the hazard ratios increased as the SUVmax increased in terms of both PFS (P=0.008) and OS (P=0.045), indicating that SUVmax predicts outcome independently of other clinical factors, such as histology and stage. Our findings indicate that FDG-PET examination can provide information useful for prognostication in NSCLC.

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.

Reference ranges for exhaled nitric oxide fraction in healthy Japanese adult population.

BACKGROUND: The measurement of the exhaled nitric oxide fraction (FE(NO)) is proposed as a useful marker of airway inflammation. In healthy adults, there have been a few studies of the reference ranges for FE(NO) in Caucasians. A community study in other regions may reveal any possible ethnic differences in the FE(NO) levels. METHODS: A total of 240 healthy adults aged between 18 to 74 years were recruited from four medical centers in Japan. Current smokers and subjects having a history of atopic disease were not included. FE(NO) was measured using an online electrochemical nitric oxide analyzer according to the current guidelines. The reference ranges for FE(NO) were estimated using two different statistical methods recommended by International Federation of Clinical Chemistry and Laboratory Medicine. RESULTS: The mean FE(NO) was 16.9 ppb (parts per billion) with a 95% prediction interval (2.5 to 97.5 percentiles) of 6.5 to 35.0 ppb in healthy Japanese adults. Normality assumptions were met for the logarithm-transformed FE(NO). The geometric mean FE(NO) was 15.4 ppb with a mean ± two standard deviations of 6.5 to 36.8 ppb. Age, gender, height, and past smoking history were not associated with the FE(NO) levels. CONCLUSIONS: The reference ranges for FE(NO) in healthy Japanese adults were similar to those of Caucasians. It seems reasonable that the upper limit of FE(NO) for healthy adults should be set at approximately 36.0 ppb irrespective of ethnic differences.

Preliminary study of positron emission tomography/computed tomography and plasma osteopontin levels in patients with asbestos-related pleural disease.

PURPOSE: The aim of this study was to compare the results of semiquantitative analysis by(18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) with plasma osteopontin levels in the same asbestos-related pleural disease population. MATERIALS AND METHODS: A total of 17 patients with asbestos-related pleural disease were prospectively recruited. They underwent PET/CT, and plasma osteopontin levels were measured. The maximum standardized uptake value (SUVmax) was determined from the most active pleural lesion in each patient. RESULTS: Malignant pleural mesothelioma (MPM) was histologically proven in 6 patients, and 11 patients had proven benign asbestos-related pleural diseases (7 pleural plaques, 4 asbestos pleurisy). Significant differences in SUVmax were found between patients with MPM and those with asbestos pleurisy (P = 0.031) and between patients with MPM and those with pleural plaques (P = 0.012). A significant difference was found in the plasma osteopontin levels between patients with asbestos pleurisy and patients with pleural plaques (Bonferroni correction, P = 0.024). The SUVmax in patients with benign asbestos-related diseases was statistically positively correlated with plasma osteopontin in the same group (Spearman's r = 0.75, P < 0.05). CONCLUSION: PET/CT might be more helpful than plasma osteopontin for distinguishing benign asbestos-related pleural diseases from MPM, and the SUVmax in benign asbestos-related pleural diseases may reflect changes in pleural inflammation.

Combined treatment with prednisolone and tacrolimus for myasthenia gravis with invasive thymoma.

We describe a case of recurrent invasive thymoma associated with myasthenia gravis that responded to combined treatment with prednisolone and tacrolimus. The patient suffered from a myasthenic crisis and received methylprednisolone pulse therapy and partial thymomectomy. Low maintenance doses of prednisolone and tacrolimus shrank the size of the invasive thymoma and maintained the patient without any myasthenic symptoms. We stress the usefulness of combined treatment with tacrolimus and prednisolone for invasive thymoma, especially for unresectable tumors.

Molecular diagnosis of activating EGFR mutations in non-small cell lung cancer using mutation-specific antibodies for immunohistochemical analysis.

PURPOSE: Therapeutic responses of non-small cell lung carcinoma (NSCLC) to epidermal growth factor receptor (EGFR)-targeted drugs, such as gefitinib and erlotinib, are closely associated with activating EGFR mutations. The most common mutations are delE746-A750 in exon 19 and L858R in exon 21, accounting for approximately 90% of all EGFR mutations. Recently, EGFR mutation-specific antibodies were developed and did well in immunohistochemical analysis, giving a sensitivity of approximately 90%. We have investigated whether this method detects activating EGFR mutations with sensitivity comparable with direct DNA sequencing, which is used to detect these mutations in NSCLC. EXPERIMENTAL DESIGN: We used antibodies specific for the E746-A750 deletion mutation in exon 19 and the L858R point mutation in exon 21 in Western blot analysis and immunohistochemistry to determine the presence of these mutations in NSCLC cell lines. We also examined these EGFR mutations in NSCLC tumor samples from 60 patients by immunohistochemically and direct DNA sequencing. RESULTS: We were able to identify EGFR mutations in NSCLC tumor samples immunohistochemically with a sensitivity of 79% using the anti-delE746-A750 antibody and 83% using the anti-L858R antibody. Additional DNA sequencing markedly improved the sensitivity obtained by immunohistochemistry. CONCLUSIONS: This simple and rapid assay for detecting EGFR mutations, even in the small bronchial biopsies obtained in stage IV NSCLC patients, will be useful for diagnosing responsiveness to EGFR-targeted drugs in patients with NSCLC. Combining this with DNA sequencing is recommended for the development of improved personalized EGFR-targeted therapeutics.