記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10-12). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10-12), followed by an additional independent risk allele at HLA-DPβ1 amino acid position 8 (OR = 0.28; P = 3.4 × 10-7). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (β = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.

DOI： 10.1038/s41467-021-21011-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/internalmedicine.5054-20

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Each of the currently available (1→3)-β-D-glucan (BDG) measurement kits follows a different measurement method and cut-off value. Comparisons of diagnostic performance for invasive fungal infections (IFIs) are desirable. Additionally, ecological considerations are becoming increasingly important in the development of new measurement kits. METHODS: The plasma BDG levels in clinical samples were measured using the following currently available kits: the Fungitec G test MKII, the Fungitec G test ES, Fungitell, the β-Glucan test Wako, and the newly developed Wako kit (Wako-Eu). Wako-Eu uses a pre-treatment solution that conforms to European regulations for the registration, evaluation, authorisation, and restriction of chemicals. The values obtained for the samples using each kit were studied and compared. RESULTS: Of the 165 patients evaluated, 12 had IFIs, including pneumocystis pneumonia, aspergillosis, and candidiasis. BDG values obtained using the kits were moderately correlated with each other. Clinical diagnoses of the evaluated cases indicated that 21 false positives were diagnosed by at least one kit. The sensitivity of the Fungitell kit was relatively low, but those of the other four were over 90%. The specificity was above 90% for all kits. For positive predictive value, the Wako and the Wako-Eu methods were superior to the others owing to fewer false positive results. CONCLUSIONS: The newly developed Wako-Eu method, which considers ecological concerns, shows diagnostic performance equivalent to that of its predecessor. To improve the diagnostic accuracy of IFIs, it is necessary to interpret the results carefully, giving due consideration to the characteristics of each measurement kit.

DOI： 10.1371/journal.pone.0255172

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION/OBJECTIVES: Interstitial lung disease (ILD) is a significant cause of mortality among patients with dermatomyositis (DM) or polymyositis (PM). There are two subtypes of PM and DM often complicated with ILD: those with anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies and those with anti-MDA-5-associated amyopathic DM (ADM). Our aim is to clarify the inflammatory and immunological differences between the disorders. METHODS: We retrospectively collected consecutive patients with anti-ARS-ILD and those with anti-MDA-5 antibody-positive ADM-ILD. The serum concentration of 38 cytokines was measured using a cytokine panel. The relative risks for anti-MDA-5 antibody-positive ADM-ILD were examined with univariate and multivariate logistic regression models. Spearman's rank correlation coefficient was calculated between cytokine levels and clinical parameters in the disease. Levels of cytokines were compared between anti-ARS-ILD and anti-MDA-5-positive ADM-ILD patients (alive or dead) using Dunnett's test. RESULTS: Twenty-three patients with anti-ARS-ILD and the same number of patients with anti-MDA-5-positive ADM-ILD were enrolled. The anti-MDA-5 group had poor survival (p = 0.025). Univariate logistic regression models showed that eotaxin, IL-10, IP-10, and MCP-1 were associated with the diagnosis of anti-MDA-5-positive ADM-ILD. Multivariate logistic regression models revealed that IP-10 was the most significantly associated (p = 0.001). Relationship analyses showed that IL-10 had significant positive correlations with CK (r = 0.5267, p = 0.009) and ferritin (r = 0.4528, p = 0.045). A comparison of the cytokine levels found that IP-10 was elevated in both patients who were alive and patients who had died with ADM-ILD compared with the levels in those with ARS-ILD (p = 0.003 and p = 0.001, respectively). CONCLUSIONS: Anti-MDA-5-positive ADM-ILD had poorer survival than anti-ARS-ILD. IP-10 seems to be most deeply involved in the pathophysiology of anti-MDA-5-associated ADM-ILD.Key Points• To clarify differences in the inflammatory and immunological features of anti-MDA-5-positive ADM-ILD and anti-ARS-ILD, we performed an observational study to measure serum cytokine concentrations before treatment using a multiplex immunoassay system.• Multivariate logistic regression models revealed that IP-10 was associated with the most significant relative risk for ADM-ILD with anti-MDA-5 antibodies.• Levels of IP-10 were elevated considerably in anti-MDA-5-positive survivors and nonsurvivors compared with the levels in anti-ARS patients.• These results suggest that IP-10 is the most deeply involved in the pathophysiology of anti-MDA-5-positive ADM-ILD.

DOI： 10.1007/s10067-020-04984-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 70-year-old man with insulinoma-associated antigen-2 autoantibodies developed diabetes mellitus (DM) without ketoacidosis after starting nivolumab to treat advanced gastric cancer. He subsequently exhibited preserved insulin-secretion capacity for over one year. Immune checkpoint inhibitors (ICIs) infrequently cause type 1 DM associated with the rapid loss of insulin secretion and ketoacidosis as an immune-related adverse event. ICIs may also cause non-insulin-dependent DM by inducing insulin resistance if there is islet autoantibody-related latent beta-cell dysfunction. The present case highlights the importance of testing blood glucose levels regularly to diagnose DM in patients treated with ICIs, even if they do not have diabetic ketoacidosis.

DOI： 10.2169/internalmedicine.3208-19

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objectives: We aimed to study sirolimus-related lung parenchymal changes by quantitative analysis of computed tomography (CT) of the lungs in patients with lymphangioleiomyomatosis (LAM). Methods: We studied 20 participants from the Multicenter Lymphangioleiomyomatosis Sirolimus Trial for Safety study, who had undergone both thin-section CT scans and pulmonary function tests at baseline, 12, and 24 months. Quantitative CT parameters such as CT-derived total lung capacity, percentage of low attenuation area (LAA%), lung density histogram, fractal property of low attenuation area, and airway dimensions were analyzed, and correlations were conducted between the longitudinal change in each quantitative CT measurement and changes in pulmonary function were examined. Among 20 participants, pre-trial (n = 8) and post-trial (n = 16) CT data were also analyzed to deduce pathophysiologic implications of the serial changes in CT parameters during trial periods. Results: FEV1 significantly increased from baseline to 24 months (slope 3.71 ± 1.50 ml/month) whereas FVC didn't during sirolimus therapy. Strikingly, LAA%, and skewness and kurtosis of density histogram significantly increased from baseline to 24 months, while mean and mode CT values significantly decreased from baseline to 24 months. Statistically significant positive correlations were found between ΔFEV1 and Δskewness (r = 0.465, p = 0.045). Taking the changes in lung density during pre-trial period into consideration, sirolimus decreases the area of -800 to -750 Housefield unit (HU) density and inhibits the decrease of -950 to -800 HU area during treatment, then producing the increased LAA% during the trial and post-trial periods. Given few sirolimus-related changes in airway dimensions, possible changes in lung mechanics may have contributed to increased FEV1. Conclusion: Our study suggests that the lung density histogram parameters, kurtosis, and skewness, may be useful as indicators of the efficacy of sirolimus.

DOI： 10.1016/j.heliyon.2020.e03345

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Very recently, a modest but significant efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation therapy for the treatment of mild to moderate autoimmune pulmonary alveolar proteinosis (aPAP) has been reported. As the ability to measure the level of GM-CSF autoantibody (GMAb) in the serum is required to decide the indication for this therapy, we developed a high-performance GMAb testing kit for clinical use. As the kit succeeded in reducing nonspecific IgG binding to the ELISA plate, the predictive performance shown in the training study to discriminate aPAP patients from healthy subjects was perfect, providing a cut-off value of 1.65 U·mL-1 in 78 patients with aPAP and 90 healthy subjects in an operator-blinded manner using logistic regression analysis. As in the validation study, serum samples from another 213 patients with aPAP were also blinded and evaluated in an operator-blinded manner against external 207 samples from patients with other types of PAP and patients exhibiting various ground-glass opacities on chest high-resolution computed tomography that require discrimination from PAP. The logistic regression analysis of these validation data sets revealed values of 97.6% and 100% for specificity and sensitivity, respectively. Thus, this new GMAb testing kit is reliable for the diagnosis of aPAP and differential diagnosis of other lung diseases.

DOI： 10.1183/23120541.00259-2019

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Pulmonary alveolar proteinosis is a disease characterized by abnormal accumulation of surfactant in the alveoli. Most cases are autoimmune and are associated with an autoantibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) that prevents clearing of pulmonary surfactant by alveolar macrophages. An open-label, phase 2 study showed some therapeutic efficacy of inhaled recombinant human GM-CSF in patients with severe pulmonary alveolar proteinosis; however, the efficacy in patients with mild-to-moderate disease remains unclear. METHODS: We conducted a double-blind, placebo-controlled trial of daily inhaled recombinant human GM-CSF (sargramostim), at a dose of 125 μg twice daily for 7 days, every other week for 24 weeks, or placebo in 64 patients with autoimmune pulmonary alveolar proteinosis who had a partial pressure of arterial oxygen (Pao2) while breathing ambient air of less than 70 mm Hg (or <75 mm Hg in symptomatic patients). Patients with severe pulmonary alveolar proteinosis (Pao2 <50 mm Hg) were excluded to avoid possible exacerbation of the disease in patients who were assigned to receive placebo. The primary end point was the change in the alveolar-arterial oxygen gradient between baseline and week 25. RESULTS: The change in the mean (±SD) alveolar-arterial oxygen gradient was significantly better in the GM-CSF group (33 patients) than in the placebo group (30 patients) (mean change from baseline, -4.50±9.03 mm Hg vs. 0.17±10.50 mm Hg; P = 0.02). The change between baseline and week 25 in the density of the lung field on computed tomography was also better in the GM-CSF group (between-group difference, -36.08 Hounsfield units; 95% confidence interval, -61.58 to -6.99, calculated with the use of the Mann-Whitney U test and the Hodges-Lehmann estimate of confidence intervals for pseudo-medians). Serious adverse events developed in 6 patients in the GM-CSF group and in 3 patients in the placebo group. CONCLUSIONS: In this randomized, controlled trial, inhaled recombinant human GM-CSF was associated with a modest salutary effect on the laboratory outcome of arterial oxygen tension, and no clinical benefits were noted. (Funded by the Japan Agency for Medical Research and Development and the Ministry of Health, Labor, and Welfare of Japan; PAGE ClinicalTrials.gov number, NCT02835742; Japan Medical Association Center for Clinical Trials number, JMA-IIA00205.).

DOI： 10.1056/NEJMoa1816216

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Mycobacterium avium complex lung disease (MAC-LD) can deteriorate rapidly to become fatal. Reported poor prognostic factors include radiographic findings, undernutrition, anemia and high inflammation test values. However, the association of these prognostic factors with the pathophysiology of the disease remains unknown. We aimed to clarify the pathophysiology of MAC-LD and develop a new biomarker that reflects the immune response to the disease. METHODS: We performed the cytokine panel analyses of serum from patients with MAC-LD and compared each cytokine level with clinically negative prognostic factors (radiographic disease type, body mass index, albumin, C-reactive protein and hemoglobin) and high-resolution CT scores. RESULTS: We analyzed 27 patients with MAC-LD, 6 with the fibrocavitary form and 21 with the nodular bronchiectatic form on high-resolution CT. Serum CXC motif ligand 10 (CXCL10) concentration was significantly elevated in patients with the fibrocavitary form (p = 0.008). CXCL10 levels correlated with body mass index (r = - 0.60, p = 0.0008), serum albumin concentration (r = - 0.45, p = 0.016) and high-resolution CT scores (r = 0.61, p = 0.0006). Among 14 patients initially untreated, antibiotic therapy was initiated for five during the study period. CXCL10 concentration was significantly higher in these patients (p = 0.046), and receiver operating characteristic analysis for CXCL10 concentration on treatment initiation produced an area under the curve of 0.844, with a sensitivity of 100%, specificity of 66.7%, and cut-off value of 366.5 pg/mL. CONCLUSION: We revealed cytokine profiles in patients with MAC-LD. Serum CXCL10 levels probably reflect the severity of MAC-LD. Our findings suggest that CXCL10 concentration may be a promising biomarker for managing treatment for patients with MAC disease of the lung.

DOI： 10.1186/s12879-019-3888-4

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DOI： 10.1186/s13256-019-2002-2

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The incidence and prevalence of autoimmune pulmonary alveolar proteinosis in Japan were previously estimated to be 0.49 and 6.2 per million, respectively. Thereafter, an increase in serological diagnosis forced a re-estimation of the incidence based on more contemporaneous data using more robust methods. Sera of 702 patients were positive for granulocyte-macrophage colony-stimulating factor autoantibody during the 2006-2016 period (group A). Of these patients, 43 were actively surveyed in Niigata prefecture (group B) for estimation of the incidence. To estimate the survival period, 103 patients (group C) were investigated retrospectively for the 1999-2017 period using restricted mean survival time. In group A, the number of patients diagnosed in each prefecture was closely correlated with the corresponding population, indicating no regional integration of onset. In group B, a total of 43 patients were diagnosed, the annual number followed a Poisson distribution and the incidence was thus estimated to be 1.65 per million. In group C, the retrospective cohort study revealed the mean survival period to be 16.1 years. Taken together, the prevalence was estimated to be 26.6 per million, indicating that the previous data for incidence and prevalence was an underestimation.

DOI： 10.1183/23120541.00190-2018

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Anti-MDA-5 antibody is closely associated with interstitial lung disease (ILD) in amyopathic dermatomyositis (ADM). Patients with ADM with anti-MDA-5 antibody sometimes develop fatal ILD in spite of intensive immunosuppressive therapy. However, an initial decrease after treatment in anti-MDA-5 antibody titers may not be predictive of subsequent better survival of the disease. METHODS: To clarify immunoregulatory features of deadly ILD in ADM with the anti-MDA-5 antibody, we retrospectively examined clinical records of consecutive patients with anti-MDA-5 antibody positive ADM-ILD with preserved serum since 2000. Serum cytokine/growth factor (GF) protein concentration was measured using a cytokine panel analysis. We compared concentrations of each cytokine/GF between survivors and non-survivors and further examined changes in cytokines/GF levels during treatment in some patients. RESULTS: Twenty-six patients were enrolled in the study. Nine out of 26 patients did not respond to intensive immunosuppressive therapy and died due to respiratory failure. We compared cytokine/GF concentrations and found that serum IL-15 before treatment was significantly elevated in non-survivors than in survivors (p < 0.05). 11 out of 17 responders and 6 of 9 dead patients had preserved serum taken more than one time. We then calculated rates of change per day (slopes) in each cytokine/GF concentration. Comparison of slopes of cytokine/GF protein over the treatment duration showed that the slopes in non-survivors were significantly increased in IL-10 and IL-15 (p < 0.01). CONCLUSIONS: IL-15, as well as IL-10, may play a key role in the progression of the patients with ADM-ILD with anti-MDA-5 antibody positive.

DOI： 10.1016/j.rmed.2018.06.012

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/internalmedicine.1008-18

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掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/internalmedicine.0942-18

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DOI： 10.2169/internalmedicine.0209-17

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Systemic sclerosis (SSc) is an intractable disease that causes fibrosis in all organs. Approximately 40% of patients with SSc have some degree of interstitial lung disease (ILD). One third of patients with SSc and ILD, approximately 15% of all patients, have pulmonary lesions, which slowly progress to respiratory failure resistant to corticosteroid and other treatments. A randomized controlled trial conducted in the United States indicated that one year of treatment with oral cyclophosphamide in patients with SSc-ILD had a significant but modest beneficial effect on lung function, dyspnea, thickening of the skin, and health-related quality of life. However, all the effects, except for a sustained impact on dyspnea, disappeared approximately one year after stopping oral administration of cyclophosphamide. A randomized controlled trial using cyclophosphamide and mycophenolate mofetil (MMF) was then held in the United States for 142 patients with SSc-ILD. Treatment of SSc-ILD with MMF for two years or cyclophosphamide for one year both resulted in significant improvements in lung function over the 2-year course of the study. Leukopenia and thrombocytopenia occurred less often in patients administered MMF than in those administered cyclophosphamide. MMF is currently not approved for the treatment of SSc-ILD in Japan. Both MMF and cyclophosphamide were effective against ILD associated with SSc and, in particular, MMF was useful in terms of tolerability. When MMF is approved, it should be positioned as one of the first treatment options for SSc-ILD, which will further enhance the treatment of this disease in Japan.

DOI： 10.1016/j.resinv.2017.11.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Society of Internal Medicine  

A 63-year-old Japanese woman with advanced lung adenocarcinoma developed isolated adrenocorticotropin deficiency caused by immune checkpoint inhibitor (ICI)-related hypophysitis following 8 months of nivolumab therapy. Prompt corticosteroid replacement therapy effectively relieved her secondary adrenal insufficiency symptoms and allowed her to pursue nivolumab therapy, which had been effective for the control of lung adenocarcinoma. Human leukocyte antigen (HLA) typing revealed the presence of the DRB1*04:05-DQA1*03:03-DQB1*04:01 haplotype, which is associated with susceptibility to autoimmune polyglandular syndrome with pituitary disorder in the Japanese population. This case suggests that genetic factors, such as HLA, contribute to the development of endocrinopathies induced by ICIs.

DOI： 10.2169/internalmedicine.9074-17

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Presepsin is a widely recognized biomarker for sepsis. However, little is known about the usefulness of presepsin in invasive fungal infection. The aim of this study was to determine the plasma levels of presepsin in fungal bloodstream infections and to investigate whether it reflects the disease severity, similar to its utility in bacterial infections. METHODS: We prospectively measured presepsin in plasma samples from participants with fungemia from April 2016 to December 2017. The associations of C-reactive protein, procalcitonin, and presepsin concentrations with the severity of fungemia were statistically analyzed. In vitro assay was performed by incubating Escherichia coli, Candida albicans, and lipopolysaccharide to whole blood cells collected from healthy subjects; after 3 h, the presepsin concentration was measured in the supernatant and was compared among the bacteria, fungi, and LPS groups. RESULTS: Presepsin was increased in 11 patients with fungal bloodstream infections. Serial measurement of presepsin levels demonstrated a prompt decrease in 7 patients in whom treatment was effective, but no decrease or further increase in the patients with poor improvement. Additionally, presepsin concentrations were significantly correlated with the Sequential Organ Failure Assessment score (r = 0.89, p < 0.001). In vitro assay with co-incubation of C. albicans and human whole blood cells indicated that the viable cells of C. albicans caused an increase in presepsin, as seen with E. coli. CONCLUSIONS: Plasma presepsin levels increased in patients with fungal bloodstream infection, with positive association with the disease severity. Presepsin could be a useful biomarker of sepsis secondary to fungal infections.

DOI： 10.1371/journal.pone.0206089

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

PurposeLymphangioleiomyomatosis is a rare lung disease caused by proliferation of abnormal smooth muscle-like cells and typically occurs in premenopausal women. Sirolimus is now the first-line drug for the treatment of lymphangioleiomyomatosis. Sirolimus-induced stomatitis is the most frequent adverse event experienced during treatment. To identify risk factors, we investigated the association of stomatitis incidence with patient background data and treatment parameters, using data from the multicenter long-term sirolimus trial.
MethodsSubjects received sirolimus for 2years at doses adjusted to maintain a trough blood level of 5 to 15ng/mL. The incidence of stomatitis was correlated with baseline demographics, clinical characteristics, and changes in the longitudinal data. Risk factors at baseline were assessed by using univariate and multivariate analyses.
ResultsThe most frequent adverse event was stomatitis, with the cumulative rate reaching 88.9% by 9months, higher than that reported in postrenal transplant patients. The repetition, the duration, and the severity of stomatitis events were variable among patients. We found that patients with low hemoglobin (Hb) (&lt;14.5g/dL) showed significantly higher incidence than those with high Hb (14.5g/dL, P&lt;.01). The cumulative rate for stomatitis incidence was significantly associated with a decrease in the mean corpuscular volume, while the Hb level was constant; thus, red blood cell count in patients increased during the study.
ConclusionsBaseline Hb levels and a decrease in mean corpuscular volume during treatment were correlated with the incidence of stomatitis.

DOI： 10.1002/pds.4259

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Thoracic Society  

Rationale: A useful semiquantitative method of using computed tomographic (CT) images to evaluate therapeutic response in pulmonary alveolar proteinosis (PAP) has not been established, although the extent score or grading score of ground-glass opacities has been used. Objectives: The purpose of this study was to establish a semiquantitative method for evaluating therapeutic response in PAP. Methods: CT scans were obtained within 1 month before and after therapy from 32 patients with PAP who participated in a multicenter phase II trial of granulocyte-macrophage colony-stimulating factor inhalation therapy. The scans were evaluated by two chest radiologists independently. Increased parenchymal opacity was evaluated on the basis of its intensity and extent (CT grade), and the severity scores were compared with CT scores based on the extent alone (CT extent), as well as on the basis of physiological and serological results. Results: CT grade score and CT extent score had significant correlationwith diffusing capacity of the lung for carbon monoxide percent predicted (%DLCO), PaO2, VC percent predicted (%VC), Krebs von den Lungen (KL)-6, and surfactant protein D. The change in CT grade score between pre- and post-treatment examinations (ΔCT grade) correlated better with difference of PaO2 between pre- and post-treatment examinations (ΔPaO2) than DCT extent (difference of CT extent score between pre- and post-treatment examinations). In univariate analysis, ΔCT grade, ΔCT extent, ΔKL-6, Δ%DLCO, Δ%VC, and change in surfactant protein D correlated significantly with ΔPaO2. Inmultivariate analysis, ΔCT grade and ΔKL-6 correlated more closely with ΔPaO2.

DOI： 10.1513/AnnalsATS.201607-574OC

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DOI： 10.1513/AnnalsATS.201607-574OC

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER THORACIC SOC  

Rationale: A useful semiquantitative method of using computed tomographic (CT) images to evaluate therapeutic response in pulmonary alveolar proteinosis (PAP) has not been established, although the extent score or grading score of ground-glass opacities has been used.
Objectives: The purpose of this study was to establish a semiquantitative method for evaluating therapeutic response in PAP.
Methods: CT scans were obtained within 1 month before and after therapy from 32 patients with PAP who participated in a multicenter phase II trial of granulocyte-macrophage colony-stimulating factor inhalation therapy. The scans were evaluated by two chest radiologists independently. Increased parenchymal opacity was evaluated on the basis of its intensity and extent (CT grade), and the severity scores were compared with CT scores based on the extent alone (CT extent), as well as on the basis of physiological and serological results.
Results: CT grade score and CT extent score had significant correlationwith diffusing capacity of the lung for carbon monoxide percent predicted (% DLCO), Pa-O2, VC percent predicted (% VC), Krebs von den Lungen (KL)-6, and surfactant protein D. The change in CT grade score between pre-and post-treatment examinations (Delta CT grade) correlated better with difference of Pa-O2 between pre-and post-treatment examinations (Delta Pa-O2) than Delta CT extent (difference of CT extent score between pre-and post-treatment examinations). In univariate analysis, Delta CT grade, Delta CT extent, Delta KL-6, Delta%DLCO, Delta%VC, and change in surfactant protein D correlated significantly with Delta Pa-O2. Inmultivariate analysis, Delta CT grade and DKL-6 correlated more closely with Delta Pa-O2.
Conclusions: Although a number of CT variables were collected, the currently proposed grading system that correlates well with Pa-O2 should be viewed as a retrospective scoring system that needs future validation with another PAP cohort.

DOI： 10.1513/AnnalsATS.201607-574OC

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BioMed Central Ltd.  

Background: Pituitary tumor apoplexy is a rare clinical syndrome caused by acute hemorrhage or infarction in a preexisting pituitary adenoma. It typically manifests as an acute episode of headache, visual disturbance, mental status changes, cranial nerve palsy, and endocrine pituitary dysfunction. However, not all patients present with classical symptoms, so it is pertinent to appreciate the clinical spectrum of pituitary tumor apoplexy presentation. We report an unusual case of a patient with pituitary tumor apoplexy who presented with periorbital edema associated with hypopituitarism. Case presentation: An 83-year-old Japanese man developed acute anterior hypopituitarism
he showed anorexia, fatigue, lethargy, severe bilateral periorbital edema, and mild cardiac dysfunction in the absence of headache, visual disturbance, altered mental status, and cranial nerve palsy. Magnetic resonance imaging showed a 2.5-cm pituitary tumor containing a mixed pattern of solid and liquid components indicating pituitary tumor apoplexy due to hemorrhage in a preexisting pituitary adenoma. Replacement therapy with oral hydrocortisone and levothyroxine relieved his symptoms of central adrenal insufficiency, central hypothyroidism, periorbital edema, and cardiac dysfunction. Conclusions: Common causes of periorbital edema include infections, inflammation, trauma, allergy, kidney or cardiac dysfunction, and endocrine disorders such as primary hypothyroidism. In the present case, the patient's acute central hypothyroidism was probably involved in the development of both periorbital edema and cardiac dysfunction. The present case highlights the need for physicians to consider periorbital edema as an unusual predominant manifestation of pituitary tumor apoplexy.

DOI： 10.1186/s13256-017-1371-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Thoracic Society  

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by the excessive accumulation of surfactant proteins within the alveolar spaces and by higher titers of autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) in the serum and bronchoalveolar lavage fluid. The antibodies inhibit the maturation and phagocytosis of alveolar macrophages. Although the standard therapy for aPAP has been whole-lung lavage (WLL), this procedure is invasive and needs to be repeated for several years. GM-CSF inhalation therapy is a new procedure for treating aPAP and can induce remission with less invasiveness, although it is generally less effective in severe cases. We evaluated five cases with remarkable improvement by using sequential GM-CSF inhalation therapy after WLL
however, the treatment failed when this therapy preceded WLL. Therefore, sequential GM-CSF inhalation after WLL may reinforce the efficiency of WLL in patients with severe aPAP.

DOI： 10.1513/AnnalsATS.201611-892BC

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DOI： 10.1513/AnnalsATS.201611-892BC

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER THORACIC SOC  

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by the excessive accumulation of surfactant proteins within the alveolar spaces and by higher titers of autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) in the serum and bronchoalveolar lavage fluid. The antibodies inhibit the maturation and phagocytosis of alveolar macrophages. Although the standard therapy for aPAP has been whole-lung lavage (WLL), this procedure is invasive and needs to be repeated for several years. GM-CSF inhalation therapy is a new procedure for treating aPAP and can induce remission with less invasiveness, although it is generally less effective in severe cases. We evaluated five cases with remarkable improvement by using sequential GM-CSF inhalation therapy after WLL; however, the treatment failed when this therapy preceded WLL. Therefore, sequential GM-CSF inhalation after WLL may reinforce the efficiency of WLL in patients with severe aPAP.

DOI： 10.1513/AnnalsATS.201611-892BC

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記述言語：英語  

A 59-year-old Japanese man diagnosed with interstitial lung disease associated with amyopathic dermatomyositis with anti-melanoma differentiation-associated gene 5 (MDA-5) antibodies was treated with intravenous methyl prednisolone (PSL) 1000 mg, oral PSL 1 mg/kg, and oral cyclosporin 200 mg daily. His respiratory condition worsened after treatment with two times of intravenous cyclophosphamide and another steroid pulse therapy as well as PSL and cyclosporin. Addition of mycophenolate mofetil (MMF), 1.5 g daily improved PaO2/FiO2 (PF) ratio of the patient from 294 to 360 at 4 weeks and 416 at 15 weeks after addition of MMF. We measured cytokine concentration in preserved serum taken at 11 and 7 weeks before addition of MMF and at 4, 11, and 15 weeks after MMF administration. Of the 28 cytokines evaluated, the concentrations of fibroblast growth factors-2 (FGF-2), chemokine (C-X3-C motif) ligand 1 (CX3CL1), interleukin (IL)-1ra, IL-17A, inducible protein 10 (IP-10), and monocyte chemotactic protein-1 (MCP-1) decreased after addition of MMF. These results suggest that MMF may be beneficial to patients with interstitial lung disease by modification of the cytokine/growth factor protein expression.

DOI： 10.1002/rcr2.235

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記述言語：日本語   出版者・発行元：(株)先端医学社  

自己免疫性肺胞蛋白症患者の血液から比重遠心法を用いて末梢血単核細胞(PBMC)を分離した。分離したB細胞とビオチン化GM-CSFを反応させ、結合した細胞をGM-CSF反応性B細胞(自己抗体BCR陽性細胞)と考え、抗ビオチン抗体ビーズを用いて磁気分離した。33検体(患者24、健常者3)の解析をおこない、全体のリード数が16万リード、合計クラスターは2万4千クラスターであった。抗体が実際に産生されていると考えられるproductive sequenceの割合は全体の76%を占めた。アイソタイプの違いについて検討し、ほぼ全ての検体においてκ鎖の場合、Vκ1およびVκ3、Lambda鎖の場合、Vλ1、Vλ2、Vλ3のシークエンスが占める割合が高かった。患者検体CDR1の配列において平均連結法を用いてAlignmentおよび樹形図解析をおこなった。GM-CSFに反応するBCR陽性B細胞とGM-CSFに反応しないBCRをもつB細胞のシークエンスの間では、お互いの配列にまったく類似性がなく、自己抗体の軽鎖配列がそれ以外の軽鎖配列と分子レベルで異なることを確認した。

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by surfactant accumulation, and is caused by disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling. Abnormalities in CSF2 receptor alpha (CSF2RA) were reported to cause pediatric hereditary PAP. We report here the first case of CSF2RA-mutated, elderly-onset hereditary (h) PAP.
Case presentation: The patient developed dyspnea on exertion, and was diagnosed with PAP at the age of 77 years, based on findings from chest computed tomography scan and bronchoalveolar lavage. She tested negative for GM-CSF autoantibodies, with no underlying disease. Her serum GM-CSF level was elevated (91.3 pg/mL), indicating GM-CSF signaling impairment and genetic defects in the GM-CSF receptor. GM-CSF-stimulated phosphorylation in signal transducer and activator of transcription 5 (STAT5) was not observed, and GM-CSF-Ra expression was defective in her blood cells. Genetic screening revealed a homozygous, single-base C &gt; T mutation at nt 508-a nonsense mutation that yields a stop codon (Q170X)-in exon 7 of CSF2RA. High-resolution analysis of single nucleotide polymorphism array confirmed a 22.8-Mb loss of heterozygosity region in Xp22.33p22.11, encompassing the CSF2RA gene. She was successfully treated with whole lung lavage (WLL), which reduced the serum levels of interleukin (IL)-2, IL-5, and IL-17, although IL-3 and M-CSF levels remained high.
Conclusions: This is the first known report of elderly-onset hPAP associated with a CSF2RA mutation, which caused defective GM-CSF-Ra expression and impaired signaling. The analyses of serum cytokine levels during WLL suggested that GM-CSF signaling might be compensated by other signaling pathways, leading to elderly-onset PAP.

DOI： 10.1186/s12890-017-0382-x

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記述言語：英語   出版者・発行元：SPRINGER LONDON LTD  

DOI： 10.1007/s10067-016-3443-2

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Kokuseido Publishing Co. Ltd  

A 57-year-old man complained of an acute onset of left shoulder pain and subsequent dyspnea in the supine position. Orthopedic, neurological, and cardio- logic work up failed to identify the cause of his symptoms. After experiencing orthopnea for 5 months, he was admitted to our hospital He was diagnosed with a bilateral phrenic nerve paralysis based on paradoxical breathing, a bilateral diaphragm elevation on radiographic imaging, and a restrictive ventilatory defect. Polysomnography showed a severe obstructive sleep apnea pattern. Arterial blood gas analysis revealed hypercapnic respiratory failure. After nocturnal non-invasive positive pressure ventilation therapy, his dyspnea promptly improved in association with less carbon dioxide retention. Furthermore, in two years, his pulmonary function also improved and returned to the normal range. Eventually, phrenic nerve involvement of neuralgic amyotrophy (NA) without any other muscle involvement was considered the causative disease. In this case, the complication of sleep-disordered breathing made it difficult to diagnose NA early in the course. NA should be con-sidered in the differential diagnosis for phrenic nerve paralysis or hypercapnic respiratory failure.

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記述言語：日本語   出版者・発行元：克誠堂出版(株)  

症例は57歳、男性。左肩の強い疼痛に引き続いて発症した起坐呼吸のため入院した。奇異性呼吸、拘束性障害、横隔膜挙上から両側横隔神経麻痺と考えられた。重症の閉塞性睡眠時無呼吸、II型呼吸不全を認め、夜間の非侵襲的陽圧換気療法を導入した。その後、年余の単位で徐々に呼吸機能は正常範囲内まで改善した。臨床経過から上肢の神経症状を伴わない神経痛性筋萎縮症と考えられた。原因不明の呼吸不全の背景に本疾患が隠れている可能性がある。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J01060&link_issn=&doc_id=20161214110010&doc_link_id=%2Fad3nkrsd%2F2016%2F007512%2F011%2F1420-1426%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fad3nkrsd%2F2016%2F007512%2F011%2F1420-1426%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：新潟急性血液浄化研究会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Thoracic Society  

Rationale: Sirolimus has been shown in a randomized, controlled clinical trial to stabilize lung function in patients with lymphangioleiomyomatosis (LAM) treated for a 12-month time period
however the pretreatment decline in lung function after the drug was discontinued indicated that continued exposure is required to suppress disease progression. Objectives: To elucidate the durability and tolerability of long-term sirolimus treatment in Asian patients with LAM. Methods: We conducted a single-arm, open-label, investigatorinitiated safety and efficacy study of sirolimus in 63 women with LAM at 9 sites in Japan. Subjects received sirolimus for 2 years at doses adjusted to maintain a trough blood level of 5-15 ng/ml. Measurements and Main Results: Fifty-two subjects (82.5%) completed the trial with mean drug compliance of more than 80% overall during the study. The number of adverse events was greatest during the initial 6 months of therapy, but they continued to occur with declining frequency throughout the 2-year study period. Of the 1,549 adverse events, 27 were classified as serious, including reversible sirolimus pneumonitis in 3 patients. New hypercholesterolemia occurred in 30 patients (48%)
microcytosis in 10 patients
loss of body weight in 33 patients
and increase in blood pressure that required treatment in 5 patients. FEV1, FVC, and quality-of-life parameters were stable in the overall study cohort during the study period, but baseline to 2-year improvements in lung function occurred in the subset of patients with a prior history of chylothorax. Conclusions: Although long-term sirolimus treatment of Asian patients with LAM was associated with a large number of adverse events, including three episodes of pneumonitis, most patients completed the 2-year course of medication with good drug compliance and stable quality of life and lung function.

DOI： 10.1513/AnnalsATS.201605-335OC

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掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER THORACIC SOC  

Rationale: Sirolimus has been shown in a randomized, controlled clinical trial to stabilize lung function in patients with lymphangioleiomyomatosis (LAM) treated for a 12-month time period; however the pretreatment decline in lung function after the drug was discontinued indicated that continued exposure is required to suppress disease progression. Objectives: To elucidate the durability and tolerability of long-term sirolimus treatment in Asian patients with LAM. Methods: We conducted a single-arm, open-label, investigator-initiated safety and efficacy study of sirolimus in 63 women with LAM at 9 sites in Japan. Subjects received sirolimus for 2 years at doses adjusted to maintain a trough blood level of 5-15 ng/ml. Measurements and Main Results: Fifty-two subjects (82.5%) completed the trial with mean drug compliance of more than 80% overall during the study. The number of adverse events was greatest during the initial 6 months of therapy, but they continued to occur with declining frequency throughout the 2-year study period. Of the 1,549 adverse events, 27 were classified as serious, including reversible sirolimus pneumonitis in 3 patients. New hypercholesterolemia occurred in

DOI： 10.1513/AnnalsATS.201605-335OC

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DOI： 10.1513/AnnalsATS.201605-335OC

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記述言語：英語   出版者・発行元：EUROPEAN RESPIRATORY SOC JOURNALS LTD  

DOI： 10.1183/13993003.congress-2016.PA3873

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Igaku-Shoin Ltd  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：W B SAUNDERS CO LTD  

Background: Patients with amyopathic dermatomyositis (ADM) sometimes develop rapidly progressive interstitial lung disease (ILD) predominantly in Asia. Although anti-CADM-140/MDA5 antibody titer could correlate with disease activity and predict the course of ILD associated with ADM, it is not clear how this antibody is involved in the pathogenesis of ILD in ADM.
Methods: We retrospectively collected clinical records and preserved serum before treatment of consecutive patients with ADM-ILD treated in the Niigata University Medical and Dental Hospital since 2000. We measured anti-CADM-140/MDA5 antibody titer and compared it between survivors and non-survivors. Serum cytokine/growth factor protein concentration was measured using a multiplex immunoassay system. The associations between anti-CADM-140/MDA5 antibody titer and each cytokine/growth factor protein concentration were evaluated.
Results: Thirteen patients were enrolled into the study. Among them, four patients did not respond to intensive immunosuppressive therapy and died. The mean anti-CADM-140/MDA5 antibody titer was significantly higher in patients who did not responded to therapy than in those who survived (p &lt; 0.05). Relationship analyses between the antibody titer and each cytokine/GF protein concentration revealed that Spearman's rank correlation coefficients were more than 0.4 in thirteen cytokine/GF proteins. In particular, the strongest correlation was found between anti-CADM-140/MDA5 antibody titer and CX3CL1 (r = 0.8897).
Conclusions: These results confirmed that anti-CADM-140/MDA5 antibody levels could predict outcomes of ADM-ILD. Relationship analyses suggested that CX3CL1 might be involved in the pathogenesis of anti-CADM-140/MDA5 antibody positive ADM-ILD. (C) 2015 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.rmed.2015.07.004

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DOI： 10.1513/AnnalsATS.201503-175LE

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Although no report has demonstrated the efficacy of corticosteroid therapy for autoimmune pulmonary alveolar proteinosis (aPAP), we sometimes encounter patients who have received this therapy for various reasons. However, as corticosteroids can suppress alveolar macrophage function, corticosteroid therapy might worsen disease severity and increase the risk of infections.
Methods: For this retrospective cohort study, we sent a screening form to 165 institutions asking for information on aPAP patients treated with corticosteroids. Of the resulting 45 patients screened, 31 were enrolled in this study. We collected demographic data and information about corticosteroid treatment period, dose, disease severity score (DSS) over the treatment period, and complications.
Results: DSS deteriorated during corticosteroid therapy in 23 cases (74.1 %) and the estimated overall cumulative worsening rate was 80.8 % for the total observation period. The worsening rate was significantly higher in patients treated with high-dose prednisolone (&gt; 18.9 mg/day, n = 16) than treated with low-dose prednisolone (&lt;= 18.9 mg/day, n = 15) divided by median daily dose (p &lt; 0.02). Of patients with worsening, one died of disseminated aspergillosis and another of respiratory failure. Infections newly emerged in 6 cases during corticosteroid therapy (p &lt; 0.05). Median serum granulocyte/macrophage colony-stimulating factor (GM-CSF) autoantibody levels were similar to previously reported data in a large cohort study.
Conclusion: The results demonstrate that corticosteroid therapy may worsen DSS of aPAP, increasing the risk for infections.

DOI： 10.1186/s12890-015-0085-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier  

Background: Several multifactorial risk indexes have been proposed by Western countries for identifying patients at a high risk of developing postoperative pulmonary complications (PPC). However, there is no consensus on how to evaluate the risk of PPC and what multifactorial risk index should be adapted for Japanese patients. This study aimed at clarifying the utility of risk indexes to predict PPC following digestive surgeries in Japanese patients. Methods: We retrospectively analyzed 892 patients who underwent digestive surgeries under general anesthesia in Niigata University Medical and Dental Hospital between January 2009 and March 2011. PPC was defined as postoperative respiratory failure and postoperative pneumonia. We calculated three risk indexes (respiratory failure risk index (RFRI), postoperative pneumonia risk index, and PPC risk score), and compared them between the PPC group and the non-PPC group. A receiver operating characteristic (ROC) curve analysis was employed to compare the usefulness of each index. Results: PPC developed in 55 patients (6.2%). All risk indexes were significantly higher in the PPC group than the non-PPC group. The category classification of the risk scores demonstrated a significant tendency to increase the incidence rate of PPC. In the ROC analysis, the area under the curve for RFRI was 0.762 (95% CI 0.697-0.826), which was the highest value observed among these indexes. Conclusions: Multifactorial risk indexes are useful tools for identifying Japanese patients at a high risk of developing PPC following digestive surgeries. Of the risk indexes evaluated in this study, RFRI is potentially the most accurate in predicting PPC.

DOI： 10.1016/j.resinv.2014.12.004

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本呼吸器学会  

CiNii Article

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その他リンク： http://search.jamas.or.jp/link/ui/2015129304

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Whole-lung lavage (WLL) remains the standard therapy for pulmonary alveolar proteinosis (PAP), a process in which accumulated surfactants are washed out of the lung with 0.5-2.0 l of saline aliquots for 10 -30 wash cycles. The method has been established empirically. In contrast, the kinetics of protein transfer into the lavage fluid has not been fully evaluated either theoretically or practically. Seventeen lungs from patients with autoimmune PAP underwent WLL. We made accurate timetables for each stage of WLL, namely, instilling, retaining, draining, and preparing. Subsequently, we measured the volumes of both instilled saline and drained lavage fluid, as well as the concentrations of proteins in the drained lavage fluid. We also proposed a mathematical model of protein transfer into the lavage fluid in which time is a single variable as the protein moves in response to the simple diffusion. The measured concentrations of IgG, transferrin, albumin, and beta(2)-microglobulin closely matched the corresponding theoretical values calculated through differential equations. Coefficients for transfer of beta(2)-microglobulin from the blood to the lavage fluid were two orders of magnitude higher than those of IgG, transferrin, and albumin. Simulations using the mathematical model showed that the cumulative amount of eliminated protein was not affected by the duration of each cycle but dependent mostly on the total time of lavage and partially on the volume instilled. Although physicians have paid little attention to the transfer of substances from the lung to lavage fluid, WLL seems to be a procedure that follows a diffusion-based mathematical model.

DOI： 10.1152/ajplung.00239.2014

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記述言語：英語   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

DOI： 10.2169/internalmedicine.54.5165

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER COLL CHEST PHYSICIANS  

Background: Treatment of autoimmune pulmonary alveolar proteinosis (aPAP) by subcutaneous injection or inhaled therapy of granulocyte-macrophage colony-stimulating factor (GM-CSF) has been demonstrated to be safe and efficacious in several reports. However, some reports of subcutaneous injection described transient benefit in most instances. The durability of response to inhaled GM-CSF therapy is not well characterized.
Methods: To elucidate the risk factors for recurrence of aPAP after GM-CSF inhalation, 35 patients were followed up, monitoring for the use of any additional PAP therapies and disease severity score every 6 months. Physiologic, serologic, and radiologic features of the patients were analyzed for the findings of 30-month observation after the end of inhalation therapy.
Results: During the observation, 23 patients remained free from additional treatments, and twelve patients required additional treatments. There were no significant differences in age, sex, symptoms, oxygenation indexes, or anti-GM-CSF antibody levels at the beginning of treatment between the two groups. Baseline vital capacity (% predicted, % VC) were higher among those who required additional treatment (P &lt;.01). Those patients not requiring additional treatment maintained the improved disease severity score initially achieved. A significant difference in the time to additional treatment between the high % VC group (% VC &gt;= 80.5) and the low % VC group was seen by a Kaplan-Meier analysis and a log-rank test (P &lt;.0005).
Conclusions: These results demonstrate that inhaled GM-CSF therapy sustained remission of aPAP in more than one-half of cases, and baseline % VC might be a prognostic factor for disease recurrence.

DOI： 10.1378/chest.13-0603

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記述言語：英語  

BACKGROUND: Secondary pulmonary alveolar proteinosis (sPAP) is a very rare lung disorder comprising approximately 10% of cases of acquired PAP. Hematological disorders are the most common underlying conditions of sPAP, of which 74% of cases demonstrate myelodysplastic syndrome (MDS). However, the impact of sPAP on the prognosis of underlying MDS remains unknown. The purpose of this study was to evaluate whether development of sPAP worsens the prognosis of MDS. METHODS: Thirty-one cases of sPAP and underlying MDS were retrospectively classified into mild and severe cases consisting of very low-/low-risk groups and intermediate-/high-/very high-risk groups at the time of diagnosis of MDS, according to the prognostic scoring system based on the World Health Organization classification. Next, we compared the characteristics, disease duration, cumulative survival, and prognostic factors of the groups. RESULTS: In contrast to previous reports on the prognosis of MDS, we found that the cumulative survival probability for mild MDS patients was similar to that in severe MDS patients. This is likely due to the poor prognosis of patients with mild MDS, whose 2-year survival rate was 46.2%. Notably, 75% and 62.5% of patients who died developed fatal infectious diseases and exacerbation of PAP, respectively, suggesting that the progression of PAP per se and/or PAP-associated infection contributed to poor prognosis. The use of corticosteroid therapy and a diffusing capacity of the lung for carbon monoxide of less than 44% were predictive of poor prognosis. CONCLUSION: Development of sPAP during the course of MDS may be an important adverse risk factor in prognosis of patients with mild MDS.

DOI： 10.1186/1471-2466-14-37

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記述言語：英語  

Occupational and environmental lung diseases are a group of pulmonary disorders caused by inhalation of harmful particles, mists, vapors or gases. Mineralogical analysis is not generally required in the diagnosis of most cases of these diseases. Apart from minerals that are encountered rarely or only in specific occupations, small quantities of mineral dusts are present in the healthy lung. As such when mineralogical analysis is required, quantitative or semi-quantitative methods must be employed. An electron probe microanalyzer with wavelength dispersive spectrometer (EPMA-WDS) enables analysis of human lung tissue for deposits of elements by both qualitative and semi-quantitative methods. Since 1993, we have analyzed 162 cases of suspected occupational and environmental lung diseases using an EPMA-WDS. Our institute has been accepting online requests for elemental analysis of lung tissue samples by EPMA-WDS since January 2011. Hard metal lung disease is an occupational interstitial lung disease that primarily affects workers exposed to the dust of tungsten carbide. The characteristic pathological findings of the disease are giant cell interstitial pneumonia (GIP) with centrilobular fibrosis, surrounded by mild alveolitis with giant cells within the alveolar space. EPMA-WDS analysis of biopsied lung tissue from patients with GIP has demonstrated that tungsten and/or cobalt is distributed in the giant cells and centrilobular fibrosing lesion in GIP. Pneumoconiosis, caused by amorphous silica, and acute interstitial pneumonia, associated with the giant tsunami, were also elementally analyzed by EPMA-WDS. The results suggest that commonly found elements, such as silicon, aluminum, and iron, may cause occupational and environmental lung diseases. © 2013 The Japanese Respiratory Society.

DOI： 10.1016/j.resinv.2013.05.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.resinv.2013.05.005

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BMJ PUBLISHING GROUP  

Background
Hard metal lung disease has various pathological patterns including giant cell interstitial pneumonia (GIP) and usual interstitial pneumonia (UIP). Although the UIP pattern is considered the prominent feature in advanced disease, it is unknown whether GIP finally progresses to the UIP pattern.
Objectives
To clarify clinical, pathological and elemental differences between the GIP and UIP patterns in hard metal lung disease.
Methods
A cross-sectional study of patients from 17 institutes participating in the 10th annual meeting of the Tokyo Research Group for Diffuse Parenchymal Lung Diseases, 2009. Nineteen patients (seven female) diagnosed with hard metal lung disease by the presence of tungsten in lung specimens were studied.
Results
Fourteen cases were pathologically diagnosed as GIP or centrilobular inflammation/fibrosing. The other five cases were the UIP pattern or upper lobe fibrosis. Elemental analyses of lung specimens of GIP showed tungsten throughout the centrilobular fibrotic areas. In the UIP pattern, tungsten was detected in the periarteriolar area with subpleural fibrosis, but no association with centrilobular fibrosis or inflammatory cell infiltration. The GIP group was younger (43.1 vs 58.6 years), with shorter exposure duration (73 vs 285 months; p &lt; 0.01), lower serum KL-6 (398 vs 710 U/mL) and higher lymphocyte percentage in bronchoalveolar lavage fluid (31.5% vs 3.22%; p &lt; 0.05) than the fibrosis group.
Conclusions
The UIP pattern or upper lobe fibrosis is remarkably different from GIP in distribution of hard metal elements, associated interstitial inflammation and fibrosis, and clinical features. In hard metal lung disease, the UIP pattern or upper lobe fibrosis may not be an advanced form of GIP.

DOI： 10.1136/bmjopen-2013-004407

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

Objective Direct hemoperfusion with polymyxin B-immobilized fiber columns (PMX-DHP) has been used for the treatment of septic shock. It was recently suggested that PMX-DHP may also be effective in acute exacerbations of idiopathic pulmonary fibrosis (IPF). However, all previous reports are case series without controls. The aim of the study was to determine the effects of PMX-DHP on the prognosis of the patients with rapidly progressive interstitial lung diseases (ILDs) in a case-control setting.
Methods We herein retrospectively examined the clinical records of consecutive patients with acute exacerbation of IPF or rapidly progressive ILDs treated in our institute. We excluded those who had been treated with steroid pulse therapy for lung diseases, including those who had been taking more than 15 mg of oral prednisolone daily, or had undergone an operation within one month before the onset of acute respiratory failure. We compared the results of the laboratory tests and survivals between patients treated with and without PMX-DHP.
Results Twenty-six patients were enrolled in the study. Among them, 13 patients were treated with PMX-DHP in addition to immunosuppressive therapy, including steroid pulse therapy. The mean survival time of patients treated with PMX-DHP tended to be longer than patients not treated with PXM-DHP (p = 0.067). Six patients who underwent PMX-DHP on the first day of steroid pulse therapy had significantly longer survival times than those who were treated with standard medication alone (p &lt; 0.01).
Conclusion These results suggest that PMX-DHP performed on the first day of steroid pulse therapy may improve the prognosis of patients with rapidly progressive ILDs.

DOI： 10.2169/internalmedicine.53.2687

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Idiopathic pulmonary fibrosis is a specific form of chronic fibrosing interstitial pneumonia that is limited to the lung. Angiotensin receptor blockers (ARBs) and peroxisome proliferator-activated receptor (PPAR) γ ligands have anti-inflammatory and anti-fibrotic effects. We investigated the effects of irbesartan-an ARB with PPAR γ activity-on the development of bleomycin-induced pulmonary fibrosis in mice. METHODS: Lung injury was induced in imprinting control region (ICR) mice by intratracheal instillation of 2mg/kg of bleomycin. The treatment group orally received 20mg/kg of irbesartan for 5 consecutive days before instillation. The mice were sacrificed and were evaluated 14 days after bleomycin instillation. RESULTS: Irbesartan reduced the fluid content and hydroxyproline level in the lung and improved the pathological findings as indicated by the Ashcroft score. Total cell counts, the numbers of macrophages, neutrophils, and lymphocytes, and the levels of transforming growth factor (TGF) β1 and monocyte chemotactic protein (MCP) 1 in the bronchoalveolar lavage fluid (BALF) were decreased. Treatment with a PPARγ antagonist GW9662 reversed some of the effects of irbesartan. CONCLUSIONS: The results of this study indicated that irbesartan attenuated the development of bleomycin-induced pulmonary fibrosis in mice by decreasing TGF-β1 and MCP-1 via blocking of ATI, by binding to CCR2b, and by PPARγ-mediated inhibition of inflammation.

DOI： 10.1016/j.resinv.2012.12.005

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Bentham Science Publishers B.V.  

Polymyositis and dermatomyositis (PM-DM) are forms of idiopathic inflammatory myositis. Interstitial lung disease (ILD) in PM-DM is recognized as a serious complication and a major cause of death in this disease. In particular, patients with clinically amyopathic dermatomyositis (ADM) sometimes develop rapidly progressive ILD that remains unresponsive to intensive immunosuppresive therapy. A novel autoantibody associated with PM-DM was identified and termed anti-CADM-140/MDA5 antibody. Anti-CADM-140/MDA5 antibody titer correlates with disease activity and predicts the course of ILD associated with ADM. Glucocorticoids are considered the first-line drug treatment for PM-DM patients with ILD, however they are often not sufficient to obtain improvement of ILD as a single agent. Furthermore, the addition of immunosuppressive drugs becomes necessary as steroid sparing agents to avoid the severe side-effects often seen with high-dose steroid treatment. Cyclophosphamide, cyclosporin, and tacrolimus were reported to be effective in treatment of refractory ILD in PM-DM. Although other immunosuppressive agents
mycophenolate mofetil, intravenous immunoglobulin, and anti-TNF agents have appeared as promising agents for refractory PM-DM, the efficacy on ILD in PM-DM is still unknown. Even if treatment is initiated early in the course of the disease, some patients still develop irreversible fatal lung fibrosis under aggressive immunosuppressive therapy. Recently, cases with rapidly progressive ILD associated with clinically ADM were successfully treated with direct hemoperfusion with polymyxin B-immobilized fiber column. © 2013 Bentham Science Publishers.

DOI： 10.2174/1573398X113099990001

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記述言語：日本語   出版者・発行元：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.62.1368_2

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記述言語：日本語   出版者・発行元：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.35.4_460_1

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記述言語：英語   出版者・発行元：EUROPEAN RESPIRATORY SOC JOURNALS LTD  

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記述言語：日本語   出版者・発行元：(一社)日本睡眠学会  

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記述言語：英語   出版者・発行元：European Respiratory Society  

DOI： 10.1183/09031936.00076711

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：W B SAUNDERS CO LTD  

Background: Autoimmune pulmonary alveolar proteinosis (aPAP) is caused by granulocyte/macrophage-colony stimulating factor (GM-CSF) autoantibodies in the lung. Previously, we reported that GM-CSF inhalation therapy improved alveolar-arterial oxygen difference and serum biomarkers of disease severity in these patients. It is plausible that inhaled GM-CSF improves the dysfunction of alveolar macrophages and promotes the clearance of the surfactant. However, effect of the therapy on components in bronchoalveolar lavage fluid (BALF) remains unclear.
Objectives: To figure out changes in surfactant clearance during GM-CSF inhalation therapy. Methods: We performed retrospective analyses of BALF obtained under a standardized protocol from the same bronchus in each of 19 aPAP patients before and after GM-CSF inhalation therapy (ISRCTN18931678, JMA-IIA00013; total dose 10.5-21 mg, duration 12-24 weeks). For evaluation, the participants were divided into two groups, high responders with improvement in alveolar-arterial oxygen difference &gt;= 13 mmHg (n = 10) and low responders with that &lt; 13 mmHg (n = 9).
Results: Counts of both total cells and alveolar macrophages in BALF did not increase during the therapy. However, total protein and surfactant protein-A (SP-A) were significantly decreased in high responders, but not in low responders, suggesting that clearance of surfactant materials is correlated with the efficacy of the therapy. Among 94 biomarkers screened in bronchoalveolar lavage fluid, we found that the concentration of interleukin-17 and cancer antigen-125 were significantly increased after GM-CSF inhalation treatment.
Conclusions: GM-CSF inhalation decreased the concentration of total protein and SP-A in BALF, and increase interleukin-17 and cancer antigen-125 in improved lung of autoimmune pulmonary alveolar proteinosis. (C) 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.rmed.2011.10.019

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

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記述言語：日本語   出版者・発行元：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.34.4_407_4

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   出版者・発行元：克誠堂出版(株)  

超硬合金肺は、超硬合金の吸入により発生するまれな職業性肺疾患である。症例が少なく臨床像が明らかではないため、全国より19例の超硬合金肺症例を集め、詳細な検討を行った。平均年齢は46.4歳、性別では男性が12名とやや多く、非喫煙者が16名と多く、平均曝露期間は10.1年であった。定型的な病理学像(巨細胞性間質性肺炎、小葉中心性炎症線維化)を呈する例は、19例中14例に認められた。定型例は、非定型例と比べ若年で、曝露期間が短く、KL-6が有意に低いことが明らかになった。(著者抄録)

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本呼吸ケア・リハビリテーション学会  

目的：呼吸機能低下患者での術後ハイリスク群を検討した．対象：術前呼吸機能検査で1秒量＜1.2 Lを満たした80例．方法：術後呼吸不全の発生について診療録より後ろ向きに調査した．結果：7例で合併症が発生した．多因子より算出した呼吸不全リスク指数は合併症群で有意に高値であった．また，同リスク指数と合併症発生頻度の間に有意な傾向性が認められた．結論：呼吸不全リスク指数は術後呼吸不全の検出に有用である．

DOI： 10.15032/jsrcr.21.1_30

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その他リンク： http://search.jamas.or.jp/link/ui/2011352296

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

急速に進行する間質性肺炎に対する抗凝固療法併用の有効性を後ろ向きに検討した。1999年4月から2010年1月までに当科に入院した特発性または続発性の間質性肺炎で、2ヵ月以内に呼吸不全が進行する症例を急速に進行する間質性肺炎と定義した。対象は20例で、基礎疾患はnon-IPF6例、IPF3例、Amyopathic DM(ADM)6例、DM2例、RA2例、MCTD1例であった。治療に抗凝固療法を併用した群をA群(n=11)、非併用群をB群(n=9)として比較検討した。Kaplan-Meier法で、A群に有意な生存期間の延長が認められた(p=0.0389)。急速に進行する間質性肺炎では、抗凝固療法の併用により予後が改善し得る可能性が示唆された。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語  

DOI： 10.1183/09031936.00092910

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

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記述言語：日本語   出版者・発行元：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.60.492_2

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記述言語：日本語   出版者・発行元：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.60.1431_3

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記述言語：日本語   出版者・発行元：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.60.1380_4

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER THORACIC SOC  

Rationale: Inhaled granulocyte/macrophage-colony stimulating factor (GM-CSF) is a promising therapy for pulmonary alveolar proteinosis (PAP) but has not been adequately studied.
Objectives: To evaluate safety and efficacy of inhaled GM-CSF in patients with unremitting or progressive PAP.
Methods: We conducted a national, multicenter, self-controlled, phase II trial at nine pulmonary centers throughout japan. Patients who had lung biopsy or cytology findings diagnostic of PAP, an elevated serum GM-CSF antibody level, and a Pa(O2) of less than 75 mm Hg entered a 12-week observation period. Those who improved (i.e., alveolar-arterial oxygen difference [A-aDO(2)] decreased by 10 mm Hg) during observation were excluded. The rest entered sequential periods of high-dose therapy (250 mu g Days 1-8, none Days 9-14; x six cycles; 12 wk); low-dose therapy (125 mu g Days 1-4, none Days 5-14; x six cycles; 12 wk), and follow-up (52 wk).
Measurements and Main Results: Fifty patients with PAP were enrolled in the study. During observation, nine improved and two withdrew; all of these were excluded. Of 35 patients completing the high- and low-dose therapy, 24 improved, resulting in an overall response rate of 62% (24/39; intention-to-treat analysis) and reduction in A-aDO(2) of 12.3 mm Hg (95% confidence interval, 8.4-16.2; n = 35, P &lt; 0.001). No serious adverse events occurred, and serum GM-CSF autoantibody levels were unchanged. A treatment-emergent correlation occurred between A-aDO(2) and diffusing capacity of the lung, and high-resolution CT revealed improvement of ground-glass opacity. Twenty-nine of 35 patients remained stable without further therapy for 1 year.
Conclusions: Inhaled GM-CSF therapy is safe, effective, and provides a sustained therapeutic effect in autoimmune PAP.

DOI： 10.1164/rccm.200906-0978OC

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC  

P&gt;Background
ONO-1301 is a novel drug that acts as a prostacyclin agonist with thromboxane A(2) (TxA(2)) synthase inhibitory activity. We investigated the effect of ONO-1301 on development of airway allergic inflammation.
Methods
Mice sensitized and challenged to ovalbumin (OVA) received ONO-1301, OKY-046 (TxA(2) synthase inhibitor), beraprost, a prostacyclin receptor (IP) agonist, ONO-1301 plus CAY10449 (selective IP antagonist) or vehicle during the challenge period. Twenty-four hours after the OVA challenge, airway hyperresponsiveness (AHR) to methacholine was assessed and bronchoalveolar lavage was performed. Lung specimens were excised for goblet cell staining and analysis of lung dendritic cells (DCs). Bone marrow-derived dendritic cells (BMDCs) were generated, in the presence or absence of drugs, for analysis of DC function.
Results
Mice that received ONO-1301 showed significantly lower AHR, airway eosinophilia, T-helper type 2 cytokine levels, mucus production and lung DCs numbers than vehicle-treated mice. These effects of ONO-1301 were mostly reversed by CAY10449. BMDCs treated with ONO-1301 alone showed lower DC functions, such as expression of costimulatory factors or stimulation to spleen T cells.
Conclusions
These data suggest that ONO-1301 may suppress AHR and airway allergic inflammation through modulation of DCs, mainly mediated through the IP receptor. This agent may be effective as an anti-inflammatory drug in the treatment of asthma.
Cite this as: M. Hayashi, T. Koya, H. Kawakami, T. Sakagami, T. Hasegawa, H. Kagamu, T. Takada, Y. Sakai, E. Suzuki, E. W. Gelfand and F. Gejyo, Clinical & Experimental Allergy, 2010 (40) 317- 326.

DOI： 10.1111/j.1365-2222.2009.03418.x

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.59.1366_3

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER COLL CHEST PHYSICIANS  

Background: Acquired pulmonary alveolar proteinosis (PAP) has been reclassified into autoimmune or secondary PAP according to the occurrence of serum granulocyte macrophage colony-stimulating factor autoantibody. Most patients undergo high-resolution CT (HRCT) scanning in order for physicians to make a differential diagnosis of diffuse lung diseases, but no information is available to distinguish the HRCT scan features of secondary PAP from those of autoimmune PAP. The objective of this study was to characterize the HRCT scan features of autoimmune and secondary PAP.
Methods: HRCT scans of 42 patients (21 patients each in the autoimmune PAP and secondary PAP groups) were centrally collected and evaluated in a blinded manner.
Results: Ground-glass opacities (GGO) were a major finding in both the autoimmune PAP and secondary PAP groups. In the secondary PAP group, GGOs typically showed a diffuse pattern (62%), whereas GGOs showed a patchy geographic pattern in the autoimmune PAP group (71%; p &lt; 0.005). The so-called "crazy-paving" appearance and subpleural sparing were frequently seen in the autoimmune PAP group (both 71%), whereas they were less frequently seen in the secondary PAP group (14% and 33%, respectively). The involved area of GGO was even in craniocaudal distribution for the secondary PAP group, whereas it was predominant in the lower lung field compared with the upper lung field in the autoimmune PAP group (p &lt; 0.05).
Conclusions: Typical HRCT scan findings for autoimmune PAP patients were GGO with a patchy geographic pattern, subpleural sparing, crazy-paving appearance, and predominance in the lower lung field. These findings were rather infrequent for secondary PAP patients. (CHEST 2009; 136:1348-135-5)

DOI： 10.1378/chest.09-0097

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Bleomycin (BLM)-induced lung injury consists of excessive inflammatory cell infiltration and fibrosis. IS-741 has been reported to be an anti-inflammatory drug through an inhibitory action on cell adhesion. In this study we investigated whether IS-741 could inhibit the progression of pulmonary fibrosis through inflammatory cell infiltration. Lung injury was induced in female C57BL/6 mice by intratracheal instillation of BLM. IS-741 was administered daily intraperitoneally. The hydroxyproline content and fluid content in the lung on Day 28 were significantly lower in the IS-741-treated mice. The histological degree of lung injury or fibrosis was reduced in IS-741-treated mice. Administration of IS-741 caused significant reduction in the absolute number of total cells, monocyte chemoattractant protein (MCP)-1, and cysteinyl leukotriene (cysLTs) levels in bronchoalveolar lavage fluid on Day 7. Furthermore, the hydroxyproline content was significantly lower in IS-741-treated mice even though IS-741 was started on Day 14 after BLM instillation. Treatment with IS-741 had an inhibitory effect on BLM-induced lung injury and fibrosis via the repression of MCP-1 or cysLTs in this murine experimental model.

DOI： 10.1007/s00408-009-9162-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

A 64-year-old Japanese female, diagnosed as dermatomyositis with acute interstitial pneumonia, complained of acute abdominal pain. Computed tomography of the abdomen showed hematoma in the right retroperitoneum and left rectus-sheath. Angiogram showed multiple small aneurysms on left iliolumbar artery and a horizontal linear flush, suggesting active bleeding foci in the muscles. Although arterial embolization therapy was effective for hemostatic treatment, she died of thrombotic thrombocytopenic purpura and multiple organ failure without respiratory insufficiency. Other causes of microaneurysm, such as systemic vasculitides or infectious diseases, were excluded. We considered that this is the first case report of dermatomyositis with hemorrhagic myositis associated with small aneurysms.

DOI： 10.1007/s00296-008-0821-3

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

症例は63歳男性。腰痛、皮膚そう痒感を主訴に、当院皮膚科に精査目的に入院した。入院時の胸部X線写真で左中下肺野に広範な浸潤影を認め、当科で精査を行った。気管支鏡検査を施行し、左B4の洗浄液より細気管支肺胞上皮癌と診断した。骨転移があり、cT4N2M1 stage IVでPS3と不良であったため、除痛目的に放射線照射を行った。その後、呼吸困難、発熱、右中下肺野に浸潤影が出現し、院内感染を考え、抗菌剤を投与したところ一旦は軽快した。12月28日に外泊したが、31日には、呼吸不全のため帰院した。すりガラス陰影が右肺野に広範に出現し、抗菌剤、ステロイドなどを投与したが、以後急速に進行した呼吸不全のため1月5日に永眠した。右側肺の生検針を用いた死後組織採取では、細気管支肺胞上皮癌が同定された。既存の肺胞壁を非破壊性に被覆するように非連続性に、増殖進展している像があり、臨床経過とあわせて対側肺への経気道転移が疑われた。以上、本例は急速な経過で肺内転移を来たし、呼吸不全にて死亡した進行非小細胞肺癌と考える。(著者抄録)

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

A 63-year-old man was admitted to our hospital, because of exacerbation of backache and erythema. At the time of admission the chest X-ray film showed infiltrative shadows in the left middle and lower lung fields. Our investigation revealed primary mucinous type bronchioloalveolar carcinoma in the left lung (cT4N2M1 Stage IV). Radiotherapy (C7-Th2, L3-L5. Total 30 Gy/10 fr) was administered to relieve his pain. After radiotherapy, he developed respiratory failure, fever, and infiltrative shadow in his chest X-ray. Antibiotic therapy improved his symptoms, laboratory findings and radiological abnormal findings. We suspected complication with nosocomial infection. However the ground-glass appearance appeared in the right lung a few days later. Although antibiotics and steroids were administered, he died of respiratory failure in 6 days. Necropsy findings revealed bronchioloalveolar carcinoma in the right lung suggesting aerogenous metastasis. Considering these facts together, we diagnosed non-small cell lung carcinoma dying of acute respiratory failure due to aerogenous metastasis.

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER JAPAN KK  

We report the case of a 44-year-old woman with disseminated Mycobacterium avium complex (MAC) infection involving multiple bone lesions despite a normal healthy status until 6 months previously. Because she was suspected to have acquired immunodeficiency, we tested interferon (IFN)-gamma production by peripheral blood mononuclear cells (PBMC) after phytohemagglutinin (PHA) or anti-CD3 stimulation, and found that these cells produced no, or undetectable, levels of IFN-gamma in the presence of the patient's plasma, but produced nearly normal levels of IFN-gamma in the presence of healthy donor plasma. Since the IgG fraction of the patient's plasma was capable of blocking in vitro responses to IFN-gamma, the cause of disseminated MAC infection in this case appeared to be anti-IFN-gamma autoantibodies. To reduce the titer of anti-IFN-gamma autoantibodies, the patient received intravenous immunoglobulin (IVIG). However, titer of autoantibodies changed little compared to that before IVIG administration. According to our literature search, this is only the second case of disseminated MAC infection associated with anti-IFN-gamma autoantibodies in Japan.

DOI： 10.1007/s10156-008-0662-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

Objective Rheumatoid arthritis (RA) is associated with numerous pulmonary manifestations. However, the inflammatory mechanism remains undetermined. We studied the features of inflammatory cells in bronchoalveolar lavage (BAL) fluid and biopsy lung tissue from patients with RA-associated lung disease.
Methods BAL findings were statistically compared between diseases. We divided RA patients into two groups, airway lesion group (AW) and interstitial lesion group (INT) according to predominant HRCT findings and compared the BAL findings. We immunohistochemically stained lung tissue for CD4, CD8, CD20, and CD163 and counted the immunopositive cells in five different regions.
Patients Twenty patients fulfilling the Japanese criteria for RA, 13 patients with systemic sclerosis (SSc), and 21 patients with polymyositis and dermatomyositis (PM-DM) with pulmonary disease detected by high-resolution CT (HRCT) were enrolled in this study.
Results As for BAL in RA, we found a lower lymphocyte frequency with higher CD4/8 ratio compared with PM-DM and a higher neutrophil percentage than both PM-DM and SSc. Nine and eleven patients with RA were classified into AW and INT groups, respectively. BAL findings did not differ between the two groups. Immunohistochemically, most CD4(+) and CD20(+) lymphocytes were accumulated in lymphoid follicles and in the alveolar wall and T-lymphocytes; in particular CD8(+) lymphocytes were predominant in lung interstitium.
Conclusion These results suggest that 1) neutrophils may play an important role, 2) the inflammatory mechanism may be similar between airway lesion and interstitial pneumonia, and 3) CD8(+) lymphocytes may be major inflammatory cells in lung interstitium in RA-associated interstitial lung disease.

DOI： 10.2169/internalmedicine.48.1841

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記述言語：日本語   出版者・発行元：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.58.421_4

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記述言語：日本語   出版者・発行元：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.31.1_43_1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Reactive oxygen species play an important role in the pathogenesis of acute lung injury and pulmonary fibrosis. The present authors hypothesise that edaravone, a free-radical scavenger, is able to attenuate bleomycin (BLM)-induced lung injury in mice by decreasing oxidative stress. Lung injury was induced in female ICR mice by intratracheal instillation of 5 mg·kg-1 of BLM. Edaravone (300 mg·kg-1) was administered by intraperitoneal administration 1 h before BLM challenge. Edaravone significantly improved the survival rate of mice treated with BLM from 25 to 90%, reduced the number of total cells and neutrophils in bronchoalveolar lavage fluid (BALF) on day 7, and attenuated the concentrations of lipid hydroperoxide in BALF and serum on day 2. The fibrotic change in the lung on day 28 was ameliorated by edaravone, as evaluated by histological examination and measurement of hydroxyproline contents. In addition, edaravone significantly increased the prostaglandin E2 concentration in BALF on day 2. In summary, edaravone was shown to inhibit lung injury and fibrosis via the repression of lipid hydroperoxide production and the elevation of prostaglandin E2 production in the present experimental murine system. Copyright©ERS Journals Ltd 2008.

DOI： 10.1183/09031936.00164407

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Background and objective: Reactive oxygen species (ROS) play an important role in the pathogenesis of acute lung injury (ALI) and pulmonary fibrosis. It was hypothesized that edaravone, a free radical scavenger, would be able to attenuate LPS-induced lung injury in mice by decreasing oxidative stress.
Methods: For the in vivo experiments, lung injury was induced in female BALB/c mice by the intranasal instillation of LPS. Edaravone was given by intraperitoneal administration 1 h before the LPS challenge. For the in vitro experiments, MH-S cells (murine alveolar macrophage cell line) were exposed to edaravone, followed by stimulation with LPS.
Results: In the LPS-induced ALI mouse model, the administration of edaravone attenuated cellular infiltration into and the concentrations of albumin, IL-6, tumour necrosis factor-alpha, keratinocyte-derived chemokine and macrophage inflammatory protein-2 in BAL fluid. In addition, the in vitro studies showed that the elevated IL-6 secretion from MH-S cells in response to LPS was significantly attenuated by co-incubation with edaravone.
Conclusions: In an experimental murine model, a free radical scavenger may prevent ALI via repression of pro-inflammatory cytokine production by lung macrophages.

DOI： 10.1111/j.1440-1843.2008.01322.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER THORACIC SOC  

Rationale Acquired pulmonary alveolar proteinosis (PAP) is a syndrome characterized by pulmonary surfactant accumulation occurring in association with granulocyte/macrophage colony-stimulating factor autoantibodies (autoimmune PAP) or as a consequence of another disease (secondary PAP). Because PAP is rare, prior reports were based on limited patient numbers or a synthesis of historical data.
Objectives: To describe the epidemiologic, clinical, physiologic, and laboratory features of autoimmune PAP in a large, contemporaneous cohort of patients with PAP.
Methods: Over 6 years, 248 patients with PAP were enrolled in a Japanese national registry, including 223 with autoimmune PAP.
Measurements and Main Results: Autoimmune PAP represented 89.9% of cases and had a minimum incidence and prevalence of 0.49 and 6.2 per million, respectively. The male to female ratio was 2.1: 1, and the median age at diagnosis was 51 years. A history of smoking occurred in 56%, and dust exposure occurred in 23%; instances of familial onset did not occur. Dyspnea was the most common presenting symptom, occurring in 54.3%. Importantly, 31.8% of patients were asymptomatic and were identified by health screening. Intercurrent illnesses, including infections, were infrequent. A disease severity score reflecting the presence of symptoms and degree of hypoxemia correlated well with carbon monoxide diffusing capacity and serum biomarkers, less well with pulmonary function, and not with granulocyte/macrophage colony-stimulating factor autoantibody levels or duration of disease.
Conclusions: Autoimmune PAP had an incidence and prevalence higher than previously reported and was not strongly linked to smoking, occupational exposure, or other illnesses. The disease severity score and biomarkers provide novel and potentially useful outcome measures in PAP.

DOI： 10.1164/rccm.200708-1271OC

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：STEP PUBLISHING LTD  

Bronchoalveolar lavage (BAL) is a technique that samples the inflammatory cells from distal airways and alveoli; however, it is unclear whether or not cellular profiles in the BAL fluid reflect the cellular components of the lung parenchyma in interstitial lung disease (ILD). The aim of this study is to compare immunophenotypes of lymphocytes between BAL fluid and human lung tissue from patients with ILD. Fourteen consecutive patients with ILD who underwent BAL and surgical lung biopsy were enrolled. The diagnosis of ILD was confirmed by the presence of clinical symptoms and impaired respiratory function and on high-resolution computed tomography (CT) of the chest. Mononuclear cells in BAL were immunophenotyped for the expression of CD3, CD4, CD8, CD19, CD45, and CD103 by flow cytometry. Lung tissue obtained by surgical biopsy was digested with collagenase and then centrifuged to extract parenchymal cells. Isolated cells were also immunophenotyped for the same CD expression. Frequencies of positive cells were compared statistically between BAL and different lobes. Seven out of 14 patients were diagnosed clinically as suffering idiopathic interstitial pneumonia. Frequency of CD19(+) cells from BAL was significantly lower than that from the upper/middle lobes (P &lt; 0.05). Frequency of CD103(+) cells from BAL was significantly higher than that from the upper/middle lobes and the lower lobe (P=0.01 and P &lt; 0.05, respectively). Comparison between different lobes demonstrated that the frequency of CD4(+) cells from the upper/middle lobes was significantly lower than that from the lower lobe (P &lt; 0.05). The results suggest that lymphocyte immunophenotype profiles from BAL may not reflect those in the inflammatory tissue of ILD.

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記述言語：日本語   出版者・発行元：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.57.1515_4

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記述言語：日本語   出版者・発行元：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.30.1_49_1

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING  

Objective: Pulmonary fibrosis is thought to be closely associated with the T-helper type-2 (Th2) immune response. Recent studies have shown that hochu-ekki-to (TJ-41), a Japanese herbal medicine, may correct the Th1/Th2 imbalance skewed to Th2. The present study was designed to investigate the preventive effect of TJ-41 on the development of bleomycin (BLM)-induced lung injury in mice.
Methods: Female C57BL/6 mice were divided into a group given ordinary feed and another group given the same feed plus TJ-41 mixed in at a dose of 1 g/kg/day. Both groups were maintained on this diet for 8 weeks before and 5 weeks after administration of 2 mg/kg BLM intratracheally.
Results: Mortality after BLM-induced lung injury was significantly lower in the TJ-41-treated mice. The hydroxyproline content and fluid content in the lung on day 35 was significantly lower in the TJ-41-treated mice. Histologically, TJ-41 reduced the number of infiltrating cells, thus ameliorating the destruction of the lung architecture, and attenuated the lung fibrosis score. Furthermore, TJ-41 inhibited the expression of the interleukin-5/interferon-gamma mRNA ratio in the lung on day 7.
Conclusion: Treatment with TJ-41 partially prevented experimental lung fibrosis through the correction of the Th1/Th2 imbalance skewed to Th2.

DOI： 10.1111/j.1440-1843.2007.01146.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER THORACIC SOC  

Rationale: Hard metal lung disease is caused by exposure to hard metal, a synthetic compound that combines tungsten carbide with cobalt as well as a number of other metals. Interstitial lung disease caused by hard metal is uniquely characterized by giant cell interstitial pneumonia. The pathogenesis of hard metal lung disease is unclear.
Objectives: To elucidate the distribution of inhaled hard metal and reactive inflammatory cells in biopsy lung tissue from patients with hard metal lung disease.
Methods: Seventeen patients with interstitial lung disease in which tungsten was detected and five control subjects were studied. Detection and mapping of elements were performed with an electron probe microanalyzer equipped with a wavelength dispersive spectrometer. We immunohistochemically stained mononuclear cells in tissue samples available from five patients, with anti-human CD4, CD8, CD20, CD68, and CD163 antibodies, and compared the distribution of positive cells with hard metal elements.
Measurements and Main Results: Thirteen of 17 patients were pathologically diagnosed as having giant cell interstitial pneumonia. Tungsten and cobalt were accumulated in the centrilobular fibrotic lesions, but were never found in the control lungs. CD8(+) lymphocytes and CD163(+) monocyte-macrophages were distributed predominantly in centrilobular fibrotic lesions around the hard metal elements. CD163(+) colocalized with tungsten. Small numbers of CD8(+) and CD163(+) cells were also immunohistochemically shown in peribronchiolar areas and alveolar walls.
Conclusions: Macrophages may phagocytose inhaled tungsten via CID163 and play an important role in forming the fibrotic lesion of hard metal lung disease with cytotoxic T lymphocytes.

DOI： 10.1164/rccm.200601-134OC

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：TAYLOR & FRANCIS INC  

The authors have investigated gene expression of ST2 in the lung tissue of a bleomycin (BLM)-induced lung fibrosis model in vivo and in a human lung fibroblast cell line, WI38, and a human type II alveolar epithelial cell line, A549, reacting to proinflammatory and type 2 helper T cell (Th2)-type cytokine stimuli in vitro. The lung mRNA expression of interleukin (IL)-4, IL-5, IL-1 beta, and tumor necrosis factor (TNT)-alpha increased significantly at day 7 after instillation of BLM, whereas interferon (IFN)-gamma mRNA expression did not increase. ST2 and transforming growth factor (TGF)-beta 1 mRNA expression of the lung increased significantly between days 7 and 21, and increased to maximal levels at day 14 post-BLM challenge. ST2 mRNA expression statistically correlated with TGF-beta 1 mPLNA expression. In addition, the combination of IL-1 beta, TAT-alpha, and IL-4 had an additive effect on ST2 mRNA expression from A549 cells and WI38 cells. These findings suggest that soluble ST2 gene may increase, possibly reflecting the development of the inflammatory process and the Th2-type immune response in the fibrotic lung tissue, and may modulate a process of pulmonary fibrosis.

DOI： 10.1080/01902140701198583

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

Objective To quantitatively isolate and immunologically phenotype mononuclear cells contained in human lung tissue.
Methods Normal appearing lung tissue as far distal to the resected lesion as possible was obtained from lung cancer patients. Lung tissue was thoroughly washed and cut into small pieces and digested with collagenase. Peripheral blood mononuclear cells (PBMNC) were prepared from controls using Ficoll gradient. Isolated cells and PBMNC were analyzed by flow cytometry. We immunohistochemically stained snap-frozen lung tissue with anti-CD3, CD4, CD8, CD20, and CD161 antibodies.
Participants Nineteen patients with lung cancer who underwent lobectomy were enrolled. Twelve healthy volunteers also participated as controls for flow cytometric analysis of PBMNC.
Results In forward scatter vs side scatter, 92.1 +/- 7.8% of isolated cells in the lymphoid population expressed leukocyte common antigen, CD45. The frequency of CD45-positive cells in the lymphoid population from lung tissue was as high as that from PBMNC (p = 0.118). CD45-positive cells were successfully further extended by anti-CD3, CD4, CD8, CD19, and CD161 antibodies. Monocyte-macrophages bearing CD68 were also detected. CD68-positive alveolar macrophages dissapeared from alveolar spaces after thorough washing by immunohistochemical staining. Mononuclear cells in the interstitium were positively stained by anti-CD3, CD4, CD8, CD20, and CD161 monoclonal antibodies.
Conclusions We could isolate interstitial cells and analyze cell surface markers via flow cytometry from fresh lung specimens by collagenase digestion without further purification. Immunohistochemistry confirmed the presence of the cells detected by flow cytometry in the lung interstitium.

DOI： 10.2169/internalmedicine.46.1857

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記述言語：日本語   出版者・発行元：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.56.358_2

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

This study was designed to investigate the effect of Hochu-ekki-to (TJ-41), a Japanese herbal medicine, on the development of lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. ALI was induced in female BALB/c mice by the intranasal administration of 0.1 mg/kg LPS. The mice were divided into a group receiving normal feed and another group receiving feed mixed with TJ-41 at a dose of 1 g/kg/day for 8 weeks before LPS challenge. In the bronchoalveolar lavage fluid, the preadministration of TJ-41 caused significant reduction in the absolute number of total cells, neutrophils, and macrophages. The preadministration of TJ-41 significantly inhibited increases in the serum level of keratinocyte chemoattractant (KC), which is a murine chemotaxin for neutrophils that corresponds to human interleukin-8, with respect to its concentration at 24 h after LPS challenge. Furthermore, the histopathologic findings indicated that alveolitis with leukocyte infiltration in the alveolar space was less severe in the TJ-41-treated mice than in the control mice. These findings indicated that the preadministration of TJ-41 could show an inhibitory effect on ALI in this experimental murine system associated with the suppression of chemokine production.

DOI： 10.1007/s00408-006-0018-z

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記述言語：英語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

Objective It is well known that the serum level of KL-6 can be an indicator of disease activity in patients with interstitial pneumonia (IP). However, surgical lung biopsy is often required for the diagnosis of IP, although this can result in IP exacerbation.
Methods The effect of surgical lung biopsy on the serum level of KL-6 in patients with IP was analyzed. Thirty-two cases of IP were examined in this study. There were no cases showing exacerbation of IP.
Results The serum level of KL-6 demonstrated 1067 +/- 550 U/ml (mean +/- SD) before lung biopsy, 991 +/- 471 U/ml a day, 824 +/- 377 U/ml 4 days and 826 +/- 384 U/ml 7 days after lung biopsy. The serum KL-6 levels on the 1st, 4th, 7th day after the lung biopsy were significantly lower than that before the lung biopsy (P &lt; 0.05, P &lt; 0.01 and P &lt; 0.01, respectively). The percent decrease of the serum KL-6 levels on the 4th day (the lowest level) was dependent on the urine volume, and the analysis of the urinary levels of KL-6 showed a transient increase in urinary KL-6 excretion, suggesting that the decrease in serum KL-6 levels associated with surgical lung biopsy may be caused by this increase in urinary KL-6 excretion.
Conclusion Surgical lung biopsy of patients with IP has little effect on the increase in serum KL-6 levels. An elevation of serum KL-6 after surgical lung biopsy may indicate exacerbation of IP.

DOI： 10.2169/internalmedicine.45.1606

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

Objective The serotonin (5-HT) 2A and 2C receptor subtype plays an important role in the maintenance of upper airway stability and normal breathing in obesity. Polymorphisms in the 5-HT 2A receptor gene (HTR2A) and 5-HT 2C receptor gene (HTR2C) are associated with various diseases. The aim of this study was to investigate whether or not the HTR2A/C genotypes are associated with obstructive sleep apnea (OSA).
Methods The PCR-restriction fragment length polymorphism method was used to determine genotypes of the HTR2A/C gene. The genotype distributions and allele frequencies were statistically analyzed. Subjects We studied 177 consecutive male patients with excessive daytime somnolence and an apnea plus hypopnea number [apnea-hypopnea index (AHI)] of greater than five per hour of sleep established by full polysomnography. One hundred Japanese men in whom OSA was clinically excluded were randomly selected as a control group.
Results Genotypes and allele frequencies of 102T/C polymorphism of the HTR2A and 796G/C polymorphism of the HTR2C did not differ between controls and patients with OSA. HTR2C polymorphism was considered inappropriate for association studies because of low frequency of the mutant allele. Multiple regression analysis showed that age and body mass index (BMI) were significantly associated with OSA, but HTR2A polymorphisms were not. HTR2A polymorphisms had no significant relationship with AHI or BMI, although further study with more samples will be needed for powerful statistical analyses.
Conclusions These results indicate that age and BMI, not these polymorphisms, are associated with OSA in this population.

DOI： 10.2169/internalmedicine.44.928

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

Objective Many Japanese patients with obstructive sleep apnea (OSA) are less obese than Caucasian OSA patients despite their similar severity of OSA, suggesting that their etiology of OSA may differ. The purpose of this study was to identify bony factors associated with OSA in the Japanese population.
Methods The clinical records of study subjects were retrospectively reviewed, and cephalometric measurements based on Sella-Nasion references and the Ricketts method were statistically compared.
Patients Two hundred and six consecutive Japanese men complaining of habitual snoring and daytime sleepiness were enrolled in the study. All subsequently underwent an overnight polysomnographic examination.
Results Multiple regression analysis showed that the body mass index (p &lt; 0.0001) and facial axis angle (p=0.007) were the dominant overall determinants for the apnea hypopnea index. The sella to nasion to subspinale angle (SNA) and sella to nasion to supramentale angle (SNB) were lower in the non-obese, severe group than for non-obese, mild and moderate patients with OSA (p=0.0047 and 0.0016, respectively).
Conclusion The risk factors for OSA in Japanese men may be obesity and the dolico facial pattern seen by the Ricketts method. In addition, a smaller SNA and SNB seem to be associated with the severity of OSA in nonobese patients.

DOI： 10.2169/internalmedicine.44.805

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

We report a case of tracheo-bronchitis in Crohn's disease. A 23-year-old Japanese woman who had been diagnosed with Crohn's disease three years previously was hospitalized. She had been suffering from dry cough for one month. Computed tomography of the chest revealed marked thickening of the tracheal wall. Bronchoscopy showed erythematous and edematous mucosa with diffuse whitish granular lesions in the trachea and bronchi. The bronchial biopsy specimens showed non-specific inflammatory infiltrates consisting of lymphocytes and plasma cells, and hyperplasia of bronchial glands. Inhaled corticotherapy, fluticasone propionate 800 mug/day, was effective for both the inflammatory mucosa and thickened tracheal wall.

DOI： 10.2169/internalmedicine.43.829

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Peroxisome proliferator-activated receptor γ (PPARγ) plays an important role in lipid metabolism, insulin sensitivity, atherogenesis, and immune regulation. A genetic polymorphism (C161T) at exon 6 of PPARγ gene (PPARG) was reported to be associated with the onset of coronary artery disease. However, there has been no report of an association with renal disease. Genomic DNAs were isolated from 225 Japanese patients with histologically confirmed immunoglobulin A nephropathy (IgAN). The PPARG C161T genotype was determined by polymerase chain reaction-restriction fragment length polymorphism. The association of the polymorphism with renal prognosis in IgAN patients was analyzed using the Kaplan-Meier method and Cox proportional hazard regression model. The PPARG polymorphism was not associated with the renal survival rate. However, when patients were stratified into those either with or without hypertension at the time of diagnosis, the renal survival of the CT/TT genotypes was significantly better in those without hypertension than those with the CC genotype. We report that the PPARG C161T polymorphism is associated with the survival of IgAN patients without hypertension. The T allele of the polymorphism might have a protective effect on the progression of IgAN.

DOI： 10.1034/j.1399-0004.2003.00154.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING ASIA  

Objective: Patients with mixed connective tissue disease (MCTD) exhibit clinical features of systemic lupus erythernatosus (SLE), systemic sclerosis (SSc), and polymyositis and dermatomyositis (PM-DM). The objective of this study was to clarify differences in BAL findings and immunophenotypes of BAL fluid (BALF) cells of patients with interstitial lung disease associated with these diseases.
Methodology: We were unable to recruit a sufficient number of SLE patients with lung disease. We compared immunophenotypes of lymphocytes and alveolar macrophages (AM) in BALF of 20 MCTD patients with those of 21 SSc and 27 PM-DM patients and tested the relationships between immunophenotypes and pulmonary function in MCTD.
Results: MCTD patients had a significantly higher CD4/CD8 ratio with more CD4 positive lymphocytes than PM-DM patients (P = 0.025). In AM phenotypes, MCTD patients had a significantly lower percentage of CD71 positive AM compared with SSc patients (P = 0.023). DLCO was negatively related to absolute numbers of CD8 positive lymphocytes (R = -0.517, P = 0.033).
Conclusions: CD4 positive lymphocytes in BALF were increased in MCTD compared to PM-DM patients, while CD71 positive AM were decreased in MCTD compared to SSc patients. CD8 positive lymphocytes correlated negatively with DLCO measurements in MCTD patients.

DOI： 10.1046/j.1440-1843.2003.00445.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER COLL CHEST PHYSICIANS  

Objectives: Vascular endothelial growth factor (VEGF) promotes angiogenesis, mediates vascular permeability, and activates and recruits monocytes. VEGF is produced in activated alveolar macrophages, in epithelioid cells, and in multinuclear giant cells of pulmonary sarcoid granulomas. Recent reports have shown that a polymorphism at - 627 of the VEGF gene is related to VEGF protein production, and a polymorphism at + 813 is associated with VEGF plasma levels. We investigated the roles of such polymorphisms in the development and extent of sarcoidosis.
Methods: We examined polymorphisms of the VEGF gene in 103 Japanese patients with sarcoidosis and 146 healthy Japanese control subjects. The position - 627 polymorphism was determined using the TaqMan (TaqMan Laboratory, University of Pittsburgh Cancer Institute; Pittsburgh, PA) polymerase chain reaction (PCR) method. For genotyping of the position + 813 polymorphism, the PCR restriction fragment length polymorphism method was performed.
Results: As for + 813 genotypes, the less-common genotypes CT and TT were found more often in control subjects than in patients (odds ratio, 0.490; 95% confidence interval, 0.276 to 0.868). A significant increase in the frequency of the T allele (p = 0.005, Pc = 0.020 after Bonferroni correction) was observed in control subjects. As for - 627 genotypes, the mean value of the FEV1/FVC percentage in GG type was lower than that in CC or CG type, however, the other clinical findings did not suggest airway diseases in the GG type.
Conclusions: We suggest that in VEGF gene polymorphisms the T allele at + 813 may decrease susceptibility to sarcoidosis.

DOI： 10.1378/chest.123.5.1520

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記述言語：日本語   出版者・発行元：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.25.6_480_2

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

Objectives Monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-lalpha exhibit chemotactic activity toward macrophages/monocytes and induce the production of inflammatory cytokines affecting granuloma formation. Recently, a single nucleotide polymorphism (SNP) in the MCP-1 distal regulatory region and a dinucleotide repeat in the MIP-1A gene promoter region were identified. We investigated the relationships between the polymorphisms and susceptibility to sarcoidosis, clinical manifestations, and BALF findings of sarcoidosis.
Methods The polymorphisms of the MCP-1 and MIP-1A genes in 118 patients with sarcoidosis and 145 healthy control subjects were examined. The MCP-1 polymorphism was genotyped by a PCR-restriction fragment length polymorphism method and the MIP-1A genotype was determined using PCR.
Results No significant difference in the genotype distribution or in the allele frequency between the patients and control subjects was observed. We found no relationship between the polymorphisms and the serum ACE level, organ involvement, roentgenographic stages, or deterioration in chest radiographs during the follow-up. A significant difference in the absolute counts of AMs in BALF of 51 patients among the genotypes of the MCP-1 gene was found (p=0.048). The AM counts in BALF of the G/A and G/G genotypes were significantly increased compared with that of the A/A genotype (p&lt;0.05).
Conclusion The polymorphisms of the MCP-1 and MIP-1A genes do not play a substantial role in genetic predisposition for sarcoidosis or in clinical manifestations of sarcoidosis in this Japanese population. The MCP-1 SNP might be related to the recruitment of monocytes/macrophages to the alveolar spaces in sarcoidosis.

DOI： 10.2169/internalmedicine.41.813

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PARTHENON PUBLISHING GROUP  

Carpal-tunnel syndrome (CTS) in long-term hemodialysis patients is caused by the deposition of amyloid as well as by the local inflammatory process. The recruitment of monocytes/macrophages in the tenosynovium, promoted by chemokines such as monocyte chemoattractant protein-1alpha (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha), is thought to play an important role in CTS development. The genetic polymorphism of these chemokines has been identified and their clinical function has been partly revealed We attempted to analyze the relationship between these polymorphisms and their susceptibility to CTS. The subjects of this study were 366 patients who underwent hemodialysis. Ninety-five patients received surgery for CTS. No significant difference was observed in the genotype distributions of MCP-1 or MIP-1alpha between patients who received CTS surgery and those that did not. However, with the use of a logistic regression model, the MCP-1 GG genotype was identified as a risk factor for the development of CTS, in addition to the duration and the age of initiation of dialysis, as confirmed by a Cox proportional hazards model. In conclusion, homozygosity for G at -2518 in the MCP-1 gene might be a candidate for the genetic marker of CTS development in Japanese hemodialysis patients.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL MUNKSGAARD  

Interleukin-18 (IL-18) and interleukin-12 (IL-12) synergistically stimulate interferon-gamma (IFN-gamma) production from Th1 cells. The levels of serum IL-18 and IFN-gamma and bronchoalveolar lavage fluid IL-18 were elevated in patients with sarcoidosis. The polymorphisms of the IL-18 gene may play a possible role in expression regulation of the gene. We investigated the roles of the polymorphisms in the development of sarcoidosis. We examined two single nucleotide polymorphisms of the IL-18 gene in 119 patients with sarcoidosis and 130 healthy control subjects. Our results showed that the frequency of sarcoidosis patients with the CA genotype at position -607 was significantly higher than that with the AA genotype (OR=2.200) and a significantly higher proportion of patients had the C allele at -607 compared with that of the controls (OR=2.123). No significant differences were seen in the distribution of the genotypes or phenotype frequencies at position 137. There was no specific organ involvement associated with a certain genotype or phenotype. In IL-18 gene polymorphisms, the C allele at position -607 might be a genetic risk factor for sarcoidosis in this Japanese population.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Purpose: The purpose of this work was to compare the CT findings of lung involvement in patients with mixed connective tissue disease (MCTD) with those in patients with other CTDs: systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and polymyositis and dermatomyositis (PM-DM).
Method: CT scans of 35 patients with interstitial lung disease and associated MCTD were evaluated retrospectively. The CT assessment included determination of the findings and evaluation of whether the findings in MCTD were different from those in other CTDs.
Results: The frequency of ground-glass opacity in MCTD was significantly lower than in CTDs (p &lt; 0.05). The frequency of honeycombing in MCTD was lower than in SSc (p &lt; 0.05) and higher than in PM-DM (p &lt; 0.005). Regarding the predominant CT patterns, the frequency of septal thickening in MCTD was significantly higher than in CTDs (p &lt; 0.05).
Conclusion: CT findings in MCTD were a combination of those in other CTDs.

DOI： 10.1097/01.RCT.0000015525.51830.61

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING ASIA  

Objective: The aim of this study was to clarify the characteristics of pulmonary function tests (PFT), especially carbon monoxide diffusion capacity (DLCO), and their correlation with clinical features and immunological findings in patients with systemic lupus erythematosus (SLE).
Methodology: Vital capacity (VC) and DLCO were analysed retrospectively in 110 sequential Japanese SLE patients with active disease between 1985 and 1999. In 38 patients, serial measurements of PFT were also assessed during high-dose corticosteroid therapy.
Results: DLCO was reduced in 52 patients (47%) and a restrictive impairment of PFT was observed in nine patients (8%). The prevalence of pulmonary fibrosis was 13%. Reduced DLCO was frequently observed, even in patients with neither pulmonary fibrosis nor a restrictive pattern. No correlation between immunological data and reduced DLCO was found, except for the presence of anti-RNP Patients with Raynaud's phenomenon showed a higher prevalence of DLco impairment than those without this phenomenon. Although immunological parameters improved significantly after the corticosteroid therapy, no significant change in the level of DLco was observed.
Conclusions: Impairment of DLCO was frequently observed in patients with SLE who had no clinical respiratory abnormalities. DLCO impairments were correlated with Raynaud's phenomenon clinically, and the presence of anti-RNP immunologically. No significant correlation was found between impairment of DLCO and disease activity of SLE.

DOI： 10.1046/j.1440-1843.2002.00361.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL MUNKSGAARD  

RANTES, a member of C-C chemokine, is known to be produced at sites of granulomatous reactions in the lung of sarcoidosis. RANTES is a potent eosinophil and lymphocyte attractant with particular preference for CD45RO(+) T cells and eosinophils. Polymorphism of the RANTES promoter has recently been shown to be related to allergic and infectious diseases; atopic dermatitis, asthma, and polymyalgia rheumatica. Considering that this might affect sarcoidosis, we studied polymorphism of the RANTES gene in 114 patients with sarcoidosis and 136 healthy control subjects. Their genotypes were determined using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Although no difference in the genotype distribution between healthy control subjects and sarcoidosis patients was identified, the difference in the frequencies of the patients with three or more organ involvement was significant (P&lt;0.01) with the frequency of those in AA genotype being elevated (P&lt;0.05). BAL findings in 48 out of 114 patients who underwent bronchoscopy were reviewed. The patients CD4/8 ratio of lymphocytes in bronchoalveolar lavage fluid in the pat with AA genotype was significantly increased (P&lt;0.05). From the results, we suggest that in RANTES gene polymorphism the homozygous A allele might be a genetic risk factor for extent disease of sarcoidosis.

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記述言語：日本語   出版者・発行元：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.50.299_4

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記述言語：日本語   出版者・発行元：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.49.835_1

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Society of Internal Medicine  

Polymyositis and dermatomyositis (PM/DM) without creatine kinase (CK) elevation shows a poor prognosis. PM/DM is complicated with interstitial lung disease (ILD), some of which progress rapidly. To clarify the clinical features of PM/DM from the viewpoint of ILD progression, the clinical data of 25 PM/DM patients with ILD were reviewed. They were classified as responders or non-responders. The patients whose ILD responded to steroid therapy and elicited good clinical courses were termed as responders. On the other hand, the patients who had rapidly progressive ILD resistent steroid therapy were considered as non-responders. The patients diagnosed to have DM were likely to be steroid-resistant. The non-responder group revealed significantly high aspartate aminotransferase (AST), low CK, low white blood cell (WBC), and low absolute lymphocyte counts in their peripheral blood. High CK/AST may be a favorable predictor of the disease. The percentages of lymphocytes in bronchoalveolar lavage fluid were increased in both groups. However, the percentages of two responders with low CK/AST were lower than those of three non-responders. A steroid-resistant ILD group with PM/DM may be clinically different from a steroid-responsive ILD group.

DOI： 10.2169/internalmedicine.37.669

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記述言語：日本語   出版者・発行元：Japan Society of Sarcoidosis and other Granulomatous Disorders  

DOI： 10.14830/jssog1987.16.145

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

A 61-year-old man with a history of hypertension and diabetes mellitus had a tooth extracted. Nine days later, he was admitted to the hospital with complaints of high fever, dyspnea, and anterior chest pain. Physical examination revealed a drowsy man for a fever of 38.2°C, blood pressure of 66/44 mmHg, and marked redness and swelling from he neck to anterior part of the chest. Laboratory examination indicated severe infection and multiple organ, consisting of cardiac, respiratory, renal, and hepatic failure, with disseminated intravascular coagulation. Chest X-ray and CT-scan films showed abscesses extending from the neck to the mediastinum, and bilateral pleural effusion. Immediately, he was treated with cathecholamines, furosemide, mechanical ventilation with a high concentration of oxygen, continuous drainage, repeated skin incisions, and broad-spectrum antibiotics. In addition, steroid pulse therapy was administered for persistent respiratory failure. On the 28th hospital day, a fistula developed between the trachea and the mediastinum, and an intratracheal tube had to be inserted through the fistula. On the 212th hospital day, after intravenous hyperalimentation, continuous intravenous insulin infusion, and administration of broad-spectrum antibodies, catecholamines, and furosemide, the patient was weaned from mechanical ventilation. A restrictive ventilatory defect due to ankylosis and atrophy of underused muscles was noted after weaning, but the PaO2 was high with a low dose of oxygen (1 to 2.1/min), and 21 months later, the blood gases were normal while the patient was breathing room air. As of January, 1996, he was undergoing rehabilitation to promote his recovery from ankylosis, muscle atrophy, and speech dysfunction.

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記述言語：日本語   出版者・発行元：Japan Society of Sarcoidosis and other Granulomatous Disorders  

DOI： 10.14830/jssog1987.15.90

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記述言語：日本語   出版者・発行元：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.18.3_270_1

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記述言語：日本語   出版者・発行元：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.18.3_269_4

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記述言語：日本語   出版者・発行元：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.18.3_270_4

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記述言語：日本語   出版者・発行元：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.17.3_271_1

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記述言語：日本語   出版者・発行元：The Japanese Respiratory Society  

六君子湯による薬剤性間質性肺炎の1例を報告した. 症例は79歳, 女性で間質性肺炎の疑いで入院した. 労作時息切れと咳嗽, 胸部X線上両肺の容積減少とびまん性粒状網状影認めた. 薬剤性間質性肺炎を疑い, 全内服薬を中止すると共に, プレドニン治療を開始したところ, 臨床症状, 検査所見, 胸部X線・CT上に改善を認めた. 経気管支肺生検では間質性肺炎像を呈し, リンパ球刺激試験・白血球遊走阻止試験では六君子湯に対し陽性を示した. 当薬剤による薬剤性間質性肺炎の報告は本邦で第1例目と思われる.

DOI： 10.11389/jjrs1963.32.84

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語  

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記述言語：日本語   出版者・発行元：東京医学社  

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その他リンク： http://search.jamas.or.jp/link/ui/2017399171

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：英語   掲載種別：速報，短報，研究ノート等（学術雑誌）   出版者・発行元：American Thoracic Society  

DOI： 10.1513/AnnalsATS.201503-175LE

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語  

J-GLOBAL

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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DOI： 10.11477/mf.1404205860

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記述言語：日本語   出版者・発行元：克誠堂出版  

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その他リンク： http://search.jamas.or.jp/link/ui/2015060036

記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

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記述言語：日本語   出版者・発行元：新潟医学会  

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その他リンク： http://search.jamas.or.jp/link/ui/2014076250

記述言語：日本語   出版者・発行元：(一社)日本睡眠学会  

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記述言語：日本語   出版者・発行元：(一社)日本アレルギー学会  

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2013&ichushi_jid=J00009&link_issn=&doc_id=20130419150191&doc_link_id=%2Fcw4aller%2F2013%2F006203%2F214%2F0404-0404%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcw4aller%2F2013%2F006203%2F214%2F0404-0404%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

多発性筋炎・皮膚筋炎は, 約40％の症例に間質性肺炎を合併する. 特に筋炎症状に乏しい皮膚筋炎では, 約50％の症例に急速進行性間質性肺炎をともない, 致死的となることが多い. これらの間質性肺炎に対して, グルココルチコイド大量静注療法, シクロスポリンやシクロフホスファミド大量静注療法などの免疫抑制薬の併用療法が行われてきた. しかし, これらの治療にもかかわらず, 進行して致死的となる間質性肺炎が経験される. 近年, 筋症状に乏しい皮膚筋炎に特異的に見られる自己抗体, 抗CADM-140抗体が見出され, 早期診断のマーカーとして期待されている. 抗CADM-140抗体陽性の皮膚筋炎にともなう間質性肺炎に対して, シクロスポリンやミコフェノール酸などの免疫抑制薬や, エンドトキシン吸着を用いた治療が試みられている.

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その他リンク： http://hdl.handle.net/10191/35872

記述言語：日本語  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：日本語   出版者・発行元：(一社)日本アレルギー学会  

DOI： 10.15036/arerugi.61.1494_3

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記述言語：日本語   出版者・発行元：科学評論社  

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その他リンク： http://search.jamas.or.jp/link/ui/2012322628

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本結核・非結核性抗酸菌症学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

臨床研修医が専門分野を選択する際、指導医の影響が大きいと報告されている。昨今、呼吸器科医師不足が指摘され、呼吸器科を志望する医師を増やすことは急務である。研修医が進路を選択する際に、何を重視するのかを明らかにし、またその過程における指導医の影響を評価する目的で、臨床研修医、若手呼吸器科医師にアンケート調査を行った。その結果、選択時に重視する点は、やりがい、医学的な興味に続き、良き指導医の存在であった。一方で、研修医1年次と2年次で、また研修医と若手呼吸器科医師で、選択時に重視する点、理想の指導医像に差異が認められた。本調査を通して、多くの臨床研修医が呼吸器科を選択するためには、呼吸器科のやりがいを伝え、興味を喚起する努力をし、研修医の経験・志向に応じ指導の仕方を変化させ、そのうえで若手呼吸器科医が目指す全人的診療を行う「良医」をロールモデルとして認識させることが必要であることが示唆された。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本アレルギー学会  

DOI： 10.15036/arerugi.60.1456_3

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：医学書院  

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その他リンク： http://search.jamas.or.jp/link/ui/2011322772

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：日本語   出版者・発行元：新潟医学会  

症例は22歳, 男性. 2008年9月中旬より喫煙を開始した. 同年下旬より乾性咳嗽, 労作時の息切れが出現. 同年10月1日, 38℃台の発熱が加わり前医を受診した. 低酸素血症と両肺野のびまん性すりガラス影を認め緊急入院したが, 翌日には呼吸状態がさらに悪化したため当科へ転院した. 気管支肺胞洗浄液にて好酸球増多の所見が得られ, その他の臨床所見をふまえ, 急性好酸球性肺炎の診断に至った. ステロイド療法へ良好に反応し, 呼吸不全の著明な改善が得られた. その後, 喫煙の再開時期に一致して咳嗽や息切れの再燃, 及び末梢血好酸球数の再上昇を認めた. 急性好酸球性肺炎は病因不明の疾患概念であるが, 吸入抗原に対するアレルギー反応の関与が疑われている. 吸入抗原のチャレンジテストにより原因物質の特定が可能であると考えられるが, 安全な負荷試験は確立されておらず施行は困難である. 本例は喫煙の再開により急性好酸球性肺炎が再燃しており, 発症の原因を特定し得た貴重な症例であった.

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：日本語   出版者・発行元：新潟医学会  

症例は70歳、女性。2005年に関節リウマチを発症し、プレドニゾロン、メトトレキサートによる治療を受けたが症状コントロール困難であった。2006年10月からタクロリムスを追加され、関節症状の改善を認めた。2007年2月末から咳嗽、喀痰、呼吸困難感、全身倦怠感が出現し、画像上両側肺野にground glass opacityを認めたため、メトトレキサート肺臓炎、ニューモシスチス肺炎を疑い、メトトレキサートとタクロリムスを中止し、メチルプレドニゾロン・パルス療法とTrimethoprim-sulfamethoxazole投与を行った。気管支肺胞洗浄液からニューモシスチスの嚢子が検出されニューモシスチス肺炎と診断した。関節リウマチに対してメトトレキサート、タクロリムスを使用する症例が近年増加しており、日和見感染のリスクが高まると考えられる。さらにメトトレキサートによる肺臓炎とニューモシスチス肺炎の鑑別も重要である。(著者抄録)

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：日本語   出版者・発行元：(一社)日本アレルギー学会  

DOI： 10.15036/arerugi.57.1392_2

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

症例は63歳の男性。めまい、多飲多尿、性欲減退などの症状で受診した。頭部MRIで下垂体の腫大があり、内分泌学的に汎下垂体機能低下を認めた。ホルモン補充療法としてヒドロコルチゾン、デスモプレシン、レボチロキシンナトリウムが開始された。胸部X線とCTで肺野の多発濃度上昇、ガリウムシンチでの肺門部への取り込み、ツ反陰性、気管支肺胞洗浄液中のリンパ球増加とCD4/8比の上昇を認めた。経気管支肺生検で組織診断は得られなかったが、臨床的に汎下垂体機能低下症を合併した中枢神経サルコイドーシスと診断した。プレドニゾロン60mg内服を開始したところ、下垂体および肺野病変の明らかな縮小が認められた。尿量は一時増加するもその後減少し、抗利尿ホルモンや下垂体前葉ホルモンの上昇傾向を認めた。本症例は症状出現から治療まで約5ヵ月経過していたが、ステロイド治療によって内分泌学的所見の改善傾向を認めた示唆に富む症例と考えられた。(著者抄録)

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：英語   掲載種別：速報，短報，研究ノート等（学術雑誌）   出版者・発行元：American Thoracic Society  

DOI： 10.1164/ajrccm.176.8.834a

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記述言語：英語   掲載種別：速報，短報，研究ノート等（学術雑誌）   出版者・発行元：AMER THORACIC SOC  

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記述言語：日本語   出版者・発行元：(一社)日本アレルギー学会  

DOI： 10.15036/arerugi.56.1098_1

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記述言語：日本語   出版者・発行元：新潟大学  

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その他リンク： http://search.jamas.or.jp/link/ui/2008088797

記述言語：英語   掲載種別：書評論文，書評，文献紹介等  

Polymyositis and dermatomyositis (PM-DM) are forms of idiopathic inflammatory myositis. Interstitial lung disease (ILD) in PM-DM is recognized as a serious complication and a major cause of death in this disease. According to the results of immunophenotyping of lymphocytes in bronchoalveolar lavage fluid, cytotoxic T lymphocytes may be major pulmonary inflammatory cells of ILD in PM-DM. Glucocorticoids are considered the first-line drug treatment for PM-DM patients with ILD, however they are often not sufficient to obtain improvement of ILD as a single agent. Furthermore, the addition of immunosuppressive drugs becomes necessary as steroid sparing agents to avoid the severe side-effects often seen with high-dose steroid treatment. Cyclophosphamide, cyclosporin, and tacrolimus were reported to be effective in treatment of refractory ILD in PM-DM. Although other immunosuppressive agents
mycophenolate mofetil, intravenous immunoglobulin, and anti-TNF agents have appeared as promising agents for refractory PM-DM, the efficacy on ILD in PM-DM is still unknown. Even if treatment is initiated early in the course of the disease, some patients still develop irreversible fatal lung fibrosis under aggressive immunosuppressive therapy. The fastest way to find the most effective treatment may be to investigate the pathogenesis of the disease in detail before initiation of immunosuppressive therapy including glucocorticoids. © 2007 Bentham Science Publishers Ltd.

DOI： 10.2174/157339807781387508

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   出版者・発行元：新潟大学  

The exercise capacity of obstructive sleep apnea syndrome (OSAS) patients has been demonstrated to be impaired, but the factors responsible are still unclear. In addition, ventilatory efficiency during exercise has never been studied in OSAS. Hypertension (HT), commonly found in OSAS patients, could be a contributing factor to exercise capacity. The aim of the study is: 1) to determine possible factors that could influence the exercise in OSAS patients, and 2) to compare the exercise capacity and ventilatory efficiency of patients with and without HT. Twenty-two male OSAS patients were submitted to cardiopulmonary exercise testing. Multiple linear regression analyses were used to find possible factors that could influence the exercise capacity and ventilatory efficiency of OSAS patients. Patients were divided into two groups according to the presence of HT, and cardiopulmonary exercise testing (CPET) results were compared between them. No factors emerged as predictors of oxygen consumption at peak exercise (FOipeak). The slope of increase of ventilation relative to carbon dioxide production (FE/FCOi-slope) was associated with body mass index (BMI) negatively and with apneahypopnea index (AHI) positively (p = 0.019 and p =0.047, respectively). There were no differences in either FOipeak or anaerobic threshold (AT) between OSAS with and without HT, but the FE/FCOi-slope was higher in the HT group (p = 0.008). Our results suggest that the severity of sleep apnea can influence the ventilatory efficiency of OSAS patients along with BMI and HT.

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その他リンク： http://search.jamas.or.jp/link/ui/2007250108

記述言語：英語   出版者・発行元：新潟大学  

Reduced fibrinolytic activity in the alveolar space of patients with interstitial pneumonia (IP) is considered the key factor in the development of pulmonary fibrosis. However, the origin of this fibrinolytic activity and its relationship to the fibrosis in IP is still unclear. Levels of the urokinase-type plasminogen activator (u-PA) and plasminogen activator inhibitor 1 (PAI-1) antigen were measured in bronchoalveolar lavage fluids (BALF) obtained from patients with IP, and the data were compared between the two groups (fibrosing group and non-fibrosing group) based mainly on honeycomb formation revealed by pulmonary high-resolution computed tomography (HRCT) and partially on lung histology. In addition, the cell surface plasmin generation of various alveolar macrophages (AM) and its correlation with the u-PA/PAI-1 levels in each of the two groups were studied. The u-PA level was significantly lower in BALF from IP patients than from sarcoidosis patients with no interstitial shadows on HRCT used as the contols. Although u-PA and PAI-1 levels did not differ between the fibrosing and the non-fibrosing group, the macrophage count and the percentage of macrophages in BALF were significantly greater in the fibrosing group. The major regulatory cytokines, interleukin 1-β and transforming growth factor-β, however, did not affect cell surface plasmin generation by AM, indicating that the AM-related fibrinolytic activity was constant. These results indicate that the decreased fibrinolytic activity in BALF is not related to AM although it is associated with the fibrosis of IP. We speculate that other cells such as alveolar epithelial cells contribute to the fibrosis although further clinical studies will be required.

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その他リンク： http://search.jamas.or.jp/link/ui/2006310593

記述言語：日本語   出版者・発行元：新潟大学  

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その他リンク： http://search.jamas.or.jp/link/ui/2005215024

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語   出版者・発行元：新潟医学会  

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その他リンク： http://search.jamas.or.jp/link/ui/2000168657