Language：Japanese   Publisher：(一社)日本内科学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Aspergillus-specific antibodies are diagnostic indicators of allergic bronchopulmonary aspergillosis (ABPA) and chronic pulmonary aspergillosis (CPA). Tests for detecting Aspergillus-specific antibodies were not used clinically in Japan, and the production of the Aspergillus precipitin test was discontinued. Thus, alternative tests for diagnosing aspergillosis are urgently needed. We retrospectively evaluated 64 patients with suspected ABPA and CPA who underwent precipitin antibody testing. Serum Aspergillus IgG levels were measured and compared using the Bordier Aspergillus fumigatus ELISA and the Platelia Aspergillus IgG (Bio-Rad) kits. Of the participants, 18 were diagnosed with CPA, and 8 were diagnosed with ABPA. Both the Bordier and Bio-Rad kits showed high sensitivity and specificity for CPA and ABPA. The area under the receiver operating characteristic curves for the Bordier and Bio-Rad kits were 0.97 and 0.95, respectively, for CPA, and 0.89 and 0.91, respectively, for ABPA. In contrast to the Bordier kit, the Bio-Rad kit showed relatively low anti-Aspergillus IgG levels and lower sensitivity to non-fumigatus Aspergillus infections. The Aspergillus-specific IgG ELISA tests showed sufficient diagnostic accuracy. Therefore, these assays are recommended as alternatives to the precipitin kit for diagnosing aspergillosis in clinical settings in Japan.

DOI： 10.3314/mmj.24.00004

PubMed

researchmap

Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

The close relationship between infectious diseases and iron metabolism is well known, but a more detailed understanding based on current knowledge may provide new insights into the diagnosis and treatment of infectious diseases, considering the growing threat of antibiotic-resistant bacteria. This study investigated adult patients with bloodstream infections, temporal changes, and relationships between blood levels of iron and related markers, including hepcidin and lipocalin-2 (LCN2). We included 144 samples from 48 patients (mean age 72 years, 50% male), with 30 diagnosed with sepsis. During the acute phase of infection, blood levels of hepcidin and LCN2 increased rapidly, whereas iron levels decreased, with values in 95.8% of cases below the normal range (40–188 μg/dL). Later, hepcidin and LCN2 decreased significantly during the recovery phase, and the decreased iron concentrations were restored. In the case of persistent inflammation, iron remained decreased. Acute LCN2 levels were significantly higher in patients with sepsis (p < 0.01). Hypoferremia induced by increased hepcidin would reduce iron in the environment of extracellular pathogens, and the increased LCN2 would inhibit siderophores, resulting in the prevention of the pathogen’s iron acquisition in each manner during the acute phase of bloodstream infection.

DOI： 10.1038/s41598-023-46383-7

researchmap

Other Link： https://www.nature.com/articles/s41598-023-46383-7

Language：Japanese   Publisher：(NPO)日本肺癌学会  

researchmap

Language：Japanese   Publisher：(NPO)日本肺癌学会  

researchmap

Language：Japanese   Publisher：(NPO)日本肺癌学会  

researchmap

Language：English  

DOI： 10.1016/j.sleep.2023.07.005

PubMed

researchmap

Language：Japanese   Publisher：日本睡眠学会・日本時間生物学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: A study is eagerly awaited that will reveal the unknown mechanisms of multiple system atrophy (MSA), in which the risk of sudden death is the greatest during sleep. The blunted pulse response to nocturnal respiratory events suggests an abnormal cardiac response to a sleep-related breathing disorder. Patients with MSA have a lower pulse event index (PEI), despite a greater hypoxic burden and a similar frequency of respiratory events. However, the evidence is speculative and not directly proven, and many limitations require further study. METHODS: We conducted a retrospective analysis of 26 patients with MSA who had undergone overnight oximetry between April 2016 and December 2022. RESULTS: The median 4% oxyhemoglobin desaturation index (ODI) was 11.6/h, the 6-bpm PEI was 8.9/h, and the PEI/ODI ratio was as low as 0.91. There were three patients with suspected sudden death; all had low PEI/ODI ratios. The PEI/ODI ratio was followed over time in seven patients, all of whom had a decrease in the ratio. However, the PEI was higher than the ODI in 12/26 (46%) of the patients. CONCLUSION: A low PEI/ODI ratio, reflecting a blunted pulse response to nocturnal respiratory events in patients with MSA, may indicate a worse prognosis. This finding and the significance of the longitudinal decrease in the PEI/ODI ratio will require a prospective study.

DOI： 10.1016/j.parkreldis.2023.105817

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(公社)日本化学療法学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Chronic intermittent hypoxia (IH) plays a significant role in the pathogenesis of obstructive sleep apnea (OSA) comorbidities. The prevalence of chronic kidney disease is higher in patients with OSA than the general population, and renal function decline is well correlated with renal tubular injury. However, little is known about the impact of OSA-induced chronic IH on the renal tubules. METHODS: We conducted a retrospective survey of clinical records performing multiple regression analysis and cluster analysis with particular attention to the 3% oxygen desaturation index (ODI) and urinary N-acetyl-β-d-glucosaminidase (NAG). RESULTS: In patients with suspicion of OSA, urinary NAG creatinine ratio (UNCR) was elevated as their 3% ODI increased (n = 197, p < 0.001), and the elevated UNCR decreased following CPAP treatment in patients with OSA (n = 46, p = 0.014). Multiple regression analysis showed that 3% ODI was associated with UNCR. Cluster analysis identified three clusters of patients with OSA, including two younger age clusters, one of which was characterized by high BMI, high 3% ODI, and high prevalence of major comorbidities. In a comparative analysis of younger age cases (age ≤ 55, n = 82), the UNCR level was higher in patients with severe 3% ODI (3% ODI > 40 events/h, n = 24) (p = 0.014). CONCLUSIONS: Our results indicate that even at younger ages, OSA patients with severe chronic IH and major comorbidities are susceptible to renal tubular damage. Early treatment with CPAP may attenuate renal tubular injury and progression toward end-stage renal disease.

DOI： 10.1016/j.sleep.2023.03.028

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：日本感染症学会・日本化学療法学会  

researchmap

Language：Japanese   Publisher：日本感染症学会・日本化学療法学会  

researchmap

Language：Japanese   Publisher：日本感染症学会・日本化学療法学会  

researchmap

Language：Japanese   Publisher：日本感染症学会・日本化学療法学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本内科学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Nasal breathing disorders are associated with obstructive sleep apnea (OSA) syndrome and influence the availability of continuous positive airway pressure (CPAP) therapy. However, information is scarce about the impact of nasal resistance assessed by rhinomanometry on CPAP therapy. This study aimed to examine the relationship between CPAP adherence and nasal resistance evaluated by rhinomanometry, and to identify clinical findings that can affect adherence to CPAP therapy for patients with OSA. This study included 260 patients (199 men, 61 women; age 58 [interquartile ranges (IQR) 50-66] years) with a new diagnosis of OSA who underwent rhinomanometry (before, and 1 and 3 months after CPAP introduction) between January 2011 and December 2018. CPAP use was recorded, and the good and poor CPAP adherence groups at the time of patient registration were compared. Furthermore, those with improved and unimproved pre-CPAP high rhinomanometry values were also compared. Their apnea-hypopnea index (AHI) by polysomnography at diagnosis was 45.6 (IQR 33.7-61.6)/hour, but the residual respiratory event (estimated AHI) at enrollment was 2.5 (IQR 1.4-3.9)/hour and the usage time was 318 (IQR 226-397) minutes, indicating that CPAP was effective and adherence was good. CPAP adherence was negatively correlated with nasal resistance (r = -0.188, p = 0.002). The participants were divided into good (n = 153) and poor (n = 107) CPAP adherence groups. In the poor adherence group, rhinomanometry values before CPAP introduction were worse (inspiration, p = 0.003; expiration, p = 0.006). There was no significant difference in patient background when comparing those with improved (n = 16) and unimproved (n = 12) pre-CPAP high rhinomanometry values. However, CPAP usage time was significantly longer in the improved group 1 month (p = 0.002) and 3 months (p = 0.026) after CPAP introduction. The results suggest that nasal resistance evaluated by rhinomanometry is a useful predictor of CPAP adherence, and that improved rhinomanometry values may contribute to extending the duration of CPAP use.

DOI： 10.1371/journal.pone.0283070

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: Benralizumab, an anti-interleukin-5 receptor chain monoclonal antibody, is used to treat severe asthma and control asthma symptoms or exacerbations. The aim of this study was to examine the changes in airway morphology using computed tomography (CT) images in accordance with clinical efficacy following the administration of benralizumab. METHODS: The clinical efficacy of benralizumab was evaluated in 11 patients with severe asthma by analyzing the changes in parameters, such as the asthma control test, asthma quality of life questionnaire, pulmonary function, and exacerbation count. We also investigated the airway wall thickness of the right bronchus (B1) and the total airway count (TAC) using CT images. RESULTS: Most patients treated with benralizumab showed improvements in asthma symptoms and exacerbations. CT imaging analyses showed a decrease in the right B1 airway wall thickness and an increase in the TAC. Correlations between blood eosinophil count and changes in CT imaging were observed. DISCUSSION/CONCLUSION: The data suggested that benralizumab has the potential to improve airway wall thickening and ventilation by alleviating the obstruction and clearing an obstructed airway.

DOI： 10.1159/000525846

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: Mucus plugs are associated with airway obstruction in severe asthma and are involved in the formation of activated eosinophils. Benralizumab, an anti-interleukin-5 receptor antibody, markedly reduces not only peripheral blood eosinophils but also airway eosinophils; however, its effects on mucus plugs have not been clarified. In this study, we examined the efficacy of benralizumab on mucus plugs using computed tomography (CT) imaging. METHODS: Twelve patients who were administered benralizumab and underwent CT before and approximately 4 months after the introduction of benralizumab were included in this study, and the number of mucus plugs before and after benralizumab administration was compared. The correlation between the clinical background and treatment effect was also examined. RESULTS: The number of mucus plugs significantly decreased after the introduction of benralizumab. The number of mucus plugs was correlated with sputum eosinophil percentage and eosinophil cationic protein in the sputum supernatants and inversely correlated with forced expiratory volume in 1 s (FEV1). Benralizumab induction resulted in a marked decrease in blood and sputum eosinophil levels and a significant improvement in asthma symptoms, quality of life scores, FEV1, and exacerbation frequency. Furthermore, there was a significant correlation between the reduction in mucus plugs and changes in the symptom score or FEV1. DISCUSSION/CONCLUSION: These data suggest that benralizumab may have the potential to improve symptoms and respiratory function in patients with severe eosinophilic asthma by reducing mucus plugs.

DOI： 10.1159/000530392

PubMed

researchmap

Language：Japanese   Publisher：(NPO)日本肺癌学会  

researchmap

Language：Japanese   Publisher：(NPO)日本肺癌学会  

researchmap

Language：Japanese   Publisher：(NPO)日本肺癌学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸ケア・リハビリテーション学会  

researchmap

Language：Japanese   Publisher：日本感染症学会東日本地方会・日本化学療法学会東日本支部  

researchmap

Language：Japanese   Publisher：日本感染症学会東日本地方会・日本化学療法学会東日本支部  

researchmap

Language：Japanese   Publisher：日本感染症学会東日本地方会・日本化学療法学会東日本支部  

researchmap

Language：Japanese   Publisher：日本感染症学会東日本地方会・日本化学療法学会東日本支部  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: This study aimed to examine the factors associated with cytomegalovirus (CMV) antigenemia and the time of onset of CMV antigenemia among patients with rheumatic diseases. METHODS: A single-center, retrospective, observational study was conducted in our institution from January 2009 to December 2017. This study included patients with rheumatic diseases who had at least one CMV antigen measurement. Multivariate analysis and receiver operating characteristic analysis was performed. RESULTS: A total of 249 patients underwent CMV antigenemia assay, and 84 (33.7%) patients tested positive. When the association between CMV antigenemia and possible associated factors was investigated, multivariate analysis showed that daily steroid dose increased the odds of having CMV [odds ratio 16.25, 95% confidence interval (CI), 5.360-49.253]. In this study, the cutoff value of daily steroid dose found in this study (0.45 mg/kg/day) was reasonable in clinical practice, and the area under the curve of the steroid dose was 0.838 [95% CI 0.781-0.882], which was the largest of the known indicators. Moreover, the median time from the start of immunosuppressive therapy to the onset of CMV antigenemia was 30 (interquartile range, 21-44) days, and most of the daily steroid users (85.7%) developed CMV antigenemia within 60 days. CONCLUSIONS: The daily steroid dose is the most important factor associated with CMV antigenemia. Therefore, monitoring and treatment strategies based on the steroid dose, especially in the initial 2 months, are important.

DOI： 10.1016/j.jiac.2022.07.004

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本睡眠学会  

researchmap

Language：English  

DOI： 10.1016/j.alit.2022.03.005

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本感染症学会  

researchmap

Language：Japanese   Publisher：(一社)日本感染症学会  

researchmap

Language：Japanese   Publisher：(一社)日本内科学会  

researchmap

Publishing type：Research paper (scientific journal)   Publisher：AME Publishing Company  

DOI： 10.21037/tlcr-21-838

researchmap

Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

背景.気管支静脈瘤は稀な疾患であり,その治療法は確立されていない.症例.78歳,女性.小児期より気管支拡張症を罹患し,膿胸の既往があった.6年前から喀血を繰り返し,計3回の気管支動脈塞栓術が行われていた.今回,喀血を契機に入院し,止血薬投与を受けたが大量喀血を来したため,気管挿管の上で人工呼吸管理となった.左下横隔動脈と左気管支動脈をゼラチンスポンジで塞栓し,止血を得た.その際の選択的動脈造影で左下横隔動脈と肺静脈との動静脈シャントを認めた.気管支鏡で観察すると,左上下葉支分岐部に気管支静脈瘤がみられ,出血源と考えられた.動脈塞栓術の2週後の気管支鏡では同部位の瘤は退縮していた.その後,再喀血なく自宅退院した.結論.気管支静脈瘤は気管支拡張症や動脈塞栓に関連して発症する可能性があり,喀血時は気管支鏡による確認が必要である.治療として異常シャントの塞栓術が有効と考えられた.(著者抄録)

researchmap

Other Link： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J00298&link_issn=&doc_id=20211216270004&doc_link_id=%2Fcf0brond%2F2021%2F004306%2F005%2F0589-0594%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcf0brond%2F2021%2F004306%2F005%2F0589-0594%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

researchmap

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J00298&link_issn=&doc_id=20211216270004&doc_link_id=10.18907%2Fjjsre.43.6_589&url=https%3A%2F%2Fdoi.org%2F10.18907%2Fjjsre.43.6_589&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00262-021-03078-0

researchmap

Other Link： https://link.springer.com/article/10.1007/s00262-021-03078-0/fulltext.html

Publishing type：Research paper (scientific journal)   Publisher：S. Karger AG  

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Psychological disorders, such as depression, are markedly prevalent in patients with airway diseases. In this study, we assessed the effect of treatment with dupilumab, an IL-4 receptor α chain antibody, on depressive symptoms in a cohort of patients with asthma with eosinophilic chronic rhinosinusitis (ECRS). &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; The study participants, diagnosed with asthma and ECRS, were assessed for symptoms and quality of life (QOL) scores for asthma and ECRS and medications. The Patient Health Questionnaire-9 (PHQ-9) scores were used to evaluate the depressive state. The depressive symptoms were compared with asthma and ECRS symptoms both at the time of initiation and after 4 months of dupilumab treatment. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Ultimately, 31 patients were included in the study. Most patients demonstrated a depressive state that was correlated with the nasal symptom score. In the evaluation 4 months after dupilumab treatment, the PHQ-9 score was significantly reduced, and the decrease was remarkable in patients whose nasal symptom score was reduced by 50% or more. Additionally, the PHQ-9 scores in patients with improved nasal and asthma symptoms were significantly reduced. &lt;b&gt;&lt;i&gt;Discussion/Conclusion:&lt;/i&gt;&lt;/b&gt; Dupilumab may improve QOL in patients with bronchial asthma with ECRS by reducing depressive symptoms through the improvement of clinical symptoms.

DOI： 10.1159/000519296

researchmap

Language：Japanese   Publisher：(NPO)日本肺癌学会  

researchmap

Language：Japanese   Publisher：(NPO)日本肺癌学会  

researchmap

Language：Japanese   Publisher：(NPO)日本肺癌学会  

researchmap

Language：Japanese   Publisher：(NPO)日本肺癌学会  

researchmap

Language：English   Publisher：(一社)日本癌学会  

researchmap

Language：English   Publisher：(一社)日本癌学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

An outbreak of serotype 19A Streptococcus pneumoniae occurred among the residents of a relief facility. Pneumonia developed in 5 of 99 residents (attack rate, 5.1%). We obtained pharyngeal specimens from non-onset residents, and S. pneumoniae was isolated from 6 individuals (6.4%), 5 of whom had serotype 19A.

DOI： 10.1017/ice.2021.328

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Background: Although immune checkpoint inhibitors (ICIs) are effective for advanced non-small cell lung cancer (NSCLC), ICIs may cause interstitial lung disease (ILD), which results in treatment discontinuation and is sometimes fatal. Despite the high incidence of ICI-related ILD, there are few cancer treatment options for patients. This study aimed to evaluate the safety and efficacy of subsequent systemic cancer therapy in NSCLC patients with ICI-related ILD. Methods: We retrospectively assessed NSCLC patients who received programmed cell death-1 (PD-1) inhibitors as first- to third-line therapy at participating institutions of the Niigata Lung Cancer Treatment Group from January 2016 to October 2017. Results: This analysis included 231 patients, 32 (14%) of whom developed ICI-related ILD. Of these patients, 16 (7%) received subsequent systemic cancer treatments. The median overall survival (OS) tended to be longer in the systemic cancer therapy group than in the no systemic cancer therapy group [22.2 months (95% CI: 1-NE) vs. 4.5 months (95% CI: 1-NE); P=0.067]. ICI-related ILD recurred in half of the patients who received systemic cancer therapy, and the median OS tended to be shorter in patients with recurrent ICI-related ILD [22.0 months (95% CI: 1-NE) vs. 7.0 months (95% CI: 1-NE); P=0.3154]. Conclusions: According to the current study, systemic cancer treatment is effective in patients with ICI-related ILD; however, its safety is uncertain because of the high risk of ICI-related ILD recurrence and poor survival outcome following ILD recurrence.

DOI： 10.21037/tlcr-21-198

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

A 31-year-old woman who was clinically diagnosed with Silver-Russell syndrome (SRS) in childhood was admitted with complaints of dyspnea. She had hypercapnic respiratory failure accompanied by nocturnal hypoventilation. Computed tomography revealed systemic muscle atrophy and superior mesenteric artery syndrome; however, the bilateral lung fields were normal. She was treated with nocturnal noninvasive positive pressure ventilation and showed improvement of respiratory failure. In this case, loss of methylation on chromosome 11p15 and maternal uniparental disomy of chromosome 7, which are the common causes of SRS, were not detected. This is a rare case of adult SRS manifesting as chronic hypercapnic respiratory failure.

DOI： 10.2169/internalmedicine.5479-20

PubMed

researchmap

Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

researchmap

Language：English  

We herein report the case of a 20 year-old-man who developed bronchiolitis obliterans after living-donor renal transplantation. The patient presented with dyspnea on exertion and wheezing two years after renal transplantation, and spirometry showed an obstructive pattern. Surgical lung biopsy revealed subepithelial fibrosis that constricted and obstructed the intrabronchiolar space. Based on these findings, the patient was diagnosed with bronchiolitis obliterans. He was prescribed bronchodilators and azithromycin, and he achieved stable respiratory function for two years. The differential diagnosis of respiratory symptoms after renal transplantation includes opportunistic infection and drug-induced lung injury; however, bronchiolitis obliterans should also be considered.

DOI： 10.1016/j.resinv.2020.12.003

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Viral pneumonia caused by varicella-zoster virus (VZV) infection is a rare but important complication, especially regarding varicella infections. Although disseminated cutaneous herpes zoster (DCHZ) is often associated with visceral diseases, there have been few reports of DCHZ-related pneumonia. We herein report a rare case of a lethal disseminated VZV infection that caused severe pneumonia in a Japanese patient who had chronic interstitial pneumonia. Physicians should consider the possibility of VZV-related pneumonia, especially in patients with a medical history of hematopoietic stem cell transplantation and immunosuppressive therapy.

DOI： 10.2169/internalmedicine.5396-20

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本内科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内科学会  

症例1は67歳男性で、Behcet病に伴う皮疹と診断され、8ヵ月前より、皮膚科からプレドニゾロン(PSL)およびジアフェニルスルホン(DDS)が処方されていた。数日前からの頭痛を訴え、室内気でSpO2 89%と低下していた。Hb 7.5g/dlと貧血あり、白血球10950/μl、CRP 20.05mg/dlと高度の炎症所見を認めた。室内気での動脈血液ガス分析(BGA)でSaO2 95.6%であり、SpO2とSaO2の乖離(saturation gap)を認め、メトヘモグロビン(MetHb)3.3%と上昇していた。症例2は69歳男性で、骨髄異形成症候群に伴うSweet病のため、3ヵ月前より皮膚科からPSLおよびDDSが処方されていた。肝機能障害のために入院となり、無症状であったが入院時よりSpO2 90%以下が持続したため、酸素吸入を開始された。その後もSpO2低値が遷延した。酸素吸入下のBGAでSaO2 90.8%と軽度のsaturation gapを認め、MetHb 7.4%と上昇していた。症例3は40歳男性で、潰瘍性大腸炎に伴う壊疽性膿皮症のため、4ヵ月前より皮膚科からDDSが処方されていた。潰瘍性大腸炎の通院治療のために来院した際、無症状であったがSpO2低下を認めたため入院した。室内気でSpO2 92%と低下していた。軽度の炎症反応上昇が認められた。BGAでSaO2 97.7%とSaturation gapを認め、MetHb 3.2%と上昇を認めた。いずれの症例も、皮膚科より処方されていたDDSによる薬剤性MetHb血症を疑い、DDS内服を中止した。その結果、1週後にはMetHb分画の低下と共にSpO2の上昇が認められた。

researchmap

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01159&link_issn=&doc_id=20210316070034&doc_link_id=10.2169%2Fnaika.110.622&url=https%3A%2F%2Fdoi.org%2F10.2169%2Fnaika.110.622&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(一社)日本内科学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸ケア・リハビリテーション学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸ケア・リハビリテーション学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Cisplatin, one of the most active anticancer agents, is widely used in standard chemotherapy for various cancers. Cisplatin is more poorly tolerated than other chemotherapeutic drugs, and the main dose-limiting toxicity of cisplatin is its nephrotoxicity, which is dose-dependent. Although less toxic methods of cisplatin administration have been established, cisplatin-induced nephrotoxicity remains an unsolved problem. Megalin is an endocytic receptor expressed at the apical membrane of proximal tubules. We previously demonstrated that nephrotoxic drugs, including cisplatin, are reabsorbed through megalin and cause proximal tubular cell injury. We further found that cilastatin blocked the binding of cisplatin to megalin in vitro. In this study, we investigated whether cilastatin could reduce cisplatin-induced nephrotoxicity without influencing the antitumor effects of cisplatin. Nephrotoxicity was decreased or absent in mice treated with cisplatin and cilastatin, as determined by kidney injury molecule-1 staining and the blood urea nitrogen content. Combined with cilastatin, a twofold dose of cisplatin was used to successfully treat the mice, which enhanced the antitumor effects of cisplatin but reduced its nephrotoxicity. These findings suggest that we can increase the dose of cisplatin when combined with cilastatin and improve the outcome of cancer patients.

DOI： 10.1038/s41598-020-80853-6

PubMed

researchmap

Language：English  

A 70-year-old man, treated for asthma for 2 years and chronic sinusitis for several months, presented with fever, numbness in the lower limbs, heaviness in the head, gross hematuria, and black stools. He also had eosinophilia, elevated serum IgG4 levels, high levels of myeloperoxidase-anti-neutrophil cytoplasmic antibodies (MPO-ANCA), and pulmonary infiltrative shadows. Bronchoscopy revealed multiple white flattened lesions (white moss) on the airway mucosa, suggesting mycobacterial infection or malignancy. A biopsy from tracheal mucosa revealed airway inflammation with marked eosinophil infiltration. The patient was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA) and treated with steroids, and all findings improved. However, a year and a half after the initiation of treatment, eosinophils and IgE gradually increased; subjective symptoms, such as asthma symptoms and numbness in the lower limbs, worsened; and ANCA, which had been negative, turned positive. Therefore, we suspected disease relapse and anti-IL-5 antibody (mepolizumab) treatment was initiated. Thereafter, ANCA turned negative again, eosinophils and IgE normalized, and subjective symptoms decreased. The presence of airway mucosal lesions in EGPA is relatively rare, and we report this case as a valuable case owing to the interesting bronchoscopic findings that are worth comprehending as a respiratory physician.

DOI： 10.1016/j.rmcr.2021.101451

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Objectives: Although immune checkpoint inhibitors (ICIs) have been shown to improve overall survival (OS) in advanced non-small-cell lung cancer (NSCLC) patients, ICIs sometimes cause various types of immune-related adverse events (irAEs), which lead to the interruption of ICI treatment. This study aims to evaluate the clinical significance of the continuation of ICIs in NSCLC patients with irAEs and to assess the safety and efficacy of the readministration of ICIs after their discontinuation due to irAEs. Methods: We retrospectively identified patients with advanced NSCLC who were treated with first- to third-line anti-programmed cell death-1 (PD-1) therapy from January 2016 through October 2017 at multiple institutions belonging to the Niigata Lung Cancer Treatment Group. Progression-free survival (PFS) and OS from the initiation of ICI treatment were analyzed in patients with and without irAEs, with and without ICI interruption, and with and without ICI readministration. A 6-week landmark analysis of PFS and OS was performed to minimize the lead-time bias associated with time-dependent factors. Results: Of 231 patients who received anti-PD-1 antibodies, 93 patients (40%) developed irAEs. Of 84 eligible patients with irAEs, 32 patients (14%) continued ICIs, and OS was significantly longer in patients who continued ICIs than that in patients who discontinued ICIs [not reached (95% CI: NE-NE) vs. not reached (95% CI: 22.4-NE); p = 0.025]. Of 52 patients who discontinued ICIs, 14 patients (6.1%) readministered ICIs, and OS in patients with ICI readministration was significantly longer than that in patients without ICI readministration [not reached (95% CI: NE-NE) vs. not reached (95% CI: 8.4-NE); p = 0.031]. Conclusion: The current study demonstrated that both the continuation and readministration of ICIs after irAE occurrence improved OS compared to the permanent interruption of ICIs in NSCLC patients with ICI-related irAEs.

DOI： 10.3389/fonc.2021.704475

PubMed

researchmap

Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

researchmap

Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

researchmap

Language：English  

DOI： 10.1016/j.alit.2020.03.009

PubMed

researchmap

Language：English  

DOI： 10.1165/rcmb.2020-0186LE

PubMed

researchmap

Language：English   Publisher：(一社)日本癌学会  

researchmap

Language：Japanese   Publisher：(NPO)日本肺癌学会  

researchmap

Language：Japanese   Publisher：(NPO)日本肺癌学会  

researchmap

Language：Japanese   Publisher：(NPO)日本肺癌学会  

researchmap

Language：Japanese   Publisher：(NPO)日本肺癌学会  

researchmap

Language：English   Publisher：(一社)日本癌学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Academy of Allergy, Asthma and Immunology  

Exercise-induced bronchoconstriction (EIB) is a phenomenon observed in asthma but is also seen in healthy individuals and frequently in athletes. High prevalence rates are observed in athletes engaged in endurance sports, winter sports, and swimming. The pathophysiology of EIB is thought to be related to hyperventilation, cold air, and epithelial damage caused by chlorine and fine particles in inspired air. Several diagnostic procedures can be used
however, the diagnosis of EIB based on self-reported symptoms is not reliable and requires an objective examination. The hyperosmolar inhalation test and eucapnic voluntary hyperpnea test, which involve indirect stimulation of the airway, are useful for the diagnosis of EIB. A short-acting β-agonist is the first choice for prevention of EIB, and an inhaled corticosteroid is essential for patients with asthma. Furthermore, treatment should accommodate antidoping requirements in elite athletes. Tailoring of the therapeutic strategy to the individual case and the prognosis after cessation of athletic activity are issues that should be clarified in the future.

DOI： 10.1016/j.jaip.2020.03.011

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

It is well known that the prevalence of asthma is higher in athletes, including Olympic athletes, than in the general population. In this study, we analyzed the mechanism of exercise-induced bronchoconstriction by using animal models of athlete asthma. Mice were made to exercise on a treadmill for a total duration of 1 week, 3 weeks, or 5 weeks. We analyzed airway responsiveness, BAL fluid, lung homogenates, and tissue histology for each period. In mice that were treated (i.e., the treatment model), treatments were administered from the fourth to the fifth week. We also collected induced sputum from human athletes with asthma and analyzed the supernatants. Airway responsiveness to methacholine was enhanced with repeated exercise stimulation, although the cell composition in BAL fluid did not change. Exercise induced hypertrophy of airway smooth muscle and subepithelial collagen deposition. Cysteinyl-leukotriene (Cys-LT) levels were significantly increased with exercise duration. Montelukast treatment significantly reduced airway hyperresponsiveness (AHR) and airway remodeling. Expression of PLA2G4 (phospholipase A2 group IV) and leukotriene C4 synthase in the airway epithelium was upregulated in the exercise model, and inhibition of PLA2 ameliorated AHR and airway remodeling, with associated lower levels of Cys-LTs. The levels of Cys-LTs in sputum from athletes did not differ between those with and without sputum eosinophilia. These data suggest that AHR and airway remodeling were caused by repeated and strenuous exercise. Cys-LTs from the airway epithelium, but not inflammatory cells, may play an important role in this mouse model.

DOI： 10.1165/rcmb.2019-0325OC

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: As indices of asthma control, exacerbations are equally important with symptoms and respiratory function. Thus, it is critical to recognize the risk factors of exacerbation. OBJECTIVE: We conducted a questionnaire survey of asthma patients in Niigata Prefecture to clarify the factors involved in asthma exacerbation. METHODS: The questionnaire survey was carried out in patients and their physicians from September to October 2014. In 2015, the same sample population also received a questionnaire about current asthma control and exacerbation. RESULTS: One hundred patients experienced asthma exacerbation during the 1-year period. There were significant differences in age, sex, history of hospitalization due to asthma, smoking history, Asthma Control Test, treatment step, and transient steroid treatment history in the previous year between the exacerbation group and non-exacerbation group. On multivariate analysis, there was a significant difference in history of transient steroid therapy, history of hospitalization associated with asthma attacks, and nonsmoking history. Cluster analysis of cases with exacerbation was classified into three clusters. Cluster 1 comprised slightly older cases with smoking history, Cluster 2 had more females, non-smoking and nonatopic cases with uncontrolled symptoms, and Cluster 3 had more females, non-smoking and mild atopic cases. CONCLUSIONS: Our findings suggest that patients with asthma exacerbation in the previous year and nonsmoking females are important targets for the study of asthma exacerbation. The adequate treatment of women patients might be important for the prevention of asthma exacerbation.

DOI： 10.12932/AP-080918-0404

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: In the past decade, the relationship between naturally occurring interferon-γ-neutralizing autoantibodies (IFNγ-Ab) and disseminated non-tuberculous mycobacteria (NTM) infection has been established. Furthermore, immune suppressive therapy aimed at the suppression of antibody production has shown efficacy as a supportive treatment. However, the nature of antibody behavior and antibody titer during the course of this disease, as well as the pathophysiological significance of IFNγ-Ab, has not yet been fully elucidated. METHODS: Thirteen Japanese subjects suffering from disseminated NTM (dNTM) infection with IFNγ-Ab were evaluated. The fluctuation of IFNγ-Ab titer and the neutralizing capacity against IFN-γ during the course of the disease were retrospectively analyzed. IFNγ-Ab titers in the sera were quantified using an enzyme-linked immunosorbent assay; neutralizing capacity was evaluated via flow cytometry. RESULTS: Serum antibody titers were not constant during the treatment period and varied over the course of the disease. The antibody titer decreased when the disease was improved by anti-mycobacterial treatment (p < 0.01) and increased as the disease progressed (p < 0.05). Even after the antibody titer decreased, the neutralizing capacity against IFN-γ was maintained by individual sera. CONCLUSIONS: Despite the improvement in the pathological condition via treatment, the patients' sera maintained neutralizing capacity against IFN-γ. Antibody titer fluctuated over the course of the disease and exhibited potential as a biomarker for judgment of the disease state.

DOI： 10.1007/s10875-020-00762-1

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Adherence Starts with Knowledge-12 (ASK-12) is a useful indicator of drug adherence. In this study, we analyzed patient background including social and psychological factors in a low-adherence group of patients with asthma defined using ASK-12. METHODS: From a questionnaire survey for patients with asthma from the Niigata Prefecture, Japan, conducted in the fall of 2016, we enrolled patients who answered all ASK-12 items and underwent a measured respiratory function test within 1 year. The low-adherence group (ASK-12 ≥ 28) was compared with the control group (ASK-12 < 28), and we conducted a cluster analysis of the low-adherence group. RESULTS: There were 170 patients in the low-adherence group and 402 patients in the control group. There was a significant difference between age, gender, working status, smoking history, the percentage of forced expiratory volume in one second (%FEV1), asthma control test (ACT), and Patient Health Questionnaire-9 (PHQ-9) score between the two groups. Logistic analysis revealed that working status (working), % FEV1 (<90%), and PHQ-9 score (>5) were independent factors for the low-adherence group. The cluster analysis identified three clusters in the low-adherence group. Among these, one cluster was characterized by elderly males with chronic obstructive pulmonary disease and another by middle-aged nonsmoking females with a depression tendency, had problems with asthma control. CONCLUSIONS: Several factors were considered to be attributed to low drug-adherence. There were several phenotypes in the low-adherence population correlated with incomplete asthma control. Intervention with drug adherence should be a future goal for asthma treatment.

DOI： 10.1016/j.alit.2019.07.006

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Although the blockade of programmed cell death 1 (PD-1)/PD-ligand (L) 1 has demonstrated promising and durable clinical responses for non-small-cell lung cancers (NSCLCs), NSCLC patients with epidermal growth factor receptor (EGFR) mutations responded poorly to PD-1/PD-L1 inhibitors. Previous studies have identified several predictive biomarkers, including the expression of PD-L1 on tumor cells, for PD-1/PD-L1 blockade therapies in NSCLC patients; however, the usefulness of these biomarkers in NSCLCs with EGFR mutations has not been elucidated. The present study was conducted to evaluate the predictive biomarkers for PD-1/PD-L1 inhibitors in EGFR-mutated NSCLCs. We retrospectively analyzed 9 patients treated with nivolumab for EGFR-mutated NSCLCs. All but one patient received EGFR-tyrosine kinase inhibitors before nivolumab treatment. The overall response rate and median progression-free survival were 11% and 33 days (95% confidence interval (CI); 7 to 51), respectively. Univariate analysis revealed that patients with a good performance status (P = 0.11; hazard ratio (HR) 0.183, 95% CI 0.0217 to 1.549), a high density of CD4+ T cells (P = 0.136; HR 0.313, 95% CI 0.045 to 1.417) and a high density of Foxp3+ cells (P = 0.09; HR 0.264, 95% CI 0.0372 to 1.222) in the tumor microenvironment tended to have longer progression-free survival with nivolumab. Multivariate analysis revealed that a high density of CD4+ T cells (P = 0.005; HR<0.001, 95% CI <0.001 to 0.28) and a high density of Foxp3+ cells (P = 0.003; HR<0.001, 95% CI NA) in tumor tissues were strongly correlated with better progression-free survival. In contrast to previous studies in wild type EGFR NSCLCs, PD-L1 expression was not associated with the clinical benefit of anti-PD-1 treatment in EGFR-mutated NSCLCs. The current study indicated that immune status in the tumor microenvironment may be important for the effectiveness of nivolumab in NSCLC patients with EGFR mutations.

DOI： 10.1371/journal.pone.0215292

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Objective High adherence to medications and accurate handling of inhaler devices are important for asthma management. However, few reports to date have simultaneously evaluated adherence and handling errors. We therefore investigated the adherence to inhaled corticosteroid (ICS) and inhaler handling errors in the same patients in cooperation with pharmacists. Methods Data were derived from a survey of physicians and pharmacists treating asthma patients who visited participating hospitals and pharmacies from July 2012 to January 2013. The patients were evaluated for asthma control using the Asthma Control Test (ACT) and for inhaler handling errors using checklists. ICS adherence was evaluated based on pharmaceutical records. Results Adherence among participants (n=290) was 33.3% (mean), and the percentage of inhaler handling errors was 20.0% (mean). Total inhalation times in the high-adherence group were fewer than those in the low-adherence group. In a comparison by device, adherence to pressurized metered dose inhalers was significantly lower than that to Diskus® inhalers, presumably attributable to the total number of inhalations per day. Adherence, handling errors, and total number of inhalations per day were significantly different between the asthma-controlled group and the uncontrolled group. A multivariate analysis showed that adherence and handling errors were independent factors contributing to asthma control. Conclusion Our data indicated that both adherence to ICS and device handling errors contributed to asthma control in this population.

DOI： 10.2169/internalmedicine.0986-18

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Objective Whether or not depression affects the control or severity of asthma is unclear. We performed a cluster analysis of asthma patients with depressive symptoms to clarify their characteristics. Methods Multiple medical institutions in Niigata Prefecture, Japan, were surveyed in 2014. We recorded the age, disease duration, body mass index (BMI), medications, and surveyed asthma control status and severity, as well as depressive symptoms and adherence to treatment using questionnaires. A hierarchical cluster analysis was performed on the group of patients assessed as having depression. Results Of 2,273 patients, 128 were assessed as being positive for depressive symptoms [DS(+)]. Thirty-three were excluded because of missing data, and the remaining 95 DS[+] patients were classified into 3 clusters (A, B, and C). The patients in cluster A (n=19) were elderly, had severe, poorly controlled asthma, and demonstrated possible adherence barriers; those in cluster B (n=26) were elderly with a low BMI and had no significant adherence barriers but had severe, poorly controlled asthma; and those in cluster C (n=50) were younger, with a high BMI, no significant adherence barriers, well-controlled asthma, and few were severely affected. The scores for depressive symptoms were not significantly different between clusters. Conclusion About half of the patients in the DS[+] group had severe, poorly controlled asthma, and these clusters were able to be distinguished by their Adherence Starts with Knowledge (ASK)-12 score, which reflects adherence barriers. The control status and severity of asthma may also be related to the age, disease duration, and BMI in the DS[+] group.

DOI： 10.2169/internalmedicine.9073-17

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

A 52-year-old man with chronic myelogenous leukemia (CML) received dasatinib after the failure of imatinib and nilotinib therapy. Two years after the initiation of dasatinib, he developed shortness of breath that gradually worsened. Chest X-ray and computed tomography scan showed pulmonary infiltrative shadows and bilateral pleural effusion. We performed a transbronchial lung biopsy and diagnosed organizing pneumonia caused by dasatinib treatment. Corticosteroid therapy was initiated after the discontinuation of dasatinib and all his symptoms were significantly improved. Because of the exacerbation of CML, the patient was treated with imatinib and then nilotinib; however, these drugs failed to decrease the leukemic cells. Re - administration of dasatinib in combination with corticosteroid therapy successfully controlled CML without recurrence of organizing pneumonia.

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Background: Interferon-γ neutralizing autoantibodies (nIFNγ-autoAbs) are reported in patients with disseminated nontuberculous mycobacteria (NTM) infection and may function by increasing the infection risk. Notwithstanding, the prevalence of nIFNγ-autoAbs as well as the clinical presentation, diagnosis, and natural history of disseminated NTM infection in these patients is poorly understood. Methods: In this retrospective observational study, data and sera for 331 Japanese subjects with mycobacterial infection were collected and analyzed. IFNγ-autoAb titers in sera were quantified using an enzyme-linked immunosorbent assay; neutralizing capacity was evaluated via flow cytometry. Results: Disseminated NTM was identified in 50 human immunodeficiency virus-uninfected patients. Of these, 30 of 37 (81%) immunocompetent patients had an increased nIFNγ-autoAb titer whereas only 1 of 13 (7.7%) immunodeficient patients had an increased nIFNγ-autoAb titer (P < .0001, χ2 test). Presenting symptoms were nonspecific and NTM infection was not included in the differential diagnosis in most cases. All patients with disseminated NTM and an increased serum nIFNγ-autoAb level received prolonged antimicrobial therapy. In 6 cases when antibiotic treatment was discontinued, NTM infection recurred and required resumption of antibiotic therapy for infection control. The mortality rate was 3.2% in disseminated NTM patients with nIFNγ-autoAbs and 21% in those without. Conclusions: nIFNγ-autoAbs were present in most patients with disseminated NTM infection without a diagnosis of clinical immunodeficiency. Diagnosis of disseminated NTM requires a high degree of suspicion and can be improved by measuring serum nIFNγ-autoAb titer. Long-term antibiotic therapy helps prevent recrudescent NTM infection.

DOI： 10.1093/cid/cix996

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Lung Cancer Society  

Objective. Sarcoidosis is a systemic disease that causes the formation of noncaseating epithelioid granuloma in various organs and which often exhibits hilar and mediastinal lymphadenopathy. Among lung cancer patients with sarcoidosis or sarcoid reactions, it is difficult to evaluate the lymph node status and stage by CT and FDG-PET/CT scans. In this study, we examined the usefulness of EBUS-TBNA in the staging of the lung cancer in patients with sarcoidosis or sarcoid reactions. Materials and Methods. We evaluated the effectiveness of EBUS-TBNA in lung cancer patients with sarcoidosis or sarcoid reactions from January 2009 to December 2016. Results. We found 4 patients who were diagnosed with lung cancer accompanied by sarcoidosis and sarcoid reactions by EBUS-TBNA. All of these patients had hilar and mediastinal lymphadenopathy. EBUS-TBNA was useful for the differential diagnosis of lymph-node metastasis of lung cancer. Three of the 4 patients were diagnosed with stage I non-small cell lung cancer and surgery was performed in 2 cases. The histopathological examination of the surgical specimens confirmed that these patients had sarcoid reactions with no lymph-node metastasis. One of the 4 patients was diagnosed with stage III non-small cell lung cancer with systemic sarcoidosis. Conclusion. EBUS-TBNA seems to be useful for the evaluation of the lymph-node status of lung cancer patients with sarcoidosis and sarcoid reactions.

DOI： 10.2482/haigan.58.88

Scopus

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：S. Karger AG  

OBJECTIVE: Chemotherapy with irinotecan plus cisplatin has shown promise in chemo-naïve small-cell lung cancer (SCLC) patients. However, irinotecan treatment for relapsed or refractory SCLC has not been adequately evaluated. This phase II study evaluated the appropriate treatment schedule of irinotecan as a single agent. This study was designed to determine the antitumor activity, toxicity, and survival in previously treated SCLC patients. METHODS: Previously treated SCLC patients with at least one platinum-based regimen received irinotecan (100 mg/m2) on days 1 and 8, every 3 weeks, until disease progression. The assessment of the response rate was the primary endpoint. RESULTS: Thirty patients were enrolled, with an objective response rate of 41.3% (95% confidence interval [CI] 25.5-59.3), and a disease control rate of 69%. Median progression-free and overall survival was 4.1 months (95% CI, 2.2-5.4) and 10.4 months (95% CI, 8.1-14), respectively. The grade 3/4 hematological toxicities were neutropenia (36.7%), thrombocytopenia (3.3%), anemia (13.3%), and febrile neutropenia (6.6%). There were no grade 4 nonhematological toxicities. Frequent grade 3 nonhematological toxicities included diarrhea (10%), anorexia (6.6%), and hyponatremia (6.6%). CONCLUSIONS: This phase II study showed a high objective response rate and long survival. Irinotecan monotherapy schedule used was well tolerated, and could be an active treatment option for these patients.

DOI： 10.1159/000486622

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

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

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOCIETY ALLERGOLOGY  

BACKGROUND: Asthma in athlete populations such as Olympic athletes has various pathogeneses. However, few reports are available on the features of asthma in the athlete population in clinical practice. In this study, we focused on classifying asthma in Japanese athlete population. METHODS: We performed a cluster analysis of data from pulmonary function tests and clinical biomarkers before administering inhaled corticosteroids (ICS) therapy in athlete population of individuals diagnosed with asthma (n = 104; male, 76.9%; median age, 16.0 years), based on respiratory symptoms and positive data on methacholine provocation tests. We also compared backgrounds, sports types, and treatments between clusters. RESULTS: Three clusters were identified. Cluster 1 (32%) comprised athletes with a less atopic phenotype and normal pulmonary function. Cluster 2 (44%) comprised athletes with a less atopic phenotype and lower percent predicted forced expiratory volume in 1 s (%FEV1) values, despite less symptomatic state. Cluster 3 (24%) comprised athletes with a strong atopic phenotype such as high eosinophil count in the blood and total serum immunoglobulin E level. After treatment with ICS or ICS plus long-acting β-adrenergic receptor agonist for 6-12 months, %FEV1 values were significantly improved in Cluster 2 athletes, whereas Cluster 3 athletes had a significant decrease in the fraction of exhaled nitric oxide compared to pretreatment values. CONCLUSIONS: These data suggest three clusters exist in Japanese athlete population with asthma. Between the clusters, the characteristics differed with regard to symptoms, atopic features, and lower %FEV1 values. The pathogeneses between clusters may vary depending on the inflammation type and airway hyperresponsiveness.

DOI： 10.1016/j.alit.2017.02.009

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

OBJECTIVE/BACKGROUND: Multiple system atrophy (MSA) frequently results in the development of sleep-disordered breathing (SDB). Few reports have described the natural course of this phenomenon. The aim of the present study was to determine the natural course of SDB and prognostic factors associated with such conditions in MSA. PATIENTS/METHODS: Twenty-four consecutive patients were recruited with probable MSA, who had not been treated with continuous positive airway pressure (CPAP) and had undergone overnight polysomnography (PSG) more than once following the development of snoring or stridor. Based on changes in the apnea-hypopnea index (AHI) over the course of the disease, patients were divided into two groups (AHI-maintained and AHI-deteriorated) and the clinical findings were compared. RESULTS: Mean duration between the first and last PSG was 2.4 ± 1.5 years, and patients underwent PSG assessment an average of 2.5 ± 0.6 times during this period. During this interval, AHI increased from 19.4 ± 22.8/hour to 34.4 ± 30.1/hour (p = 0.006), although spontaneous improvement was observed in 29% of patients. Following the first PSG, all patients were diagnosed with obstructive sleep apnea; however, the SDB type changed from obstructive sleep apnea to central sleep apnea in 3 of the 24 (13%) patients during the period between the first and last PSG. CONCLUSIONS: Although SDB associated with MSA exacerbates with disease progression, spontaneous improvement in AHI may occur in some patients. Earlier development of snoring or stridor may predict rapid progression of SDB in MSA.

DOI： 10.1016/j.sleep.2017.01.020

Web of Science

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

Serum (1→3) beta-D-glucan (BG) measurement is a useful test for systemic mycoses, and often used. On the other hand, various factors, including administration of intravenous immunoglobulins (IVIG) may cause false-positives. In the present study, we measured BG concentration of seven IVIG preparations with three lots respectively. BG levels varied with individual IVIG preparations (<3.0 - >300 pg/mL), and contamination from manufacturing processes was suspected.

With serum BG concentration of clinical specimens obtained in Niigata University Medical & Dental Hospital, the difference between before and after administration of IVIG were calculated.

The false-positive rate of BG due to IVIG administration was 9.8 %, and the positive predective value was reduced to 37.5%. Above all, administration of IVIG can complicate the BG test's interpretation, and caution is required.

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOCIETY ALLERGOLOGY  

BACKGROUND: Sublingual immunotherapy (SLIT) has received attention as a method for allergen immunotherapy. However, the mechanism of SLIT has not yet been fully investigated. Therefore, we evaluated the effects of SLIT in a murine asthma model, sensitized by intranasal administration of house dust mite (HDM) extracts. METHODS: Female BALB/c mice were intranasally exposed to HDM for either 3 or 5 weeks (5 consecutive days per week). Mice were administered either low-dose (0.5 mg/day) or high-dose (5 mg/day) sublingual HDM extracts for 2 weeks, followed by an additional week of intranasal exposure. Airway hyperresponsiveness (AHR), bronchoalveolar lavage fluid (BALF) cell count, cytokine levels in the BALF and lymph node cell culture supernatants, and allergen-specific antibodies were measured. Lung histology was also investigated. RESULTS: In mice sensitized for 5 weeks, high-dose SLIT ameliorated AHR, airway eosinophilia and goblet cell metaplasia. In mice sensitized for 3 weeks, even low dose SLIT ameliorated AHR and airway eosinophilia. Th2 cytokine levels in culture supernatants of submandibular lymph node cells in high-dose SLIT mice decreased, whereas IL-10 levels increased. Total IgA in BALF increased in mice sensitized for 3 or 5 weeks, and high-dose SLIT also increased allergen-specific IgG2a in mice sensitized for 5 weeks. CONCLUSIONS: These data suggest that earlier induction of SLIT in HDM-sensitized mice provides superior suppression of AHR and goblet cell metaplasia. The modulation of allergen specific IgG2a and local IgA might play a role in the amelioration of AHR and airway inflammation.

DOI： 10.1016/j.alit.2016.05.012

Web of Science

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Allergology  

DOI： 10.15036/arerugi.66.971

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

The adoptive transfer of effector T cells combined with lymphodepletion has demonstrated promising antitumor effects in mice and humans, although the availability of tumor-specific T cells is limited. We and others have also demonstrated that the transfer of polyclonal naïve T cells induces tumor-specific effector T cells and enhances antitumor immunity after lymphodepletion. Because tumors have been demonstrated to induce immunosuppressive networks and regulate the function of T cells, obtaining a sufficient number of fully functional naïve T cells that are able to differentiate into tumor-specific effector T cells remains difficult. To establish culture methods to obtain a large number of polyclonal T cells that are capable of differentiating into tumor-specific effector T cells, naïve T cells were activated with anti-CD3 mAbs in vitro. These cells were stimulated with IL-2 and IL-7 for the CD8 subset or with IL-7 and IL-23 for the CD4 subset. Transfer of these hyperexpanded T cells after lymphodepletion showed significant antitumor efficacy, and tumor-specific effector T cells were primed from these expanded T cells in tumor-bearing hosts. Moreover, these ex vivo-expanded T cells maintained T cell receptor diversity and showed long-term persistence of memory against specific tumors. Further analyses revealed that combination therapy consisting of vaccination with dendritic cells that were co-cultured with irradiated whole tumor cells and the transfer of ex vivo-expanded T cells significantly enhanced antitumor immunity. These results indicate that the transfer of ex vivo-expanded polyclonal T cells can be combined with other immunotherapies and augment antitumor effects.

DOI： 10.1371/journal.pone.0183976

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Begell House Inc.  

The effectiveness of lymphodepletion in antitumor immunity has been well established. Although recent studies have elucidated some of the broad mechanisms underlying the augmentation of antitumor immunity by lymphodepletion, such as increased availability of cytokines due to the elimination of cellular elements and improvement in tumor antigen presentation, the precise mechanisms remain unclear. Previous studies have focused on the enhancement of the functions of transferred antitumor CD8+ T cells after lymphodepletion. In this review, we discuss the important role of other immune cells in the effectiveness of lymphodepletion. Recent studies have demonstrated that lymphodepletion enhances not only transferred tumor-specific CD8+ T cells but also tumor-specific CD4+ T cells and polyclonal naïve T cells. Moreover, recipient immune cells, including CD8+ T cells, regulatory T cells, dendritic cells, and macrophages, are involved in the augmentation of antitumor effects by lymphodepletion. These host cells can survive lymphodepletive therapies and play a role in the development of antitumor immunity after lymphodepletion. Improvements in the understanding of lymphodepletion allow us to design effective cancer immunotherapy.

DOI： 10.1615/CritRevImmunol.2018019497

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

BACKGROUND: Nephrotoxicity is the major side effect that limits the dose of cisplatin that can be safely administered, and it is a clinical problem in cancer patients who received cisplatin combination chemotherapy. Recent evidence has demonstrated that patients with chronic kidney disease (CKD) have an increased risk of developing acute kidney injury (AKI). The present study was conducted to evaluate the prevalence of CKD risk factors in patients who received cisplatin and to assess the correlation between CKD risk factors and cisplatin-induced AKI. METHODS: We retrospectively analyzed 84 patients treated with cisplatin combination chemotherapy for thoracic malignancies. AKI was defined as a decrease in the estimated glomerular filtration rate (eGFR) > 25% from base line, an increase in the serum creatinine (sCre) level of > 0.3 mg/dl or ≥ 1.5 times the baseline level. RESULTS: Eighty of the 84 patients (95.2%) had at least one risk factor for CKD. All enrolled patients received cisplatin with hydration, magnesium supplementation and mannitol. Cisplatin-induced AKI was observed in 18 patients (21.4%). Univariate analysis revealed that cardiac disease and use of non-steroidal anti-inflammatory drugs (NSAIDs) were associated with cisplatin-induced nephrotoxicity (odds ratios [OR] 6 and 3.56, 95% confidence intervals [CI] 1.21-29.87 and 1.11-11.39, p = 0.04 and p = 0.04, respectively). Multivariate analysis revealed that cisplatin nephrotoxicity occurred significantly more often in patients with both risk factors (OR 13.64, 95% CI 1.11-326.83, p = 0.04). Patients with more risk factors for CKD tended to have a greater risk of developing cisplatin-induced AKI. CONCLUSIONS: We should consider avoiding administration of cisplatin to patients with CKD risk factors, particularly cardiac disease and NSAID use.

DOI： 10.1186/s12885-016-2271-8

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Antitumor immunity is augmented by cytotoxic lymphodepletion therapies. Adoptively transferred naive and effector T cells proliferate extensively and show enhanced antitumor effects in lymphopenic recipients. Although the impact of lymphodepletion on transferred donor T cells has been well evaluated, its influence on recipient T cells is largely unknown. The current study demonstrates that both regulatory T cells (Tregs) and effector CD8(+) T cells from lymphopenic recipients play critical roles in the development of antitumor immunity after lymphodepletion. Cyclophosphamide (CPA) treatment depleted lymphocytes more efficiently than other cytotoxic agents; however, the percentage of CD4(+)CD25(+) Foxp3(+) Tregs was significantly increased in CPA-treated lymphopenic mice. Depletion of these chemoresistant Tregs following CPA treatment and transfer of naive CD4(+) T cells augmented the antitumor immunity and significantly suppressed tumor progression. Further analyses revealed that recipient CD8(+) T cells were responsible for this augmentation. Using Rag2(-/-) mice or depletion of recipient CD8(+) T cells after CPA treatment abrogated the augmentation of antitumor effects in CPA-treated reconstituted mice. The transfer of donor CD4(+) T cells enhanced the proliferation of CD8(+) T cells and the priming of tumor-specific CD8(+) T cells originating from the lymphopenic recipients. These results highlight the importance of the recipient cells surviving cytotoxic regimens in cancer immunotherapies.

DOI： 10.4049/jimmunol.1401468

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

OBJECTIVE: Eosinophilic inflammation in the respiratory tract is a hallmark of bronchial asthma. In naïve cases, the inflammatory profile is associated with disease severity and reactivity to inhaled corticosteroids (ICS). Sustained airway eosinophilia has been reported during ICS treatment. However, the immunological characteristics of these cases are not known and it is unclear if this situation contributes to asthma control. This study was performed to determine the answer of these questions. METHODS: To compare phenotypes of eosinophilic and non-eosinophilic asthma (EA and NEA, respectively) under ICS treatment, clinical data were obtained from asthmatic subjects (n = 22) and healthy controls (n = 10), and the leukocyte compositions of induced sputum and peripheral blood were determined. T lymphocyte profiles in systemic blood were assessed by flow cytometry. RESULTS: A higher frequency of emergency room visits was observed in the NEA group, which had a higher neutrophil count relative to the total inflammatory cell population in induced sputum than the EA group (59.5 versus 36.6%; p < 0.01). The fraction of helper T (Th)17 lymphocytes as well as the ratio of Th17 to regulatory T cells (Treg) in the peripheral blood was higher in the NEA than in the EA group (0.24 versus 0.13; p < 0.05). CONCLUSIONS: Th17 were more prevalent than Treg cells in the peripheral blood of NEA patients under ICS treatment, corresponding to neutrophil-dominant airway inflammation and a severe asthmatic phenotype. Thus, an imbalance in Th17/Treg may be associated with the pathogenesis of NEA in patients undergoing ICS treatment.

DOI： 10.3109/02770903.2014.975357

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：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

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOCIETY ALLERGOLOGY  

BACKGROUND: Asthma has a higher prevalence in athlete populations such as Olympic athletes than in the general population. Correct diagnosis and management of asthma in athletes is important for symptom control and avoidance of doping accusations. However, few reports are available on asthma treatment in the athlete population in clinical practice. In this study, we focused on the clinical efficacy of inhaled corticosteroid (ICS) for asthma in a Japanese athlete population. METHODS: The study subjects included athletes who visited the Niigata Institute for Health and Sports Medicine, Niigata, Japan for athletic tests and who were diagnosed with asthma on the basis of respiratory symptoms and positive results in a bronchodilator or bronchial provocation test such as exercise, hypertonic saline, or methacholine provocation. The athletes received ICS alone for at least 3 months, and the clinical background, sports type, and treatment efficacy were analyzed. RESULTS: The study population comprised 80 athletes (59 men and 21 women) with a median age of 16.0 years. Regarding sports type, 28 athletes engaged in winter sports (35%), 22 in endurance sports (27.5%), and 25 in indoor sports (31.3%). Although ICS is the primary treatment in athlete asthma, 16.3% of the athletes showed an unsatisfactory response to treatment according to the Global Evaluation of Treatment Effectiveness (GETE). These subjects were characterized by a decreased response to methacholine and lower values for FEV1/FVC and type 2 helper T cell (Th2)-associated biomarkers relative to responsive athletes. In multivariate analysis, FEV1/FVC and the logarithm to the base 10 of the IgE level were independently associated with the ICS response. CONCLUSIONS: These data suggest that ICS is effective for asthma in most athletes. However, certain asthmatic athletes are less responsive to ICS than expected. The pathogenesis in these subjects may differ from that of conventional asthma characterized by chronic allergic airway inflammation.

DOI： 10.1016/j.alit.2014.10.004

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

BACKGROUND: Active suppression induced by regulatory T (Treg) cells is reported to be one of the mechanisms involved in oral tolerance. All-trans retinoic acid (ATRA) has been reported to affect Treg cell differentiation. The present study examined the effects of ATRA on the induction of oral tolerance in a murine model of bronchial asthma. METHODS: BALB/c mice were sensitized to and challenged with ovalbumin (OVA) through feeding followed by OVA challenges. In some study groups ATRA was orally administered concomitantly with OVA feeding either in the presence or absence of the retinoic acid receptor antagonist LE135. Lung CD4+ T cells were isolated from mice exposed to ATRA and/or OVA, and transferred to control mice. Airway hyperresponsiveness (AHR), cell counts and cytokine levels in bronchoalveolar lavage (BAL) fluid, and lung histology were assessed. RESULTS: Concomitant administration of ATRA with OVA ameliorated AHR, airway eosinophilia, elevation of cytokines in BAL fluid and goblet cell metaplasia. The proportion of Treg cells in the lungs was increased in mice treated with OVA and ATRA, as compared to those treated with OVA only. Transfer of lung CD4+ T cells from mice treated with OVA and ATRA induced suppression of AHR and airway inflammation. LE135 completely reversed the effects of ATRA on AHR, airway allergic inflammation and the number of Treg cells in the lungs. CONCLUSION: These data suggested that oral administration of ATRA with OVA had the potential to enhance oral tolerance in this murine model of bronchial asthma. These effects were mediated, at least in part, by Treg cell expansion.

DOI： 10.1159/000437326

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOCIETY ALLERGOLOGY  

BACKGROUND: Depression has been linked to poorer asthma control in asthmatic patients. Although the Japanese version of the Asthma Control Test (ACT-J) is frequently used as a simple, practical evaluation tool in clinical care settings in Japan, knowledge regarding its efficacy for assessing asthma control in asthmatic patients with depression is limited. Thus, we retrospectively investigated cut-off values of the ACT-J for well-controlled asthma, and explored depression's influence on the test with a questionnaire survey. METHODS: Data were analyzed on 1,962 adult asthmatic patients who had completed both the ACT-J and the Japanese version of the Patient Health Questionnaire-9 (J-PHQ-9) in 2008 questionnaire survey conducted by the Niigata Asthma Treatment Study Group. Patients were classified into low (LD: J-PHQ-9 score of 0-4) or high depression (HD: J-PHQ-9 score of 5-27) groups. In both groups, the efficacy of the ACT-J was confirmed. We then compared the optimal cut-off points for uncontrolled asthma in both groups by performing a receiver operating characteristic (ROC) analysis, using the original classification referred to the GINA classification as the "true" classification. RESULTS: Cronbach's alpha in the LD and HD group was 0.808 and 0.740 respectively. In both groups, the sub-group with existence of work absenteeism or frequent attacks during the previous 12 months scored lower on the ACT-J. The area under the curve and optimal cut-off point for patients with LD and HD were 0.821 and 0.846, and 23 and 20 respectively. CONCLUSIONS: The efficacy of the ACT-J was confirmed in depressive patients with asthma. Because asthma control as evaluated with the ACT-J can be worse than actual control under depressive states, physicians should also pay attention to a patient's depressive state at evaluation. Further investigations focus on the association between the ACT-J and depression are required.

DOI： 10.2332/allergolint.14-OA-0708

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOCIETY ALLERGOLOGY  

BACKGROUND: Influenza infection is known to be an exacerbating factor in the control of asthma, therfore its prevention is critical in managing asthma. The aim of this study was to investigate the influenza A H1N1 2009 pandemic virus (H1N1 pdm09) infection in adult asthmatic patients. METHODS: Data were obtained from a questionnaire-based survey of asthmatic patients conducted from September to October 2010 in Niigata Prefecture. Patient background, H1N1 pdm09 infection, vaccination status, and asthma exacerbation due to influenza infection were analyzed. RESULTS: In total, 2,555 cases were analyzed. The incidence of the infection was 6.7% (95% confidence interval [CI]: 5.7-7.6), and the rate of vaccination was 63.9% (95% CI: 62.1-65.8). The odds ratio (OR) for vaccination against the infection among adult patients and younger patients (≤ the median age) were 0.61 (95% CI: 0.45-0.84) and 0.62 (95% CI: 0.42-0.90), respectively. However, OR among the older patient (> median age) were 1.38 (95%CI: 0.66-2.89). The rate of infection-induced asthma exacerbation was 23.2% (95% CI: 18.6-29.6), and the OR for vaccination against the infection-induced asthma exacerbation was 1.42 (95% CI: 0.69-2.92). CONCLUSIONS: The effectiveness of the vaccination against the H1N1 pdm09 virus was confirmed during the first pandemic season, but it was limited. Further investigation on H1N1 pdm09 virus infection in asthmatics will be required.

DOI： 10.2332/allergolint.13-OA-0609

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：INFORMA HEALTHCARE  

OBJECTIVE: While the majority of individuals with asthma retain normal lung function over time, some exhibit accelerated lung function decline. Preservation of lung function is an important aspect of asthma management. Whether the asthma guidelines can prevent lung function decline remains controversial. This study was performed to determine the distribution of asthmatic subjects with greater lung function decline and to identify characteristic clinical features of such subjects treated in accordance with clinical guidelines by using hierarchical cluster analysis. METHODS: Eighty-six asthmatic subjects without a history of smoking were assessed with respect to eight variables selected from clinical phenotypes by using step-wise multiple regression analysis. Hierarchical cluster analysis using Ward's method generated a dendrogram for estimation of the number of clusters within the population and the differences between them. RESULTS: Three distinct clusters were identified. Cluster 1 (n = 40) comprised women with late-onset asthma. Cluster 2 (n = 17) comprised subjects with early-onset asthma, atopy and long disease duration. Cluster 3 (n = 29) predominantly comprised older men who had late-onset asthma, a lower prevalence of exacerbation and a lower predicted % forced expiratory volume in 1 s (FEV1) at baseline. Subjects in cluster 3 showed a mean decline in FEV1 of 69 mL/year, which was the greatest lung function decline among the three clusters. CONCLUSION: We identified a subgroup of patients with accelerated lung function decline despite appropriate asthma treatment based on guidelines constructed by using subjective symptoms.

DOI： 10.3109/02770903.2013.852201

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Subjects exposed to non-tuberculous mycobacterium (NTM) species do not always develop an active disease, which likely reflects underlying host susceptibility factors. Recent reports have shown that anti interferon gamma (IFN-γ) neutralizing autoantibodies (IFN-γ Ab) are associated with the development of disseminated NTM in patients without known evidence of immunodeficiency. The purpose of this study is to establish the screening method if subjects have IFN-γ Ab. Whole blood was obtained from patients with disseminated NTM, those with pulmonary NTM, and healthy controls. The neutralizing capacity to IFN-γ activity was assessed as an inhibition of Signal Transducer and Activation of Transcription 1 (STAT-1) phosphorylation in leukocyte after stimulation with exogenous IFN-γ by flow cytometer. The strength of phosphorylation was described as STAT1 phosphorylation index. Antigen capture assay was performed to measure the relative titer of Immunoglobulin-G fraction of IFN-γ Ab. STAT1 phosphorylation by IFN-γ was significantly inhibited in the leukocytes from patients with disseminated NTM compared to that in healthy subjects, while this inhibition was not observed in patients with pulmonary NTM. All subjects with inhibited STAT1 phosphorylation had high titer of Immunoglobulin-G that reacted with IFN-γ in the antigen capture assay. The measurement of STAT1 phosphorylation index in whole blood leukocytes and antigen capture assay are simple and useful method for detection of anti-IFN-γ neutralizing autoantibodies, and is valuable in the pathophysiological diagnosis of disseminated NTM patients without obvious immunodeficiency.

DOI： 10.1016/j.jiac.2013.08.003

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

ONO-1301, a novel prostacyclin agonist with thromboxane A2 synthase inhibitory activity, is a useful agent for ameliorating airway allergic inflammation; however, its short-action feature implies a requirement for the frequent administration of this drug. Therefore, we investigated the effects of ONO-1301-loaded poly (d,l-lactic-co-glycolic acid) microspheres (ONO-1301MS; to release ONO-1301 for 3 weeks) on the airway inflammation and remodeling in chronic house dust mite (HDM)-induced model. Balb/c mice were exposed to an HDM extract intranasally for 5 days/week for 5 consecutive weeks. The mice received a single subcutaneous injection of ONO-1301MS or vehicle after 3 weeks of HDM exposure, followed by 2 additional weeks of HDM exposure. Forty-eight hours after the last HDM exposure, airway hyperresponsiveness to methacholine was assessed and bronchoalveolar lavage was performed. Lung specimens were excised and stained to check for goblet cell metaplasia, airway smooth muscle hypertrophy, and submucosal fibrosis. Mice receiving ONO-1301MS showed significantly lower airway hyperresponsiveness, airway eosinophilia, and induced T helper 2 cytokine production compared with mice receiving the vehicle. Histological findings such as goblet cell metaplasia, airway smooth muscle hypertrophy, and submucosal fibrosis were decreased in ONO-1301MS-treated mice compared with vehicle-treated mice. A single administration of ONO-1301MS achieved sustained elevation of its circulating level for 3 weeks. These data suggest that a single administration of ONO-1301MS may suppress airway hyperresponsiveness, airway allergic inflammation, and development of airway remodeling in chronic HDM-induced asthma model. This agent may be effective as an anti-inflammatory and remodeling drug in the practical treatment of asthma.

DOI： 10.1016/j.ejphar.2013.09.051

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Allergology  

BACKGROUND: The 2006 Global Initiative for Asthma (GINA 2006) guidelines emphasize the importance of evaluating the control rather than the severity of asthma. The Asthma Control Test (ACT) is well known to be an excellent tool for evaluating asthma control in the clinical setting. This study aimed to evaluate the ACT, Japanese version (ACT-J) as a predictor of asthma control as defined by the GINA 2006 guidelines in actual clinical practice. METHODS: A cross-sectional analysis comparing the ACT-J score and GINA classification of asthma control among 419 patients of primary care physicians and specialists was performed using the data from a 2010 questionnaire-based survey conducted by the Niigata Asthma Treatment Study Group. RESULTS: The optimal cut-off point of the ACT-J score for predicting GINA-defined asthma control was 23, with ACT-J scores of ≥23 and ≤22 predicting controlled and uncontrolled asthma with area under the receiver operating characteristics curve values of 0.76 [95% confidence interval (CI): 0.72-0.81] and 0.93 [95% CI: 0.90-0.97], respectively. CONCLUSIONS: ACT scores of ≥23 and ≤22 are useful for identifying patients with controlled and uncontrolled asthma, respectively, as defined by GINA 2006, and the latter is more strongly predictive than the former. The reason for the higher cut-off point of the ACT-J relative to other versions of the ACT is unclear and warrants further investigation.

DOI： 10.2332/allergolint.13-OA-0535

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The 2006 Global Initiative for Asthma (GINA 2006) guidelines emphasize the importance of evaluating the control rather than the severity of asthma. The Asthma Control Test (ACT) is well known to be an excellent tool for evaluating asthma control in the clinical setting. This study aimed to evaluate the ACT, Japanese version (ACT-J) as a predictor of asthma control as defined by the GINA 2006 guidelines in actual clinical practice. METHODS: A cross-sectional analysis comparing the ACT-J score and GINA classification of asthma control among 419 patients of primary care physicians and specialists was performed using the data from a 2010 questionnaire-based survey conducted by the Niigata Asthma Treatment Study Group. RESULTS: The optimal cut-off point of the ACT-J score for predicting GINA-defined asthma control was 23, with ACT-J scores of ≥23 and ≤22 predicting controlled and uncontrolled asthma with area under the receiver operating characteristics curve values of 0.76 [95% confidence interval (CI): 0.72-0.81] and 0.93 [95% CI: 0.900.97], respectively. CONCLUSIONS: ACT scores of ≥23 and ≤22 are useful for identifying patients with controlled and uncontrolled asthma, respectively, as defined by GINA 2006, and the latter is more strongly predictive than the former. The reason for the higher cut-off point of the ACT-J relative to other versions of the ACT is unclear and warrants further investigation.

DOI： 10.2332/allergolint.13-OA-0535

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOCIETY ALLERGOLOGY  

BACKGROUND: The Asthma Control Test (ACT) is frequently used for the evaluation of asthma control in clinical care setting because it does not require the use of pulmonary function tests, which can be difficult for general practitioners to use. However, few large-scale studies have investigated the efficacy of the Japanese version ACT (J-ACT) in actual use during clinical care. METHODS: The aim of this study was to analyze the efficacy of the J-ACT in a clinical care setting. Using data from a 2008 questionnaire survey including the J-ACT by the Niigata Asthma Treatment Study Group, we compared the ACT scores of 2233 patients with respect to multiple parameters, including the severity by Japanese Society of Allergology and the attack frequency. Using the definition of asthma control partially referred to Global Initiative for Asthma (GINA) guidelines from the survey data, the accuracy screening and determination of optimal ACT cutpoints were performed by retrospective analysis. RESULTS: Cronbach's α for the J-ACT was 0.785. Patients with more severe asthma and more frequent asthma attacks had lower ACT scores than did patients with less severe, less frequent attacks. The optimal ACT cutpoints were 24 for the controlled asthma and 20 for the uncontrolled asthma. CONCLUSIONS: Our study, the first large-scale investigation of the efficacy of the J-ACT, determined that this evaluation tool is highly efficacious in establishing the level of asthma control. However, the determination of accurate cutpoints for the J-ACT will require more clear definitions of asthma control in future prospective studies.

DOI： 10.2332/allergolint.12-OA-0453

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

Cytotoxic lymphodepletion therapies augment antitumor immune responses. The generation and therapeutic efficacy of antitumor effector T cells (T(E)s) are enhanced during recovery from lymphopenia. Although the effects of lymphodepletion on naive T cells (T(N)s) and T(E)s have been studied extensively, the influence of lymphodepletion on suppressor cells remains poorly understood. In this study, we demonstrate a significant increase of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) in sublethally irradiated lymphopenic mice. These radio-resistant Tregs inhibited the induction of T(E)s in tumor-draining lymph-nodes (TDLNs) during recovery from lymphopenia. The transfer of T(N)s into lymphopenic tumor-bearing mice resulted in some antitumor effects; however, Treg depletion after whole-body irradiation and reconstitution strongly inhibited tumor progression. Further analyses revealed that tumor-specific T cells were primed from the transferred T(N)s, whereas the Tregs originated from irradiated recipient cells. As in irradiated lymphopenic mice, a high percentage of Tregs was observed in cyclophosphamide-treated lymphopenic mice. The inhibition of Tregs in cyclophosphamide-treated mice significantly reduced tumor growth. These results indicate that the Tregs that survive cytotoxic therapies suppress antitumor immunity during recovery from lymphopenia and suggest that approaches to deplete radio and chemo-resistant Tregs can enhance cancer immunotherapies.

DOI： 10.1182/blood-2012-02-411124

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOCIETY ALLERGOLOGY  

BACKGROUND: Previous studies show that depression plays an important role in asthma. However, the association between asthma control and severity, and depression is inconclusive. METHODS: To investigate the association between asthma control and severity, and depression, we assessed differences in asthma control and asthma severity between groups with various grades of depressive state as defined by the PHQ-9 score using data from the Japanese version of Patient Health Questionnaire-9 (J-PHQ-9) and a questionnaire survey including the Asthma Control Test (ACT). RESULTS: The ACT scores in the symptom-screen positive (SP) and major/other depressive disorder (MDD/ODD) group were significantly lower than those in the symptom-screen negative (SN) and non-MDD/ODD groups, respectively. The rate of step1 and of step 3 and 4 in the SP group were significantly lower and higher than those in the SN group, respectively. When the SP group was divided into three, that is minimal, mild, and more than mild (MTM) depressive state subgroups, the ACT scores in the mild and MTM depressive state subgroups were significantly lower than those in the minimal depressive state subgroup. When the MTM subgroup was divided into moderate, moderate-severe and severe depressive state groups, however, there was no significant variation in ACT score and asthma severity among these three depressive state groups. CONCLUSIONS: This study is the first, large-scale investigation of the use of the J-PHQ-9 in asthma patients. Using the J-PHQ-9 and the questionnaire, there was a clear association between asthma control and severity, and depression. As the depression became more severe, the existence of other depression-associated factors unrelated to asthma control and severity might be assumed, although further investigation will be required.

DOI： 10.2332/allergolint.11-OA-0413

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOCIETY ALLERGOLOGY  

BACKGROUND: Although the association between asthma control and body mass index (BMI) has been thoroughly investigated, most of this work has focused on the influence on asthma incidence or the effect of obesity on asthma control. To date, there have been no published studies on the influence of underweight on asthma control. METHODS: The aim of this study was to investigate the influence of underweight, as defined by the Japan Society for the Study of Obesity (JASSO), on asthma control in Japanese asthmatic patients. Using data from questionnaire surveys administered by the Niigata Asthma Treatment Study Group, we compared asthma control, as measured by the Asthma Control Test (ACT), between a normal weight group (18.5kg/m2 =< BMI < 25kg/m2) and an underweight group (BMI < 18.5kg/m2). RESULTS: Of the asthmatic patients who completed the 2008 and 2010 surveys, 1464 and 1260 cases were classified as being in the normal weight group, and 174 and 155 cases were classified as being in the underweight group. The ACT score (median, [interquartile range]) in the underweight group in 2008 (22, [19-24]) and 2010 (23, [19-25]) was significantly lower than that in the normal group in 2008 (23, [20-25]) and in 2010 (24, [21-25]). CONCLUSIONS: This study is the first, large-scale investigation of the influence of underweight on asthma control, and we have confirmed an adverse influence in a clinical setting. A potential mechanism for this interaction was unknown. Further investigation will be required.

DOI： 10.2332/allergolint.12-OA-0425

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER THORACIC SOC  

Airway remodeling in bronchial asthma results from chronic, persistent airway inflammation. The effects of the reversal of airway remodeling by drug interventions remain to be elucidated. We investigated the effects of ONO-1301, a novel prostacyclin agonist with thromboxane inhibitory activity, on the prevention and reversibility of airway remodeling in an experimental chronic asthma model. Mice sensitized and challenged to ovalbumin (OVA) three times a week for 5 consecutive weeks were administered ONO-1301 or vehicle twice a day from the fourth week of OVA challenges. Twenty-four hours after the final OVA challenge, airway hyperresponsiveness (AHR) was assessed, and bronchoalveolar lavage was performed. Lung specimens were excised for staining to detect goblet-cell metaplasia, airway smooth muscle, and submucosal fibrosis. Mice administered ONO-1301 showed limited increases in AHR compared with mice administered the vehicle. The histological findings of airway remodeling were improved in ONO-1301-treated mice compared with vehicle-treated mice. Presumably, these therapeutic effects of ONO-1301 are attributable to the up-regulation of production of hepatocyte growth factor (HGF) in lung tissue, because the neutralization of HGF by antibodies prevented the effects of ONO-1301 on AHR and airway remodeling. Mice administered ONO-1301 showed similar levels of AHR and airway remodeling as mice administered montelukast, a cysteinyl-leukotriene-1 receptor antagonist, and lower levels were observed in mice administered dexamethasone. These data suggest that ONO-1301 exerts the effect of reversing airway remodeling, at least in part through an elevation of HGF in the lungs, and may be effective as an anti-remodeling drug in the treatment of asthma.

DOI： 10.1165/rcmb.2011-0350OC

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

BACKGROUND: Oral tolerance is a classically used strategy for antigen-specific systemic immunotherapy. However, the roles of IL-17 in modification of oral tolerance are not yet understood. OBJECTIVE: To define the effects of IL-17 on the modification of oral tolerance, the effects of transfer of Th17 cells, administration of IL-17 or anti-IL-17 antibody (αIL-17Ab) to a murine allergic airway inflammation model were investigated. METHODS: Mice sensitized to and challenged with OVA, received OVA feeding, followed by OVA challenges. Transfer of Th17 cells, administration of IL-17 or αIL-17Ab were executed during OVA feeding. Airway hyperresponsiveness (AHR), airway inflammation, Th2 cytokine response and lung pathology were assessed. RESULTS: Administration of IL-17 as well as transfer of Th17 cells aggravated AHR and airway allergic inflammation as compared with the findings in mice subjected to OVA feeding alone, whereas administration of αIL-17Ab ameliorated AHR and airway eosinophilia. The effects of Th17 transfer were presumably attributable to augmentation of endogenous IL-6 production in gut. The number of Foxp3-positive regulatory T (Treg) cells in lungs and Payer's patches was increased in the OVA fed mice, whereas the number of these cells was decreased in the mice subjected to OVA feeding + Th17 cell transfer. Neutralization of IL-6 by monoclonal antibody in the mice subjected to OVA feeding + transfer of Th17 cells restored the effects of oral tolerance. CONCLUSIONS AND CLINICAL RELEVANCE: These data suggest that IL-17 may inhibit the induction of tolerance to antigen through, at least in part augmenting IL-6 production, thereby suppressing the expansion of Treg cells.

DOI： 10.1111/j.1365-2222.2012.04006.x

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Despite the advances of asthma management and the accompanying improved asthma control, many problems related to asthma management still remain. The Niigata Asthma Treatment Study Group has been regularly collecting information via surveys since 1998 using a questionnaire, on problems related to asthma management; various studies on asthma management have been reported using data from the questionnaire. METHODS: The aim of this study was to investigate the changes in asthma control and management for every two-year period using the data from 1998 to 2008; future problems requiring resolution were extracted and discussed. RESULTS: The number of cases surveyed each year was about 3,000 (2,593-3,347 cases). The changes in the data from 1998 to 2008, including asthma attacks and symptoms rate, indicated the improvement of asthma control with the spread of medication according to the guidelines; of particular note, there was a 24.1% increase in the usage rate of inhaled corticosteroids during the study period. From 2002 to 2008, however, some asthmatic conditions seemed to show no improvement with regards to asthma control related to the rates of changes in peak flow met

DOI： 10.2169/internalmedicine.51.6586

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

BACKGROUND: Despite the advances of asthma management and the accompanying improved asthma control, many problems related to asthma management still remain. The Niigata Asthma Treatment Study Group has been regularly collecting information via surveys since 1998 using a questionnaire, on problems related to asthma management; various studies on asthma management have been reported using data from the questionnaire. METHODS: The aim of this study was to investigate the changes in asthma control and management for every two-year period using the data from 1998 to 2008; future problems requiring resolution were extracted and discussed. RESULTS: The number of cases surveyed each year was about 3,000 (2,593-3,347 cases). The changes in the data from 1998 to 2008, including asthma attacks and symptoms rate, indicated the improvement of asthma control with the spread of medication according to the guidelines; of particular note, there was a 24.1% increase in the usage rate of inhaled corticosteroids during the study period. From 2002 to 2008, however, some asthmatic conditions seemed to show no improvement with regards to asthma control related to the rates of changes in peak flow meter use, leukotriene receptor antagonist use and oral sustained-released theophylline use. Moreover, there was no decrease in the occurrence of emergency episodes related to asthma deaths. CONCLUSION: In the actual clinical setting, asthma control seems to be progressing well with the appropriate changes of medication according to the guidelines, and in part due to inhaled corticosteroid use. However, there were two problems which need to be addressed: 1) no improvement in some asthmatic conditions and 2) the occurrence of emergency episodes related to asthma deaths. In the future, it will be necessary to manage asthma in view of these points.

DOI： 10.2169/internalmedicine.51.6586

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Allergology  

BACKGROUND: The effect of inhaled corticosteroid (ICS) on the bone status of asthmatic patients is still uncertain, because it can differ by race and because there have been few cases in Japan. In this study, the bone status of ICS users with asthma was evaluated in an actual clinical setting in Japan. METHODS: In 7 participating hospitals, ICS users with asthma and control subjects were age- and gender-matched and recruited into this study. To assess bone status, ultrasound measurements of each individual's calcaneus were made using an AOS-100. The ratio of the osteo sono-assessment index (OSI) to the average OSI corrected for age and gender was denoted as %OSI and used for quantitative assessment. The second %OSI measurement was performed 6 months after the first %OSI one. During the study period, individual treatment remained unchanged. RESULTS: There were no significant differences in the 1st and 2nd %OSI between the ICS users and control subjects. However, the 2nd %OSI significantly decreased compared with 1st %OSI in female ICS users, although there were no significant changes in the male and female control subjects and male ICS users. CONCLUSIONS: The 6 month management of asthma in the actual clinical setting, including regular ICS use, might have a harmful influence on the bone status of female asthmatic patients. It may be necessary to manage and treat female patients for potent corticosteroid-induced osteoporosis, although further analyses of bone status in asthma patient ICS users will be required.

DOI： 10.2332/allergolint.10-OA-0276

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

We report a case of Churg-Strauss syndrome (CSS) complicated by severe cardiac failure and peripheral neuropathy. Two courses of methylprednisolone pulse therapy were unable to control the disease activity. Repeated intravenous administration of high-dose human immunoglobulin (IVIg) was added together with intravenous cyclophosphamide pulse therapy (IVCY), and the patient's cardiac function and neurological symptoms were gradually ameliorated without any adverse event. Although glucocorticoid and cyclophosphamide comprise the standard therapy for patients with CSS, a number of patients with severe complications appear to be resistant to such conventional treatment. IVIg is thought to be an effective therapeutic option for such patients.

DOI： 10.2169/internalmedicine.50.4648

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

BACKGROUND Despite the use of inhaled corticosteroid (ICS) becoming increasingly widespread, many problems related to asthma management still need to be addressed. One of them, obesity, has been reported to exert a harmful influence on asthma control. However, there have been few reports focusing not only on both obesity and its influence on Japanese asthma patients but also on the Japanese definition of obesity, as defined by the Japan Society for the Study of Obesity (JASSO). AIMS & METHODS The aim of this study was to confirm the influence of obesity, as defined by the JASSO, on asthma management in Japanese asthmatic patients. Using data from the Niigata Asthma Treatment Study Group 2008 questionnaire survey, differences between the "normal" group (18.5 kg/m(2) ≤ BMI <25 kg/m(2)) and the "obese" group (25 kg/m(2) ≤ BMI) were analyzed. RESULTS There was a significantly lower step 1 rate (19.4% v.s. 26.8%) and a higher proportion of patients using inhaled salmeterol (43.6% v.s. 35.8%) and leukotriene receptor antagonist (49.8% v.s. 40.8%) in the obese group relative to the normal group, although there were no significant differences in indicators of asthma control, including asthma control test scores. CONCLUSION This study investigated influences of JASSO-defined obesity on asthma severity and management in a clinical setting in Japan. It is possible that there are strong interactions between asthma and obesity, such as obesity causing decreased ICS therapy efficacy and leukotriene (LT)-related inflammation, although further investigation is necessary.

DOI： 10.2169/internalmedicine.50.5474

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND Despite the use of inhaled corticosteroid (ICS) becoming increasingly widespread, many problems related to asthma management still need to be addressed. One of them, obesity, has been reported to exert a harmful influence on asthma control. However, there have been few reports focusing not only on both obesity and its influence on Japanese asthma patients but also on the Japanese definition of obesity, as defined by the Japan Society for the Study of Obesity (JASSO). AIMS &amp; METHODS The aim of this study was to confirm the influence of obesity, as defined by the JASSO, on asthma management in Japanese asthmatic patients. Using data from the Niigata Asthma Treatment Study Group 2008 questionnaire survey, differences between the &quot;normal&quot; group (18.5 kg/m(2) &lt;/= BMI &lt;25 kg/m(2)) and the &quot;obese&quot; group (25 kg/m(2) &lt;/= BMI) were analyzed. RESULTS There was a significantly lower step 1 rate (19.4% v.s. 26.8%) and a higher proportion of patients using inhaled salmeterol (43.6% v.s. 35.8%) and leukotriene receptor antagonist (49.8% v.s. 40.8%) in the obese group relative to the normal group, although there were no significant differences in indicators of asthma control, including

DOI： 10.2169/internalmedicine.50.5474

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Invariant NKT cells (iNKT cells) play a pivotal role in the development of allergen-induced airway hyperresponsiveness (AHR) and inflammation. However, it is unclear what role they play in the initiation (sensitization) phase as opposed to the effector (challenge) phase. The role of iNKT cells during sensitization was examined by determining the response of mice to intratracheal transfer of OVA-pulsed or OVA-alpha-galactosylceramide (OVA/alphaGalCer)-pulsed bone marrow-derived dendritic cells (BMDCs) prior to allergen challenge. Wild-type (WT) recipients of OVA-BMDCs developed AHR, increased airway eosinophilia, and increased levels of Th2 cytokines in bronchoalveolar lavage fluid, whereas recipients of OVA/alphaGalCer BMDCs failed to do so. In contrast, transfer of these same OVA/alphaGalCer BMDCs into IFN-gamma-deficient (IFN-gamma(-/-)) mice enhanced the development of these lung allergic responses, which was reversed by exogenous IFN-gamma treatment following OVA-BMDC transfer. Further, Jalpha18-deficient recipients, which lack iNKT cells, developed the full spectrum of lung allergic responses following reconstitution with highly purified WT liver or spleen iNKT cells and transfer of OVA-BMDCs, whereas reconstituted recipients of OVA/alphaGalCer BMDCs failed to do so. Transfer of iNKT cells from IFN-gamma(-/-) mice restored the development of these responses in Jalpha18-deficient recipients following OVA-BMDC transfer; the responses were enhanced following OVA/alphaGalCer BMDC transfer. iNKT cells from these IFN-gamma(-/-) mice produced higher levels of IL-13 in vitro compared with WT iNKT cells. These data identify IFN-gamma as playing a critical role in dictating the consequences of iNKT cell activation in the initiation phase of the development of AHR and airway inflammation.

DOI： 10.4049/jimmunol.0902301

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Allergology  

BACKGROUND: The prevalence of bronchial asthma (BA) in youth is increasing in Japan, but very few athletes are reported to be affected with BA. The aim of this study is to analyze pulmonary function test (PFT) in athletes from the aspect of BA retrospectively. METHODS: Medical history questionnaires of 2111 athletes (male: 1549, female: 562) were reviewed. All athletes participated in the institute's athletic test for the first time, from April 2003 through March 2006. Athletes were categorized into three groups; current-BA confirmed and treated by the physician, possible-BA according to the allergic history and/or BA symptoms, and non-BA that is neither of the above two groups. The PFT data were then analyzed. RESULTS: There were 24 current-BA (1.1%), 137 possible-BA (6.5%), and 183 cases with a past history of BA (PH; 8.7%). Percent of predicted forced expiratory volume in 1 second (%FEV1) and of predicted peak expiratory flow rate (%PEF) in current-BA (86.2+/-17.7% and 81.6+/-19.1%, respectively) and possible-BA (84.7+/-14.6% and 81.2+/-17.3%, respectively) were significantly lower than those in non-BA (93.9+/-13.7% and 93.8+/-19.8%, respectively), without any significant difference between current-BA and possible-BA. Athletes with PH show impaired obstructive indices; even in non-BA with PH showed lower %FEV1 (91.3+/-13.9%, p<0.05) and %PEF (86.8+/-17.8%, p<0.001) than non-BA without PH (94.0+/-13.7% and 94.2+/-19.9%, respectively). CONCLUSIONS: The incidence of BA in Japanese athletes may be higher than currently recognized. More intervention is encouraged for the diagnosis of BA, to avoid any fatal asthma during sports by initiating preventive therapy.

DOI： 10.2332/allergolint.09-OA-0098

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

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.

DOI： 10.1111/j.1365-2222.2009.03418.x

Web of Science

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

A 68-year-old man who was given a diagnosis of interstitial pneumonia. Chest computerized tomography (CT) revealed subpleural honeycomb formations and traction bronchiectasis. Three months after the diagnosis of interstitial pneumonia, he noticed neurological symptoms, such as facial spasms, dysphagia, muscle rigidity and muscle cramp, and repeatedly received clonazepam. He was diagnosed with stiff-person syndrome on electromyography when he was hospitalized due to aspiration pneumonia. He has needed continuous rehabilitation due to the progression of neurological symptoms despite the partial efficacy of anti-epilepsy agents. We report a case of interstitial pneumonia with stiff-person syndrome.

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

BACKGROUND: Although it is well established that the incidence of bronchial asthma is higher in the athlete population than in the general population, little information exists about the efficacy of treatment of bronchial asthma in the athlete population. OBJECTIVES: We conducted this study with the objective of determining the efficacy of treatment of bronchial asthma in an athlete population living in Niigata Prefecture, Japan. METHODS: We conducted a retrospective study of bronchial asthma in an athlete population. Athletes diagnosed as having asthma, based on the Global Initiatives for Asthma (GINA) guidelines, who visited the Niigata Institute for Health and Sports Medicine between January 2007 and June 2008 were enrolled in this study. We compared two groups of patients, a group treated with ciclesonide (CIC) alone and another treated with montelukast alone, with the treatment duration lasting at least 3 months in both groups. The CIC or montelukast groups were compared in terms of the clinical symptoms, pulmonary function parameters, and fraction of exhaled nitric oxide (FENO). RESULTS: There were no significant differences in the sex distribution, age, frequency of symptoms, pulmonary function parameters, or other examination data before treatment between the CIC and montelukast groups. The CIC group tended to show better symptom control and to need fewer changes of treatment than the montelukast group. While improvements of the pulmonary function parameters and FENO values were observed in the CIC group, no significant changes of these parameters were observed in the montelukast group. CONCLUSIONS: These data suggest that CIC offers greater promise for the control of asthma than montelukast in the athlete population, although further investigation is required.

DOI： 10.3109/02770900903229693

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Allergology  

BACKGROUND: It is known that a wide variety of factors exacerbate asthma; however, few studies have investigated the factors that exacerbate asthma from a patient's perspective. The aim of this study was to analyze the factors that exacerbate asthma, based on a questionnaire completed by asthma patients in Niigata Prefecture. METHODS: Based on questionnaires given to 3085 patients who visited the medical institutes in the Niigata Prefecture monthly from September through October 2006, groups stratified by sex, age, disease type and disease severity, were analyzed for factors contributing to asthma exacerbation, as described in the guideline of the Japanese Society of Allergology. RESULTS: The leading exacerbating factor chosen by patients was a change in the weather, followed by smoking, allergen exposure, fatigue, stimulants, and air pollutants. Respiratory infection, widely recognized as a critical factor of severe exacerbation, was ranked seventh. Allergen exposure and air pollutants were prominent in younger individuals, whereas respiratory infection tended to be more common in elderly subjects. Allergen exposure, air pollutants, and exercise were significantly more common in atopic-type patients, in contrast with respiratory infection in non-atopic-type patients. According to multiple regression analysis, poor asthma control during the last one year was associated with changes in the weather, whereas the non-atopic disease type was related to exacerbation by respiratory infection. Current smoking was associated with both factors. CONCLUSIONS: Many factors exacerbate asthma, depending on the individual case and his/her background. These data suggest that changes in the weather may be more important factor for patients in asthma exacerbation.

DOI： 10.2332/allergolint.09-OA-0095

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER THORACIC SOC  

Dendritic cells (DCs) are considered to be the most efficient antigen-presenting cells. Intratracheal administration of allergen-pulsed bone marrow-derived dendritic cells (BMDCs) before allergen challenge induces airway hyperresponsiveness (AHR) and inflammation. Ovalbumin (OVA)-pulsed BMDCs from wild-type (WT) mice were transferred into naive WT, CD4(-/-), CD8(-/-), or IL-13(-/-) mice. Two days (short protocol) or 10 days (long protocol) after BMDC transfer, mice were challenged with 1% OVA for 3 days and assayed 2 days later. Transfer of OVA-primed BMDCs into BALB/c or C57BL/6 mice elicited AHR in both protocols. Airway eosinophilia, Th2 cytokines, or goblet cell metaplasia were increased in the long but not short protocol. Lung T cells from both protocols produced Th2 cytokines in response to OVA in vitro. Carboxyfluorescein diacetate succinimidylester-labeled BMDCs were observed in bronchoalveolar lavage (BAL) fluid and lung parenchyma at early time points, and were detected in draining lymph nodes 48 hours after transfer. CD8(-/-) mice developed AHR comparable to WT mice in the short protocol, but decreased levels of AHR, airway eosinophilia, Th2 cytokines in BAL fluid, and goblet cell metaplasia compared with WT mice in the long protocol. CD4(-/-) or IL-13(-/-) mice did not develop AHR or airway inflammation in either protocol. These data suggest that allergen-pulsed BMDCs initiate development of AHR that is dependent initially on CD4(+) T cells, and at later time periods on CD8+ T cells and IL-13. Thus, the timing of allergen challenge after transfer of allergen-pulsed BMDC affects the development of AHR and airway inflammation.

DOI： 10.1165/rcmb.2008-0256OC

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Allergology  

BACKGROUND: Inhaled corticosteroid (ICS) has played an important role in the management of asthma. Although several kinds of ICSs are currently available, there is no established strategy for ICS selection. METHODS: Using the data from the 2004 questionnaire surveys by the Niigata Asthma Treatment Study Group, we analyzed relationships between each patient and the ICS employed on the basis of patient background, asthma control and treatment, and indicated characteristics of ICS selection by the physician. RESULTS: Of 2852 cases, 2279 (79.9%) were ICS users, and 1513 (66.4% of ICS users) were classified as being in the fluticasone propionate (FP) group, 438 (19.2%) in the budesonide (BUD) group, and 240 (10.5%) in the hydrofluoroalkane-beclomethasone (HFA-BDP) group, indicating that FP was a standard ICS in this study. The mean age was significantly lower in the BUD group (52.3+/-18.2 years) and was significantly higher in the HFA-BDP group (59.9+/-17.0 years) than that in the FP group (55.8+/-16.6 years). The proportion of female patients was significantly higher not in the HFA-BDP (46.5%) but in the BUD group (59.0%) than in the FP group (51.1%). These results indicated that BUD was frequently prescribed to young female and HFA-BDP was employed in the elderly patients irrespective of gender compared with FP. CONCLUSIONS: Our study indicates that ICS selection is reasonably adapted to each patient's background at least in the surveyed area. We need to elucidate the characteristics of ICS selection further in the future as new ICS and devices are developed.

DOI： 10.2332/allergolint.08-OA-0077

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Suppressing the abnormalities associated with asthma has been difficult to accomplish using immunotherapy or vaccination once the disease is established. The effector cells necessary for effective immunization/vaccination and immunotherapy of asthma are also not well understood. Therefore, we vaccinated allergen (OVA)-sensitized mice to determine whether therapeutic immunization could suppress airway hyperresponsiveness (AHR) and inflammation and to identify key immune effector cells and cytokines. Mice were immunized with a vaccine comprised of Ag and cationic liposome-DNA complexes (CLDC), a vaccine which has previously been shown to elicit strong CD4(+) and CD8(+) T cell responses and activation of Th1 immunity. We showed that immunization with the OVA-CLDC vaccine significantly suppressed AHR, eosinophilia, goblet cell metaplasia, and Th2 cytokine production. In contrast, immunization with CLDC alone suppressed eosinophilia and Th2 cytokine production, but failed to suppress AHR and goblet cell changes. Using adoptive transfer experiments, we found that suppression of AHR was mediated by Ag-specific CD8(+) T cells and was dependent on IFN-gamma production by the transferred T cells. Thus, we conclude that generation of strong, allergen-specific CD8(+) T cell responses by immunization may be capable of suppressing AHR and allergic airway inflammation, even in previously sensitized and challenged mice.

DOI： 10.4049/jimmunol.0803967

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：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

Web of Science

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

A 63-year-old man was admitted because of dizziness, polydipsia, polyuria, and diminished libido. His brain MRI showed swelling of the pituitary gland. Because of panhypopituitarism suggested by hormonal examination, hydrocortisone, desmopressin and levothyroxine sodium were started as hormone replacement therapy. He was given a clinical diagnosis of central neurosarcoidosis with panhypopituitarism because of the presence of an abnormal lung shadow, positive gallium scintigram in bilateral hilar lymph nodes, negative tuberculin skin test, lymphocytosis and a high CD4/8 ratio in bronchoalveolar lavage fluid. After prednisolone therapy, his lung shadow and pituitary swelling reduced significantly. Anti-diuretic hormones and anterior pituitary hormones tended to increase, and his urine volume also decreased. This case suggested that endocrinological abnormalities in central neurosarcoidosis might be improved by prednisolone therapy even if the initiation of treatment is delayed.

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Dendritic cells (DC) are important APCs that control allergen-induced airway responses by interacting directly with T cells. Leukotriene B(4) (LTB(4)), interacting with its high-affinity receptor, LTB(4) receptor 1 (BLT1), is known to attract and activate leukocytes during inflammation. We have previously shown that BLT1 expression on Ag-primed T cells is required for the development of airway hyperresponsiveness (AHR; Miyahara et al. 2005. Am. J. Respir. Crit. Care Med. 172: 161-167). However, the role for the LTB(4)-BLT1 pathway in DC function in allergen-induced airway responses has not been defined. Bone marrow-derived DCs (BMDC) were generated. Naive BALB/c mice received OVA-pulsed BLT1-deficient (BLT1(-/-)) BMDCs or wild-type BMDCs intratracheally and were then challenged with OVA for 3 days. Airway responses were monitored 48 h after the last allergen challenge. BLT1(-/-) BMDCs showed normal maturation judged from surface expression of CD markers. Compared with recipients of wild-type BMDCs, mice that received BLT1(-/-) BMDCs developed significantly lower AHR to inhaled methacholine, lower goblet cell metaplasia, and eosinophilic infiltration in the airways and decreased levels of Th2 type cytokines in the bronchoalveolar lavage fluid. Migration of BLT1(-/-) BMDCs into peribronchial lymph nodes was significantly impaired compared with BLT1(+/+) BMDCs after intratracheal instillation. These data suggest that BLT1 expression on DCs is required for migration of DCs to regional lymph nodes as well as in the development of AHR and airway inflammation.

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY-ELSEVIER  

BACKGROUND: RNA interference is an endogenous cellular mechanism in which short interfering RNAs (siRNAs) direct the sequence specific degradation of a target mRNA. siRNAs can be synthesized with chemical modifications to increase stability and reduce double-stranded RNA-induced immune responses without affecting their ability to elicit degradation of target mRNA. OBJECTIVES: This study examined the use of chemically modified siRNAs in a mouse model of allergen-induced airway hyperresponsiveness. METHODS: Chemically modified siRNAs were designed and screened in a cell-based reporter assay. The most potent siRNAs were then screened in bone marrow-derived mast cells to demonstrate efficacy in primary cells. RESULTS: A candidate siRNA was formulated and administered to sensitized mice just before airway challenge with allergen. Administration of the siRNA was shown to reduce airway resistance significantly in sensitized and challenged mice by 60%, whereas a control siRNA had no effect. CONCLUSION: These data demonstrate the effectiveness of introducing targeted siRNAs to prevent induction of allergen-induced airway dysfunction and suggest potential therapeutic applications.

DOI： 10.1016/j.jaci.2007.08.029

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATL ACAD SCIENCES  

Naturally occurring Foxp3(+)CD4(+)CD25(+) T cells (nTregs) isolated from lungs of naive mice regulate allergic airway hyperresponsiveness (AHR) and inflammation. Here, we demonstrate the critical requirement for engagement of MHC class I on CD4(+)CD25(+) T cells by CD8 for the functional activation of these nTregs. Suppression of allergen-induced AHR and inflammation by nTregs was abolished in mice treated with anti-CD8. Correspondingly, decreased levels of IL-10 and TGF-beta and increased levels of Th2 cytokines in bronchoalveolar lavage were detected in these treated mice. Similarly, nTregs isolated from beta2m(-/-) mice or from mice treated with anti-MHC I antibody in vitro before intratracheal transfer failed to modulate AHR or inflammation. Coculture of nTregs with CD8(+) T cells increased IL-10 and TGF-beta. Addition of anti-MHC I or anti-CD8 reduced IL-10 and TGF-beta. These results demonstrate that functional activation of nTregs requires the interaction between MHC I on CD4(+)CD25(+) T cells and CD8.

DOI： 10.1073/pnas.0706765104

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

CD4+ T cells, particularly Th2 cells, play a pivotal role in allergic airway inflammation. However, the requirements for interactions between CD4+ and CD8+ T cells in airway allergic inflammation have not been delineated. Sensitized and challenged OT-1 mice in which CD8+ T cells expressing the transgene for the OVA(257-264) peptide (SIINFEKL) failed to develop airway hyperresponsiveness (AHR), airway eosinophilia, Th2 cytokine elevation, or goblet cell metaplasia. OT-1 mice that received naive CD4+IL-4+ T cells but not CD4+IL-4- T cells before sensitization developed all of these responses to the same degree as wild-type mice. Moreover, recipients of CD4+IL-4+ T cells developed significant increases in the number of CD8+IL-13+ T cells in the lung, whereas sensitized OT-1 mice that received primed CD4+ T cells just before challenge failed to develop these responses. Sensitized CD8-deficient mice that received CD8+ T cells from OT-1 mice that received naive CD4+ T cells before sensitization increased AHR and eosinophil numbers in bronchoalveolar lavage fluid when challenged with allergen. In contrast, sensitized CD8-deficient mice receiving CD8+ T cells from OT-1 mice without CD4+ T cells developed reduced AHR and eosinophil numbers in bronchoalveolar lavage fluid when challenged. These data suggest that interactions between CD4+ and CD8+ T cells, in part through IL-4 during the sensitization phase, are essential to the development of CD8+IL-13+ T cell-dependent AHR and airway allergic inflammation.

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Allergology  

BACKGROUND: Perimenstrual asthma (PMA) has been documented in 30% to 40% of asthmatic women; the characteristics of PMA have also been well described. However, there have been few epidemiological investigations of PMA in practice. In this study, we analyzed PMA based on a questionnaire survey carried out in Japan and compared the results with those of studies reported previously. METHODS: For 8 weeks from September through October 2004, a questionnaire survey was administered to patients with bronchial asthma and their attending physicians. The questionnaire surveyed asthma control, asthma-related emergencies and satisfaction in daily life. The attending physicians were questioned about patient profiles and medications. All female patients who were menstruating during the survey period and who were known to have asthma exacerbation related to menstruation were allocated to the PMA group; those who were not were allocated to the non-PMA group. RESULTS: The rate of PMA in female patients who were menstruating during the survey period was 11.3% in this study. Characteristic features of the PMA group (n = 54) included more severe disease, worsened disease control and more aggressive patient management, including increased oral corticosteroid use compared with the non-PMA group. The rates of emergency episodes in the PMA group were higher than in the non-PMA group. There was a significant increase in aspirin intolerant asthma (AIA, 25.5%) in the PMA group compared with the non-PMA group (8.4%). CONCLUSIONS: Attention should be paid to the lack of knowledge regarding PMA in patients with asthma in actual clinical settings. The low rate of PMA reported in this study may be due to the study method using self-reports of PMA by patients without sufficient knowledge, and may not be an accurate representation of the actual incidence of the disease. The clinical similarity of PMA to AIA in this study may also provide a new insight into the mechanism of PMA.

DOI： 10.2332/allergolint.O-06-475

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER THORACIC SOC  

RATIONALE: Arhgef1 is an intracellular protein, expressed by hematopoietic cells, that regulates signaling by both G protein-coupled receptors and RhoA, and, consequently, is required for appropriate migration and adhesion of diverse leukocyte populations. OBJECTIVES: To evaluate a possible contribution for Arhgef1 in the development of airway inflammation and airway hyperreactivity. METHODS: Arhgef1-deficient (Arhgef1-/-) and wild-type (WT) mice were sensitized and airway challenged, followed by measurement of airway responsiveness to inhaled methacholine. Inflammation was assessed by several parameters that included flow cytometric analysis and histology. Arhgef1-deficient recipients were reconstituted with WT T lymphocytes before sensitization and challenge, and again measured for airway responsiveness and inflammation. Cytokine production in response to specific antigen was measured in cultures of isolated leukocytes from lung and spleen and compared with the levels generated in lung and spleen explant cultures. MEASUREMENTS AND MAIN RESULTS: Arhgef1-/- mice display significantly reduced airway hyperreactivity, Th2 cytokine production, and lung inflammation, despite intact systemic immunity. After airway challenge of Arhgef1-/- mice, antigen-specific T cells were present in mutant lungs, but were found to interact with CD11c+ cells at a significantly reduced frequency. Adoptive transfer of WT T cells into Arhgef1-/- mice restored airway hyperreactivity and inflammation. CONCLUSIONS: These data demonstrate that T cells depend on Arhgef1 to promote lung inflammation. Moreover, a deficiency in Arhgef1 results in reduced T cell-CD11c+ antigen-presenting cell interaction, and likely underscores the inability of Arhgef1-/- mice to mount an adaptive immune response to airway challenge.

DOI： 10.1164/rccm.200702-270OC

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY-ELSEVIER  

BACKGROUND: IL-10 affects dendritic cell (DC) function, but the effects on airway hyperresponsiveness (AHR) and inflammation are not defined. OBJECTIVE: We sought to determine the importance of IL-10 in regulating DC function in allergen-induced AHR and airway inflammation. METHODS: DCs were generated from bone marrow in the presence or absence of IL-10. In vivo IL-10-treated DCs from IL-10(+/+) and IL-10(-/-) donors pulsed with ovalbumin (OVA) were transferred to naive or sensitized mice before challenge. In recipient mice AHR, cytokine levels, cell composition of bronchoalveolar lavage (BAL) fluid, and lung histology were monitored. RESULTS: In vitro, IL-10-treated DCs expressed lower levels of CD11c, CD80, and CD86; expressed lower levels of IL-12; and suppressed T(H)2 cytokine production. In vivo, after transfer of OVA-pulsed IL-10-treated DCs, naive mice did not have AHR, airway eosinophilia, T(H)2 cytokine increase in BAL fluid, or goblet cell metaplasia when challenged, and in sensitized and challenged mice IL-10-treated DCs suppressed these responses. Levels of IL-10 in BAL fluid and numbers of lung CD4(+)IL-10(+) T cells were increased in mice that received OVA-pulsed IL-10-treated DCs. Transfer of IL-10-treated DCs from IL-10-deficient mice were ineffective in suppressing the responses in sensitized and challenged mice. CONCLUSIONS: These data demonstrate that IL-10-treated DCs are potent suppressors of the development of AHR, inflammation, and T(H)2 cytokine production; these regulatory functions are at least in part through the induction of endogenous (DC) production of IL-10. CLINICAL IMPLICATIONS: Modification of DC function by IL-10 can attenuate lung allergic responses, including the development of AHR.

DOI： 10.1016/j.jaci.2007.01.039

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER THORACIC SOC  

IL-18 is known to induce IFN-gamma production, which is enhanced when combined with IL-2. In the present study, we investigated whether the combination of exogenous IL-2 and IL-18 alters airway hyperresponsiveness (AHR) and airway inflammation. Sensitized mice exposed to ovalbumin (OVA) challenge developed AHR, inflammatory cells in the bronchoalveolar lavage (BAL) fluid, and increases in levels of Th2 cytokines and goblet cell numbers. The combination of IL-2 and IL-18, but neither alone, prevented these changes while increasing levels of IL-12 and IFN-gamma. The combination of IL-2 and IL-18 was ineffective in IFN-gamma-deficient and signal transducer and activator of transcription (STAT)4-deficient mice. Flow cytometry analysis showed significant increases in numbers of IFN-gamma-positive natural killer (NK) cells in the lung after treatment with the combination therapy, and transfer of lung NK cells isolated from sensitized and challenged mice treated with the combination significantly suppressed AHR and BAL eosinophilia. These data demonstrate that the combination of IL-2 and IL-18 prevents AHR and airway inflammation, likely through IL-12-mediated induction of IFN-gamma production in NK cells.

DOI： 10.1165/rcmb.2006-0231OC

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Peripheral tolerance to allergens is mediated in large part by the naturally occurring lung CD4(+)CD25(+) T cells, but their effects on allergen-induced airway responsiveness have not been well defined. Intratracheal, but not i.v., administration of naive lung CD4(+)CD25(+) T cells before allergen challenge of sensitized mice, similar to the administration of the combination of rIL-10 and rTGF-beta, resulted in reduced airway hyperresponsiveness (AHR) and inflammation, lower levels of Th2 cytokines, higher levels of IL-10 and TGF-beta, and less severe lung histopathology. Significantly, CD4(+)CD25(+) T cells isolated from IL-10(-/-) mice had no effect on AHR and inflammation, but when incubated with rIL-10 before transfer, suppressed AHR, and inflammation, and was associated with elevated levels of bronchoalveolar lavage TGF-beta levels. By analogy, anti-TGF-beta treatment reduced regulatory T cell activity. These data identify naturally occurring lung CD4(+)CD25(+) T cells as capable of regulating lung allergic responses in an IL-10- and TGF-beta-dependent manner.

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

The FcR common gamma-chain (FcRgamma) is an essential component of the receptors FcepsilonRI, FcgammaRI, and FcgammaRIII, which are expressed on many inflammatory cell types. The role of these receptors in the initiation or maintenance of allergic inflammation has not been well defined. FcRgamma-deficient (FcRgamma(-/-)) and control (wild-type (WT)) mice were sensitized and subsequently challenged with OVA. Following sensitization and challenge to OVA, FcRgamma-deficient (FcRgamma(-/-)) mice developed comparable levels of IgE and IgG1 as WT mice. However, numbers of eosinophils, levels of IL-5, IL-13, and eotaxin in bronchoalveolar lavage fluid, and mononuclear cell (MNC) proliferative responses to OVA were significantly reduced, as was airway hyperresponsiveness (AHR) to inhaled methacholine. Reconstitution of FcRgamma(-/-) mice with whole spleen MNC from WT mice before sensitization restored development of AHR and the numbers of eosinophils in bronchoalveolar lavage fluid; reconstitution after sensitization but before OVA challenge only partially restored these responses. These responses were also restored when FcRgamma(-/-) mice received T cell-depleted MNC, T and B cell-depleted MNC, or bone marrow-derived dendritic cells before sensitization from FcR(+/+) or FcgammaRIII-deficient but not FcRgamma(-/-) mice. The expression levels of FcgammaRIV on bone marrow-derived dendritic cells from FcR(+/+) mice were found to be low. These results demonstrate that expression of FcRgamma, most likely FcgammaRI, on APCs is important during the sensitization phase for the development of allergic airway inflammation and AHR.

Web of Science

PubMed

researchmap

Language：Japanese   Publisher：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.56.1082_2

CiNii Article

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY-ELSEVIER  

BACKGROUND: The pathophysiology of the early- and late-phase nasal response to allergen challenge is not completely defined. Recent technical advances enable direct monitoring of these responses in mice. OBJECTIVE: IL-13 is detected in the nasal membranes of both human beings and mice with allergic rhinitis, but its role in disease pathogenesis is unclear. We measured early and late nasal allergic responses after treatment with soluble IL-13Ralpha2-IgG fusion protein (sIL-13Ralpha2-Fc), and in IL-13-deficient mice (IL-13(-/-)). METHODS: IL-13(-/-) mice (BALB/c background) and wild-type mice were sensitized to ovalbumin by intraperitoneal injection and then challenged intranasally with ovalbumin without sedation. The sIL-13Ralpha2-Fc or control human IgG was administered by intraperitoneal (i.p.) injection 24 hours and 1 hour before each ovalbumin challenge. Early nasal responses after the 4th ovalbumin challenge and late nasal responses 24 hours after the 6th ovalbumin challenge were assessed. RESULTS: Sensitized/challenged wild-type mice treated with sIL-13Ralpha2-Fc or IL-13(-/-) mice demonstrated significantly reduced late nasal responses in face of persistent nasal tissue eosinophilia; the early nasal response was little affected by targeting IL-13. Goblet cell hyperplasia was not detected in nasal membranes. CONCLUSION: The data indicate that IL-13 is a major contributor to the development of a late nasal response with little influence on the early response, and without affecting nasal eosinophilic inflammation. Inhibition of IL-13 may have an important therapeutic application in preventing the persistent nasal blockage in allergic rhinitis. CLINICAL IMPLICATIONS: Current therapies for allergic rhinitis may not take into account the important differences in the pathophysiology of the early and late responses and the important role of IL-13 in sustaining chronic nasal congestion and obstruction.

DOI： 10.1016/j.jaci.2006.06.014

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER THORACIC SOC  

RANTES (CC chemokine ligand 5) contributes to airway inflammation through accumulation of eosinophils, but the exact role of RANTES (CCL5) is not defined. C57BL/6 mice, sensitized by injection of ovalbumin (OVA) on Days 1 and 14, were challenged with OVA on Days 28, 29, and 30 (3 challenges, short-term-challenge model) or on Days 28, 29, 30, 36, 40, 44, and 48 (7 challenges, repeated-challenge model) and evaluated 48 h later. Anti-mouse RANTES was given intravenously, and recombinant mouse RANTES or PBS was given intratracheally. These reagents were given on Days 28, 29, and 30 in the short-term-challenge study and on Days 44 and 48 in the repeated-challenge study. After short-term challenge, there were no effects after administration of anti-RANTES or RANTES. In the repeated-challenge study, although control mice showed a decrease in airway hyperresponsiveness, administration of anti-RANTES sustained and enhanced airway hyperresponsiveness and increased goblet cell numbers. In contrast, administration of RANTES normalized airway function but reduced goblet cell numbers. IL-12 and IFN-gamma levels in BAL decreased in the anti-RANTES group and increased in the RANTES group. IFN-gamma-producing CD4 T cells in lung, and IFN-gamma production from lung T cells in response to OVA in the anti-RANTES group, were significantly decreased but were increased in the RANTES group. Anti-IFN-gamma, administered with RANTES, decreased the effects of RANTES on AHR after repeated challenge. These data indicate that RANTES plays a role in the regulation of airway function after repeated allergen challenge, in part through modulation of levels of IFN-gamma and IL-12.

DOI： 10.1165/rcmb.2005-0394OC

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER THORACIC SOC  

We evaluated the role of Syk, using an inhibitor, on allergen-induced airway hyperresponsiveness (AHR) and airway inflammation in a system shown to be B cell- and mast cell-independent. Sensitization of BALB/c mice with ovalbumin (OVA) and alum after three consecutive OVA challenges resulted in AHR to inhaled methacholine and airway inflammation. The Syk inhibitor R406 (30 mg/kg, administered orally, twice daily) prevented the development of AHR, increases in eosinophils and lymphocytes and IL-13 levels in bronchoalveolar lavage (BAL) fluid, and goblet cell metaplasia when administered after sensitization and before challenge with OVA. Levels of IL-4, IL-5, and IFN-gamma in BAL fluid and allergen-specific antibody levels in serum were not affected by treatment. Because many of these responses may be influenced by dendritic cell function, we investigated the effect of R406 on bone marrow-derived dendritic cell (BMDC) function. Co-culture of BMDC with immune complexes of OVA and IgG anti-OVA together with OVA-sensitized spleen mononuclear cells resulted in increases in IL-13 production. IL-13 production was inhibited if the BMDCs were pretreated with the Syk inhibitor. Intratracheal transfer of immune complex-pulsed BMDCs (but not nonpulsed BMDCs) to naive mice before airway allergen challenge induced the development of AHR and increases in BAL eosinophils and lymphocytes. All of these responses were inhibited if the transferred BMDCs were pretreated with R406. These results demonstrate that Syk inhibition prevents allergen-induced AHR and airway inflammation after systemic sensitization and challenge, at least in part through alteration of DC function.

DOI： 10.1165/rcmb.2005-0298OC

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER THORACIC SOC  

RATIONALE: There is conflicting information about the development and resolution of airway inflammation and airway hyperresponsiveness (AHR) after repeated airway exposure to allergen in sensitized mice. METHODS: Sensitized BALB/c and C57BL/6 mice were exposed to repeated allergen challenge on 3, 7, or 11 occasions. Airway function in response to inhaled methacholine was monitored; bronchoalveolar lavage fluid inflammatory cells were counted; and goblet cell metaplasia, peribronchial fibrosis, and smooth muscle hypertrophy were quantitated on tissue sections. Bone marrow-derived dendritic cells were generated after differentiation of bone marrow cells in the presence of growth factors. RESULTS: Sensitization to ovalbumin (OVA) in alum, followed by three airway exposures to OVA, induced lung eosinophilia, goblet cell metaplasia, mild peribronchial fibrosis, and peribronchial smooth muscle hypertrophy; increased levels of interleukin (IL)-4, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor, transforming growth factor-beta(1), eotaxin-1, RANTES (regulated on activation, normal T-cell expressed and secreted), and OVA-specific IgG1 and IgE; and resulted in AHR. After seven airway challenges, development of AHR was markedly decreased as was the production of IL-4, IL-5, and IL-13. Levels of IL-10 in both strains and the level of IL-12 in BALB/c mice increased. After 11 challenges, airway eosinophilia and peribronchial fibrosis further declined and the cytokine and chemokine profiles continued to change. At this time point, the number of myeloid dendritic cells and expression of CD80 and CD86 in lungs were decreased compared with three challenges. After 11 challenges, intratracheal instillation of bone marrow-derived dendritic cells restored AHR and airway eosinophilia. CONCLUSIONS: These data suggest that repeated allergen exposure leads to progressive decreases in AHR and allergic inflammation, through decreases in myeloid dendritic cell numbers.

DOI： 10.1164/rccm.200505-783OC

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Allergology  

<b>Background:</b> Because bronchial inflammation was recognized as a basic component of bronchial asthma, the strategy for asthma management has changed in the last two decades. In Japan there are few clinico-epidemiological reports of changes in the management of bronchial asthma in actual practice.<br> In this study, we analyzed practical asthma management in Japan, and examined changes in the prevalence of asthma medication and relation between these changes and the level of asthma control and management.<br> <b>Methods:</b> From 1998 to 2002, questionnaires on asthma control, asthma related emergent episodes and satisfaction in daily life. Questionnaires were distributed to adult asthmatic patients. Questionnaires about the patients' profiles and medication were also given to the patients' doctors.<br> <b>Results:</b> The total number of patient responders was approximately 2500—3300 per year. The rate of peak flow meter (PEFM) use was under approximately only 40% and plateaued from 2000 to 2002. The percentage of inhaled corticosteroid use and leukotriene receptor antagonist use increased, from 62.0%, 27.2% to 77.4%, 40.6% respectively. Indicators for asthma control, including presence of attacks and sleep disturbance, were significantly improved. Limited to PEFM users, there was an improvement hospitalization, ambulance use or ED visits and in satisfaction in daily life based on a Quality of Life (QOL) indicator.<br> <b>Conclusions:</b> These results indicate that the prevalence of anti-inflammatory agents, including inhaled corticosteroids and leukotriene receptor antagonist, was associated with an adequate improvement in asthma control in clinical practice. In asthma management in clinical practice, prevalence of PEFM may play an important role in the improvement of asthma related emergent episodes or QOL.<br>

DOI： 10.2332/allergolint.54.555

CiNii Article

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING  

OBJECTIVE: Prevention of deaths due to asthma is one of the most important issues in asthma management. However, there are few epidemiological studies of asthma deaths in Japan. METHODOLOGY: Over an 8-week period in Niigata Prefecture, Japan, a questionnaire on asthma control and emergency episodes was administered to adult asthmatic patients. A questionnaire was also given to the patients' physicians to obtain further clinical information. Patients who became unconscious during episodes of asthma, or who required intubation and ventilation, were allocated to a near-fatal asthma group (NFA). Patients who did not fulfill these criteria were allocated to the non-NFA group. The NFA group was divided into two subgroups, based on the date of their last NFA episode (old NFA>or= 5 years and recent NFA<4 years). RESULTS: Characteristic features of the NFA group included severe disease (23.1%vs 7.6%) with more aggressive patient management, including inhaled corticosteroid use (84.3%vs 72.0%). Multiple regression analysis confirmed that aspirin-intolerant asthma (AIA) was strongly associated with NFA. There was no difference in the incidence of AIA between the recent and old NFA patients. This suggests the incidence of AIA in NFA did not improve over time. CONCLUSIONS: A history of AIA may be a useful indicator of potential NFA and allow preventative methods to be introduced. It is therefore important to obtain a history of AIA and to be aware of the risk of NSAID administration to these patients.

DOI： 10.1111/j.1440-1843.2005.00740.x

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER THORACIC SOC  

RATIONALE: Leukotriene B4 (LTB4) is a rapidly synthesized, early leukocyte chemoattractant that signals via its cell surface receptor, leukotriene B4 receptor 1 (BLT1), to attract and activate leukocytes during inflammation. A role for the LTB4-BLT1 pathway in allergen-induced airway hyperresponsiveness and inflammation is not well defined. OBJECTIVES: To define the role of the LTB4 receptor (BLT1) in the development of airway inflammation and altered airway function. METHODS: BLT1-deficient (BLT1 -/-) mice and wild-type mice were sensitized to ovalbumin by intraperitoneal injection and then challenged with ovalbumin via the airways. Airway responsiveness to inhaled methacholine, bronchoalveolar lavage fluid cell composition and cytokine levels, and lung inflammation and goblet cell hyperplasia were assessed. RESULTS: Compared with wild-type mice, BLT1 -/- mice developed significantly lower airway responsiveness to inhaled methacholine, lower goblet cell hyperplasia in the airways, and decreased interleukin (IL)-13 production both in vivo, in the bronchoalveolar lavage fluid, and in vitro, after antigen stimulation of lung cells in culture. Intracellular cytokine staining of lung cells revealed that bronchoalveolar lavage IL-13 levels and numbers of IL-13(+)/CD4+ and IL-13(+)/CD8+ T cells were also reduced in BLT1 -/- mice. Reconstitution of sensitized and challenged BLT1 -/- mice with allergen-sensitized BLT1 +/+ T cells fully restored the development of airway hyperresponsiveness. In contrast, transfer of naive T cells failed to do so. CONCLUSION: These data suggest that BLT1 expression on primed T cells is required for the full development of airway hyperresponsiveness, which appears to be associated with IL-13 production in these cells.

DOI： 10.1164/rccm.200502-205OC

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Recent studies in both human and rodents have indicated that in addition to CD4+ T cells, CD8+ T cells play an important role in allergic inflammation. We previously demonstrated that allergen-sensitized and -challenged CD8-deficient (CD8-/-) mice develop significantly lower airway hyperresponsiveness (AHR), eosinophilic inflammation, and IL-13 levels in bronchoalveolar lavage fluid compared with wild-type mice, and that all these responses were restored by adoptive transfer of in vivo-primed CD8+ T cells or in vitro-generated effector CD8+ T cells (T(EFF)). Recently, leukotriene B4 and its high affinity receptor, BLT1, have been shown to mediate in vitro-generated T(EFF) recruitment into inflamed tissues. In this study we investigated whether BLT1 is essential for the development of CD8+ T cell-mediated allergic AHR and inflammation. Adoptive transfer of in vivo-primed BLT1+/+, but not BLT1-/-, CD8+ T cells into sensitized and challenged CD8-/- mice restored AHR, eosinophilic inflammation, and IL-13 levels. Moreover, when adoptively transferred into sensitized CD8-/- mice, in vitro-generated BLT1+/+, but not BLT1-/-, T(EFF) accumulated in the lung and mediated these altered airway responses to allergen challenge. These data are the first to show both a functional and an essential role for BLT1 in allergen-mediated CD8+ T(EFF) recruitment into the lung and development of AHR and airway inflammation.

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.14442/general2000.5.7

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing  

Background: It is very important to use anti-inflammatory agents, including inhaled corticosteroids, in the management of asthma because bronchial inflammation is a fundamental component of bronchial asthma. Although management according to this strategy is recommended in several countries, the actual situation of asthmatic patients in Japan is poorly understood. To clarify the actual management of asthma in Japan, the present study was undertaken. Methods: In 1998, for 8 weeks from September through to October, questionnaires on asthma control and satisfaction in daily life were given to asthmatic patients. In addition, questionnaires regarding patient profiles and medication were given to the patients' physicians. The same questionnaires were repeated in 1999 and 2000. The information obtained from the same patients and their physicians who responded in each of the three years was used for analysis. Results: We analyzed 840 cases. During this period, over 80% of patients used oral theophylline, although the percentage of patients using inhaled steroids and leukotriene receptor antagonists increased from 67.0 and 29.8% in 1998 to 75.1 and 34.2%, respectively, in 2000. Asthma control (including the presence of attacks and self-evaluation by each patient), asthma-related symptoms and sleep disturbance improved significantly. However, there was no improvement in satisfaction in daily life of asthmatic patients surveyed. Multiple-regression analysis revealed that self-evaluation of asthma control by each patient was significantly related to improvement in satisfaction in daily life. Conclusion: These results indicate that anti-inflammatory agents, including inhaled corticosteroids and leukotriene receptor antagonists, contributed to improved asthma control, whereas oral theophylline is characteristically used in Niigata Prefecture, Japan. However, not all asthma-related problems, such as satisfaction in daily life, improved and self-evaluation of asthma control by patients may play a key role in improving their satisfaction in daily life.

DOI： 10.1111/j.1440-1592.2004.00311.x

Scopus

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：OCEAN SIDE PUBLICATIONS INC  

Recent studies have shown that fluticasone propionate (FP) was more effective than beclomethasone dipropionate (BDP) inhalation even at a dose reduced by twofold or more in the treatment of bronchial asthma. Here, we,further compared the effectiveness of FP and BDP, including rates of drug compliance. Forty-two symptomatic patients were treated by BDP (1000+/-345; mean+/-SD; mug/day) for 8 weeks, followed by FP at one-half the respective dose, and peak expiratory flow and forced expiratory volume in I second were investigated. In addition, the patients were asked about drug compliance and factors related to compliance (expressed using a visual analogue scale). Significant increases of peak expiratory flow (from 316+/-96 L/minute to 345+/-86 L/minute) and forced expiratory volume in 1 second (from 1.7+/-0.5 L to 1.9+/-0.4 L) were found. Furthermore, significantly higher scores were obtained for compliance and various factors related to compliance. These data indicate that FP is more effective than a twofold higher dosage of BDP and that better compliance with the use of FP, probably because of improved various factors associated with FP compliance, contributes to FP efficacy.

Web of Science

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing  

Background: Because the mean lifespan is increasing and the percentage of elderly people among the population as a whole is also increasing, the management of elderly bronchial asthma patients will be an important issue in medicine in the future. In the present study, based on questionnaires given to 3224 asthmatic patients in Niigata Prefecture, the characteristics, management and circumstances of elderly asthmatic patients were investigated. Methods: Questionnaires were completed by asthmatic patients and their physicians in participating institutions within Niigata Prefecture from September to October 1999. Patients more than 65 years of age were defined as elderly asthmatic patients and a comparison was made between these patients and younger asthmatic patients who were less than 64 years of age and were used as a control group. Results: In the classification of bronchial asthma, a greater frequency of infectious and mixed-type bronchial asthma was found in the elderly, whereas the use of peak flow meters was lower in this group. Significant differences were found for both selfevaluation of the condition of the asthma and satisfaction with daily life between the two age groups. A lower incidence of ambulance use, emergency room visits and use of inhaled steroids was observed in elderly patients, although the incidence of hospitalization and use of oral steroids was higher. The discrepancy between objective and subjective evaluation of asthma control, the incidence of the use of both inhaled and oral steroids and the low use of peak flow meters were problematic in the elderly. Conclusions: Based on sufficient consideration of the problems specifically related to elderly asthmatic patients, adequate education and careful management of asthma in this group are required, and the accumulation of these steps will result in the achievement of the guidelines final goals.

DOI： 10.1046/j.1440-1592.2002.00270.x

Scopus

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER-VERLAG  

Eosinophilic bronchitis is an essential component of bronchial asthma, and eosinophils play an important role. We studied the effect of eosinophils on cell surface plasmin generation by bronchial epithelial cells, because plasmin is thought to be involved in bronchial tissue repair/remodeling by means of fibrinolysis and the activation of proteases such as matrix metalloproteases. Plasmin was generated from exogenous plasminogen on the cell surface of cultured bronchial epithelial cells, NCI-H292. Transforming growth factor beta (TGF-beta) treatment resulted in reduced cell surface plasmin generation and a large increase in plasminogen activator inhibitor-type 1 (PAI-1) antigen production in NCI-H292 cells, whereas no conspicuous effects were observed with IL-1 beta and TNF alpha treatment (regulators in pulmonary epithelial cells). On the other hand, this cell surface plasmin generation was reduced by co-incubation with Eol-1, an eosinophil cell line. The addition of TGF-beta antisense and anti-TGF-beta antibodies attenuated this adverse effect of Eol-1 cell co-incubation. These data suggest that eosinophils play an inhibitory role on cell surface plasmin generation by bronchial epithelial cells by means of the up-regulation of PAI-1 expression induced by TGF-beta. Therefore, the accumulation of eosinophils in bronchial walls is thought to be involved in bronchial tissue repair/remodeling in asthma through this protease network.

DOI： 10.1007/s004080000042

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：MUNKSGAARD INT PUBL LTD  

In humans, the numbers of erythrocytes and granulocytes, but not that of lymphocytes, tend to increase in parallel. To determine the mechanism, we investigated how the administration of erythropoietin induces the expansion of erythroid cells and other lineage cells in the bone marrow, liver, and other organs of mice. When mice were injected twice (days 1 and 2) with erythropoietin at a dose of 20 or 200 IU/day/ mouse, a prominent expansion of TER 19+ (erythroid cells) and Gr-1high cells (granulocytes) occurred in the liver, spleen, and bone marrow day 3 after the initial injection. On the other hand, lymphoid cells, including NK cells, extrathymic T cells, and conventional T cells, did not expand. In parallel with the expansion of erythroid cells and granulocytes, the levels of c-kit(+)Lin- cells increased in the liver and bone marrow. Despite the increase in the proportion of c-kit(+) Lin(-) cells, the generation of lymphocytes (e.g., T cells) decreased when such bone marrow cells were injected to scid mice. These results suggest that erythropoietin has the ability to induce the expansion of not only erythroid cells but also granulocytes in the liver, spleen, and bone marrow. Furthermore, c-kit+ progenitors which may commit themselves to erythroid and myeloid cells, but not to lymphoid cells, were also activated in the liver and bone marrow of mice treated with erythropoietin.

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMEDICAL RESEARCH PRESS LTD  

Mice were treated with Ubenimex, which is clinically used as an immunopotentiator for patients with acute myelogenic leukemia, to examine how this drug modulates the immune system. Ubenimex (0.1 or 1.0 mg/day/mouse) was orally administered for a week and the phenotype of leukocytes in the liver, spleen, thymus, and bone marrow was analyzed by immunofluorescence tests. The proportion and number of extrathymic T cells (i.e., IL-2R beta(+)CD3(int)) and NK cells (i.e, IL-2 beta(+)CD3(-)) increased in the liver, while those of granulocytes (i.e., Mac-1(+)Gr-1(+)) increased in the bone marrow of mice treated with Ubenimex. In parallel with this numerical increase, the cytotoxicity of extrathymic T cells and NK cells in the liver and the level of Ca2+ influx from granulocytes in the bone marrow were also augmented. These results help elucidate the mechanisms underlying the immunopotentiation ascribed to Ubenimex.

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE LTD  

Both MRL-lpr/lpr (lpr) and BXSB mice fall victim to autoimmune disease as a function of age. To combine their properties, brother-sister mating of (female lpr x male BXSB)F1 mice was done. Mice for mating were selected according to indicators of early onset of glomerulonephritis and subsequent early death (i.e., EOD). This mating was continued for more than 16 generations. The EOD mice thus established had homozygous H-2k/k, lpr/lpr, and possible yaa/- (in the case of males). The average life span of males was 83 days while that of females was 126 days. After 12 weeks of age, the majority (> 80%) of male EOD mice were characterized by the abnormality of urine due to glomerulonephritis. We then characterized how glomerulonephritis was evoked, especially in terms of expanding lymphocyte subsets in various immune organs. Similar to the case of parental lpr mice, the major expanding cells were CD4-8-B220+ TCRint cells in the immune organs and kidney. In addition, myeloid cells were found to infiltrate the kidney. This massive infiltration of both TCRint cells and myeloid cells might be responsible for the onset of acute glomerulonephritis. Even after more than 50 generations, these EOD mice still carry both lpr and yaa genes. These results suggest that EOD mice might be a very useful tool for the study of acute lupus glomerulonephritis which is evoked by the genetic abnormalities.

DOI： 10.1046/j.1365-2249.1999.00847.x

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC  

It is known that ALY/Nsc Jcl-aly/aly (aly/aly) mice that congenitally lack lymph nodes fall victim to Sjögren syndrome as a function of age. We investigated how TCRint cells of extrathymic origin and TCRhigh cells of thymic origin are distributed in various organs of these mice. Although the distribution of T-cell subsets was not different between control aly/+ and aly/aly mice in youth in any of the tested organs, the proportion of TCRint cells in the liver and spleen of aly/aly mice increased with aging. Usually, TCRint cells in the liver comprise a half-and-half mixture of a NK1. 1(+) subset (i.e., NKT cells) and a NK1.1(-) subset. In constrast, almost all expanding TCRint cells in various immune organs of aly/aly mice were found to be NK1.1(-). A large proportion of lymphocytes, including NK cells and TCRint cells, were also present in the salivary glands of aly/aly mice. Interestingly, these TCRint cells in the salivary glands contained an NK1.1(+) subset (i.e., NKT cells) that used an invariant chain of Valpha14Jalpha281 for TCRalphabeta (>50%). Moreover, gammadeltaT cells that used Vgamma 1, 2, 4/Vdelta 1, 4, 6 mRNAs, different from those of gammadeltaT cells in the liver and intestine, were abundant. Possibly reflecting the in situ generation of these T cells in the salivary glands, the expression of RAG-2 mRNA was evident by the RT-RCR method. These results suggest that (i) inflammatory lymphocytes that evoke Sjögren syndrome in aly/aly mice are NK cells or TCRint cells (both NK1.1(+) and NK1.1(-) subsets) and (ii) TCRint cells in the salivary glands might be generated in situ.

DOI： 10.1006/cimm.1998.1450

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE LTD  

The appendix as well as the small intestine have recently been found to carry c-kit+ stem cells which give rise to extrathymic T cells. In this study, the properties of c-kit+ stem cells in the appendix of mice were further characterized. When appendix mononuclear cells (MNC) were cultured in the presence of stem cell factor, interleukin-3, interleukin-6 and erythropoietin on a methylcellulose culture plate, the population of c-kitdull Lin- and that of c-kithi Lin- cells expanded. Morphological study revealed that these c-kithi Lin- cells were basophilic granular cells (possibly mast cells). Both populations of cultured appendix MNC were then injected into severe combined immunodeficient mice or cultured with Tst-4 thymic stroma cells. These in vivo and in vitro studies demonstrated that c-kitdull Lin- cells were oligopotent haemopoietic progenitor cells which gave rise to extrathymic T cells, while c-kithi Lin- cells lacked haemopoietic progenitor cell activity. In contrast to c-kit+ stem cells in the bone marrow, those in the appendix did not give rise to myeloid cells and conventional thymic T cells under any of the conditions tested. The present results suggest that the appendix primarily comprises c-kit+ cells which give rise to basophilic granular cells and extrathymic T cells and that such c-kit+ cells have the ability to replicate themselves in culture in vitro.

DOI： 10.1046/j.1365-2567.1999.00686.x

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE LTD  

A particular T cell population expressing NK cell markers, CD56 and CD57, exists in humans. Many CD56+ T and CD57+ T cells (i.e. NK T cells) exist in the liver and increase in number in the blood with ageing. They may be a human counterpart of extrathymic T cells, similar to NK1.1+ CD3int cells seen in mice. We investigate here the existence of such NK T cells in human cord blood and the in vitro expansion of these cells by the stimulation of human recombinant IL-2 (rIL-2). There were very small populations (< 1.0%) of CD56+ T cells, CD57+ T cells, and gamma delta T cells in cord blood. However, all of these populations increased in number after birth and with ageing. When lymphocytes in cord blood were cultured with rIL-2 (100 U/ml) for 14 days, CD56+ T cells expanded up to 25% of T cells. CD57+ T cells were never expanded by these in vitro cultures. The expansion of gamma delta T cells (mainly V gamma9- nonadult type) also occurred in the in vitro culture. A considerable proportion of CD56+ T cells was found to use V alpha24 (i.e. equivalent to invariant V alpha14 chain used by murine NK T cells) for TCR alpha beta. These results suggest that neonatal blood contains only a few NK T cells but CD56+ NK T cells and gamma delta T cells are able to expand in vitro.

DOI： 10.1046/j.1365-2249.1998.00645.x

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC  

Estrogen was administered to B6 (NK1.1+ strain), BALB/c (Mls-1b2a, V beta 3+ cells being forbidden clone), or (B6 x BALB/c) F1 mice (1 mg/mouse). On days 3 and 10, the number of cells yielded by the liver doubled, whereas that yielded by the thymus decreased prominently. The numbers of cells in the spleen, bone marrow, and blood were unchanged. c-kit+ stem cells, which give rise to multilineage cells, were present in the liver and bone marrow. The proportion of such c-kit+ cells in the liver increased while that in the bone marrow decreased on day 3. Therefore, the absolute number of c-kit+ stem cells increased severalfold in the liver and clusters of lymphoid cells became visible in the parenchymal space. At that time, the expression of recombination activating gene-1 and -2 mRNAs became prominent. Reflecting these phenomena, the number and proportion of IL-2R beta+ CD3int cells (i.e., primordial T cells) increased in the liver on days 3 and 10. An increase in the number of proportion of such CD3int cells was seen even in the thymus and uterus. In parallel with the increase of CD3int cells, the proportion of granulocytes also increased in various organs on day 3. Forbidden clones were present in either the NK1.1+ or the NK1.1- subset of CD3int cells in (B6 x BALB/c) F1 mice treated with estrogen and liver mononuclear cells in such mice acquired potent cytotoxicity against syngeneic thymocytes. These results reveal that estrogen has the ability to potentiate the generation of self-reactive T cells and granulocytes in the liver and other organs.

DOI： 10.1006/cimm.1998.1245

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS  

Granulocytes and extrathymic T cells are often activated simultaneously, but they are absolutely separate populations in normal mice. However, some abnormal extrathymic T cells (i.e., CD3int cells) seen in mice carrying the lpr gene were found to express a granulocyte marker, Gr-1. Such mice include MRL-lpr/lpr mice and SCG mice. In parallel with an age-associated increase of IL-2Rbeta(low)CD3int cells which contained double-negative CD4-8- and B220+CD2- cells, Gr-1+CD3int cells increased in number in the lymph nodes and other peripheral organs. In addition to a major population of IL-2Rbeta(low)CD3int cells, there is a small population of IL-2Rbeta(high)CD3int cells which produce normal Fas mRNA and Fas molecule from the lpr gene. It was found that both IL-2Rbeta(low)CD3int and IL-2Rbeta(high)CD3int cell populations contained Gr-1+ cells. IL-2Rbeta(high)CD3int cells tended to contain a higher proportion of Gr-1+ cells than did IL-2Rbeta(low)CD3int cells. More interestingly, Gr-1+CD3int cells expressed a considerable level of mRNA of the mG-CSF receptor, similar to granulocytes. The present study thus yielded further information on an unusual property of abnormally expanding CD3int cells in mice carrying the lpr gene.

DOI： 10.1006/cimm.1997.1104

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

The new additional operation for the prevention of the gastric stasis after the selective gastric vagotomy with antrectomy (SV+A) was performed. Our additional operative procedure was followed: After selective gastric vagotomy and antrectomy, gastroduodenostomy was anastomosed at acute angle with the longitudinalis of the stomach. Then, both lesser and greater omentum were incised outside of the gastric vessels. After these procedure, posterior wall sided to lesser curvature was fixed with the edge of the hepatogastric ligament and posterior wall sided to greater curvature was fixed with the retroperitoneum inferior to the pancreas by several sutures. The outcome of these treatments of the additional operation on SV+A enabled to shorten the duration of drainage of gastric juice, as well as smooth intake. By fluoroscopic examination one month after operation, gastric stasis was observed on SV+A due to the contrast medium stored in the ptotic corpus, whereas, in the case of SV + A with our additional operation, smooth gastric emptying was observed without any stasis of the contrast medium, because the corpus was placed upper from the anastomosis portion. In conclusion, our additional operation to SV+A was able to perform easy and safely, and was observed the effective prevention of gastric stasis. © 1986, Japan Society of Smooth Muscle Research. All rights reserved.

DOI： 10.1540/jsmr1965.22.503

Scopus

PubMed

researchmap

Language：Japanese   Publisher：(株)日本医事新報社  

researchmap

Language：Japanese   Publisher：(一社)日本内科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内科学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：English  

Background: The anti-immunoglobulin E monoclonal antibody, omalizumab, is used to treat severe asthma and has the potential to ameliorate airway inflammation. However, the effect of omalizumab in ameliorating upper airway inflammation has not been fully elucidated. Objective: We investigated the association of upper and lower airway inflammation with the response to omalizumab treatment. Methods: We used the Global Evaluation of Treatment Effectiveness to assess the efficacy of omalizumab in treating 16 patients with severe asthma. We also investigated the symptom score, short-acting β-agonist inhaler use, pulmonary function, biomarkers, computed tomography scans, and nasal mucosa pathology at omalizumab initiation and after four months of treatment. Results: When the fraction of exhaled nitric oxide (FeNO) and the percentage of sputum eosinophil were used as indicators of lower airway inflammation, positive correlations were found between CD20 B-cell, mast cell, and eosinophil counts in the nasal mucosa. Improved asthma symptoms were observed in 12 of the 16 severe asthma cases. The FeNO and eosinophil levels in the nasal tissue, prior to the administration of omalizumab were predictors of the response to asthma treatment. Conclusions: These findings suggest heterogeneity among people with severe asthma. In addition, the phenotype associated with response to omalizumab, leading to improvement in asthma symptoms, comprises upper airway eosinophilia and high FeNO levels.

DOI： 10.1080/02770903.2018.1541357

PubMed

researchmap

Language：Japanese   Publisher：(NPO)日本肺癌学会  

researchmap

Language：Japanese   Publisher：(株)日本医事新報社  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸ケア・リハビリテーション学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸ケア・リハビリテーション学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸ケア・リハビリテーション学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸ケア・リハビリテーション学会  

researchmap

Language：English   Publisher：日本癌学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(株)日本医事新報社  

researchmap

Language：Japanese   Publisher：(NPO)日本臨床運動療法学会  

researchmap

Language：Japanese   Publisher：(一社)日本感染症学会  

[目的]国内3種の(1→3)-β-D-グルカン(以下β-D-グルカン)測定試薬における測定結果と患者の臨床背景を比較し,深在性真菌症の診断における有用性および試薬間での測定結果の乖離,偽陽性の要因について評価する.[方法]新潟大学医歯学総合病院において2017年8月から2017年11月にかけてβ-D-グルカン検査が提出された患者を対象とし,測定残余血漿を用いて以下の3試薬について測定した.(1)ファンギテックGテストMKII「ニッスイ」(以下MKII法),(2)ファンギテックGテストES「ニッスイ」(以下ES法),(3)β-グルカンテストワコー(以下ワコー法).[成績]171患者,245検体が対象となった.深在性真菌症患者は疑診を含め7例であった.β-D-グルカン測定値は,同一検体間の比較でMKII法が最も高く,次いでES法,ワコー法の順であったが,互いに有意に相関していた.感度,特異度,陽性的中率,陰性的中率などの診断特性は各試薬によって異なっていた.MKII法で偽陽性を比較的多く認めたものの,深在性真菌症(疑診含む)診断におけるROC曲線下面積には有意差はなかった.いずれかの試薬による偽陽性を呈した14例について,階層型クラスター分析を用いて分類したところ,偽陽性のパターンに一定の傾向が認められた.[結論]各測定試薬によるβ-D-グルカン測定の結果は概ね相関しているが,測定値は大きく異なっており,異なる試薬同士の比較は困難である.深在性真菌症診断における差は小さいが,それぞれの試薬の診断特性を理解し使用するべきである.また試薬によって偽陽性の原因が異なる可能性が示唆された.(著者抄録)

researchmap

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00276&link_issn=&doc_id=20190821320003&doc_link_id=10.11150%2Fkansenshogakuzasshi.93.500&url=https%3A%2F%2Fdoi.org%2F10.11150%2Fkansenshogakuzasshi.93.500&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(一社)日本睡眠学会  

researchmap

Language：Japanese   Publisher：(一社)日本睡眠学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：English  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

症例は73歳、男性。初診時の精査で特発性間質性肺炎と診断された。副腎皮質ステロイドの開始から20ヵ月後にすりガラス影が出現し、病理学的所見、血清抗GM-CSF抗体陽性から自己免疫性肺胞蛋白症(aPAP)と診断した。初診時の保存血清でも抗GM-CSF抗体陽性であり、気管支肺胞洗浄液にPAS陽性物質が存在していることを確認した。潜在的なaPAPがステロイド治療を経て顕在化した経過が考えられた。典型的な臨床所見を呈さない潜在的なaPAPが存在することに留意する必要性が示唆された。(著者抄録)

researchmap

Language：Japanese   Publisher：(一社)日本呼吸ケア・リハビリテーション学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸ケア・リハビリテーション学会  

researchmap

Language：Japanese   Publisher：(NPO)日本肺癌学会  

researchmap

Language：English   Publisher：日本癌学会  

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2018-2717

Web of Science

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

researchmap

Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

researchmap

Language：Japanese   Publisher：(株)癌と化学療法社  

症例は52歳、男性。慢性骨髄性白血病(CML)に対してX-4年からメシル酸イマチニブ(imatinib mesylate、以下イマチニブ)、X-2年からニロチニブ、X-1年からダサチニブを開始された。X年11月ごろより息切れが出現し、胸部X線、胸部CTで浸潤影、両側胸水を認めた。抗菌薬と利尿剤を開始されたが改善を認めず、当科を紹介受診した。経気管支肺生検で得られた生検組織で肺胞腔内にポリープ状線維化巣を認め、器質化肺炎と診断した。ダサチニブを中止してステロイド治療を行い、臨床症状、画像所見の改善を認めた。その後CMLに対して、イマチニブ、ニロチニブを投与したが治療効果を認めなかった。ステロイド併用下でダサチニブを再投与し、器質化肺炎の再燃なくCMLをコントロールすることができた。ダサチニブによる器質化肺炎はまれであり、これまで報告はない。ステロイド治療によりダサチニブの再投与が可能であった器質化肺炎の症例を経験したので、文献的考察を含め報告する。(著者抄録)

researchmap

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J00296&link_issn=&doc_id=20180528410016&doc_link_id=%2Fab8gtkrc%2F2018%2F004505%2F017%2F0851-0854%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2018%2F004505%2F017%2F0851-0854%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(一社)日本感染症学会  

researchmap

Language：Japanese   Publisher：(一社)日本感染症学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(NPO)日本肺癌学会  

目的. サルコイドーシスやサルコイド反応は肺門・縦隔リンパ節腫大を呈し、これらを合併した肺癌症例には、リンパ節病変の評価が治療方針決定上で問題となる。本研究では、これらサルコイド反応合併肺癌症例の病期診断におけるEBUS-TBNAの有用性を検討した。対象と方法. 2009年1月から2016年12月に気管支鏡検査を実施され、サルコイドーシス/サルコイド反応と肺癌の合併と診断された症例におけるEBUS-TBNAの有効性について検討した。結果. EBUS-TBNAにより、サルコイドーシス/サルコイド反応と肺癌との合併と診断された症例は4例であった。造影CT、FDG-PET/CTでは癌のリンパ節転移とサルコイドーシス/サルコイド反応の鑑別は困難であった。4例中3例はI期の非小細胞肺癌と診断され、2例は手術が施行された。術後検体でも転移はなく、granulomaが認められたことから、サルコイド反応と診断された。4例中1例は全身性サルコイドーシスに合併したIII期の肺癌症例であった。結論. サルコイドーシス/サルコイド反応合併肺癌症例におけるN因子の評価に、EBUS-TBNAは有用であると考えられる。(著者抄録)

researchmap

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J01244&link_issn=&doc_id=20180515270004&doc_link_id=%2Fec7jaluc%2F2018%2F005802%2F004%2F0088-0092%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fec7jaluc%2F2018%2F005802%2F004%2F0088-0092%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(公社)日本化学療法学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：新潟医学会  

一般集団と比較して、アスリート集団で、気管支喘息罹患率が高値であることが報告されている。国立スポーツ科学センターでは2012年のロンドン五輪に参加する日本選手団に対して、呼吸機能検査を行い、約12%のアスリートを喘息と診断した(一般集団は5%)。新潟県スポーツ医科学センターにおいても、中高校生を中心に、10年前より、アスリート喘息の診断、治療を行っており、そのデータより10%以上のアスリートは喘息と診断される。種目別でみると耐久種目や冬季種目に高い罹患率を認める。アスリート喘息においても、治療は吸入ステロイドを中心とした治療になるが、一部に吸入ステロイドの効果が乏しい症例もあり、このような症例において、治療戦略をどうするかが今後の課題である。(著者抄録)

researchmap

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J00990&link_issn=&doc_id=20180801120001&doc_link_id=%2Fdg3nigta%2F2018%2F013202%2F001%2F0035-0038%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2018%2F013202%2F001%2F0035-0038%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)医薬ジャーナル社  

[目的]配合剤を含む吸入ステロイド薬(ICS)を使用しているにも関わらず,コントロール不良の気管支喘息患者において,チオトロピウムソフトミスト製剤の効果および同剤が効果的な患者背景を検討する。[方法]中等症から重症の気管支喘息で,ICSを使用中にも関わらずコントロール不良の時に,チオトロピウムソフトミスト製剤を使用した患者を対象とした。同剤を使用した患者に対し,Global Evaluation of Treatment Effectiveness(GETE)または増悪抑制,呼吸機能改善を評価し,改善群と無効群において患者背景の違いを2群間で比較した。[結果]72例を対象に解析を行った。症状改善群(GETEで著効とされた,または増悪が著明に抑制された症例)は32例で,咳嗽症状の改善が多く見られた。無効群との比較では,前年の増悪回数が有効群で有意に多かった。呼吸機能改善群(FEV1[1秒量]が150mL以上改善)は19例で,無効例と比較すると,非喫煙症例が有意に少なく,治療前のFEV1は有意に低値であった。症状のみ改善群,呼吸機能改善群,無効群の3群を比較すると,呼吸機能改善群は男性優位,治療前のFEV1が低値で喫煙関連が考えられた。一方,症状のみ改善する症例は女性優位で,症状として咳嗽が多く,閉塞性障害が少ない症例であった。また末梢血好酸球が多い症例は,無効群が有意に高い傾向であった。[結語]チオトロピウムソフトミスト製剤は閉塞性障害の強い症例または増悪回数の多い症例で効果が高いが,その反応群に違いがある可能性のあることが示唆された。(著者抄録)

DOI： 10.20837/1201801112

researchmap

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J00065&link_issn=&doc_id=20180117200015&doc_link_id=10.20837%2F1201801112&url=https%3A%2F%2Fdoi.org%2F10.20837%2F1201801112&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY  

Web of Science

researchmap

J-GLOBAL

researchmap

Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：Japanese Society of Allergology  

DOI： 10.15036/arerugi.67.1269

Scopus

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本呼吸ケア・リハビリテーション学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸ケア・リハビリテーション学会  

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

DOI： 10.15036/arerugi.66.971

researchmap

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J00009&link_issn=&doc_id=20170922280001&doc_link_id=%2Fcw4aller%2F2017%2F006608%2F001%2F0971-0990%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcw4aller%2F2017%2F006608%2F001%2F0971-0990%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publisher：日本癌学会  

researchmap

Language：Japanese   Publisher：(一社)日本睡眠学会  

researchmap

Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸ケア・リハビリテーション学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本感染症学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本内科学会  

researchmap

Language：Japanese   Publisher：(一社)日本感染症学会  

researchmap

Language：Japanese   Publisher：(一社)日本感染症学会  

researchmap

Language：Japanese   Publisher：(一社)日本感染症学会  

[目的]静注用ヒト免疫グロブリン製剤(以下,IVIG製剤)が,(1→3)-β-Dグルカン(以下,β-D-グルカン)の測定結果に及ぼす影響を明らかにする.[方法]国内で使用可能なIVIG製剤7種に含有されるβ-D-グルカン濃度を,各製剤3ロットずつ(ファンギテックGテストMKII,以下MKII法),βグルカンテストワコー(以下ワコー法)を用い測定した.また,新潟大学医歯学総合病院で2012年1月から2013年12月にかけてIVIG製剤が使用され,その前後でβ-D-グルカンが測定されている成人例を対象に,β-D-グルカン値の挙動を検討した.[成績]IVIG製剤ごとにβ-D-グルカン含有量は大きく異っていた(MKII法:7.3〜300以上pg/mL,ワコー法:3.5以下-288.8pg/mL)が,ロット間での違いは限定的であり,製造工程での混入が推定された.2種類の測定キットによるβ-D-グルカン測定結果間の相関係数rは0.90と一定の相関が見られた.調査の対象となった臨床検体51例(年齢中央値64歳,男性60.1%)中,他の要因を除外し,IVIG製剤投与によるβ-D-グルカン偽陽性と考えられた症例は5例(9.8%)で,β-D-グルカンの最高値は57.1pg/mL,使用前後の変動幅は最大で44.5pg/mLであった.[結論]IVIG製剤の種類によりβ-D-グルカン含有量は大きく異なっていた.IVIG製剤の投与によると推定される血清β-D-グルカン値の偽陽性率は9.8%であった.またIVIG製剤投与後の陽性予測値は37.5%と低値であり,IVIG製剤使用後のβ-D-グルカン測定結果の解釈には注意が必要と思われた.(著者抄録)

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER THORACIC SOC  

Web of Science

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER THORACIC SOC  

Web of Science

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER THORACIC SOC  

Web of Science

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER THORACIC SOC  

Web of Science

researchmap

Language：Japanese   Publisher：(NPO)日本肺癌学会  

researchmap

Language：Japanese   Publisher：(NPO)日本肺癌学会  

researchmap

Language：Japanese   Publisher：(NPO)日本肺癌学会  

researchmap

Language：Japanese   Publisher：(一社)日本睡眠学会  

researchmap

Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

researchmap

Language：Japanese   Publisher：(一社)日本睡眠学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap

Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

researchmap

Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

researchmap

Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

researchmap

Language：Japanese   Publisher：(一社)日本感染症学会  

researchmap

Language：Japanese   Publisher：(一社)日本感染症学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本結核病学会  

researchmap

Language：Japanese   Publisher：(一社)日本感染症学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸器学会  

researchmap

Language：Japanese   Publisher：(一社)日本内科学会  

researchmap

Language：Japanese   Publisher：(株)日本臨床社  

researchmap

Language：Japanese   Publisher：(株)医薬ジャーナル社  

気管支喘息および慢性閉塞性肺疾患(Chronic Obstructive Pulmonary Disease:COPD)の治療は、吸入薬が主体である。吸入薬として新たに追加されたものは、気管支喘息の適応が拡大されたチオトロピウム(ソフトミスト)と、COPDにおけるウメクリジニウム臭化物/ビランテロールトリフェニル酢酸塩と、アクリジニウム臭化物およびチオトロピウム臭化物/オロダテロール塩酸塩である。その他、分子標的薬としてのモノクローナル抗体の治験が進んでおり、特にIL(インターロイキン)-5、IL-13の抗体は、中等症から重症症例でのランダム化試験において、急性増悪の抑制、呼吸機能の改善などの効果を認めており、今後本邦での実臨床に登場する可能性が高い。(著者抄録)

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER THORACIC SOC  

Web of Science

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER THORACIC SOC  

Web of Science

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER THORACIC SOC  

Web of Science

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER THORACIC SOC  

Web of Science

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER THORACIC SOC  

Web of Science

researchmap

Language：Japanese   Publisher：(NPO)日本肺癌学会  

researchmap

Language：Japanese   Publisher：(一社)日本臨床スポーツ医学会  

researchmap

Language：Japanese   Publisher：(NPO)日本肺癌学会  

researchmap

Language：Japanese   Publisher：(NPO)日本肺癌学会  

researchmap

Language：Japanese   Publisher：(一社)日本呼吸ケア・リハビリテーション学会  

researchmap

Language：Japanese   Publisher：(一社)日本睡眠学会  

researchmap

Language：Japanese   Publisher：(一社)日本睡眠学会  

researchmap

Language：Japanese   Publisher：(一社)日本老年医学会  

DOI： 10.3143/geriatrics.52.94

researchmap

Language：Japanese   Publisher：(一社)日本アレルギー学会  

researchmap