Published papers

Background: Allergic bronchopulmonary aspergillosis (ABPA) develops in the presence or absence of asthma, either atopic or nonatopic. We have tried to explore the essential components in the pathogenesis of the disease, which are either consistent and variable according to the presence and type of asthma. Methods: Non-cystic fibrosis ABPA cases satisfying Asano's criteria were extracted from a prospective registry of ABPA and related diseases in Japan between 2013 and 2023. According to the type of preceding asthma, ABPA was classified into three groups: ABPA sans asthma (no preceding asthma), ABPA with atopic asthma, and ABPA with nonatopic asthma. Exploratory and confirmatory factor analyses were performed to identify the components that determined the clinical characteristics of ABPA. Results: Among 106 cases of ABPA, 25 patients (24%) had ABPA sans asthma, whereas 57 (54%) and 24 (23%) had ABPA with atopic and nonatopic asthma, respectively. Factor analysis identified three components: allergic, eosinophilic, and fungal. Patients with atopic asthma showed the highest scores for the allergic component (p <.001), defined by total and allergen-specific IgE titers and lung opacities, and the lowest scores for the fungal component defined by the presence of specific precipitin/IgG or positive culture for A. fumigatus. Eosinophilic components, including peripheral blood eosinophil counts and presence of mucus plugs/high attenuation mucus in the bronchi, were consistent among the three groups. Conclusion: The eosinophilic component of ABPA is considered as the cardinal feature of ABPA regardless of the presence of preceding asthma or atopic predisposition.

Inhalers are commonly used to treat asthma and chronic obstructive pulmonary disease. Regular and correct usage of inhalers is necessary for effective use. However, approximately 70% of patients do not use their inhalers as directed. This is due to a lack of understanding about the medication and misunderstanding of directions. Assessment of patients' inhaler techniques are usually conducted in person. However, doctors or pharmacists have no objective information regarding how patients use their inhalers at home. Therefore, monitoring daily inhaler use is necessary for precise medical treatment. This article proposes an inhalation monitoring device using an inertial measurement unit (IMU). The IMU is used to measure a patient's inhalation motion. Incorrect inhalation usage can be determined by comparing the measurement data against data that indicate correct usage. The experimental results show the utility of the proposed device.

Nitric oxide (NO) is produced in the body and has been shown to have diverse actions in the abundance of research that has been performed on it since the 1970s, leading to Furchgott, Murad, and Ignarro receiving the Nobel Prize in Physiology or Medicine in 1998. NO is produced by nitric oxide synthase (NOS). NOS is broadly distributed, being found in the nerves, blood vessels, airway epithelium, and inflammatory cells. In asthma, inflammatory cytokines induce NOS activity in the airway epithelium and inflammatory cells, producing large amounts of NO. Measurement of fractional exhaled nitric oxide (FeNO) is a simple, safe, and quantitative method of assessing airway inflammation. The FeNO measurement method has been standardized and, in recent years, this noninvasive test has been broadly used to support the diagnosis of asthma, monitor airway inflammation, and detect asthma overlap in chronic obstructive pulmonary disease (COPD) patients. Since the normal upper limit of FeNO for healthy Japanese adults is 37 ppb, values of 35 ppb or more are likely to be interpreted as a signature of inflammatory condition presenting features with asthma, and this value is used in clinical practice. Research is also underway for clinical application of these measurements in other respiratory diseases such as COPD and interstitial lung disease. Currently, there remains some confusion regarding the significance of these measurements and the interpretation of the results. This statement is designed to provide a simple explanation including the principles of FeNO measurements, the measurement methods, and the interpretation of the measurement results.

Background: In Japan, Mycobacterium avium complex lung disease (MAC-LD) is the most common in nontuberculous mycobacterial lung disease. Patients often experience adverse events, resulting in the discontinuation of treatment, which causes treatment failure. The JADER (Japanese Adverse Drug Event Report) database is a database of adverse events that allows us to collect real-world data on adverse events. We can collect large-scale data cost-effectively and detect signals of potential adverse events such as reporting odds ratio (ROR) by using spontaneous reporting systems. In this study, we aimed to elucidate the adverse events of clarithromycin (CAM), ethambutol (EB), and rifampicin (RFP) using the JADER database. Methods: We included cases of MAC-LD between April 2004 and June 2017. We investigated sex, age, and medications that may have caused the adverse events, outcomes, and time of onset. We calculated the safety signal index as the ROR. Time-to-event analysis was performed using the Weibull distribution. Results: The total number of adverse events of CAM, EB, and RFP was 2780, with 806 patients. In the overall adverse events, hematologic and lymphatic disorders were the most common adverse events, with 17.3%, followed by eye disorders (16.6%), and hepatobiliary disorders (14.0%). The outcomes were as follows: recovery, 40.0%; remission, 27.1%; non-recovery, 11.2%; and death, 7.1%. Regarding the most common onset time of CAM, EB, and RFP was within 120 days at 40%, 181–300 days at 43.6%, and within 120 days at 88.5%. For CAM, the RORs of infections and infestations, hepatobiliary system disorders, and immune system disorders were 4.13 (95% confidence interval [CI], 2.3–7.44), 2.61 (95% CI, 1.39–4.91), and 2.38 (95% CI, 1.04–5.44). For EB, the ROR of eye disorders was 215.79 (95% CI, 132.62–351.12). For RFP, the RORs of renal and urinary tract disorders and investigations were 7.03 (95% CI, 3.35–14.77) and 6.99 (95% CI, 3.22–15.18). The β value of EB was 2.07 (95% CI, 1.48–2.76), which was classified as a wear-out failure type. Conclusions: For MAC-LD, the adverse event which has the highest ROR is infections and infestations in CAM, eye disorders in EB, renal and urinary tract disorders in RFP. Adverse events of EB occur after 180 days, whereas the adverse events of CAM and RFP occur early in the course of treatment.

Group 2 innate lymphoid cells (ILC2s) produce large amounts of type 2 cytokines including interleukin-5 (IL-5) and IL-13 in response to various stimuli, causing allergic and eosinophilic diseases. However, the cell-intrinsic regulatory mechanisms of human ILC2s remain unclear. Here, we analyze human ILC2s derived from different tissues and pathological conditions and identify ANXA1, encoding annexin A1, as a commonly highly expressed gene in non-activated ILC2s. The expression of ANXA1 decreases when ILC2s activate, but it increases autonomously as the activation subsides. Lentiviral vector-based gene transfer experiments show that ANXA1 suppresses the activation of human ILC2s. Mechanistically, ANXA1 regulates the expression of the metallothionein family genes, including MT2A, which modulate intracellular zinc homeostasis. Furthermore, increased intracellular zinc levels play an essential role in the activation of human ILC2s by promoting the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways and GATA3 expression. Thus, the ANXA1/MT2A/zinc pathway is identified as a cell-intrinsic metalloregulatory mechanism for human ILC2s.

Objective: Background: Case Report: Conclusions: Unusual clinical course Diffuse alveolar hemorrhage (DAH) caused by direct oral anticoagulants (DOACs) has increased in recent years with the increase in prescriptions of DOACs. Generally, DOACs are considered to have a lower bleeding risk than the traditional anticoagulant, warfarin. However, major bleeding, including DAH, due to DOACs can be seen in clinical practice, and there are few reports to elucidate when DOAC-associated alveolar hemorrhage occurs and whether DOAC-induced DAH has a trigger. An 80-year-old man diagnosed and treated for atrial fibrillation with apixaban 2.5 mg twice daily for 1 year before admission, underwent 2 invasive medical procedures over a short period of time. Hemoptysis began after the procedures. He experienced shortness of breath and rapidly progressive hypoxic respiratory failure. His postsurgical oxygen saturation level dropped rapidly. Chest radiography and computed tomography images showed pulmonary infiltration and ground-glass opacity in both lungs. Apixaban treatment was discontinued, and mechanical ventilation was initiated. Bronchoalveolar lavage cytology revealed hemosiderin-laden macrophages. A diagnosis of diffuse alveolar hemorrhage (DAH) was made. In previous reports about DAH caused by DOACs, most patients had bleeding triggers; drug interactions in patients taking DOACs are one of such triggers. Although DOACs are relatively safe for elderly patients, DAH can occur in patients receiving either earlystage or long-term treatment. The onset of DOAC-associated DAH is not limited to the early stages of medication initiation. Various triggers can induce DAH in patients receiving DOACs.

An association between coronavirus disease 2019 (COVID-19) and the ABO blood group has been reported. However, such an association has not been studied in the Japanese population on a large scale. Little is known about the association between COVID-19 and ABO genotype. This study investigated the association between COVID-19 and ABO blood group/genotype in a large Japanese population. All Japanese patients diagnosed with COVID-19 were recruited through the Japan COVID-19 Task Force between February 2020 and October 2021. We conducted a retrospective cohort study involving 1790 Japanese COVID-19 patients whose DNA was used for a genome-wide association study. We compared the ABO blood group/genotype in a healthy population (n = 611, control) and COVID-19 patients and then analyzed their associations and clinical outcomes. Blood group A was significantly more prevalent (41.6% vs. 36.8%; P = 0.038), and group O was significantly less prevalent (26.2% vs. 30.8%; P = 0.028) in the COVID-19 group than in the control group. Moreover, genotype OO was significantly less common in the COVID-19 group. Furthermore, blood group AB was identified as an independent risk factor for most severe diseases compared with blood group O [aOR (95% CI) = 1.84 (1.00–3.37)]. In ABO genotype analysis, only genotype AB was an independent risk factor for most severe diseases compared with genotype OO. Blood group O is protective, whereas group A is associated with the risk of infection. Moreover, blood group AB is associated with the risk of the “most” severe disease.

Background: Multiple prolonged symptoms are observed in patients who recover from an acute COVID-19 infection, which is defined as long COVID. General fatigue is frequently observed in patients with long COVID during acute and post-acute phases. This study aimed to identify the specific risk factors for general fatigue in long COVID. Methods: Hospitalized patients with COVID-19 aged over 18 years were enrolled in a multicenter cohort study at 26 medical institutions. Clinical data during hospitalization and patient-reported outcomes after discharge were collected from medical records, paper-based questionnaires, and smartphone apps. Results: Among prolonged symptoms through 1-year follow-ups, general fatigue was the most interfering symptom in daily life. Patients with protracted fatigue at all follow-up periods had lower quality of life scores at the 12-month follow-up. Univariate logistic regression analysis of the presence or absence of general fatigue at the 3-month, 6-month, and 12-month follow-ups identified asthma, younger age, and female sex as risk factors for prolonged fatigue. Multivariable logistic regression analysis revealed that asthma was an independent risk factor for persistent fatigue during the 12-month follow-up period. Longitudinal changes in the symptoms of patients with or without asthma demonstrated that general fatigue, not cough and dyspnea, was significantly prolonged in patients with asthma. Conclusions: In a Japanese population with long COVID, prolonged general fatigue was closely linked to asthma. A preventive approach against COVID-19 is necessary to avoid sustained fatigue and minimize social and economic losses in patients with asthma.

Purpose: The status of dupilumab self-injection at home is not well understood. We therefore aimed to identify the barriers to adherence to dupilumab self-injection. Patients and Methods: This non-interventional open-label study was conducted between March 2021 and July 2021. Patients with atopic dermatitis, bronchial asthma, and chronic rhinosinusitis with nasal polyps receiving dupilumab, from 15 sites, were requested to complete a self-administered questionnaire regarding the frequency and effectiveness of dosing as well as their use and satisfaction with dupilumab. Barriers to adherence were assessed using the Adherence Starts with Knowledge-12. Results: We included 331 patients who used dupilumab for atopic dermatitis (n = 164), chronic rhinosinusitis with nasal polyps (n = 102), and bronchial asthma (n = 65). The median efficacy of dupilumab scored 9.3 on the visual analog scale. Overall, 85.5% of the patients self-injected dupilumab, and 70.7% perfectly complied with the established injection dates. The pre-filled pen was significantly superior to the conventional syringe in terms of usability, operability, ease of pushing the plunger, and patient satisfaction. However, the pre-filled pen caused more pain during self-injection than did the syringe. Multivariate logistic regression analysis showed that adherence decreased with longer dupilumab treatment duration (p = 0.017) and was not associated with age, sex, underlying disease, or device type. There was a difference in responses related to “inconvenience/forgetfulness” between the good and poor adherence groups. Conclusion: The pre-filled dupilumab pen was superior to the syringe in terms of usability, operability, ease of pushing the plunger, and satisfaction. Repetitive instructions are recommended for preventing poor adherence to dupilumab self-injection.

Lung cancer and chronic obstructive pulmonary disease are leading causes of morbidity and mortality worldwide, and cigarette smoking is a main risk factor for both. The presence of emphysema, an irreversible lung disease, further raises the risk of lung cancer in patients with chronic obstructive pulmonary disease. The mechanisms involved in smoke-induced tumorigenesis and emphysema are not fully understood, attributable to a lack of appropriate animal models. Here, we optimized a model of cigarette smoke (CS)-induced lung cancer and emphysema in A/J mice treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a potent carcinogen. We investigated whether variations in CS exposure patterns with the same total amount and duration of exposure affect tumorigenesis and/or development of emphysema. Continuous CS exposure for 3 months significantly suppressed 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced development of adenomas and adenocarcinomas; however, emphysema independently developed during this period. Surprisingly, intermittent CS exposure increased the severity of emphysema and resulted in a higher incidence of adenocarcinomas. Furthermore, intermittent CS exposure elicited a marked increase in M2-polarized macrophages within and near the developed tumors. By employing a CS exposure protocol with repeated cycles of cessation and relapse, we provide evidence that intermittent CS exposure enhances tumorigenesis and emphysema progression more than that of continuous CS exposure.

A 72-year-old man was admitted due to dyspnea on exertion with interstitial shadows and elevated serum creatinine kinase (CK). Despite a close examination, which included magnetic resonance imaging (MRI), we could not diagnose myopathy. Prednisolone was administered and gradually tapered. One year later, anti-signal recognition particle (SRP) antibody was confirmed and he was re-admitted for hypoxemia with elevated CK. MRI revealed muscle edema and a histopathological examination of a muscle biopsy specimen showed necrotizing myopathy. Prednisolone, cyclosporine, and intravenous immunoglobulin were administered. Physicians should carefully monitor muscle symptoms and serum CK levels in cases of interstitial lung disease with anti-SRP antibodies.

INTRODUCTION: We aimed to study the prevalence and types of sleep apnea (SA) as well as their clinical characteristics in atrial fibrillation (AF) ablation candidates in Japan. METHODS: Before catheter ablation, 197 consecutive AF patients (age: 60+/-9years, body mass index; 25.0+/-3.0) were evaluated with portable polygraphy. We compared the clinical characteristics, according to the severity of SA as well as its types, as defined by the presence of obstruction and the mixed vs. central apnea indices. RESULTS: The mean apnea-hypopnea index (AHI) was 17.7+/-11.9, with 135 AF patients having an AHI >/=10 (68.5%). Patients with an AHI >/=10 had a significantly higher body mass index, plasma brain natriuretic peptide (BNP) level, prevalence of hypertension, and larger left atrial size. Among patients with an AHI >/=10, the incidence of obstructive-dominant SA was 60.9% and that of central-dominant SA was 7.6%. The prevalence of hypertension was significantly higher in obstructive-dominant SA patients (obstructive vs. central: 48.3% vs. 20.0%, P=0.038). The obstructive apnea index correlated with plasma BNP level and age, but the central and mixed apnea indices did not. CONCLUSIONS: The prevalence of SA was common in AF ablation candidates, even without an obesity epidemic, and the SA type was predominantly obstructive. Portable polygraphy was useful for detecting undiagnosed SA patients in AF ablation candidates.

BACKGROUND: Asthma is characterized by airway inflammation and obstruction with eosinophil infiltration into the airway. Arachidonic acid, an omega-6 fatty acid, is metabolized into cysteinyl leukotriene with pro-inflammatory properties for allergic inflammation, whereas the omega-3 fatty acid eicosapentaenoic acid (EPA) and its downstream metabolites are known to have anti-inflammatory effects. In this study, we investigated the mechanism underlying the counter-regulatory roles of EPA in inflamed lungs. METHODS: Male C57BL6 mice were sensitized and challenged by ovalbumin (OVA). After EPA treatment, we evaluated the cell count of Bronchoalveolar lavage fluid (BALF), mRNA expressions in the lungs by q-PCR, and the amounts of lipid mediators by liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomics. We investigated the effect of the metabolite of EPA by in vivo and in vitro studies. RESULTS: Eicosapentaenoic acid treatment reduced the accumulation of eosinophils in the airway and decreased mRNA expression of selected inflammatory mediators in the lung. Lipidomics clarified the metabolomic profile in the lungs. Among EPA-derived metabolites, 12-hydroxy-17,18-epoxyeicosatetraenoic acid (12-OH-17,18-EpETE) was identified as one of the major biosynthesized molecules; the production of this molecule was amplified by EPA administration and allergic inflammation. Intravenous administration of 12-OH-17,18-EpETE attenuated airway eosinophilic inflammation through downregulation of C-C chemokine motif 11 (CCL11) mRNA expression in the lungs. In vitro, this molecule also inhibited the release of CCL11 from human airway epithelial cells stimulated with interleukin-4. CONCLUSION: These results demonstrated that EPA alleviated airway eosinophilic inflammation through its conversion into bioactive metabolites. Additionally, our results suggest that 12-OH-17,18-EpETE is a potential therapeutic target for the management of asthma.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is an allergic pulmonary disease characterized by a hypersensitivity reaction to Aspergillus species colonizing the airways. The clinical characteristics of ABPA may differ depending on genetic and environmental background. We performed a nationwide survey to determine the clinical characteristics of ABPA in Japan. METHODS: In 2013, a questionnaire on physician-diagnosed ABPA/allergic bronchopulmonary mycosis was sent to 903 medical centers specializing in respiratory or allergic diseases. Cases fulfilling the following criteria were categorized as possible ABPA-central bronchiectasis (ABPA-CB): 1) presence of specific serum immunoglobulin E (IgE) antibodies or a positive skin reaction to Aspergillus, and 2) bronchiectasis or mucoid impaction in the central bronchi. RESULTS: Of 499 physician-diagnosed cases reported by 132 clinical centers, 358 cases met the criteria for possible ABPA-CB. Median age of ABPA-CB onset was 57 (interquartile range, 44-68) years; later-onset disease, developing >/=50 years of age, accounted for 66% of the cases and was associated with female sex, delayed onset of asthma, and lower levels of serum IgE. A third of the patients (120 patients, 34%) exhibited low levels of serum total IgE (<1000 IU/mL). Aspergillus species were isolated from sputum in 126/213 cases (59%), and Schizophyllum commune was identified in 12 (6%) patients. During the course of the treatment, ABPA recurred in 169 (48%) cases. CONCLUSIONS: This nationwide survey identified several unique clinical characteristics of ABPA in Japan, such as late-onset, relatively lower serum IgE levels, and frequent recurrences/flares.

Aim of this study was to examine the association between the severity of obstructive sleep apnea (OSA) and dysglycemia in Japanese individuals with and without type 2 diabetes (T2DM). We enrolled 115 individuals diagnosed with OSA with an apnea hypopnea-index (AHI) >/= 20 in whom continuous positive airway pressure (CPAP) therapy was introduced (N = 115, 44 with T2DM, age 62 +/- 11 years, BMI 27.0 +/- 4.4 kg/m(2) and AHI median 36.1; interquartile range 27.2-48.1). During admission, the severity of OSA was evaluated by polysomnography, and its association with glycated hemoglobin (HbA1c) level was examined. Continuous glucose monitoring (CGM) was also conducted during the admission in 94 individuals. Apnea-hypopnea index (AHI), non-rapid eye movement (REM) AHI, minimum peripheral capillary oxygen saturation (SpO2) and percentage of sleep time (%TST) with SpO2 < 90% were significantly associated with HbA1c level in total and non-diabetic individuals (all p < 0.05) but not in those with T2DM, the majority of whom were treated with anti-diabetic medications. The associations of the non-REM AHI and %TST with SpO2 < 90% with HbA1c level remained significant after adjustment for age, sex and BMI in non-diabetic and T2DM subjects treated with dietary therapy only. Mean glucose level, but not SD or coefficient of variation of glucose, assessed by CGM was significantly associated with AHI and non-REM AHI in non-diabetic subjects after adjustment for age, sex and BMI. In conclusion, the severity of OSA was associated with increased HbA1c level independently of BMI in Japanese individuals, especially in those without diabetes.

For single-cell experiments, it is important to accurately count the number of viable cells in a nanoliter well. We used a deep learning-based convolutional neural network (CNN) on a large amount of digital data obtained as microscopic images. The training set consisted of 103 019 samples, each representing a microscopic grayscale image. After extensive training, the CNN was able to classify the samples into four categories, i.e., 0, 1, 2, and more than 2 cells per well, with an accuracy of 98.3% when compared to determination by two trained technicians. By analyzing the samples for which judgments were discordant, we found that the judgment by technicians was relatively correct although cell counting was often difficult by the images of discordant samples. Based on the results, the system was further enhanced by introducing a new algorithm in which the highest outputs from CNN were used, increasing the accuracy to higher than 99%. Our system was able to classify the data even from wells with a different shape. No other tested machine learning algorithm showed a performance higher than that of our system. The presented CNN system is expected to be useful for various single-cell experiments, and for high-throughput and high-content screening.

OBJECTIVE AND DESIGN: An animal experiment was performed to demonstrate the anti-inflammatory effects of an alpha-lipoic acid (ALA) derivative, dihydrolipoyl histidinate zinc complex (DHLHZn) for acute lung injury (ALI) and to investigate the mechanism of action. MATERIAL: Rats were randomly divided into three experimental groups: control group (n = 17), DHLHZn(-) group (n = 11, ALI model rats), and DHLHZn(+) group (n = 12, ALI model rats treated by DHLHZn). TREATMENT: Lipopolysaccharides (LPS, 10 mg/kg) were administered intratracheally in the DHLHZn(-) group and the DHLHZn(+) group. For the DHLHZn(+) group, DHLHZn (100 mg/kg) was administered intraperitoneally 2 h prior to LPS administration. METHODS: Four hours after LPS administration, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. The findings were analyzed using the Mann-Whitney U test. RESULTS: Total number of cells, number of neutrophils and lymphocytes, levels of various inflammatory cytokines, and NF-kB p65 concentration of BALF were significantly lower in the DHLHZn(+) group than in the DHLHZn(-) group (p < 0.05). ALI pathology scores were significantly lower in the DHLHZn(+) group than in the DHLHZn(-) group (p < 0.001). CONCLUSIONS: Anti-inflammatory effects of DHLHZn for ALI were demonstrated by BALF and histopathological findings. The mechanism of action of DHLHZn was considered to be via inhibition of the NF-kB signaling pathway. DHLHZn is thus suggested to be a new prophylactic agent for ALI.

BACKGROUND: Some patients with severe asthma also have fungal sensitization and are considered to have severe asthma with fungal sensitization. However, there is limited information on the clinical features of SAFS. OBJECTIVE: To investigate the clinical characteristics of severe asthma with fungal sensitization. METHODS: The present study enrolled 124 patients with severe asthma. We evaluated clinical aspects, such as various serum cytokines, fractional exhaled nitric oxide, pulmonary function, and serum immunoglobulin E (IgE). Fungal sensitization was assessed by determining serum levels of IgE specific to fungal allergens (Aspergillus, Alternaria, Candida, Cladosporium, Penicillium, and Trichophyton species and Schizophyllum commune). The protocol was registered at a clinical trial registry (www.umin.ac.jp/ctr/index-j.htm; UMIN 000002980). RESULTS: Thirty-six patients (29%) showed sensitization to at least 1 fungal allergen. The most common species were Candida (16%), Aspergillus (11%), and Trichophyton (11%). The rate of early-onset asthma (<16 years of age) was higher in patients with fungal sensitization than in those without fungal sensitization (45% vs 25%; P = .02). Interleukin-33 levels were higher in patients with fungal sensitization than in those without fungal sensitization. Of patients with atopic asthma, Asthma Control Test scores were worse in patients with multiple fungal sensitizations than in patients with a single fungal sensitization or those without fungal sensitization. CONCLUSION: Severe asthma with fungal sensitization is characterized by early onset of disease and high serum levels of interleukin-33. Multiple fungal sensitizations are associated with poor asthma control. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN-CTR; www.umin.ac.jp/ctr/index-j.htm): UMIN 000002980.