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Yoshihisa Ishiura, Shosaku Nomura, Yuka Ishii, Kai Imai, Yusuke Sawai, Takeshi Tamaki, Toshiki Shimizu, Naoyuki Miyashita, Tomoki Ito First Department of Internal Medicine, Kansai Medical University, Osaka, JapanCorrespondence: Yoshihisa Ishiura, First Department of Internal Medicine, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka, 570-8507, Japan, Tel +81-6-6992-1001, Fax +81-6-6993-9837, Email ishiuray@takii.kmu.ac.jpAbstract: Cough, a frequent symptom encountered in clinical practice, often has a considerable impact on patients’ lives. There is an urgent need to investigate more potent antitussive treatments for chronic refractory cough, particularly atopic cough, which is a major cause of chronic refractory cough in Japan. Previous studies have shown that eosinophilic tracheobronchitis with hypersensitivity to sensory nerve C-fibers is the pathophysiology of atopic cough. Gefapixant is a first-in-class P2X3 antagonist that has recently become available for clinical use in patients with refractory coughs. A 64-year-old female non-smoker presented to our hospital with a complaint of chronic intractable cough due to atopic cough. Addition of gefapixant (90 mg/day) to her previous treatment improved her distressing cough, despite the partial efficacy of many other drugs. The findings of this case demonstrate that P2X3 inhibition is a viable therapeutic option for patients with chronic refractory cough caused by atopic cough. This case report offers valuable information regarding currently available treatment options for refractory chronic refractory cough caused by atopic cough. There remains an urgent need to clarify the disease entities presenting with chronic cough that can be effectively treated by inhibiting P2X3.Plain Language Summary: There is an urgent need to investigate more potent antitussive treatments for chronic refractory cough, because cough has a considerable impact on patients’ lives. Previous studies have shown that eosinophilic tracheobronchitis with hypersensitivity of sensory nerve C-fibers is the pathophysiology of atopic cough, which is a major cause of chronic cough in Japan. Gefapixant is a first-in-class P2X3 antagonist that has recently become available for clinical use in patients with refractory coughs. Herein, we present the case of a 64-year-old female with a refractory atopic cough. The gefapixant add-on improved her distressing cough, indicating that P2X3 inhibition could be a viable therapeutic option for patients with chronic refractory cough caused by atopic cough.Keywords: chronic cough, atopic cough, gefapixant, P2X3

Yoshihisa Ishiura,1 Masaki Fujimura,2 Noriyuki Ohkura,3 Johsuke Hara,3 Kahori Nakahama,1 Yusuke Sawai,1 Takeshi Tamaki,1 Ryuta Murai,1 Toshiki Shimizu,1 Naoyuki Miyashita,1 Shosaku Nomura1 1First Department of Internal Medicine, Kansai Medical University, Osaka, Japan; 2Respiratory Medicine, National Hospital Organization Nanao Hospital, Nanao, Japan; 3Respiratory Medicine, Kanazawa University Hospital, Kanazawa, JapanCorrespondence: Yoshihisa Ishiura, First Department of Internal Medicine, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka, 570-8507, Japan, Tel +81-6-6992-1001, Fax +81-6-6993-9837, Email ishiura-@p2322.nsk.ne.jp; ishiuray@takii.kmu.ac.jpPurpose: The ‘treatable traits’ strategy for patients with chronic inflammatory airway diseases, especially asthma and chronic obstructive pulmonary disease (COPD), is a focus of interest, because it implements precision and personalized medicine. Asthma-COPD overlap (ACO), a phenotype involving both asthma and COPD, is an important disease entity because patients with ACO have significantly worse outcomes, conferring greater economical and social burdens. Some guidelines for ACO recommend add-on therapy of long-acting muscarinic antagonists to inhaled corticosteroids and long-acting β2 agonists. However, this approach is based on extrapolation from patients with asthma or COPD alone. Consequently, a ‘treatable traits’ approach suitable for ACO remains obscure.Methods: A 12-week open-label cross-over pilot study was conducted in patients with ACO to investigate the effect of tiotropium bromide (TIO) 5 μg/day add-on therapy to fluticasone propionate/formoterol fumarate (FP/FM) 500/20 μg/day compared with FP/FM 500/20 μg/day alone. A 4-week run-in period and two 4-week treatment periods were included.Results: A total of 18 male patients with stable ACO participated in this pilot study. All patients were ex-smokers. Mean values ± standard deviation (SD) for forced expiratory volume in 1 second (FEV1) were 1.21 ± 0.49 L after the run-in period, 1.20 ± 0.51 L after the FP/FM combination therapy period, and 1.30 ± 0.48 L after the TIO add-on therapy to FP/FM period. FEV1 values after the TIO add-on therapy FP/FM period were significantly higher than those after the run-in period (p < 0.01).Conclusion: TIO add-on therapy to FP/FM in patients with ACO, considered difficult to treat because of the presence of both asthma and COPD, resulted in improvements in lung function parameters in this real-world pilot study, indicating the potential value of TIO add-on therapy as a “treatable traits” option for standard treatment for ACO.Keywords: treatable trait, asthma-COPD overlap, tiotropium, fluticasone, formoterol, triple therapy

Nobuyasu Ishii, Toshiki Shimizu, Yoshihisa Ishiura, Hideki Amuro, Tohru Nishizawa, Takeshi Tamaki, Shosaku Nomura First Department of Internal Medicine, Kansai Medical University, Moriguchi-City, Osaka, 570-8507, JapanCorrespondence: Toshiki ShimizuFirst Department of Internal Medicine, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi-City, Osaka, 570-8507, JapanTel + 81-6-6992-1001Fax + 81-6-6992-1066Email shimizto@takii.kmu.ac.jpBackground: Tocilizumab (TCZ) is humanized monoclonal antibody against the interleukin-6 (IL-6) and receptor that has prominent efficacy for the treatment of rheumatoid arthritis (RA). We conducted a retrospective observational study to determine how long TCZ controls RA.Patients and Methods: We retrospectively reviewed the medical records of RA patients treated with TCZ. The aim of this study was to evaluate the contribution of clinical parameters to disease control time (DCT) in RA patients.Results: Overall, 144 patients were enrolled in the study. The median age of patients was 66 years (range: 34– 85 years). In univariate analysis, DCT was significantly increased in patients who had never received previous biologic disease-modifying anti-rheumatic drugs treatment (P = 0.0064). We also analyzed the contribution of the base line value of C-reactive protein (CRP) to DCT. We divided the patients with RA into two groups according to a cutoff value of 1.000 mg/dl. The median control times were 77.5 months (95% confidence interval [CI]: 44.8–not reached to median) and 34.5 months (95% CI: 17.0– 79.3) for patients with high and low CRP value, respectively. In univariate analysis, DCT was significantly increased in patients with a high CRP value (P = 0.0283). Multivariate analysis clearly revealed that a high baseline CRP value was an independent favorable predictive factor for longer DCT (hazard ratio, 0.608, 95% CI: 0.378– 0.981, P = 0.0416).Conclusion: These data clearly demonstrate that the baseline value of CRP was closely associated with long time DCT in patients of RA treated with TCZ.Keywords: rheumatoid arthritis, tocilizumab, C-reactive protein, platelet large cell ratio, disease control time

Yoshihisa Ishiura,1,2 Masaki Fujimura,3 Noriyuki Ohkura,4 Johsuke Hara,4 Kazuo Kasahara,4 Nobuyasu Ishii,1 Yusuke Sawai,1 Toshiki Shimizu,1 Takeshi Tamaki,1 Shosaku Nomura1 1First Department of Internal Medicine, Kansai Medical University, Moriguchi, Osaka, Japan; 2Respiratory Medicine, Toyama City Hospital, Toyama, Japan; 3Respiratory Medicine, National Hospital Organization Nanao Hospital, Nanao, Japan; 4Respiratory Medicine, Kanazawa University Hospital, Kanazawa, JapanCorrespondence: Yoshihisa IshiuraFirst Department of Internal Medicine, Kansai Medical University, Kansai Medical University Medical Center, 10-15 Fumizono-Cho, Moriguchi, Osaka 570-8507, JapanTel +81-6-6992-1001Fax +81-6-6993-9837Email ishiura-@p2322.nsk.ne.jpPurpose: Asthma-chronic obstructive pulmonary disease overlap (ACO), characterized by airway limitation, is an important condition with high incidence and mortality. Although some guidelines recommend triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting β2 agonists, this treatment approach is based on the extrapolation of data from studies of asthma or chronic obstructive pulmonary disease (COPD) alone.Methods: A 12-week, randomized, open-label cross-over pilot study was conducted in 19 patients with ACO to investigate the effect of triple therapy with glycopyrrolate (GLY) 50 μg/day on budesonide/formoterol fumarate (BUD/FORM) 640/18 μg/day. The study period included a 4-week wash-out, 4-week run-in, and 4-week treatment period. Respiratory function tests, fractional exhaled nitric oxide (FeNO), a COPD assessment test (CAT) and an asthma control questionnaire (ACQ) were carried out 0, 4, and 8 weeks after randomization.Results: A total of 19 patients with stable ACO (19 males and no females) with a mean age of 70.7 ± 7.6 years (± standard deviation, SD; range 55– 83 years) participated in this study. All patients were ex-smokers with a smoking history of 63.1 ± 41.1 pack-years (± SD). Mean values for inspiratory capacity (IC), an index of hyperinflation of the lung that causes exertional dyspnea and reduced exercise, were 1.93 L (± 0.47 L) after the run-in, 1.85 L (± 0.51 L) after the BUD/FORM dual therapy period and 2.11 L (± 0.58 L) after the BUD/GLY/FORM triple therapy period. IC values after the BUD/GLY/FORM triple therapy were significantly higher than those after the run-in (p < 0.02). FeNO values, ACQ, and CAT scores were not significantly different among the run-in, wash-out, and triple-therapy periods.Conclusion: The present pilot study showed that triple therapy with BUD/GLY/FORM results in an improvement in lung function parameters including IC, indicating the potential value of triple therapy as standard treatment for ACO.Keywords: asthma-COPD overlap, budesonide, glycopyrrolate, formoterol fumarate, triple therapy

Seitaro Omoto,1 Takehito Taniura,2 Tohru Nishizawa,3 Takeshi Tamaki,3 Akira Shouzu,4 Shosaku Nomura3 1Division of Internal Medicine, Korigaoka Yukeikai Hospital, 2Division of Internal Medicine, Daiwa Hospital, 3First Department of Internal Medicine, Kansai Medical University, 4Division of Internal Medicine, Saiseikai Izuo Hospital, Osaka, Japan Background: Advanced glycation end products, selectins, and adiponectin play important roles in the development of atherosclerosis in individuals with diabetes. Sitagliptin has been shown to reduce the concentration of glycated hemoglobin in diabetic patients. However, its effects on soluble receptor for advanced glycation end products (sRAGEs), selectins, and adiponectin in these patients are poorly understood. This study was conducted to assess the effects of sitagliptin on the circulating levels of sRAGEs, monocyte chemoattractant protein-1 (MCP-1), selectins, and adiponectin in patients with type 2 diabetes. Methods: Diabetic patients eligible for sitagliptin monotherapy or combination therapy (eg, sitagliptin plus a sulfonylurea) were administered sitagliptin (50 mg/day) for 6 months. Levels of soluble P-selectin (sP-selectin), soluble E-selectin (sE-selectin), soluble vascular cell adhesion molecule-1 (sVCAM-1), MCP-1, sRAGEs, and adiponectin were measured by ELISA at baseline and after 3 and 6 months of treatment. Results: At baseline, the levels of MCP-1, sP-selectin, sE-selectin, and sVCAM-1 were higher and the level of adiponectin was lower in diabetic patients than in nondiabetic patients. Sitagliptin therapy for 3 and 6 months significantly reduced plasma levels of sP-selectin, sE-selectin, sVCAM-1, and MCP-1 relative to baseline, while significantly increasing adiponectin levels. sRAGEs did not exhibit a statistical significance, although there was an increasing tendency. Furthermore, the reductions in sP-selectin, sE-selectin, sVCAM-1, and MCP-1 during sitagliptin therapy were significantly greater in responders, defined as patients with a significant increase in adiponectin levels, than in nonresponders. In contrast, responders showed a significant increase in the plasma concentration of sRAGEs. Conclusion: Sitagliptin shows an adiponectin-dependent anti-atherothrombotic effect, which may be beneficial for primary prevention of atherothrombosis, in patients with type 2 diabetes. Keywords: type 2 diabetes mellitus, sitagliptin, sRAGE, selectins, sVCAM-1, adiponectin

Ryotaro Ozasa, Masaaki Hotta, Hideaki Yoshimura, Takahisa Nakanishi, Takeshi Tamaki, Shinya Fujita, Naoto Nakamichi, Michihiko Miyaji, Kazuyoshi Ishii, Tomoki Ito, Shosaku NomuraFirst Department of Internal Medicine, Kansai Medical University, Osaka, JapanAbstract: Plasma cell leukemia (PCL) is a rare disease that represents approximately 4% of plasma cell malignant disorders. PCL consists of two variants: primary PCL presents in patients with no previous history of multiple myeloma, while secondary PCL consists of a leukemic transformation in a previously recognized multiple myeloma. Primary PCL is an extremely resistant, rapidly progressive, fatal disease, with a median overall survival of 6.8 months. There is no standard therapeutic strategy, because no treatment option has been prospectively evaluated. We describe a successful case of newly diagnosed primary PCL, treated with a regimen that included bortezomib, followed by auto stem cell transplantation and nonmyeloablative allogeneic stem cell transplantation. Our patient has maintained remission status for over 12 months since undergoing the allogeneic stem cell transplantation. This strategy is promising for PCL, which, though an extremely resistant disease, may become curable.Keywords: plasma cell leukemia, multiple myeloma, bortezomib, stem cell transplantation

Shosaku Nomura1, Takehito Taniura2, Akira Shouzu3, Seitarou Omoto4, Norihito Inami4, Shinya Fujita1, Takeshi Tamaki1, Takashi Yokoi1, Toshiki Shimizu1, Tomoki Ito11First Department of Internal Medicine, Kansai Medical University, Osaka, Japan; 2Department of Internal Medicine, Ueda Hospital, Osaka, Japan; 3Department of Internal Medicine, Saiseikai Izuo Hospital, Osaka, Japan; 4Second Department of Internal Medicine, Kansai Medical University, Osaka JapanAbstract: The effects of statins on two platelet activation markers, plasiminogen activator inhibitor (PAI)-1 and adiponectin, were investigated in 68 patients with hyperlipidemia. The patients were treated with pitavastatin with a dosage of 2 mg daily. The plasma levels of platelet-derived microparticles (PDMP), soluble CD40 ligand (sCD40L), sP-selectin, PAI-1, and adiponectin were measured at baseline and after 6 months of treatment in both groups. In hyperlipidemic patients, the plasma levels were higher in PDMP, sCD40L, sP-selectin, and PAI-1, and lower in adiponectin, compared to the normolipidemic controls. Plasma PDMP and sCD40L were positively correlated, while plasma adiponectin was negatively correlated with the plasma levels of PAI-1. No significant differences were observed in the plasma levels of PDMP, sCD40L, sP-selectin, and PAI-1 before and after treatment. A significant increase in plasma adiponectin levels was observed after 6 months of treatment with pitavastatin. When the patients treated with pitavastatin were divided into two groups according to the adiponectin response to pitavastatin treatment, significant decreases in plasma PAI-1, PDMP, and sCD40L levels were observed after pitavastatin treatment in the responder group. These findings suggest that PDMP, sCD40L, and PAI-1 may participate in the development of atherothrombosis in patients with hyperlipidemia, and that pitavastatin may exert an adiponectin-dependent anti-atherothrombotic effect in hyperlipidemic patients.Keywords: hyperlipidemia, PAI-1, pitavastatin, adiponectin, atherothrombosis

Takashi Yokoi, Takeshi Tamaki, Toshiki Shimizu, Shosaku NomuraFirst Department of Internal Medicine, Kansai Medical University, Moriguchi City, Osaka, JapanBackground: Low-dose metronomic (LDM) chemotherapy is a novel approach that involves frequent administration of a low dose of chemotherapeutic agent without a long interval.Purpose: The aim of this clinical pilot study was to evaluate the toxicity and efficacy of LDM chemotherapy with weekly low-dose docetaxel for previously treated non-small cell lung cancer (NSCLC).Patients and methods: The enrolled patients received 15 mg/m2 of docetaxel intravenously on a weekly basis without any interval.Results: Twenty-seven patients were enrolled in the study; 20 were men, and seven were women. The median age was 62 years (range: 32–75). Eleven patients were stage IIIB, and 16 were stage IV. The Eastern Cooperative Oncology Group performance status was 0 or 1. There was no severe hematological adverse effect; importantly, there was no neutropenia or thrombocytopenia. The objective response rate was 7.4% and the disease control rate was 51.9%. The median survival time was 16.4 months (95% CI: 5.7–36.4).Conclusion: Our preliminary results indicate that our metronomic regimen was well tolerated and active in patients with previously treated NSCLC. Thus, further investigation of this LDM regimen is warranted.Keywords: optimal biological dose, metronomic chemotherapy, docetaxel

Parkinson’s disease (PD) is a degenerative neurological disorder defined by the deterioration and loss of dopamine-producing neurons in the substantia nigra, leading to a range of motor impairments and non-motor symptoms. The underlying mechanism of this neurodegeneration remains unclear. This research examined the neuroprotective properties of Ecklonia cava polyphenols (ECPs) in mitigating neuronal damage induced by rotenone via the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)–antioxidant response element (ARE) pathway. Using human neuroblastoma SH-SY5Y cells and PD model mice, we found that ECP, rich in the antioxidant polyphenol phlorotannin, boosted the gene expression and functionality of the antioxidant enzyme NAD(P)H quinone oxidoreductase-1. ECP also promoted Nrf2 nuclear translocation and increased p62 expression, suggesting that p62 helps sustain Nrf2 activation via a positive feedback loop. The neuroprotective effect of ECP was significantly reduced by Compound C (CC), an AMP-activated protein kinase (AMPK) inhibitor, which also suppressed Nrf2 nuclear translocation. In PD model mice, ECPs improved motor functions impaired by rotenone, as assessed by the pole test and wire-hanging test, and restored intestinal motor function and colon tissue morphology. Additionally, ECPs increased tyrosine hydroxylase expression in the substantia nigra, indicating a protective effect on dopaminergic neurons. These findings suggest that ECP has a preventative effect on PD.

Abstract Background We have suggested “Revised Nutritional Reference Values for Feeding at Evacuation Shelters” (Revised RV) as a daily nutritional recommendation for meals served at evacuation shelters where poor diets had been reported. Since there are no meal examples to satisfy the Revised RV, our objectives were, for the future meal provision, to develop nutritionally adequate meal plans using the foods served at shelters in the past and to examine if the Revised RV could be met by changing combination of foods available. Methods In this case study using secondary data, we analyzed food weights of 86 meals served and recorded at 12 shelters after the heavy rains in July 2020. We obtained these data from Kumamoto Prefecture that was damaged and asked us dietary assessment for nutrition assistance. Foods were classified into 3 types according to the check mark in the record sheets: food aid (commercial packaged food), boxed meal, and hot meal service. We counted serving frequency of each food and analyzed nutritional differences by their combinations. Menus were devised by choosing foods that were served more frequently or were more nutritious among those served at shelters. The target values for one meal were set at 1/3 of the Revised RV for energy, protein, vitamins B1, B2, and C, and salt. Results None of the meals served in the shelters satisfied the target. We created 2 menus using food aid only: (#1 curry doughnut, milk with long shelf-life, and orange jelly) and (#2 salmon rice ball, ham and cheese sandwich, and vegetable juice); 1 menu by combination of boxed meal and food aid: (#3 boxed meal and vegetable juice); and 2 menus by combination of hot meal service and food aid: (#4 chicken meatball soup, packaged tofu, soy sauce, preprocessed white rice, and bottled green tea) and (#5 bamboo shoots rice, chicken and vegetable miso soup, and bottled green tea). Planned menus generally contained more energy, protein, and vitamins and less salt than the meals served. Their vitamin C contents were especially higher. Conclusion Nutritionally adequate meals could be planned by changing the combination of foods available in shelters.

The relationship between the exchange stiffness constant of a perpendicular medium, and high-density recording characteristics was investigated by micromagnetic simulation. As the exchange stiffness increases, larger magnetic clusters are formed in the ac-erased magnetization state. The shortest recordable bit length of the medium corresponds to the cluster size observed in the ac-erased magnetization state. The slope of the magnetization loop also correlates with the average magnetic cluster size. Index Terms--Exchange stiffness, magnetic cluster size, magnetization loop, simulation.