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Yoichi Nishii,1 Kazuki Furuhashi,1 Saki Nakamura,1 Miho Nishio,1 Yuki Nakamura,1 Kengo Ushiro,1 Kentaro Ito,1 Tadashi Sakaguchi,1 Yuta Suzuki,1 Kentaro Fujiwara,1 Taro Yasuma,2 Tetsu Kobayashi,3 Corina D’Alessandro-Gabazza,2 Esteban C Gabazza,2 Osamu Taguchi,1 Osamu Hataji1 1Respiratory Center, Matsusaka Municipal Hospital, Matsusaka, Mie, Japan; 2Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Tsu-city, Mie, Japan; 3Department of Pulmonary and Critical Care Medicine, Faculty and Graduate School of Medicine, Mie University, Tsu-city, Mie, JapanCorrespondence: Esteban C GabazzaDepartment of Immunology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu-city, Mie, 514-8507, JapanTel +81 59 231 5017Fax +81 59 231 5225Email gabazza@doc.medic.mie-u.ac.jpIntroduction: Many patients with nontuberculous mycobacteria pulmonary disease are asymptomatic. The disease diagnosis is confirmed in only a small proportion of patients with radiological findings suspicious for nontuberculous mycobacteria pulmonary disease. Thus, many patients remained undiagnosed. Here, we evaluated the diagnostic value of digital polymerase chain reaction (PCR) in nontuberculous mycobacteria pulmonary disease.Methods: We prospectively evaluated 123 patients with radiological findings suspicious for nontuberculous mycobacteria pulmonary disease. Digital PCR was performed using bronchial lavage fluid, sputum, saliva, blood, and urine.Results: The culture of bronchial washing fluid was positive for nontuberculous mycobacteria in 53 patients and negative in 70. The positive detection rate of nontuberculous mycobacteria by digital PCR in patients with positive culture (n = 53) was as follows: bronchial lavage fluid 100%, sputum 62.9%, saliva 41.5%, blood 7.5%, and urine 3.8%. All patients with two or more positive partitions for nontuberculous mycobacteria in the digital PCR of bronchial lavage fluid showed nontuberculous mycobacteria growth in the bronchial lavage fluid culture. The digital PCR analysis of the bronchial lavage fluid showed a high sensitivity (100%), specificity (85.7%), positive predictive value (84.1%), negative predictive value (100%), and a high concordance rate (91.9%) with the bronchial lavage fluid culture results. In addition, the culture of bronchial lavage fluid was positive for nontuberculous mycobacteria in patients with two or more positive partitions in the digital PCR of sputum and saliva with a combined positive predictive value of 81.1%.Conclusion: Digital PCR analysis of nontuberculous mycobacteria in bronchial lavage fluid shows a high concordance rate with the bronchial lavage fluid culture results and a high positive predictive value using both sputum and saliva, suggesting the potential usefulness of dPCR for diagnosis of nontuberculous mycobacteria pulmonary disease in clinical practice.Keywords: digital PCR, nontuberculous mycobacteria pulmonary disease, diagnosis, bronchial lavage fluid culture, bronchoscopy

Hiroshi Saito,1 Yuya Nakamura,2,3 Masahiro Inagaki,2,4 Shiho Yamadera,5 Hideo Misawa,2,3 Naoki Sato,2,6 Tatsunori Oguchi,2 Takae Inagaki,7 Yuya Tsuji,2 Mayumi Tsuji,2 Isao Ohsawa,3 Hiromichi Gotoh,3 Yuji Kiuchi2 1JA Hiroshima Genneral Hospital, Hatsukaichi City, Hiroshima, Japan; 2Department of Pharmacology, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan; 3Saiyu Soka Hospital, Soka City, Saitama, Japan; 4Faculty of Arts and Sciences at Fujiyoshida, Showa University, Fujiyoshida City, Yamanashi, Japan; 5Department of Hospital Pharmaceutics, Showa University School of Pharmacy, Shinagawa-ku, Tokyo, Japan; 6Department of Research Center, Tanabe Pharmacy Inc., Chuo-ku, Tokyo, Japan; 7Graduate School of Nursing and Rehabilitation Science, Yokohama City, Kanagawa, JapanCorrespondence: Yuya Nakamura Email y.nakamura@med.showa-u.ac.jpPurpose: Lipopolysaccharides (LPS) induce inflammation by binding to the Toll-like receptor (TLR) 4 complex, including LPS-binding protein (LBP). The anti-inflammatory effects of linagliptin in LPS-induced inflammation in the TLR4-independent pathway have not been examined before. We examined the anti-inflammatory effects of linagliptin in the TLR4- and the LBP-independent pathway.Methods: U937 cells were cultured in the medium supplemented with 10% fetal bovine serum (FBS) and treated with 100 nM phorbol myristate acetate for 48 h. Cells were then left untreated or were treated with 10 μg/mL anti-TLR4 antibodies alone or in combination with linagliptin for 1 h in media supplemented with or without 10% FBS. The cells were divided into 5 groups: a) control cells (untreated) b) cells treated with LPS c) cells treated with 10 μg/mL anti-TLR4 antibodies d) cells treated with LPS and 10 μg/mL anti-TLR4 antibodies and e) cells treated with LPS, 10 μg/mL anti-TLR4 antibodies, and linagliptin. The LPS concentrations used were 50 pg/mL or 100 pg/mL for cells treated in the presence of 10% FBS and 100 pg/mL or 1 μg/mL for cells treated in the absence of FBS. Linagliptin concentrations of 1 nM, 10 nM, and 100 nM were used for treatment. The supernatants were analyzed for interleukin (IL)-6 production after 24 h of various treatments.Results: LPS increased IL-6 production compared to the untreated control cells, and anti-TLR4 antibody suppressed LPS-induced increased IL-6 levels. Linagliptin suppressed LPS-induced IL-6 production in a concentration-dependent manner in the presence of FBS. However, only 100 nM linagliptin could suppress LPS-induced IL-6 production in the absence of FBS.Conclusion: Concentration-dependent and -independent inflammatory suppression was observed following linagliptin treatment after LPS induction in an experimental model of TLR4 inhibition by anti-TLR4 antibodies. Our results showed that linagliptin may inhibit inflammation through multiple mechanisms centered around the TLR-4-mediated pathway.Keywords: lipopolysaccharide, U937 cells, fetal bovine serum, anti- toll-like receptor 4 antibody, interleukin-6

Masaki Nakano,1,* Haruka Yui,1,* Shingo Kikugawa,2 Ryosuke Tokida,3 Noriko Sakai,4 Naoki Kondo,5 Naoto Endo,5 Hirotaka Haro,6 Hiroki Shimodaira,1 Takako Suzuki,1,7 Hiroyuki Kato,1 Jun Takahashi,1 Yukio Nakamura1 1Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Nagano, 390-8621, Japan; 2DNA Chip Research Inc., Minato-ku, Tokyo, 105-0022, Japan; 3Rehabilitation Center, Shinshu University Hospital, Matsumoto, Nagano, 390-8621, Japan; 4Department of Orthopaedic Surgery, New Life Hospital, Obuse, Nagano, 381-0295, Japan; 5Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, 951-8510, Japan; 6Department of Orthopaedic Surgery, University of Yamanashi Graduate School of Medicine, Chuo, Yamanashi, 409-3898, Japan; 7Department of Human Nutrition, Faculty of Human Nutrition, Tokyo Kasei Gakuin University, Chiyoda-ku, Tokyo, 102-8341, Japan*These authors contributed equally to this workCorrespondence: Yukio NakamuraDepartment of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, JapanTel +81-263-37-2659Fax +81-263-35-8844Email yxn14@aol.jpObjective: Osteoarthritis (OA) is a common and degenerative joint disorder in the elderly. A greater importance of understanding the relationship between genetic factors and OA prevalence has emerged with population aging. We therefore investigated the associations of several bone disease-related genetic variants with the prevalence of OA and osteoporosis in Japanese elderly women from the Obuse study cohort, which was randomly sampled from a basic town resident registry.Methods and Results: In total, 206 female participants (mean ± standard deviation age: 69.7 ± 11.0 years) who completed OA, bone mineral density, and genotype assessments were included. The number of patients diagnosed as having knee/hip OA and osteoporosis was 59 (28.6%) and 30 (14.6%), respectively. Fisher’s exact testing revealed significant relationships between the minor T allele of LDL receptor related protein 5 (LRP5) rs3736228 and the prevalence of knee/hip OA and osteoporosis. The respective odds ratios (ORs) of the TT genotype for knee/hip OA and osteoporosis were 7.28 (95% confidence interval [CI] 2.22– 28.08) and 5.24 (95% CI 0.95– 26.98). An additional subgroup analysis for knee OA revealed that the frequency of the common C allele of methylenetetrahydrofolate reductase (MTHFR) rs1801133 had a statistically significant protective association with the prevalence of knee OA (OR 0.58, 95% CI 0.35– 0.97).Conclusion: In sum, the present study demonstrated significant associations of LRP5 rs3736228 and MTHFR rs1801133 with knee/hip OA and osteoporosis prevalences and knee OA prevalence, respectively, in Japanese elderly women. These results will help further the understanding of OA pathogenesis and related genetic risk factors.Keywords: genetic variant, LRP5, MTHFR, osteoarthritis, osteoporosis

Takashige Momose,1 Yukio Nakamura,2 Masaki Nakano,2 Takashi Maeda,1 Susumu Morioka,3 Atsushi Sobajima,1 Yukio Nakatsuchi,1 Jun Takahashi,2 Masashi Nawata1 1Department of Orthopaedic Surgery, Marunouchi Hospital, Matsumoto, Nagano, 390-8601, Japan; 2Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Nagano, 390-8621, Japan; 3Department of Orthopaedic Surgery, Chikuma Central Hospital, Chikuma, Nagano, 387– 8512, JapanCorrespondence: Yukio NakamuraDepartment of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, JapanTel +81-263-37-2659Fax +81-263-35-8844Email yxn14@aol.jpObjective: This study aimed to evaluate the short- to mid-term clinical results of posterior-stabilized trabecular metal total knee arthroplasty (TKA) with cementless fixation of all components and investigate the radiographic changes of tibial and patellar components and cut bone surfaces over time.Methods: We retrospectively collected the data of 128 knees from 88 consecutive patients who had undergone initial TKA with NexGen LPS-Flex TM implants. A total of 66 knees from 45 patients (mean ± standard deviation age: 70.3 ± 7.5 years) met the selection criteria, which had been employed cementless fixation of all parts and at least 3 years of postoperative follow-up duration. Clinical evaluations included range of motion, conventional knee score, function score, postoperative complications, and revision. For radiological evaluations, the bone contact surface of each implant was divided into 7 zones for tibial component and 2 zones for patellar component. Each region was examined immediately after surgery, at 6 and 12 months, and then every year afterwards.Results: The mean observation period of 45 subjects was 4.2 years. Adequate fixation of tibial components was maintained during follow-up, although the patellar components of 2 knees required revision after repeated falls. No loosening was observed in any implants. The initial gap in tibial components disappeared in all knees, and a reactive line remained in 4 knees. There were no revisions, except for 2 cases, which were ascribed to patellar component fracture caused by repeated falls.Conclusion: Cementless posterior-stabilized trabecular metal TKA appears to be a good surgical option. Longer-term examination for revision cases is required to validate our results.Keywords: cementless fixation, short- to mid-term clinical outcomes, total knee arthroplasty, trabecular metal components

Maude Laberge,1– 3 Caroline Sirois,2– 5 Carlotta Lunghi,3,6 Myriam Gaudreault,7 Yumiko Nakamura,8 Carolann Bolduc,4 Marie-Laure Laroche9,10 1Department of Operations & Decision Systems, Faculty of Administration, Université Laval, Quebec City, Quebec, Canada; 2Vitam, Centre de recherche en santé durable-Université Laval, Quebec, Canada; 3Centre de recherche du CHU de Québec-Université Laval, Quebec City, Quebec, Canada; 4Faculty of Pharmacy, Université Laval, Quebec City, Quebec, Canada; 5Institut National de santé publique du Québec, Quebec City, Quebec, Canada; 6Department of Health Sciences, Université du Québec à Rimouski, Rimouski, Quebec, Canada; 7Faculty of Administration, Université Laval, Quebec City, Quebec, Canada; 8College of Medicine, University of Florida, Gainesville, FL, USA; 9Centre de Pharmacovigilance, de Pharmacoépidémiologie et d’information sur les médicaments, Service de Pharmacologie, Toxicologie et Pharmacovigilance, CHU de Limoges, Limoges, France; 10Laboratoire Vie-Santé, Faculté de Médecine, Université de Limoges, Limoges, FranceCorrespondence: Maude LabergeDepartment of Operations & Decision Systems, Faculty of Administration, Université Laval, 2325 rue de la Terrasse, Bureau 2519, Quebec City, Québec, G1V 0A6, CanadaTel +1 418-656-2131 ext 407670Fax +1 418-656-2180Email Maude.laberge@fsa.ulaval.caPurpose: To conduct a systematic review of the economic impact of interventions intended at optimizing medication use in older adults with multimorbidity and polypharmacy.Methods: We searched Ovid-Medline, Embase, CINAHL, Ageline, Cochrane, and Web of Science, for articles published between 2004 and 2020 that studied older adults with multimorbidity and polypharmacy. The intervention studied had to be aimed at optimizing medication use and present results on costs.Results: Out of 3,871 studies identified by the search strategy, eleven studies were included. The interventions involved different provider types, with a majority described as a multidisciplinary team involving a pharmacist and a general practitioner, in the decision-making process. Interventions were generally associated with a reduction in medication expenditure. The benefits of the intervention in terms of clinical outcomes remain limited. Five studies were cost-benefit analyses, which had a net benefit that was either null or positive. Cost-utility and cost-effectiveness analyses resulted in incremental cost-effectiveness ratios that were generally within the willingness-to-pay thresholds of the countries in which the studies were conducted. However, the quality of the studies was generally low. Omission of key cost elements of economic evaluations, including intervention cost and payer perspective, limited interpretability.Conclusion: Interventions to optimize medication use may provide benefits that outweigh their implementation costs, but the evidence remains limited. There is a need to identify and address barriers to the scaling-up of such interventions, starting with the current incentive structures for pharmacists, physicians, and patients.Keywords: polypharmacy, economic evaluation, potentially inappropriate medication, cost-effectiveness, cost-utility, cost-benefit

Masushi Kohta,1 Yoshinori Nakamura,2,3 Shunji Yunoki4 1Medical Engineering Laboratory, ALCARE Co., Ltd, Tokyo, Japan; 2Department of Medical Home Healthcare Center, Tenri Hospital Shirakawa Branch, Nara, Japan; 3Pressure Injury Research Center for Home Healthcare, Nara, Japan; 4Biotechnology Group, Tokyo Metropolitan Industrial Technology Research Institute, Tokyo, JapanCorrespondence: Masushi KohtaMedical Engineering Laboratory, ALCARE Co., Ltd, 1-21-10 Kyojima, Sumida-ku, Tokyo, 131-0046, JapanTel +81-3-3611-1101Fax +81-3-3613-6894Email mkouta@alcare.co.jpPurpose: This study evaluated the effect of a new secondary dressing used as a topical aid sliding sheet for friction and shear force reduction on the mechanical stresses generated on human skin, including interface friction and internal shear force and pressure, using a polyurethane gel-based skin model. A case study was conducted to propose on how to clinically use the topical aid sliding sheet for pressure injury treatment in a home-care setting.Methods: A polyurethane gel-based skin model mimicking the mechanical properties of human skin was prepared. In parallel measurement of interface friction and internal shear force and pressure was performed using an experimental model consisting of the skin model, primary wound dressing, topical aid sliding sheet, and three-axis tactile sensor. The skin model was covered with the following single or combined dressings: group A, silicone-faced absorbent dressing (control); group B, silicone-faced absorbent dressing plus film dressing; and group C, silicone-faced absorbent dressing plus topical aid sliding sheet. Clinically, a standard primary wound dressing was applied to a female patient (age, 101 years) with pressure injury on the sacral region, and the dressing was overwrapped with the topical aid sliding sheet.Results: The static and dynamic coefficients of friction were significantly lower in group C than in groups A and B (p < 0.05). The detected shear force in the skin model was reduced to approximately 66% and 62% in group C versus groups A and B, respectively (p < 0.05). Clinically, the patient’s ulcer underwent complete epithelialization without wound-related complications.Conclusion: The topical aid sliding sheet significantly reduced interface friction and internal shear forces in the present skin model. The case study’s result showed the topical aid sliding sheet had the potential to use for pressure injury treatment at a home care.Keywords: pressure ulcer, tissue viability, dressing, mechanical force, wound care, shear force, friction

Masushi Kohta,1 Takehiko Ohura,2 Katsuyuki Okada,3 Yoshinori Nakamura,4 Eiko Kumagai,5 Hitomi Kataoka,6 Tomomi Kitagawa,7 Yuki Kameda,8 Toshihiro Kitte9 1Medical Engineering Laboratory, ALCARE Co. Ltd., Tokyo, Japan; 2Pressure Ulcers and Wound Healing Research Center, Sapporo, Japan; 3Department of Dermatology, Kiryu Kosei General Hospital, Kiryu, Japan; 4Department of Medical Home Healthcare Center, Tenri Hospital Shirakawa Branch, Tenri, Japan; 5Murata Day Surgery & WOC Clinic, Sendai, Japan; 6Department of Nursing, Yamagata University, Yamagata, Japan; 7Department of Nursing, Hikone Municipal Hospital, Hikone, Japan; 8Wound Care Marketing Division, ALCARE Co Ltd., Tokyo, Japan; 9Department of Health Care Policy, Shiga Government Office, Otsu, JapanCorrespondence: Masushi KohtaMedical Engineering Laboratory, ALCARE Co., Ltd., 1-21-10 Kyojima, Sumida-ku, Tokyo 131-0046, JapanTel +81-3-3611-1101Fax +81-3-3613-6894Email mkouta@alcare.co.jpPurpose: The Pressure Injury Primary Risk Assessment Scale for Home Care (PPRA-Home) was developed to predict pressure injury risk in geriatric individuals requiring long-term care in home settings. This study aimed to compare the convergent validity of the PPRA-Home to that of the two other standardized pressure injury prevention scales: the Braden and Ohura-Hotta (OH) scales.Methods: A multicenter, cross-sectional study was conducted with 34 home-based geriatric support service providers located in five Japanese districts. The study included 69 participants (30 had a pressure injury and 39 did not) who were at classified at care levels of 1 through 5 under Japan’s long-term care insurance system. Care managers served as assessors for the PPRA-Home, while physicians or certified expert nurses served as assessors for the Braden and OH scales. Convergent validity was investigated by examining correlation coefficients between total scores on the PPRA-Home and the other two scales. Receiver operating curve analysis was used to quantify each scale’s accuracy for the two groups: those with and without a pressure injury.Results: The PPRA-Home was found to be negatively correlated with the Braden scale (r=− 0.79, p< 0.05), and positively correlated with the OH scale (r=0.58, p< 0.05). The area under the curve (AUC) for the PPRA-Home, Braden scale, and OH scale were 0.737, 0.814, and 0.794, respectively. A PPRA-Home cutoff score of 4 had a sensitivity of 63.3% and specificity of 81.6%.Conclusion: The AUC for the PPRA-Home as scored by care managers was similar to those of the Braden and OH scales as scored by physicians or expert nurses. More research on the PPRA-Home’s content and predictive validity is required.Keywords: pressure ulcer, risk assessment, geriatrics, wound care

Masushi Kohta,1 Takehiko Ohura,2 Kunio Tsukada,3 Yoshinori Nakamura,4 Mishiho Sukegawa,5 Eiko Kumagai,6 Yuki Kameda,7 Toshihiro Kitte8 1Medical Engineering Laboratory, ALCARE Co. Ltd., Tokyo, Japan; 2Pressure Ulcers and Wound Healing Research Center, Sapporo, Japan; 3Takaoka Ekinan Clinic, Takaoka, Japan; 4Department of Medical Home Healthcare Center, Tenri Hospital Shirakawa Branch, Tenri, Japan; 5Miyama-Takinoi Comprehensive Community Support Center, Funabashi, Japan; 6Murata Day Surgery & WOC Clinic, Sendai, Japan; 7Wound Care Marketing Division, ALCARE Co Ltd., Tokyo, Japan; 8Department of Health Care Policy, Shiga Government Office, Otsu, Shiga, JapanCorrespondence: Masushi KohtaMedical Engineering Laboratory, ALCARE Co., Ltd., Tokyo, JapanEmail mkouta@alcare.co.jpPurpose: The aim of the current study was to assess the inter-rater reliability and agreement of the Pressure Injury Primary Risk Assessment Scale for Home Care (PPRA-Home), a risk assessment scale recently developed for Japan-specific social welfare professionals called care managers, to predict pressure injury risk in geriatric individuals who require long-term home care needs.Methods: A multicenter cross-sectional study was conducted at 30 home-based geriatric support services facilities located at four local districts in Japan. Eligible participants were individuals who needed partial or full assistance for daily living under Japan’s long-term care insurance system (care levels 1– 5). The degree of agreement and kappa coefficient were calculated for each item and the total score, after which inter-rater reliability was determined. The effect of the participant’s care level on reliability was also evaluated as secondary analysis.Results: A total of 96 participants were assessed by 83 care managers (two assessors scored each participant). The degree of agreement and calculated kappa coefficient of the PPRA-Home total score were 59% and 0.72, respectively, with the inter-rater reliability for the total score determined to be “Substantial”. Our subgroup analysis showed that the inter-rater reliability differed according to the participant’s care level. Accordingly, the kappa coefficient for the total score was lower in subgroup “care level 1– 3” than in subgroup “care level 4– 5” (0.51 and 0.76, respectively).Conclusion: Our result showed that the PPRA-Home has substantial inter-rater reliability for evaluation of risks of pressure injury development at home care. However, some research focusing on intra-later reliability and validity of the PPRA-Home with adequate sample sizes are required to provide categorical conclusions on whether it can be used for the risk assessment scale in actual clinical settings.Keywords: pressure ulcer, risk assessment, reproducibility, agreement, geriatrics

Manami Kinjo, Kazuki Masuda, Yu Nakamura, Satoru Taguchi, Mitsuhiro Tambo, Takatsugu Okegawa, Hiroshi Fukuhara Department of Urology, Kyorin University School of Medicine, Tokyo 181-8611, JapanCorrespondence: Manami Kinjo Tel +81 422 47 5511Fax +81 422 42 8431Email kinjo_1702@yahoo.co.jpPurpose: Urinary incontinence (UI) is a common health-related problem in the female population and has a negative impact on many aspects of patients’ quality of life including mental problems. This study evaluated the mental effects of mid-urethral sling (MUS) surgery in female patients with stress UI or stress UI-dominant mixed UI.Patients and Methods: Women with stress UI or stress UI-dominant mixed UI who underwent MUS surgery and were enrolled in this study and followed up for 12 months. The International Consultation of Incontinence Questionnaire-Short Form (ICIQ-SF) and the Hospital Anxiety and Depression Scale (HADS) at baseline and 12 months after the MUS to evaluate the efficacy of the surgery.Results: At baseline, proportions of the patients with anxiety (HADS-Anxiety score of ≥ 8) and depression (HADS-Depression score of ≥ 8) were 21.6% (22/102) and 24.5% (25/102), respectively. At 12 months postoperatively, the median ICIQ-SF score, HADS-Anxiety score, and HADS-Depression score were significantly improved compared with their baseline values (p< 0.001 for ICIQ-SF and HADS-Depression, p=0.011 for HADS-Anxiety). At 12 months postoperatively, changes in the ICIQ-SF and HADS-A scores showed a moderate correlation (r = 0.578, p < 0.001), and changes in the ICIQ-SF and HADS-D scores had a strong correlation (r = 0.838, p < 0.001).Conclusion: This study demonstrated that MUS surgery significantly improved UI, anxiety, and depression with significant correlations in their symptoms. This suggests that improvement of the patients’ UI helped to relieve their symptoms of anxiety and depression.Keywords: urinary incontinence, anxiety, depression, mid-urethral sling surgery

Tatsuya Ogawa, 1 Yosuke Ishitsuka, 1 Yoshiyuki Nakamura, 1 Naoko Okiyama, 1 Rei Watanabe, 1, 2 Yasuhiro Fujisawa, 1 Manabu Fujimoto 1, 2 1Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; 2Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Osaka, JapanCorrespondence: Yosuke IshitsukaDepartment of Dermatology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, JapanTel +81-29-853-3128Fax +81-29-853-3217Email yosuke.ishitsuka@md.tsukuba.ac.jpIntroduction: The stratum corneum protects against the entry of pathogens, allergens, and irritants while preventing dehydration. The Kelch-like erythroid cell-derived protein with cap-n-collar homology-associated protein 1 (KEAP1)/NF-E2-related factor 2 (NRF2) system maintains skin barrier homeostasis. Aggregated evidence suggests that NRF2-mediated antioxidative response is hardwired into the stratified squamous epithelia. Honey and chamomile have long been regarded as natural antioxidants. Nonetheless, it is still unclear whether they activate the KEAP1/NRF2 system in the epidermis and could promote epidermal barrier recovery.Methods: To address the abovementioned issue, we explored the antioxidative property of honey/chamomile extract by using non-cell-based KEAP1-inhibition assay and cultured human epidermal keratinocytes.Results: Herein we report that the extract inhibited KEAP1-NRF2 interaction and induced keratinocyte production of antioxidant small proline-rich protein.Conclusion: Our results may offer an opportunity to develop cosmetic products that boost NRF2-mediated antioxidative/antiaging, epidermis-intrinsic bio-responses.Keywords: NRF2, honey, chamomile, keratinocyte

Takashi Ono,1,2 Katsuhito Kinoshita,1 Takuya Iwasaki,1 Yosai Mori,1 Ryohei Nejima,1 Yasuko Nakamura,3 Shiro Amano,4 Makoto Aihara,2 Kazunori Miyata1 1Miyata Eye Hospital, Miyakonojo, Miyazaki, Japan; 2Department of Ophthalmology, The University of Tokyo, Tokyo, Japan; 3Kagoshima Miyata Eye Clinic, Kagoshima, Japan; 4Inouye Eye Hospital, Tokyo, JapanCorrespondence: Takashi OnoMiyata Eye Hospital, 6-3, Kuraharacho, Miyakonojo, Miyazaki 885-0051, JapanTel +81-986-22-1441Fax +81-986-24-2174Email taono-tky@umin.ac.jpPurpose: To investigate the clinical courses of patients with corneal endothelial dysfunction due to Gomphocarpus physocarpus milky latex-induced injury.Patients and methods: In this retrospective case series, we included consecutive patients who visited Miyata Eye Hospital or Kagoshima Miyata Eye Clinic between October 2010 and August 2017 and had corneal edema caused by G. physocarpus milky latex-induced injury. Patient information and data on central corneal thickness (CCT), corneal endothelial cell density (ECD), best-corrected visual acuity (BCVA), and treatment were retrospectively reviewed.Results: Five eyes of four patients were included. The mean age was 79.0 ± 7.1 years. All patients complaining of symptoms visited the hospital 1 or 2 days after the injury. All patients had corneal edema; two of the five eyes showed hyperemia, whereas none showed corneal epithelial defect or blepharitis. The mean CCT was 699.8 ± 95.9 μm at the first visit and decreased to 563.2 ± 74.0 μm 1 week after the injury with treatment with topical steroids and antibiotics. The mean ECD and BCVA were 2695.8 ± 191.3 cells/mm2 and 0.22 ± 0.19 at the first visit and 2826.0 ± 132.9 cells/mm2 and 0.10 ± 0.09 one week after the injury, respectively.Conclusion: G. physocarpus caused transient dysfunction of the corneal endothelium and thereby, corneal edema. Accurate diagnosis with history taking is important to ascertain the types of plants the patient has touched and to exclude other possible diagnoses.Keywords: Asclepias physocarpus, corneal endothelial dysfunction, corneal edema, plant toxin

Naoki Sato,1,2 Yuya Nakamura,1,3 Shiho Yamadera,4 Masahiro Inagaki,1,5 Sachiyo Kenmotsu,5 Hiroshi Saito,4,6 Tatsunori Oguchi,1 Mayumi Tsuji,1 Hirokazu Chokki,1 Isao Ohsawa,3 Hiromichi Gotoh,3 Shinichi Iwai,6 Yuji Kiuchi1 1Department of Pharmacology, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan; 2Department of Research Center, Tanabe Pharmacy Inc., Tokyo, Japan; 3Department of Nephrology, Saiyu Soka Hospital, Soka City, Saitama-ken, Japan; 4Department of Hospital Pharmaceutics, Showa University School of Pharmacy, Shinagawa-ku, Tokyo, Japan; 5Fuculty of Arts and Sciences at Fujiyoshida, Showa University, Fujiyoshida City, Yamanashi-ken, Japan; 6Department of Healthcare and Regulatory Sciences, Showa University School of Pharmacy, Shinagawa-ku, Tokyo, JapanCorrespondence: Yuya NakamuraDepartment of Pharmacology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, JapanTel +81-3-3784-8125Fax +81-3-3787-4790Email y.nakamura@med.showa-u.ac.jpPurpose: Dipeptidyl peptidase-4 inhibitors, including linagliptin, prevent inflammation. However, the in vitro effects of linagliptin are unclear. Moreover, although linagliptin inhibits lipopolysaccharide (LPS)-induced inflammation, the anti-inflammatory effects of linagliptin in this context are not concentration-dependent. In the absence of LPS-binding protein (LBP), the pro-inflammatory effects of LPS involve pathways other than the Toll-like receptor (TLR) 4 pathway. Here, we aimed to determine the anti-inflammatory mechanisms of linagliptin in an experimental model in which LBP was added to the medium.Methods: Human U937 monocytes were cultured at 1 × 106 cells/mL in Roswell Park Memorial Institute medium and differentiated into macrophages using phorbol myristate acetate. All processes were carried out in medium containing 10% fetal bovine serum (FBS). After 48 hrs of culture, we replaced the medium and pretreated the cells with 100, 250, 500, or 2500 nM linagliptin for 1 hr. We exchanged the medium again, and the cells were treated with 1 ng/mL LPS with or without 100, 250, 500, or 2500 nM linagliptin. Interleukin (IL)-6 and LBP in the supernatant, nuclear factor (NF)-κB/p65 in the nucleus, and reactive oxygen species (ROS) in the cells, as important markers of the mechanism of inflammation induction by LPS, were measured using enzyme-linked immunosorbent assay kits.Results: Linagliptin significantly prevented LPS-stimulated IL-6 production and intranuclear NF-κB/p65 levels in a concentration-dependent manner. LPS-induced intracellular ROS levels were significantly decreased by linagliptin at all concentrations. LBP levels were markedly higher in FBS-containing medium than in medium without FBS. However, LBP levels did not change following administration of linagliptin and/or LPS.Conclusion: Concentration-dependent and -independent inflammatory suppression was observed following linagliptin treatment in the context of LPS-induced pro-inflammatory responses. Thus, our findings suggested that linagliptin induced two different mechanisms to repress inflammation, i.e., TLR4-dependent and -independent mechanisms.Keywords: linagliptin, lipopolysaccharide-binding protein, interleukin-6, intranuclear subunit of nuclear factor-κB/p65, reactive oxygen species

Kazuki Furuhashi,1,2 Tomoyuki Fujisawa,1 Dai Hashimoto,3 Yousuke Kamiya,1 Hideki Yasui,1 Masato Karayama,1 Yuzo Suzuki,1 Hironao Hozumi,1 Noriyuki Enomoto,1 Yutaro Nakamura,1 Naoki Inui,1,4 Takafumi Suda1 1Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan; 2Department of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan; 3Department of Respiratory Medicine, Seirei Hamamatsu General Hospital, Hamamatsu, Japan; 4Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, JapanCorrespondence: Kazuki FuruhashiSecond Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, JapanTel +81 53 435 2870Fax +81 53 435 2096Email k.furu@hama-med.ac.jpIntroduction: Fluticasone furoate (FF)/vilanterol (VI) dry powder inhaler (DPI) is the only once-daily maintenance inhaled corticosteroid (ICS)/long-acting β2 adrenergic agonist (LABA) combination for asthma. We aimed to compare the clinical effects of once-daily FF/VI and twice-daily budesonide (BUD)/formoterol (FM) DPI in patients with controlled stable asthma.Methods: We performed a randomized crossover trial in which stable asthmatic patients controlled on ICS/LABA received 8 weeks of FF/VI (100/25 μg 1 puff once-daily) or BUD/FM (160/4.5 μg 2 puffs twice-daily) DPI treatment. After a 4–8-week washout period, patients received another crossover treatment for 8 weeks. We assessed pulmonary function, the 5-item version asthma control questionnaire (ACQ5), the asthma control test (ACT), and fractional exhaled nitric oxide (FeNO) at baseline and after 8 weeks of treatment (week 8). As the primary outcome was change in force expiratory volume in 1 s (FEV1) between baseline and week 8, we evaluated the incidence of asthma exacerbation and adherence barrier questionnaire (Ask-12) at week 8.Results: Twenty-three patients were initially enrolled in this study; however, one patient had to be excluded. The FF/VI DPI treatment group showed a similar magnitude of change in FEV1 between baseline and week 8 as the BUD/FM DPI treatment group. In addition, there were no significant differences in pulmonary function tests, ACQ5 scores, ACT scores, and FeNO between baseline and week 8 in both groups. Although the incidence of exacerbation did not differ between groups, the Ask-12 score in the FF/VI DPI group was significantly lower than that in the BUD/FM DPI group.Conclusions: The present study indicates that once-daily FF/VI DPI is not inferior to twice-daily BUD/FM DPI in clinical effect and more likely to improve inconvenience and forgetfulness in inhalation adherence barriers for stable asthma control therapy. Once-daily FF/VI DPI may be an effective alternative for asthma maintenance treatment.Keywords: fluticasone furoate/vilanterol, budesonide/formoterol, stable asthma, randomized crossover trial, inhalation adherence barriers

Yuzo Suzuki,1 Naoki Inui,1 Masato Karayama,1 Shiro Imokawa,2 Takashi Yamada,3 Koushi Yokomura,4 Kazuhiro Asada,5 Hideki Kusagaya,6 Yusuke Kaida,7 Hiroyuki Matsuda,8 Naoki Koshimizu,9 Mikio Toyoshima,10 Masafumi Masuda,11 Hiroshi Hayakawa,12 Hironao Hozumi,1 Kazuki Furuhashi,1 Noriyuki Enomoto,1 Tomoyuki Fujisawa,1 Yutaro Nakamura,1 Takafumi Suda11Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan; 2Department of Respiratory Medicine, Iwata City Hospital, Iwata, Japan; 3Department of Respiratory Medicine, Shizuoka City Shizuoka Hospital, Shizuoka, Japan; 4Department of Respiratory Medicine, Seirei-Mikatahara Hospital, Hamamatsu, Japan; 5Department of Respiratory Medicine, Shizuoka General Hospital, Shizuoka, Japan; 6Department of Respiratory Medicine, Shizuoka Saiseikai Hospital, Shizuoka, Japan; 7Department of Respiratory Medicine, JA Shizuoka Kohseiren Enshu Hospital, Hamamatsu, Japan; 8Department of Respiratory Medicine, Shizuoka Red Cross Hospital, Shizuoka, Japan; 9Department of Respiratory Medicine, Fujieda City Hospital, Fujieda, Japan; 10Department of Respiratory Medicine, Hamamatsu Rosai Hospital, Hamamatsu, Japan; 11Department of Respiratory Medicine, Shizuoka City Shimizu Hospital, Shizuoka, Japan; 12Department of Respiratory Medicine, Tenryu Hospital, National Hospital Organization, Hamamatsu, JapanCorrespondence: Yuzo SuzukiSecond Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama Higashi-ku, Hamamatsu, Shizuoka 431-3192, JapanTel +81 53 435 2263Fax +81 53 435 2354Email yuzosuzu@hama-med.ac.jpBackground: Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor, has been shown to improve survival in non-small cell lung cancer (NSCLC). The possible involvement of PD-1 axis in the pathogenesis of inflammatory lung disease, such as chronic obstructive pulmonary disease (COPD) has also been reported. However, effects of PD-1 blockade on the respiratory system remain unknown.Objectives: This prospective study aimed to investigate whether inhibition of the PD-1 axis altered lung inflammation and pulmonary function in NSCLC patients with and without COPD.Method: This was a prospective multi-center study. Measurements of fractioned exhaled nitric oxide (FeNO) and pulmonary function were performed before and after 4 cycles of nivolumab therapy.Results: A total of 137 patients with NSCLC were initially enrolled, and subsequently 95 patients (41 COPD and 54 non-COPD) receiving 4 cycles of nivolumab administration were included. After anti-PD-1 therapy, FeNO levels were significantly elevated together with increase in peripheral eosinophils. Interestingly, significant FeNO elevation was only found in COPD patients without increased peripheral eosinophils, but this was not the case in non-COPD patients. Additionally, COPD patients exhibited significant increases in FVC and FEV1 but no changes in dyspnea scales, and acute exacerbation did not occur during the therapy.Conclusion: Our observations suggest that anti-PD-1 therapy changed FeNO levels and pulmonary function in NSCLC patients. This therapy does not worsen COPD in terms of symptoms, pulmonary function, or acute exacerbation.Keywords: immune checkpoint inhibitor, programmed death 1, PD-1, non-small cell lung cancer, NSCLC, chronic obstructive pulmonary disease, COPD

Masato Karayama,1 Naoki Inui,1,2 Hideki Yasui,1 Masato Kono,1 Hironao Hozumi,1 Yuzo Suzuki,1 Kazuki Furuhashi,1 Dai Hashimoto,1 Noriyuki Enomoto,1 Tomoyuki Fujisawa,1 Yutaro Nakamura,1 Hiroshi Watanabe,2 Takafumi Suda11Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan; 2Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu 431-3192, JapanPurpose: The diagnosis and severity of chronic obstructive pulmonary disease (COPD) are defined by airflow limitation using spirometry. However, COPD has diverse clinical features, and several phenotypes based on non-spirometric data have been investigated. To identify novel phenotypes of COPD using radiologic data obtained by three-dimensional computed tomography (3D-CT).Patients and methods: The inner luminal area and wall thickness of third- to sixth-generation bronchi and the percentage of the low-attenuation area (less than −950 HU) of the lungs were measured using 3D-CT in patients with COPD. Using the radiologic data, hierarchical clustering was performed. Respiratory reactance and resistance were measured to evaluate functional differences among the clusters.Results: Four clusters were identified among 167 patients with COPD: Cluster I, mild emphysema with severe airway changes, severe airflow limitation, and high exacerbation risk; Cluster II, mild emphysema with moderate airway changes, mild airflow limitation, and mild dyspnea; Cluster III, severe emphysema with moderate airway changes, severe airflow limitation, and increased dyspnea; and Cluster IV, moderate emphysema with mild airway changes, mild airflow limitation, low exacerbation risk, and mild dyspnea. Cluster I had the highest respiratory resistance among the four clusters. Clusters I and III had higher respiratory reactance than Clusters II and IV.Conclusions: The 3D-CT-based radiologic phenotypes were associated with the clinical features of COPD. Measurement of respiratory resistance and reactance may help to identify phenotypic differences.Keywords: airway, chronic obstructive pulmonary disease, clustering analysis, emphysema, phenotype, three-dimensional computed tomography

Masashi Uehara,1 Yukio Nakamura,1 Jun Takahashi,1 Takako Suzuki,1 Mari Iijima,2 Yuko Arakawa,3 Koichi Ida,4 Tomoki Kosho,5,6 Hiroyuki Kato1 1Department of Orthopaedic Surgery, Shinshu University School of Medicine; 2Department of Clinical Nutrition, Shinshu University School of Medicine; 3Department of Dentistry and Oral Surgery, Shinshu University School of Medicine; 4Department of Obstetrics and Gynecology, Shinshu University School of Medicine; 5Department of Medical Genetics, Shinshu University School of Medicine; 6Center for Medical Genetics, Shinshu University Hospital, Matsumoto, Japan Abstract: Appropriate management for osteoporosis in adult patients with Prader-Willi syndrome (PWS) has not been established. We report on a 21-year-old woman with PWS, who underwent denosumab treatment for osteoporosis. She presented with fractures and was shown to have very low bone mineral density (BMD), while she had been treated with supplementation of growth hormone for 7–14 years of age and estrogen from 15 years of age. BMD was monitored in the total hip region by dual-energy X-ray absorptiometry. Laboratory tests included bone-specific alkaline phosphatase, urinary type I collagen amino-terminal telopeptide, tartrate-resistant acid phosphatase 5b, 1-alpha, 25-dihydroxyvitamin D3, and parathyroid hormone. BMD and laboratory data were evaluated before and at 4, 8, and 13 months of treatment. After 13 months of denosumab therapy, BMD increased by 4.5%, and bone turnover markers notably improved. No fractures occurred. To the best of our knowledge, this is the first report to describe the clinical outcomes of denosumab treatment for osteoporosis in patients with PWS. Based on our findings, denosumab could represent an effective treatment option for osteoporosis in PWS patients. Keywords: bone mineral density, denosumab, fracture, case report, osteoporosis

Sho Tanaka,1 Midori Fujishiro,2 Yoshihiro Nakamura,1 Yoshinari Hatanaka,1 Masanori Abe1 1Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan; 2Division of Diabetes and Metabolic Diseases, Nihon University School of Medicine, Tokyo, Japan Abstract: Aberrant cortisol secretion responses after exogenous stimuli such as upright posture, eating a mixed meal or receiving agents influencing aberrant G-protein-coupled receptors in adrenal glands, are often observed in patients with bilateral macronodular adrenal hyperplasia (BMAH). However, little is known about whether this aberrant response is retained after unilateral adrenalectomy. Here, we describe a 61-year-old postmenopausal Japanese woman with unsatisfactorily controlled hypertension who was referred to us for further investigation due to her pre-obesity characteristics (body mass index 28.4 kg/m2). Cushing’s signs and serum cortisol at 16.2 µg/dL with undetectable adrenocorticotropic hormone indicated adrenal Cushing’s syndrome. Adrenal imaging revealed bilaterally enlarged adrenal glands with 131-I adosterol uptake; hence, BMAH was diagnosed. Preoperatively, in vivo screening for aberrant adrenal receptors revealed an aberrant response of cortisol secretion on metoclopramide challenge. The patient underwent unilateral adrenalectomy; thereafter, glucocorticoid replacement therapy was reduced to hydrocortisone 15 mg/day at postoperative day 6. Fasting morning serum cortisol level measured at postoperative day 8 was 2.96 µg/dL, suggesting adrenal insufficiency. However, following metoclopramide administration serum cortisol level rose to 19.7 µg/dL, indicating potential efficient adrenal function. Aberrant cortisol secretory capacity was thus preserved in BMAH, even in a state of adrenal insufficiency after unilateral adrenalectomy. Caution should be exercised when assessing the hypothalamus-pituitary-adrenal axis, because in this patient, a high cortisol level did not guarantee appropriate adrenal function when the patient was challenged by exogenous stimuli. Keywords: adrenal glands, Cushing’s syndrome, glucocorticoids, hydrocortisone, metoclopramide, receptors, G-protein-coupled

Takako Suzuki,1 Yukio Nakamura,1,2 Hiroyuki Kato1 1Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Japan; 2Department of Orthopaedic Surgery, Showa Inan General Hospital, Komagane, Japan Background: This 3-year retrospective study compared the outcomes of bisphosphonate-pretreated denosumab therapy with or without vitamin D and calcium supplementation in postmenopausal osteoporosis (OP) patients with rheumatoid arthritis (RA).Materials and methods: Fifty-eight patients under long-term denosumab treatment were divided into groups without (denosumab group; 31 cases) or with (combination group; 27 cases) vitamin D and calcium supplementation. The bone markers of BAP, TRACP-5b, and urinary NTX were measured at baseline and every year for 3 years. We also evaluated bone mineral density (BMD) of the lumbar 1–4 vertebrae (L-BMD) and bilateral total hips (H-BMD) at the same time points.Results: There were no significant differences in the percent changes of serum albumin-corrected calcium between the groups. The percent change in TRACP-5b was significantly higher in the combination group at 2 years. Serum 25-hydroxyvitamin D status was persistently high during therapy in both groups, with significant percent increases over baseline at 2 and 6 months in both groups and at 24 months in the combination group. The percent increase from baseline of serum zinc was significantly higher at 3 years in the combination group over the denosumab group. L-BMD and H-BMD were significantly increased at every time point for 3 years vs pretreatment levels in both groups and were significantly higher in the combination group at all time points.Conclusion: Compared with denosumab monotherapy, the combination group displayed significantly increased serum zinc, L-BMD, and H-BMD at 3 years in OP patients with RA. Thus, calcium and vitamin D supplementation may be beneficial to enhance BMD gains, but not necessarily 25-hydroxyvitamin D status, in patients with OP and RA under denosumab. Keywords: 25(OH)D, bone mineral density, bone-related minerals, denosumab, osteoporosis, rheumatoid arthritis

JLab E12-19-002 Experiment is planned to measure the Λ-binding energies of 3ΛH [Jπ = 1/2+ or 3/2+(T = 0)] and 4ΛH (1+) at JLab Hall C. The expected accuracy for the binding-energy measurement is |ΔBtotal Λ | ≃ 70 keV. The accurate spectroscopy for these light hypernuclei would shed light on the puzzle of the small binding energy and short lifetime of 3ΛH, and the chargesymmetry breaking in the ΛN interaction. We aim to perform the experiment in 2025.

Masashi Uehara,1 Yukio Nakamura,1 Jun Takahashi,1 Mikio Kamimura,2 Fumihiro Isobe,1 Tomomi Yamaguchi,3,4 Tomoki Kosho,3,4 Shigeharu Uchiyama,1,5 Takako Suzuki,1 Hiroyuki Kato1 1Department of Orthopedic Surgery, Shinshu University School of Medicine, Asahi, Matsumoto, Japan; 2Center for Osteoporosis and Spinal Disorders, Kamimura Orthopedic Clinic, Kotobuki, Matsumoto, Japan; 3Department of Medical Genetics, Shinshu University School of Medicine, Asahi, Matsumoto, Japan; 4Center for Medical Genetics, Shinshu University Hospital, Asahi, Matsumoto, Japan; 5Department of Orthopedic Surgery, Okaya City Hospital, Honmachi, Okaya, Japan Background: The natural history and pathogenesis of the skeletal abnormalities found in neurofibromatosis type 1 (NF1) are poorly understood, and the therapeutic options for these manifestations remain limited. This report first describes the clinical outcomes of denosumab treatment for a patient with NF1 suffering from osteoporosis. Methods: We enrolled a patient with NF1 under denosumab treatment for osteoporosis, prior fractures, and no improvement in bone mineral density (BMD) over 3 years of alendronate therapy. BMD was monitored by dual-energy X-ray absorptiometry. Tested laboratory data included bone-specific alkaline phosphatase, urinary type I collagen amino-terminal telopeptide, tartrate-resistant acid phosphatase 5b, 1-alpha, 25-dihydroxyvitamin D3, and parathyroid hormone. BMD and laboratory data were evaluated before, between 2 and 4 months, and at 6, 12, 18, and 24 months of treatment. Case presentation: During 2 years of denosumab therapy for osteoporosis in a 58-year-old female NF1 patient with prior fractures, BMD increased by 6.5% in the lumbar spine and 10.6% in the total hips, and bone turnover markers were notably improved. No fractures occurred during the latter half of treatment. Conclusion: Denosumab represents an effective treatment option for osteoporosis in NF1 patients. Keywords: denosumab, fracture, neurofibromatosis type 1, osteoporosis

Yukio Nakamura,1,2 Mikio Kamimura,3 Hidefumi Koiwai,4 Hiroyuki Kato1 1Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Japan; 2Department of Orthopedic Surgery, Showa-Inan General Hospital, Komagane, Japan; 3Center of Osteoporosis and Spinal Disorders, Kamimura Orthopedic Clinic, Matsumoto, Japan; 4Koiwai Orthopedic Clinic, Komoro, Japan Abstract: Low bone mineral density (BMD) is one of the most frequent complications of anorexia nervosa (AN). We report the clinical outcomes of a female patient with severe AN, whose chest had become deformed due to thoracic fracture. Lumbar BMD was 0.358 g/cm2 (T-score = −6.3), and total hip BMD was 0.411 g/cm2 (T-score = −4.4). Active vitamin D increased these parameters by 81.0% and 57.4%, respectively, but a drop in her nutrition status afterward resulted in a sharp decrease in BMD values. These findings suggest that adequate nutrient intake is essential for effective osteoporosis treatment in patients with AN. Keywords: anorexia nervosa, bone mineral density, daily teriparatide, osteoporosis

Masashi Uehara, Yukio Nakamura, Jun Takahashi, Takako Suzuki, Hiroyuki Kato Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Japan Background: Multiple-system atrophy (MSA) is an α-synucleinopathy with a very aggressive course and poor prognosis, which lacks efficient treatment. Thus, MSA represents a serious health and social problem. Progressive stridor and acute laryngeal obstruction likely occur in MSA; however, little is known about the bone metabolism or efficacy of bone absorption drugs, such as denosumab, in osteoporosis with MSA. Case presentation and methods: Two male patients with osteoporosis in MSA presented to our institution (at 54 and 68 years of age). Denosumab was started after the diagnosis of osteoporosis in MSA, and the therapy was continued for 18–24 months. Results: Lumbar and hip bone mineral density showed a 3.5% and 0.6% increase at 24 months or a 10.3% and 3.2% increase at 18 months, respectively. Bone turnover markers were also improved in the two cases during follow-up. No fractures or other complications were recorded during the observation period. Conclusion: This is the first study describing osteoporosis in two patients with MSA being treated by osteoporotic treatment. Based on our findings, it can be concluded that denosumab may be an effective therapy for osteoporosis in MSA. Keywords: bone metabolism, denosumab, multiple-system atrophy, osteoporosis, bone mineral density

Mikio Kamimura,1 Akira Taguchi,2 Yukio Nakamura,3,4 Hidefumi Koiwai,5 Shota Ikegami,3 Shigeharu Uchiyama,3 Hiroyuki Kato3 1Center for Osteoporosis and Spinal Disorders, Kamimura Orthopedic Clinic, Matsumoto, Japan; 2Department of Oral and Maxillofacial Radiology, Matsumoto Dental University, Shiojiri, Japan; 3Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Japan; 4Department of Orthopedic Surgery, Showa-Inan General Hospital, Komagane, Japan; 5Koiwai Orthopedic Clinic, Komoro, Japan Background: While it is well known that teriparatide (TPTD) increases bone mineral density (BMD) in osteoporotic patients, it is unknown whether TPTD pretreatment affects BMD after denosumab (DMAb) therapy.Methods: Fifty-seven patients in TPTD-pretreated group and 35 patients in DMAb-alone group had been further analyzed, all of whom were treated by DMAb for 1.5 years. Vitamin D (400 IU) and Ca (600 mg) supplementation was used in all patients. The BMD of lumbar 1–4 vertebrae (L-BMD), bilateral total hips (H-BMD), and bilateral femoral neck (FN-BMD) was quantified at first visit, and at 4, 8, 12, and 18 months after daily TPTD treatment following four times DMAb treatment.Results: There were significant differences in L-BMD (p=0.004) and H-BMD (p=0.026) at baseline between TPTD-pretreated and DMAb-alone groups, although there was no significant difference in FN-BMD between the two groups. The increase of L-BMD by DMAb therapy was less in TPTD-pretreated group than in DMAb-alone group. There was no significant difference in H-BMD, although percent changes of H-BMD tended to be higher in the TPTD-pretreated group than those in the DMAb-alone group. Percent change in FN-BMD at 4 months (p=0.067) and 12 months (p=0.057) tended to be higher in TPTD-pretreated group than in DMAb-alone group. Percent change in FN-BMD at 18 months was significantly higher in TPTD-pretreated group (p=0.004) than in DMAb-alone group.Conclusion: These findings suggest that the pretreatment of TPTD might have enhanced the increase of BMD in cortical bones treated by DMAb. Thus, it is favorable that TPTD can be used for osteoporotic patients who have high fracture risks with cortical bones. Keywords: bone mineral density, cancelleous bones, cortical bone, daily teriparatide, denosumab, osteoporosis

Takako Suzuki,1 Yukio Nakamura,1,2 Hiroyuki Kato1 1Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, 2Department of Orthopedic Surgery, Showa-Inan General Hospital, Komagane, Japan Introduction: The aim of this 18-month retrospective study was to evaluate the differences in outcomes of denosumab with tumor necrosis factor (TNF) inhibitors (TNFis), tocilizumab (TCZ), or abatacept (ABT) treatment in osteoporosis (OP) patients with rheumatoid arthritis (RA). Patients and methods: Patients were divided into TNFis-treated (TNF group; 44 cases), TCZ-treated (TCZ group; 8 cases), or ABT-treated (ABT group; 14 cases) groups. We measured serum bone-specific alkaline phosphatase (BAP) and tartrate-resistant acid phosphatase 5b (TRACP-5b) at baseline and every 3 months for 18 months and assessed bone mineral density (BMD) of the lumbar 1–4 vertebrae (L-BMD) and total hip BMD (H-BMD) at baseline and every 6 months for 18 months. Results: There were no significant differences in the percent changes in BAP, TRACP-5b, or L-BMD among the groups. The percent change in H-BMD was significantly increased in the TCZ group at 12 months or at 12 and 18 months, compared with that in the ABT group or TNF group, respectively. The percent change in L-BMD was significantly increased at 12 months in the TCZ and TNF groups, and at 18 months in all the 3 groups compared with pretreatment levels, whereas the percent change in H-BMD was significantly higher at 6, 12, and 18 months in the TCZ group, at 12 and 18 months in the TNF group, and at 18 months in the ABT group, compared with pretreatment levels. Conclusion: Our findings suggest that TCZ might be more useful than TNF or ABT in light of the observed H-BMD increases with denosumab therapy for OP patients with RA. Keywords: abatacept, denosumab, rheumatoid arthritis, TNF inhibitors, tocilizumab

Yukio Nakamura,1,2 Mikio Kamimura,3 Akio Morikawa,4 Akira Taguchi,5 Takako Suzuki,1 Hiroyuki Kato1 1Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, 2Department of Orthopedic Surgery, Showa-Inan General Hospital, Komagane, 3Center for Osteoporosis and Spinal Disorders, Kamimura Orthopaedic Clinic, Matsumoto, 4Department of Surgery, Showa-Inan General Hospital, Komagane, 5Department of Oral and Maxillofacial Radiology, School of Dentistry, Matsumoto Dental University, Shiojiri, Japan Background: The aim of this study was to evaluate the effects of denosumab in patients with osteoporosis (OP) and non-metastatic breast cancer following treatment of 1) surgery, 2) surgery and aromatase inhibitors, and 3) surgery, aromatase inhibitors, and anti-cancer agents, compared with those in primary OP patients. Patients and methods: In this retrospective 24-month study, patients were divided into the primary OP group (34 cases) or OP receiving breast cancer treatment group (breast cancer group; 17 cases). We measured serum calcium, whole parathyroid hormone (PTH), 1,25OH2D3, bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase-5b (TRACP-5b), and bone mineral density (BMD) of the lumbar 1–4 vertebrae (L-BMD) and bilateral total hips (H-BMD) for 24 months. Results: The percent changes of serum calcium in the breast cancer group were significantly lower than those in the primary OP group at 1 week, 1 and 12 months. The percent changes of whole PTH in the primary OP group were significantly lower than those in the breast cancer group at 2 and 4 months. Significant differences were found between the groups at 18 months (-34.5% in the primary OP group and -52.6% in the breast cancer group, respectively) for the percent changes of BAP. Significant differences were found between the groups at 12, 18, and 24 months (-39.7% in the primary OP group and -64.0% in the breast cancer group at 24 months, respectively) for the percent changes of TRACP-5b. The percent changes of L-BMD and H-BMD were significantly increased at 12, 18, and 24 months in both the primary OP group (7.0% and 4.7% at 24 months, respectively) and breast cancer group (8.0% and 5.4% at 24 months, respectively), compared with pre-treatment levels. Significant differences were not found between the groups for the percent changes of L-BMD and H-BMD. Conclusion: Denosumab significantly increased L-BMD and H-BMD to comparable degrees in both groups; therefore, it represents a good therapeutic option for OP receiving breast cancer treatment as well as primary OP. Also, vitamin D supplementation is required due to the potential hypocalcemia, and estrogen may be responsible for the decrease of serum calcium in the breast cancer patients. Keywords: bone mineral density, bone turnover markers, breast cancer, denosumab, osteoporosis

Yukio Nakamura,1,2 Takako Suzuki,1 Hiroyuki Kato1 1Department of Orthopedic Surgery, Shinshu University School of Medicine, Matsumoto, Japan; 2Department of Orthopedic Surgery, Showa-Inan General Hospital, Komagane, Japan Abstract: A worldwide health concern, osteoporosis (OP), increases the risk of bone fracture and results in morbidity. This study examined whether the representative bone absorption marker serum tartrate-resistant acid phosphatase 5b (TRACP-5b) or bone formation marker bone alkaline phosphatase (BAP) could estimate primary OP status and denosumab efficacy in a real-world setting. We retrospectively enrolled 114 female postmenopausal primary OP patients in Japan. Values and percent changes in TRACP-5b, BAP, lumbar 1–4 bone mineral density (L-BMD), and total hip BMD (H-BMD) were assessed before treatment and at 4, 8, and 12 months of therapy to identify the correlations between the percent changes in bone metabolic markers and BMD. We also established two sets of subgroups based on the upper limits of reference values in Japan for serum: TRACP-5b (

Yusuke Nakamura,1 Jörg Mahlich1,2 1Health Economics, Janssen Pharmaceutical K.K., Tokyo, Japan; 2Düsseldorf Institute for Competition Economics (DICE), University of Düsseldorf, Düsseldorf, Germany Background: No study has examined the financial impact of relapses on schizophrenia from the perspective of Japanese society. This study aimed to estimate the societal costs in Japan caused by the relapses of schizophrenia.Methods: The societal costs in Japan in 2013 due to relapses of schizophrenia were estimated by summing the productivity loss and deadweight loss caused by schizophrenia relapses in 2013. Deterministic sensitivity analysis was conducted for deadweight loss rate, relapse rate, and patient income.Results: Japan incurred JPY 55,039 million societal costs because of relapses in 2013. This consists of JPY 3,990 million for productivity loss and JPY 51,049 million for deadweight loss. Rate of deadweight loss is the most significant cost driver in the sensitivity analysis.Conclusion: Relapses of schizophrenia could generate huge amount of societal costs by reducing labor productivity and economic efficiency. To curb these costs, relapse prevention is desired in treating schizophrenia. Keywords: schizophrenia, relapses, societal costs, productivity loss, deadweight loss, Japan

Mikio Kamimura,1 Shigeharu Uchiyama,2 Yukio Nakamura,2,3 Shota Ikegami,2 Keijiro Mukaiyama,2 Hiroyuki Kato2 1Center for Osteoporosis and Spinal Disorders, Kamimura Orthopaedic Clinic, Matsumoto, Japan; 2Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Japan; 3Department of Orthopedic Surgery, Showa-Inan General Hospital, Komagane, Japan Abstract: This study aimed to clarify the effects of short-term bisphosphonate (BP) administration in Japanese osteoporotic patients retrospectively. Daily minodronate (MIN) at 1 mg/day (MIN group) or weekly risedronate (RIS) at 17.5 mg/week (RIS group) was primarily prescribed for each patient. We analyzed the laboratory data of 35 cases (18 of MIN and 17 of RIS) before the start of treatment and at 4 months afterward. The changes in 25(OH)D3, whole parathyroid hormone (PTH), serum pentosidine, and the bone turnover markers urinary cross-linked N-telopeptide of type I collagen (NTX), serum tartrate-resistant acid phosphatase (TRACP)-5b, bone-specific alkaline phosphatase (BAP), and undercarboxylated osteocalcin were evaluated. Overall, serum 25(OH)D3 was significantly decreased from 21.8 to 18.4 ng/mL at 4 months, with a percent change of –14.7%. Whole PTH increased significantly from 23.4 to 30.0 pg/mL, with a percent change of 32.1%. Serum pentosidine rose from 0.0306 to 0.0337 µg/mL, with a percent change of 15.2%. In group comparisons, 25(OH)D3 and pentosidine showed comparable changes in both groups after 4 months of treatment, whereas whole PTH became significantly more increased in the MIN group. All bone turnover markers were significantly decreased at 4 months in both groups. Compared with the RIS group, the MIN group exhibited significantly larger value changes for urinary NTX, serum TRACP-5b, and BAP at the study end point. This study demonstrated that serum 25(OH)D3 became significantly decreased after only 4 months of BP treatment in Japanese osteoporotic patients and confirmed that MIN more strongly inhibited bone turnover as compared with RIS. Keywords: minodronate, risedronate, 25(OH) vitamin D3, parathyroid hormone, pentosidine

Noriyuki Kanzaki,1 Yuta Otsuka,1 Takayuki Izumo,1 Hiroshi Shibata,1 Hideyuki Nagao,2 Keita Ogawara,3 Hiroshi Yamada,3 Seiji Miyazaki,3 Yutaka Nakamura3 1Institute for Health Care Science, Suntory Wellness Ltd, Seika-cho, Soraku-gun, Kyoto, Japan; 2Research Institute of Sports Medical Science, Tokai University, Hiratsuka, Kanagawa, Japan; 3School of Physical Education, Tokai University, Hiratsuka, Kanagawa, Japan Background: Previously, we demonstrated that glucosamine-containing supplementation was effective for improving locomotor functions, especially walking speed. However, the biomechanical mechanism of efficacy has not been elucidated. This study aimed to address this challenge in subjects with knee pain, using a motion capture system. Methods: An open label study was conducted in 30 Japanese subjects with knee pain. The subjects were administered a daily supplement containing 1,200 mg of glucosamine hydrochloride, 60 mg of chondroitin sulfate, 45 mg of type II collagen peptides, 90 mg of quercetin glycosides, 10 mg of imidazole peptides, 1 mg of proteoglycan, and 5 µg of vitamin D (GCQID). The intervention continued for 16 weeks. Efficacy for locomotor functions involving the knee joint was evaluated mainly using the Japanese Knee Osteoarthritis Measure (JKOM) and the 5-question Geriatric Locomotive Function Scale (GLFS-5). To examine the biomechanical mechanism of efficacy for locomotor functions, motions of subjects in a normal walking state were captured. Gait analysis was conducted and efficacy for gait parameters such as normal walking speed, stride length, cadence, and angle of soles was evaluated. Results: GCQID significantly improved total scores on the JKOM and GLFS-5. In gait analysis, normal walking speed, stride length, and angle of soles at the end of the stance phase were all significantly increased, but cadence did not change significantly during the intervention period. There were significant intercorrelations of changes in normal walking speed, stride length, and angle of soles at the end of the stance phase, and between changes in stride length and total JKOM score. Conclusion: A GCQID supplement may increase walking speed through increased stride length and angle of kicking from the ground during steps, which might be mainly associated with alleviated knee pain. Keywords: locomotive syndrome, GLFS-5, normal walking speed, stride length, toe angle

Yukio Nakamura,1,2 Mikio Kamimura,3 Shota Ikegami,1 Keijiro Mukaiyama,4 Masatoshi Komatsu,1 Shigeharu Uchiyama,1 Hiroyuki Kato11Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, 2Department of Orthopaedic Surgery, Showa Inan General Hospital, Komagane, 3Center of Osteoporosis and Spinal Disorders, Kamimura Clinic, Matsumoto, 4Department of Orthopaedic Surgery, Azumi General Hospital, Azumino, JapanAbstract: The syndrome of pregnancy- and lactation-associated osteoporosis is a rare disorder whose precise etiology and treatment are largely unknown. We herein report two such cases occurring in the early postpartum period that led to multiple fragility compression fractures. Combination therapy of vitamin D and vitamin K enabled a marked gradual increase in bone mineral density.Keywords: fracture, vitamin D, vitamin K, bone mineral density

We are investigating the direct determination and non-perturbative renormalisation of gluon matrix elements. Such quantities are sensitive to ultra– violet fluctuations, and are in general statistically noisy. To obtain statistically significant results, we extend an earlier application of the Feynman–Hellmann theorem to gluonic matrix elements to calculate a renormalisation factor in the RI – MOM scheme, in the quenched case. This work demonstrates that the Feynman–Hellmann method is capable of providing a feasible option for calculating gluon quantities.

Naoki Inui,1,2 Sayomi Matsushima,1 Shinpei Kato,1 Hideki Yasui,1 Masato Kohno,1 Tomoyuki Fujisawa,1 Noriyuki Enomoto,1 Yutaro Nakamura,1 Mikio Toyoshima,3 Takafumi Suda1 1Second Division, Department of Internal Medicine, 2Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Handayama, Hamamatsu, Japan; 3Department of Respiratory Medicine, Hamamatsu Rosai Hospital, Shougen-cho, Hamamatsu, JapanAbstract: The forced oscillation technique (FOT) can measure respiratory mechanics and has attracted attention in chronic obstructive pulmonary disease (COPD). We aimed to evaluate the effects of only indacaterol and tiotropium monotherapies on airflow limitation and respiratory impedance. Pulmonary function tests, COPD assessment test (CAT), and multifrequency FOT with MostGraph-01 were performed at the beginning and after 8 weeks of treatment with indacaterol or tiotropium. The resistance index, resistance at 5 Hz (R5), resistance at 20 Hz (R20), reactance index, reactance at 5 Hz (X5), resonant frequency (Fres), and low-frequency reactance area (ALX) were determined at whole-breath, inspiratory, and expiratory phases. Eighty-two patients (mean age: 73 years; mean forced expiratory volume in 1 second (FEV1): 61.6%±19.0% predicted) were randomized to indacaterol or tiotropium treatment. Both bronchodilators improved airflow limitation, with mean trough improvements in FEV1 of 165 mL and 80 mL in the indacaterol and tiotropium groups, respectively. The CAT score decreased in the indacaterol group (P

Masaoki Wada,1,2 Taro Takeshima,1 Yosikazu Nakamura,3 Shoichiro Nagasaka,4 Toyomi Kamesaki,1 Hiroshi Oki,2 Eiji Kajii1 1Division of Community and Family Medicine, Center for Community Medicine, Jichi Medical University, Tochigi, Japan; 2Oki Clinic, Ibaraki, Japan; 3Department of Public Health, Jichi Medical University, Tochigi, Japan; 4Department of Internal Medicine, Division of Endocrinology and Metabolism, Jichi Medical University, Tochigi, Japan Objective: Dizziness and vertigo are highly prevalent symptoms among patients presenting at primary care clinics, and peripheral vestibular disorder (PVD) is their most frequent cause. However, the incidence of PVD has not been well documented. This study aimed to investigate the incidence of dizziness, vertigo, and PVD among patients presenting at a primary care clinic. Design: This was an observational study. Setting and participants: Between November 2011 and March 2013, we observed 393 patients, all at least 20 years old, who had been treated for chronic diseases such as hypertension, dyslipidemia, and diabetes mellitus for at least 6 months at a primary clinic (Oki Clinic) in Japan. Outcome: The main outcome of interest was new incidence of dizziness, vertigo, and PVD events. During the 1-year follow-up period, the otorhinolaryngologist diagnosed and reported new PVD events. Results: The mean age of the 393 participants at entry was 65.5 years. Of the study participants, 12.7%, 82.4%, and 92.6% had diabetes mellitus, hypertension, and dyslipidemia, respectively. We followed up all the participants (100%). During the 662.5 person-years of follow-up, 121 cases of dizziness or vertigo (dizziness/vertigo) and 76 cases of PVD were observed. The incidence of dizziness/vertigo and PVD was 194.7 (95% confidence interval: 161.6–232.6) per 1,000 person-years and 115.7 (95% confidence interval: 92.2–142.6) per 1,000 person-years, respectively. There were 61 cases of acute peripheral vestibulopathy, 12 of benign paroxysmal positional vertigo, and three of Meniere's disease among the 76 PVD patients. Conclusion: We reported the incidence of dizziness/vertigo among Japanese primary care clinic patients, which was higher than that usually observed in the general population. Furthermore, we described the incidence of PVD and found that it was a major cause of dizziness/vertigo. Keywords: dizziness, incidence, primary health care, observational study

We have upgraded the new Tibet ASgamma experiment in China since 2014 to measure the chemical composition of cosmic rays around the knee. This hybrid experiment consist of an air-shower-core detector array (YAC-II) to detect high energy electromagnetic component, the Tibet air-shower array (Tibet-III) and a large underground water-Cherenkov muon-detector array (MD). We have carried out a detailed air-shower Monte Carlo (MC) simulation to study the performance of the hybrid detectors by using CORSIKA (version 7.5000), which includes EPOS-LHC, QGSJETII-04, SIBYLL2.1 and SIBYLL2.3 hadronic interaction models. The preliminary results of the interaction model checking above 50 TeV energy region are reported in this paper, and the primary proton and helium spectra in the energy range 50 TeV to 1015 eV was derived from YAC-I data and is smoothly connected with direct observation data at lower energies and also with our previously reported works at higher energies within statistical errors. The knee of the (P+He) spectra is located around 400 TeV. The interaction model dependence in deriving the primary (P+He) spectra is found to be small (less than 25% in absolute intensity, 10% in position of the knee), and the composition model dependence is less than 10% in absolute intensity.

We analyze the temporal variation of the solar diurnal anisotropy of the multi-TeV cosmic-ray intensity observed with the Tibet air shower array from 2000 to 2009, covering the maximum and minimum of the 23rd solar cycle. We comfirm that a remarkable additional anisotropy component is superposed on the Compton-Getting anisotropy at 4.0 TeV, while its amplitude decreases at higher energy regions. In constrast to the additional anisotropy reported by the Matsushiro experiment at 0.6 TeV, we find the residual component measured by Tibet at multi-TeV energies is consistent with being stable, with a fairly constant amplitude of 0.041% ± 0.003% and a phase at around 07.17 ± 00.16 local solar time at 4.0 TeV. This suggests the additional anisotropy observed by the Tibet experiment could result from mechanisms unrelated to solar activities.

A hybrid experiment has been started by the ASγ experiment at Yangbajing (4300m a.s.l.) in Tibet since May 2009, that consists of a high-energy air-shower-core array (YAC-I) and a high-density air-shower array (Tibet-III). In this paper, we report our results to check the hadronic interaction models SIBYLL2.3, SIBYLL2.1, EPOS-LHC and QGSJETII-04 in the multi-tens TeV energy region using YAC-I+Tibet-III experimental data from May 2009 through January 2010. The effective live time is calculated as 106.05 days. The results show that the description of transverse momentum, inelastic cross-section and inelasticity for the 4 hadronic interaction models is consistent with YAC-I experimental data within 15% systematic errors range in the forward region below 100 TeV. Among them, the EPOS-LHC model is the best hadronic interaction model. Furthermore, we find that the H4a composition model is the best one below the 100 TeV energy region.

Yoshie Maitani,1 Yuri Nakamura,1 Masao Kon,1 Emi Sanada,1 Kae Sumiyoshi,1 Natsuki Fujine,1 Masumi Asakawa,2 Masaki Kogiso,2 Toshimi Shimizu21Institute of Medicinal Chemistry, Hoshi University, Tokyo, Japan; 2Nanotube Research Center (NTRC), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, JapanAbstract: The size and shape of intravenously injected particles can affect their biodistribution and is of importance for the development of particulated drug carrier systems. In this study, organic nanotubes (ONTs) with a carboxyl group at the surface, a length of approximately 2 µm and outer diameter of 70–90 nm, were injected intravenously into tumor-bearing mice. To use ONTs as drug carriers, the biodistribution in selected organs of ONTs postinjection was examined using irinotecan, as an entrapped water-soluble marker inside ONTs, and gadolinium-chelated ONT, as an ONT marker, and compared with that of a 3 µm fluorescently labeled spherical microparticle which was similar size to the length of ONTs. It was found that for irinotecan, its active metabolite and gadolinium-chelated ONTs were highly accumulated in the lung, but to a lower level in the liver and spleen. On the other hand, microparticles deposited less in the lung and more highly in the liver. Moreover, histologic examination showed ONTs distributed more in lung tissues in part, whereas microparticles were present in blood vessels postinjection. These preliminary results support the notion of using negatively charged ONTs as intravascular carriers to maximize accumulation in the lung whilst reducing sequestration by the liver and spleen. This finding suggested that ONTs are potential carriers for lung-targeting drug delivery.Keywords: organic nanotube, lung, biodistribution, microparticle, particle shape