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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

Yoshihisa Ohashi,1 Kensuke Fukushima,1 Kentaro Uchida,1 Tomohisa Koyama,1 Maho Tsuchiya,1 Hiroki Saito,1 Katsufumi Uchiyama,2 Naonobu Takahira,3 Gen Inoue,1 Masashi Takaso1 1Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, 252-0374, Japan; 2Department of Patient Safety and Healthcare Administration, Kitasato University School of Medicine, Sagamihara City, Kanagawa, 252-0374, Japan; 3Department of Rehabilitation, Kitasato University School of Allied Health Sciences, Sagamihara City, Kanagawa, 252-0374, JapanCorrespondence: Kensuke FukushimaDepartment of Orthopaedic Surgery, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara City, Kanagawa, 252-0374, JapanTel +81-42-778-9343Fax +81-42-778-5850Email kenfu@r4.dion.ne.jpBackground: In patients with hip osteoarthritis (OA), pain at rest, unlike pain on activity, is due to pain mechanisms that cannot be explained by nociceptive pain. However, it remains unclear whether central sensitization (CS) is one of the causes of exacerbated pain at rest in patients with hip OA. Therefore, we investigated the differences in causative factors and postoperative course of total hip arthroplasty (THA) between preoperative pain at rest and on activity in patients with hip OA.Methods: In total, 120 patients (125 hips, 22 men and 98 women, aged 64.5± 1.0 years) with hip OA were included. Preoperative pain at rest and on activity and CS were assessed using the visual analog scale (VAS) and CS Inventory (CSI), respectively. Postoperative assessments were evaluated using the Japanese Orthopedic Association Hip Disease Evaluation Questionnaire (JHEQ); pain, satisfaction, function, and mental scores were evaluated 6 and 12 months after THA.Results: Multivariate regression analysis indicated the CSI score as affecting VAS for pain at rest (β=0.067, P=0.002) but not VAS for pain on activity (β=0.036, P=0.073). VAS for pain at rest had a weak negative correlation with satisfaction and pain scores at both 6 and 12 months after THA (satisfaction, r=− 0.309, − 0.278; pain, r=− 0.202, − 0.22). VAS for pain on activity was not correlated with JHEQ. The CSI score had a weak or moderate negative correlation with three scores other than the function score at both 6 and 12 months after THA (satisfaction, r=− 0.266, − 0.213; pain, r=− 0.332, − 0.203, mental, r=− 0.427, − 0.370). The function score was weakly correlated with the CSI score only 6 months after THA (function, r=− 0.231, − 0.190).Conclusion: A higher level of preoperative pain at rest, a CS-related symptom, may affect postoperative pain persistence and dissatisfaction in patients with hip OA.Keywords: central sensitization, pain at rest, postoperative pain, hip osteoarthritis, total hip arthroplasty

Hironi Makita,1,2,* Masaru Suzuki,1,* Satoshi Konno,1 Kaoruko Shimizu,1 Yasuyuki Nasuhara,1 Katsura Nagai,1,3 Yasushi Akiyama,3 Satoshi Fuke,4 Hiroshi Saito,5 Takeshi Igarashi,5 Kimihiro Takeyabu,6 Masaharu Nishimura1,2 1Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan; 2Hokkaido Medical Research Institute for Respiratory Diseases, Sapporo, Japan; 3Center for Respiratory Diseases, JCHO Hokkaido Hospital, Sapporo, Japan; 4Department of Internal Medicine, KKR Sapporo Medical Center, Sapporo, Japan; 5Department of Internal Medicine, Hokkaido Chuo Rosai Hospital, Iwamizawa, Japan; 6Department of Respiratory Medicine, Otaru Kyokai Hospital, Otaru, Japan*These authors contributed equally to this workCorrespondence: Masaharu NishimuraDepartment of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, JapanTel +81 11 706 5911Fax +81 11 706 7899Email ma-nishi@med.hokudai.ac.jpPurpose: Causes of death may be unique and different in Japanese patients with COPD because they are generally older, thinner, experience fewer exacerbations, and live longer than those in other countries. We investigated the detailed mortality profile in the Hokkaido COPD cohort study, which completed a 10-year follow-up with a very low dropout rate.Patients and Methods: We prospectively examined the 10-year natural history in 279 Japanese patients with COPD (GOLD 1, 26%; GOLD 2, 45%; GOLD 3, 24%; and GOLD 4, 5%). The majority of patients were male, and the average age at baseline was 69 years old. About 95% of all patients had accurate mortality data. The risk factors for mortality were also analyzed.Results: During the 10 years, 112 patients (40%) died. Their median survival time was 6.1 years (interquartile range: 4.7– 7.9 years), and age at death was 79 ± 6 years old (mean ± SD). Respiratory diseases, including pneumonia, were the leading causes of death in 45 (40%), followed by lung cancer in 24 (21%), other cancers in 18 (16%), and cardiovascular diseases in 12 (11%). In particular, lung cancer-related death was equally distributed across all COPD stages, with a higher proportion of lung cancer in the relatively younger generation (< 64 years old). Older age at baseline, lower BMI, and severer emphysema were significant risk factors for all-cause mortality.Conclusion: The unique mortality profile observed in this study should be considered when designing strategies for the management of patients with COPD in any geographic region.Keywords: chronic obstructive pulmonary disease, mortality, cause of death, cohort study

Yuka Ohe, Sachio Fushida, Takahisa Yamaguchi, Jun Kinoshita, Hiroto Saito, Koichi Okamoto, Keishi Nakamura, Hidehiro Tajima, Itasu Ninomiya, Tetsuo Ohta Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, JapanCorrespondence: Sachio FushidaDepartment of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa 920-8641, JapanTel +8176-265-2362Email fushida@staff.kanazawa-u.ac.jpIntroduction: Platelets are one factor promoting tumor development. Conversely, lymphocytes are one factor for immune protection. The peripheral blood platelets–lymphocyte ratio (PLR) is useful as an inflammation/immune indicator to predict postoperative recurrence and prognosis of a variety of malignancies. The peripheral blood neutrophil–lymphocyte ratio (NLR) has also been reported as a useful inflammation/immune indicator. However, there are few studies evaluating the relationship between these peripheral blood indicators and the effectiveness of chemotherapy. Thus, we examined these relationships in gastric cancer patients.Patients and Methods: Between 2005 and 2018, 41 gastric cancer patients treated with preoperative DCS therapy (docetaxel, cisplatin, and S-1) therapy followed by gastrectomy were evaluated. Data for peripheral blood tests prior to the initiation of chemotherapy were used. The effectiveness of chemotherapy was determined using Response Evaluation Criteria in Solid Tumors (RECIST) and the pathological response of primary lesions (Ef grade). The relationship between the blood test results and the effectiveness of chemotherapy was evaluated.Results: Each optimal cut-off value of peripheral inflammation/immune indicators was calculated through ROC curves. Although the pathological responder (Ef grade 2 or 3) revealed significantly better prognosis than the non-responder (Ef grade 0-1b), no relationship was found between responder according to RECIST and prognosis (P=0.014, P=0.992). In univariate analysis, a low PLR (< 180, P=0.005), low NLR (< 2.6, P=0.019), high lymphocyte (≥ 1.43, P=0.019) and high PNI (≥ 40, P=0.032) were identified as prognostic markers, whereas PLR was the only marker correlated with pathological response (P=0.031).Conclusion: PLR obtained prior to chemotherapy might be a useful indicator for predicting chemosensitivity owing to the simplicity of its procedure.Keywords: gastric cancer, preoperative chemotherapy, chemosensitivity, platelet-lymphocyte ratio

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

Hitoki Saito,1 Momoko Ebashi,2 Masaru Kushimoto,3 Jin Ikeda,3 Fujiko Egashira,1 Suguru Yamaguchi,1 Kentaro Watanabe1 Katsuhiko Ogawa,2,4 Yutaka Suzuki,3,4 Hisamitsu Ishihara,1 Midori Fujishiro1,4 1Division of Diabetes and Metabolic Diseases, Nihon University School of Medicine, Tokyo, Japan; 2Division of Neurology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan; 3Division of General Medicine, Department of Internal Medicine, Nihon University, Tokyo, Japan; 4Department of Internal Medicine, Nihon University Hospital, Tokyo, Japan Abstract: Patients with diabetes mellitus (DM) are at increased risk of infections, with the urinary tract being the most frequent infection site. Incomplete bladder emptying, frequent urination and abdominal distension are typical symptoms of urinary tract infections (UTIs). A 68-year-old female with a long history of poorly controlled type 2 DM (T2DM) visited our hospital complaining of urinary retention, which was initially diagnosed as cystitis by another doctor. The urologist at our hospital identified a skin rash extending from the left hip to her genital area. A dermatologist was consulted. She was clinically diagnosed with herpes zoster (HZ) involving the left sacral dermatome area. As Elsberg syndrome (ES) was suspected, a lumbar puncture was performed, revealing aseptic meningitis associated with varicella zoster virus (VZV) infection. Intravenous acyclovir with urinary catheterization in combination with methylprednisolone pulse therapy resulted in a good clinical course. HZ very uncommonly involves sacral dermatomes, but it can develop in patients with prolonged poorly controlled DM. Furthermore, early diagnosis can be difficult when patients have diabetic peripheral neuropathy, which may mask symptoms related to skin lesions. Because this disease is potentially severe, detailed examination is important for clinicians managing patients with DM who have complaints indicative of urinary tract disorders. Keywords: herpes zoster, urinary retention, diabetic neuropathy

Daisuke Kobayashi,1,2 Yuichiro Shindo,2 Ryota Ito,2,3 Mai Iwaki,4,5 Junya Okumura,2,6 Toshihiro Sakakibara,2,7 Ikuo Yamaguchi,8 Tetsuya Yagi,9 Tomohiko Ogasawara,4 Yasuteru Sugino,6 Hiroyuki Taniguchi,7 Hiroshi Saito,10 Hideo Saka,11 Takashi Kawamura,1 Yoshinori Hasegawa2 On behalf of the Central Japan Lung Study Group 1Kyoto University Health Service, Kyoto, Japan; 2Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan; 3Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 4Department of Respiratory Medicine, Nagoya Daini Red Cross Hospital, Nagoya, Japan; 5Department of Respiratory Medicine, Kasugai Municipal Hospital, Kasugai, Japan; 6Department of Respiratory Medicine, Toyota Memorial Hospital, Toyota, Japan; 7Department of Respiratory Medicine and Allergy, Tosei General Hospital, Seto, Japan; 8Department of Central Laboratory, Toyohashi Municipal Hospital, Toyohashi, Japan; 9Department of Infectious Diseases, Nagoya University Hospital, Nagoya, Japan; 10Department of Respiratory Medicine, Aichi Cancer Center Aichi Hospital, Okazaki, Japan; 11Department of Respiratory Medicine, National Hospital Organization, Nagoya Medical Center, Nagoya, Japan Background: Appropriate initial antibiotic treatment and avoiding administration of unnecessary broad-spectrum antibiotics are important for the treatment of pneumonia. To achieve this, assessment of risk for drug-resistant pathogens (DRPs) at diagnosis is essential.Purpose: The aim of this study was to validate a predictive rule for DRPs that we previously proposed (the community-acquired pneumonia drug-resistant pathogen [CAP-DRP] rule), comparing several other predictive methods.Patients and methods: A prospective observational study was conducted in hospitalized patients with community-onset pneumonia at four institutions in Japan. Pathogens identified as not susceptible to ceftriaxone, ampicillin–sulbactam, macrolides, and respiratory fluoroquinolones were defined as CAP-DRPs.Results: CAP-DRPs were identified in 73 (10.1%) of 721 patients analyzed. The CAP-DRP rule differentiated low vs high risk of CAP-DRP at the threshold of ≥3 points or 2 points plus any of methicillin-resistant Staphylococcus aureus specific factors with a sensitivity of 0.45, specificity of 0.87, positive predictive value of 0.47, negative predictive value of 0.87, and accuracy of 0.79. Its discrimination performance, area under the receiver operating characteristic curve, was 0.73 (95% confidence interval 0.66–0.79). Specificity of the CAP-DRP rule against CAP-DRPs was the highest among the six predictive rules tested.Conclusion: The performance of the predictive rules and criteria for CAP-DRPs was limited. However, the CAP-DRP rule yielded high specificity and could specify patients who should be treated with non-broad-spectrum antibiotics, eg, a non-pseudomonal β-lactam plus a macrolide, more precisely. Keywords: antibiotic resistance, algorithms, community-acquired pneumonia, healthcare-associated pneumonia

Yuka Hasebe,1 Kenji Kashiwagi,1 Toyoaki Tsumura,2 Yasuyuki Suzuki,3 Keiji Yoshikawa,4 Hirotaka Suzumura,5 Toshine Maeda,6 Ryuji Takeda,7 Hitomi Saito,8 Makoto Araie8 1Department of Ophthalmology, University of Yamanashi, Yamanashi, Japan; 2Department of Ophthalmology, Fussa Hospital, Tokyo, Japan; 3Department of Ophthalmology, Tokai University, Kanagawa, Japan; 4Yoshikawa Eye Clinic, Tokyo, Japan; 5Suzumura Eye Clinic, Tokyo, Japan; 6Maeda Eye Clinic, Tokyo, Japan; 7Faculty of Agriculture, Kinki University, Nara, Japan; 8Department of Ophthalmology, Kanto Central Hospital of the Mutual Aid Association of Public School, Tokyo, Japan Purpose: We investigated patient adherence and factors related to a newly introduced prostaglandin analog and timolol fixed-combination eye drops (PGTFC).Patients and methods: The Glaucoma Research on Adherence to fixed-Combination Eye drops in Japan (GRACE) study group performed a nationwide prospective questionnaire survey. Participants in this study were patients with glaucoma who were scheduled to receive any type of PGTFC for the first time. The participants answered a questionnaire on the day of PGTFC introduction and again at a return visit 4–6 weeks after PGTFC introduction. The physicians in charge were asked to complete a separate questionnaire on the day of PGTFC introduction. One of two leaflets was randomly delivered to each participant before the description of the PGTFC. One leaflet explained how to correctly instill the eye drops, and the other explained the clinical meaning of intraocular pressure reduction in addition to explaining how to correctly instill the eye drops. Nonadherence was defined as forgetting to instill the eye drops one or more times during the week before the return visit.Results: In total, 3,597 patients (age, 68.4±12.2 years) met the study protocol requirements. PGTFC introduction significantly reduced the number of antiglaucoma eye drops from 1.93±0.78 to 1.34±0.54 (P

Norio Yasui-Furukori,1 Natsumi Tarakita,1 Waka Uematsu,2 Hisao Saito,2 Kazuhiko Nakamura,1 Chikara Ohyama,3 Norio Sugawara4 1Department of Neuropsychiatry, Graduate School of Medicine, Hirosaki University, Hirosaki, 2Department of Urology, Oyokyo Kidney Research Institute, Hirosaki, 3Department of Urology, Graduate School of Medicine, Hirosaki University, Hirosaki, 4Department of Clinical Epidemiology, Translational Medical Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan Objectives: Delirium signifies underlying brain dysfunction; however, its clinical significance in hemodialysis remains unclear. In this study, we sought to determine whether the occurrence of delirium during hemodialysis was associated with higher mortality.Patients and methods: This was a retrospective, 10-year cohort study. This study was performed at the urology department located within a hospital in Oyokyo, Hirosaki. We analyzed 338 of 751 patients who underwent hemodialysis. Psychiatrists diagnosed patients with delirium according to the corresponding DSM-IV-TR criteria. Cox proportional hazard regression, which was adjusted for patient age at the time of hemodialysis initiation, sex, and the presence of diabetes mellitus, was performed. Hazard ratios (HRs) and their 95% CIs were also reported.Results: In total, 286 patients without psychiatric diseases and 52 patients with delirium were evaluated. Eighty percent of patients with delirium died within 1 year of hemodialysis initiation, while only 22% of patients without delirium died within the same time period (P

Accurately quantifying the above-ground carbon stock of tropical rainforest trees is the core component of “Reduction of Emissions from Deforestation and Forest Degradation-plus” (REDD+) projects and is important for evaluating the effects of anthropogenic global change. We used high-resolution optical imagery (IKONOS-2) to identify individual tree crowns in intact and degraded rainforests in the mountains of Northern Borneo, comparing our results with 50 ground-based plots dispersed in intact and degraded forests, within which all stems > 10 cm in diameter were measured and identified to species or genus. We used the dimensions of tree crowns detected in the imagery to estimate above-ground biomasses (AGBs) of individual trees and plots. To this purpose, preprocessed IKONOS imagery was segmented using a watershed algorithm; stem diameter values were then estimated from the cross-sectional crown areas of these trees using regression relationships obtained from ground-based measurements. Finally, we calculated the biomass of each tree (AGBT, in kg), and the AGB of plots by summation (AGBP, in Mg ha-1). Remotely sensed estimates of mean AGBT were similar to ground-based estimates in intact and degraded forests, even though small trees could not be detected from space-borne sensors. The intact and degraded forests not only had different AGB but were also dissimilar in biodiversity. A tree-centric approach to carbon mapping based on high-resolution optical imagery, could be a cheap alternative to airborne laser-scanning.

Tetsu Tomita,1 Norio Yasui-Furukori,1 Norio Sugawara,1,2 Kohei Ogasawara,3 Koki Katagai,3 Hisao Saito,4 Kaori Sawada,5 Ippei Takahashi,5 Kazuhiko Nakamura1 1Department of Neuropsychiatry, Graduate School of Medicine, Hirosaki University, Hirosaki, Japan; 2Aomori Prefectural Center for Mental Health and Welfare, Aomori, Japan; 3School of Medicine, Hirosaki University, Hirosaki, Japan; 4Department of Urology, Oyokyo Kidney Research Institute, Hirosaki, Japan; 5Department of Social Medicine, Graduate School of Medicine, Hirosaki University, Hirosaki, Japan Background: We investigated the prevalence of depression in hemodialysis (HD) patients using the Center for Epidemiologic Studies for Depression (CES-D) scale and the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (SCID) and compared the rates with those of community dwelling people in Japan.Patients and methods: A total of 99 patients undergoing HD were recruited. Blood sampling was performed no later than 2 weeks prior to assessment. As a reference group for SCID and CES-D evaluation, 404 age- and sex-matched healthy controls who had participated in the Iwaki Health Promotion Project were included in this study. The SCID and the CES-D scale were administered to all participants to diagnose their depression. Participants who met the criteria of a major depressive episode according to the SCID were classified as SCID depression and the participants whose CES-D score was 16 or higher were classified as CES-D depression.Results: Ninety-nine HD patients completed the evaluation and data collection. There were no significant differences in age, sex, or CES-D scores between HD patients and controls. There were 12 cases of SCID depression in HD patients and four cases in controls. There was a significant difference between HD patients and controls in the prevalence of SCID depression. There were no significant differences between the two groups with regard to demographic or clinical data. There were 19 HD patients and 24 controls who showed CES-D depression. There was no significant difference between HD patients and controls in the prevalence of CES-D depression. There was a significant difference in potassium level between the two groups, but there were no significant differences in any of the other items.Conclusion: There were significantly more HD patients showing SCID depression than controls in the present study. In clinical settings, the SCID might be useful in surveying cases of depression detected by screening tools among HD patients. Keywords: depression, Center for Epidemiologic Studies for Depression, Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis

Tetsu Tomita,1 Norio Yasui-Furukori,1 Masaki Oka,1 Takaaki Shimizu,2 Aya Nagashima,2 Kento Mitsuhashi,2 Hisao Saito,3 Kazuhiko Nakamura1 1Department of Neuropsychiatry, Graduate School of Medicine, 2School of Medicine, Hirosaki University, 3Department of Urology, Oyokyo Kidney Research Institute, Hirosaki, Japan Background: Many studies have investigated insomnia and the factors associated with this condition in hemodialysis (HD) patients, although the influence of HD duration has not been thoroughly investigated. In the present study, we investigated the factors, especially the duration of HD, associated with insomnia in HD patients.Patients and methods: A total of 138 patients undergoing HD were recruited, and the Japanese version of the Pittsburgh Sleep Quality Index (PSQI) was used to assess the quality of sleep. Subjects with a total PSQI score up to 4 and those with a score of at least 5 were identified as normal subjects and subjects with insomnia, respectively. Additionally, we assessed restless legs syndrome, depression using the Center for Epidemiologic Studies Depression Scale, and health-related quality of life (QOL) using the Short Form 8 Health Survey. We divided the subjects into two groups according to the median HD duration.Results: The prevalence rate of insomnia was 54.3% among all the subjects. Twenty-one subjects (15.2%) had depression, 26 (18.8%) had restless legs syndrome, and 75 (54.3%) had insomnia. The median HD duration was 4 years. The scores of components 1 and 4 of the PSQI, subjective sleep quality and habitual sleep efficiency, did not show a significant difference between the normal and insomnia groups. The score of component 7, daytime dysfunction, showed a significant difference between the short and long HD duration groups. In multiple regression analysis, the score of the Short Form 8 Health Survey showed a significant association with the PSQI score in the long HD duration group, but no variable showed a significant association in the short HD duration group.Conclusion: Patients with a longer duration of HD indicated that insomnia has an influence on their daily activities, with a significant association between insomnia and QOL. Greater attention should be paid to poor QOL and troubles in daily activities caused by insomnia in patients with a longer HD duration. Keywords: sleep disorders, kidney, quality of life, duration of hemodialysis

Hitoshi Saito,1,2 Koichiro Nomura,1,2,† Shinji Abe,1,2 Takashi Motegi,2,3 Takeo Ishii,2,3 Kumiko Hattori,2,3 Yuji Kusunoki,2,3 Akihiko Gemma,2 Kozui Kida2,3 1Department of Respiratory Medicine, Tokyo Metropolitan Hiroo Hospital, 2Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan, 3Respiratory Care Clinic, Nippon Medical School †Koichiro Nomura passed away on July 30, 2014 Objective: Comorbidities are characteristic of COPD. However, little is known about the secondary manifestations of COPD in the gastrointestinal tract. Therefore, we aimed to explore the long-term effects of gastrectomy in patients with spirometry-defined COPD or those at risk of COPD.Participants: Subjects included 87 patients either with COPD or at risk of COPD (symptomatic) who underwent gastrectomy between December 2003 and October 2013 (group A), and 174 patients either with COPD or at risk of COPD, matched by age (±5 years), sex, and forced expiratory volume in 1 second (FEV1) as percentage of predicted (FEV1% predicted) (±5%) (group B).Methods: All patients underwent routine blood chemistry and pulmonary function tests, arterial blood gas analysis, 6-minute walk test (6MWT), high-resolution chest computed tomography scans, and nutritional assessments.Results: The mean duration postgastrectomy was 18.3±15.4 years. The mean FEV1 and FEV1% predicted were 2.07±0.76 L and 74.6±24.5%, respectively. Univariate analysis indicated that group A patients had significantly lower body mass index, fat-free mass index, and serum hemoglobin and albumin concentration (all P=0.00), and walked a significantly shorter distance in the 6MWT (P

Yoshitaka Kubo, Takahiro Koji, Kenji Yoshida, Hideo Saito, Akira Ogawa, Kuniaki Ogasawara Department of Neurosurgery, Iwate Medical University, Morioka, Japan Abstract: Aneurysms at non-branching sites in the supraclinoid internal carotid artery (ICA) can be classified as “blood blister-like aneurysms” (BBAs), which have blood blister-like configurations and fragile walls. While surgical treatment for the BBA in the acute stage is recommended, the optimal surgical procedure remains controversial. In the study reported here, we describe the case of a 37-year-old woman with a ruptured BBA in the ophthalmic segment of the right ICA who underwent wrap-clipping with external carotid artery–internal carotid artery bypass by intraoperative estimation of the measurement of cortical cerebral blood flow (CoBF) using a thermal diffusion flow probe. Trapping of the ICA in the acute stage of subarachnoid hemorrhage may result in ischemic complications secondary to hemodynamic hypoperfusion or occlusion of the perforating artery, and/or delayed vasospasm, even with concomitant bypass surgery. We believe that it is important to perform scheduled external carotid artery–internal carotid artery bypass before trapping of the ICA in patients with a ruptured BBA in the acute stage of subarachnoid hemorrhage and to perform wrap-clipping rather than trapping. This would provide much more CoBF if a reduction of CoBF occurs after trapping occlusion of the ICA including a ruptured BBA according to intraoperative CoBF monitoring. As far as we are aware, the case reported here is the first report on high-flow bypass and wrap-clipping for a ruptured BBA of the ICA using intraoperative monitoring of cerebral hemodynamics. Keywords: surgery, cortical blood flow, external carotid artery–internal carotid artery bypass, subarachnoid hemorrhage

Chika Saigo,1 Yui Nomura,1 Yuko Yamamoto,1 Masataka Sagata,1 Rika Matsunaga,1 Hirofumi Jono,1,2 Kazuhiko Nishi,3 Hideyuki Saito1,2 1Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 2Department of Pharmacy, Kumamoto University Hospital, 3Department of Hemo-Dialysis, Kumamoto University Hospital, Kumamoto, Japan Abstract: Indoxyl sulfate (IS), a putative low-molecular weight uremic toxin, is excreted in the urine under normal kidney function, but is retained in the circulation and tissues during renal dysfunction in acute kidney injury and chronic kidney disease. IS, which is one of the most potent inducers of oxidative stress in the kidney and cardiovascular system, is enzymatically produced in the liver from indole by cytochrome P450-mediated hydroxylation to indoxyl, followed by sulfotransferase-mediated sulfate conjugation. We used rat liver S9 fraction to identify inhibitors of IS production. After testing several compounds, including phytochemical polyphenols, we identified meclofenamate as a potent inhibitor of IS production with an apparent IC50 value of 1.34 µM. Ischemia/reperfusion (I/R) of rat kidney caused a marked elevation in the serum IS concentration 48 hours after surgery. However, intravenous administration of meclofenamate (10 mg/kg) significantly suppressed this increase in the serum level of IS. Moreover, IS concentrations in both kidney and liver were dramatically elevated by renal I/R treatment, but this increase was blocked by meclofenamate. Serum creatinine and blood urea nitrogen were markedly elevated in rats after renal I/R treatment, but these increases were significantly restored by administration of meclofenamate. Renal expression of both basolateral membrane-localized organic anion transporters rOAT1 and rOAT3 was downregulated by I/R treatment. However, expression of rOAT1 and rOAT3 recovered after administration of meclofenamate, which is associated with the inhibition of I/R-evoked elevation of prostaglandin E2. Our results suggest that meclofenamate inhibits hepatic sulfotransferase-mediated production of IS, thereby suppressing serum and renal accumulation of IS. Meclofenamate also prevents the prostaglandin E2-dependent downregulation of rOAT1 and rOAT3 expression. In conclusion, meclofenamate was found to elicit a nephropreventive effect in ischemic acute kidney injury. Keywords: uremic toxins, hepatic sulfotransferase, renal ischemia/reperfusion, renal tubular cell

Mitsunori Harada,1 Caname Iwata,2 Hiroyuki Saito,1 Kenta Ishii,1 Tatsuyuki Hayashi,1 Masakazu Yashiro,3 Kosei Hirakawa,3 Kohei Miyazono,2 Yasuki Kato,1 Mitsunobu R Kano21Research Division, NanoCarrier Co, Ltd, Chiba, Japan; 2Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; 3Department of Surgical Oncology, Osaka City University, Osaka, JapanAbstract: Drug release rate is an important factor in determining efficacy and toxicity of nanoscale drug delivery systems. However, optimization of the release rate in polymeric micellar nanoscale drug delivery systems has not been fully investigated. In this study NC-6301, a poly(ethylene glycol)-poly(aspartate) block copolymer with docetaxel (DTX) covalently bound via ester link, was synthesized with various numbers of DTX molecules bound to the polymer backbone. The number of DTX molecules was determined up to 14 to achieve an optimal release rate, based upon the authors' own pharmacokinetic model using known patient data. Efficacy and toxicity of the formulation was then tested in animals. When administered three times at 4-day intervals, the maximum tolerated doses of NC-6301 and native DTX were 50 and 10 mg/kg, respectively, in nude mice. Tissue distribution studies of NC-6301 in mice at 50 mg/kg revealed prolonged release of free DTX in the tumor for at least 120 hours, thus supporting its effectiveness. Furthermore, in cynomolgus monkeys, NC-6301 at 6 mg/kg three times at 2-week intervals showed marginal toxicity, whereas native DTX, at 3 mg/kg with the same schedule, induced significant decrease of food consumption and neutrophil count. NC-6301 at 50 mg/kg in mice also regressed a xenografted tumor of MDA-MB-231 human breast cancer. Native DTX, on the other hand, produced only transient and slight regression of the same tumor xenograft. NC-6301 also significantly inhibited growth of OCUM-2MLN human scirrhous gastric carcinoma in an orthotopic mouse model. Total weight of metastatic lymph nodes was also reduced. In conclusion, NC-6301 with an optimized release rate improved the potency of DTX while reducing its toxicity.Keywords: drug release, breast cancer, gastric cancer

A low-cost subsurface irrigation system can generate benefits for small-scale farmers who have scarce water resources. A ring-shaped emitter made from a standard rubber hose has been developed and introduced for subsurface irrigation in Indonesia. It is a low-cost irrigation technology based on indigenous materials and skills. To build a ring-shaped emitter of the original design, a rubber hose is bent into a ring shape with a diameter of about 20 cm, and then five 5-mm holes are drilled into it at even intervals. Next, the entire ring-shaped hose is covered with a permeable textile so that water can infiltrate in all directions around the buried emitter. Water is applied from a water tank connected to the emitter by adjusting the pressure head imposed at the inlet of the emitter. Although it has been successfully used in practice, the performance of the ring-shaped emitter has not been evaluated in detail. Additionally, because the ring-shaped hose is fully covered with the textile, it may be difficult to detect any malfunctions or repair it. To promote the ring-shaped emitter for subsurface irrigation among small-scale farmers in arid or semi-arid regions, it is important to design an emitter that is easy to maintain. This study proposes a reduction in the number of holes and a change of covering method. Because the number of experiments that can be carried out to evaluate the performance of alternative ring-shaped emitters is usually limited, numerical simulations can be performed in addition to experiments. The main objectives of this study thus were 1) to experimentally investigate the water movement around a buried ring-shaped emitter and 2) to numerically evaluate the effect of modifying the design of the ring-shaped emitter on soil water dynamics around the emitter. Numerical simulations were carried out using HYDRUS, one of the most complete packages for simulating variably-saturated water flow in two- or three-dimensional domains. HYDRUS simulations in a fully three-dimensional domain were performed using the soil hydraulic parameters that were optimized against experimental data collected during experiments with the original ring-shaped emitter. Simulation results confirmed that reducing the number of holes does not significantly affect the water availability in silt for model plants, such as tomato and strawberry, and that covering the entire emitter is not necessary. Partially covering the emitter allows one to maintain the emitter much more easily compared to the original fully-covered emitter.

An artificial capillary barrier (CB), which consists of two layers of gravel and coarse sand, was used to improve the soil water retention capacity of the root zone of sandy soil for the cultivation of Japanese spinach (Brassica rapa var. perviridis). The performance of a CB under specific conditions can be evaluated using numerical simulations. However, there have been relatively few numerical studies analyzing soil water dynamics in CB systems during crop growth. The objectives of this study were (i) to evaluate the performance of a CB during the cultivation of Japanese spinach irrigated at different rates and (ii) to investigate the effect of the irrigation schedule on root water uptake. Numerical analysis was performed using HYDRUS-1D after the soil hydraulic properties of the CB materials were determined. In most cases, the HYDRUS-1D results agreed well with the experimental soil water content data without any calibration when the dual-porosity model describing soil hydraulic properties was used for gravel and coarse sand. We found that the dual-porosity model was able to attenuate the unrealistically steep reduction in the unsaturated hydraulic conductivity predicted by the single-porosity model. The numerical simulations also showed that the CB played an important role in maintaining plant-available water in the root zone while maximizing the water use efficiency. The numerical simulations revealed that the irrigation frequency could be reduced by half during the early growth stage, and the water use efficiency could be greatly improved with the CB layer installed.