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Samiratu Mahazu,1,2 Isaac Prah,1,3 Yusuke Ota,1 Takaya Hayashi,3 Masato Suzuki,4 Mitsunori Yoshida,5 Yoshihiko Hoshino,5 Yukihiro Akeda,6 Toshihiko Suzuki,7 Tomoko Ishino,2 Anthony Samuel Ablordey,8 Ryoichi Saito1 1Department of Molecular Microbiology, Tokyo Medical and Dental University, Tokyo, Japan; 2Department of Parasitology and Tropical Medicine, Tokyo Medical and Dental University, Tokyo, Japan; 3Department of Molecular Virology, Tokyo Medical and Dental University, Tokyo, Japan; 4Antimicrobial Resistance Research Center, National Institute of Infectious Diseases, Tokyo, Japan; 5Department of Mycobacteriology, Leprosy Research Center, National Institute of Infectious Diseases, Tokyo, Japan; 6Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan; 7Department of Bacterial Pathogenesis, Tokyo Medical and Dental University, Tokyo, Japan; 8Department of Bacteriology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, GhanaCorrespondence: Anthony Samuel Ablordey; Ryoichi Saito, Email aablordey@noguchi.ug.edu.gh; r-saito.mi@tmd.ac.jpPurpose: Colistin is classified by the World Health Organization (WHO) as a critically important and last-resort antibiotic for the treatment of infections caused by carbapenem-resistant bacteria. However, colistin resistance mediated by chromosomal mutations or plasmid-linked mobilized colistin resistance (mcr) genes has emerged.Methods: Thirteen mcr-positive Aeromonas species isolated from water samples collected in Eastern Ghana were analyzed using whole-genome sequencing (WGS). Antimicrobial susceptibility was tested using the broth microdilution method. Resistome analysis was performed in silico using a web-based platform.Results: The minimum inhibitory concentration (MIC) of colistin for all except three isolates was > 4 μg/mL. Nine new sequence types were identified and whole-genome analysis revealed that the isolates harbored genes (mcr-3-related genes) that code for Lipid A phosphoethanolamine transferases on their chromosomes. BLAST analysis indicated that the amino acid sequences of the mcr-3-related genes detected varied from those previously reported and shared 79.04– 99.86% nucleotide sequence identity with publicly available mcr-3 variants and mcr-3-related phosphoethanolamine transferases. Analysis of the genetic context of mcr-3-related genes revealed that the genetic environment surrounding mcr-3-related genes was diverse among the different species of Aeromonas but conserved among isolates of the same species. Mcr-3-related-gene-IS-mcr-3-related-gene segment was identified in three Aeromonas caviae strains.Conclusion: The presence of mcr-3-related genes close to insertion elements is important for continuous monitoring to better understand how to control the mobilization and dissemination of antibiotic resistance genes.Keywords: Aeromonas spp, colistin, mcr-3-related gene, phosphoethanolamine transferases, whole genome analysis

Masafumi Seki,1,* Haruka Karaushi,1,* Noriko Arai,2 Takeshi Hayashi,2 Kotaro Mitsutake1 1Division of Infectious Diseases and Infection Control, Saitama Medical University International Medical Center, Hidaka City, Saitama, Japan; 2Division of Neurology, Saitama Medical University International Medical Center, Hidaka City, Saitama, Japan*These authors contributed equally to this workCorrespondence: Masafumi Seki, Division of Infectious Diseases and Infection Control, Saitama Medical University International Medical Center, Yamane 1397-1, Hidaka City, Saitama, 350-1298, Japan, Tel +81-42-984-4392, Fax +81-42-984-0280, Email sekimm@saitama-med.ac.jpBackground: Secondary bacterial infection was initially rare in SARS-CoV-2 infectious disease (COVID-19) patients, but COVID-19-associated bacterial infectious diseases have recently been increasing. Furthermore, it might be difficult to distinguish COVID-19 from bacterial meningitis by the symptoms, and one might be uncertain about antibiotic therapy for Listeria meningitis infection—typically caused by eating contaminated food—in elderly persons and pregnant women.Case Report: A 96-year-old woman who had been living alone was found to have SARS-CoV-2 infection in February 2023. She was admitted to our hospital with high fever and disturbance of consciousness and was started on treatment with remdesivir. Two days later, her consciousness was still disturbed, and she was found to have a stiff neck. In addition, increased white blood cell counts and C-reactive protein suggested bacterial infection. Therefore, a lumbar puncture was done, and Listeria monocytogenes was ultimately isolated from blood cultures and its genetic material was detected in cerebrospinal fluid. She had previously eaten refrigerated food and cheese products. Intravenous ampicillin 1.0 g 6×/day was started, but one week later, loss of consciousness continued, and the cerebrospinal findings were not improved, although nasal swab became negative for SARS-CoV-2. Intravenous sulfamethoxazole/trimethoprim (ST) 80/400 mg 3×/day was added, and her consciousness and fever improved by one week later. A drug rash appeared after ST was started, and she was switched to meropenem. Her condition finally improved.Conclusion: COVID-19-associated secondary listeria infection was found in an elderly woman. She was treated with not only ampicillin, but also ST and meropenem. Meningitis caused by Listeria monocytogenes should be considered as a secondary complication and carefully treated with antibiotics during the period of the COVID-19 pandemic.Keywords: penicillin, carbapenem, antibiotics, drug rash, SARS-CoV-2

Mototsugu Shimokawa,1,2,&ast; Naoki Haratake,3,&ast; Kazuki Takada,4 Gouji Toyokawa,5 Shinkichi Takamori,6 Fumitaka Mizuki,7 Tomoyoshi Takenaka,3 Toshinobu Hayashi8 1Department of Biostatistics, Graduate School of Medicine, Yamaguchi University, Yamaguchi, Japan; 2Cancer Biostatistics Laboratory, Clinical Research Institute, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan; 3Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 4Department of Surgery, Saiseikai Fukuoka General Hospital, Fukuoka, Japan; 5Department of Surgery, National Hospital Organization Fukuoka National Hospital, Fukuoka, Japan; 6Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan; 7Center for Clinical Research, Yamaguchi University Hospital, Yamaguchi, Japan; 8Department of Pharmaceutical and Health Care Management, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan&ast;These authors contributed equally to this workCorrespondence: Mototsugu Shimokawa, Department of Biostatistics, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, Japan, Tel +81-836-22-2805, Fax +81-836-22-2805, Email moto@yamaguchi-u.ac.jp Toshinobu Hayashi, Department of Pharmaceutical and Health Care Management, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan, Tel +81-92-871-6631, Email toshinobu@fukuoka-u.ac.jpPurpose: The incidence of delayed chemotherapy-induced nausea and vomiting (CINV) in patients with non-small cell lung cancer (NSCLC) receiving carboplatin (CBDCA)-based chemotherapy (CBDCA + pemetrexed or paclitaxel) has not been clearly described. Therefore, we attempted to evaluate whether delayed CINV could be controlled using a combination of three antiemetics and identify individual risk factors.Methods: We pooled data from two prospective observational studies, namely a nationwide survey of CINV and a prospective, observational study in Japan, to assess whether delayed CINV could be controlled using a combination of three antiemetics and identified individual risk factors via inverse probability treatment-weighted analysis.Results: In total, 240 patients were evaluable in this study (median age, 66 years; male, 173; female, 67). The three-antiemetic regimen controlled delayed nausea (31.6% vs 47.3%) and vomiting (5.1% vs 23.1%) better than two antiemetics. Younger age (< 70 years; odds ratio [OR] = 2.233), motion sickness (OR = 3.472), drinking habits (OR = 1.972), receipt of the CBDCA + pemetrexed regimen (OR = 2.041), and the use of two antiemetics (OR = 1.926) were risk factors for delayed nausea. Female sex (OR = 3.372), drinking habits (OR = 2.272), receipt of the CBDCA+ pemetrexed regimen (OR = 2.314), and the use of two antiemetics (OR = 6.830) were risk factors for delayed vomiting.Conclusion: Female sex, younger age, and receipt of the CBDCA + pemetrexed regimen increased the risk of CINV. Therefore, we recommend additional supportive antiemetics treatment for these patients.Keywords: NSCLC, aprepitant, carboplatin, nausea, vomiting

Hiroharu Kamioka,1 Yasunori Mori,2 Takahiko Horiuchi,3 Takahito Hayashi,4 Koichiro Ohmura,5 Satoru Yamaguchi,6 Mitsutoshi Kato7 1Faculty of Regional Environment Science, Tokyo University of Agriculture, Tokyo, Japan; 2Mie Prefecture Health and Environment Research Institute, Yokkaichi, Mie, Japan; 3Department of Internal Medicine, Kyushu University Beppu Hospital, Beppu, Oita, Japan; 4Department of Legal Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan; 5Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan; 6Department of Oriental Medicine, Saitama Medical University, Saitama, Japan; 7Kato Clinic of Internal Medicine, Tokyo, JapanCorrespondence: Hiroharu KamiokaFaculty of Regional Environment Science, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-Ku, Tokyo 156-8502, JapanTel/Fax +81 35477 2587Email h1kamiok@nodai.ac.jpPurpose: To clarify the relationship between daily hot water bathing (HWB) at home and glycemic control in middle-aged and elderly ambulatory patients with type 2 diabetes mellitus (T2DM).Methods: We defined hemoglobin A1c (HbA1c) as the main outcome. We set 7.0% based on the mean value of the dependent variable as the cut-off point for analysis. Frequency of HWB was an explanatory variable. A two-sample t-test was used to compare between groups with continuous variables. Multiple logistic regression analysis was performed for frequency, adjusted age, sex, BMI, T2DM duration (Model 1), and other confounding factors (Model 2). Odds ratio (OR) and 95% confidence interval (95% CI) were calculated.Results: Among 838 patients, there was a significant difference (p< 0.001) in age between males (n=528, 62.8± 8.7 years) and females (n=310, 65.0± 8.1 years). In Model 1, compared with participants who used HWB more than seven times a week, those with poorly controlled HbA1c were significantly associated with low frequency of HWB: four to six times a week (OR 1.32, 95% CI 0.87– 1.99) and less than three times a week (OR 1.43, 95% CI 0.98– 2.10); p-value for overall trend was 0.041. In Model 2, p-value for overall trend was 0.138.Conclusion: A higher frequency of HWB was moderately associated with a decreased risk of poor glycemic control in middle-aged and elderly ambulatory patients with T2DM.Keywords: hot water bathing, type 2 diabetes, hemoglobin A1c, middle-aged and elderly ambulatory patients

Ai Takemura,1 Tatsuro Egawa,2 Takuji Tanaka,3 Takashi Kuramoto,4 Tatsuya Hayashi,2 Akihiko Ishihara1 1Laboratory of Cell Biology and Life Science, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto 606-8501, Japan; 2Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto 606-8501, Japan; 3Department of Diagnostic Pathology, Gifu Municipal Hospital, Gifu 500-8513, Japan; 4Department of Animal Science, Faculty of Agriculture, Tokyo University of Agriculture, Atsugi 243-0034, JapanCorrespondence: Ai TakemuraDepartment of Sports Research, Japan Institute of Sport Sciences, Tokyo 115-0056, JapanTel +81-75-753-2996Fax +81-75-753-6771Email takemura.ai.46c@kyoto-u.jpPurpose: In rodents, dextran sulfate sodium (DSS)-induced diarrhea and colonic inflammation have similar symptoms to those of ulcerative colitis in humans. We examined the effects of exposure to mild hyperbaric oxygen (MHO) at an atmospheric pressure of 1317 hPa with 40% oxygen on DSS-induced diarrhea and colonic inflammation in rats.Methods: Five-week-old male Kyoto Apc Delta (KAD) rats (n = 12) were administered 2% DSS through drinking water for 1 week. Subsequently, DSS-treated male rats were not subjected to any further treatment (n = 6) or exposed to MHO (n = 6) for 2 weeks. Age-matched KAD rats not subjected to DSS treatment or exposed to MHO were used as the control group (n = 6).Results: Control rats did not exhibit diarrhea and colonic inflammation. However, DSS-treated rats exhibited diarrhea and colonic inflammation, regardless of exposure to MHO. Exposure to MHO for 2 weeks led to decreased incidence of diarrhea in DSS-treated rats (p < 0.05). Exposure to MHO had no effect on colonic inflammation in DSS-treated rats (p = 0.12).Conclusion: Exposure to MHO for 2 weeks can improve diarrhea but cannot attenuate colonic inflammation, possibly due to the short exposure duration (2 weeks) used in this study.Keywords: colonic inflammation, dextran sulfate sodium, Kyoto Apc Delta rats, mild hyperbaric oxygen, oxidative metabolism

Kazuhiko Watanabe,1 Ayumi Onoue,1 Kenichi Kubota,2 Noritaka Higashi,2 Toshinari Hayashi,3 Tohru Tsuda,4 Hisamitsu Omori1 1Department of Biomedical Laboratory Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0976, Japan; 2Department of Respiratory Medicine, Japanese Red Cross Kumamoto Health Care, Kumamoto 861-8528, Japan; 3Tokorozawa Respiratory Clinic, Tokorozawa, Saitama, Japan; 4Kirigaoka Tsuda Hospital, Kitakyusyu, Fukuoka, JapanCorrespondence: Hisamitsu OmoriDepartment of Biomedical Laboratory Sciences, Faculty of Life Sciences, Kumamoto University, 4-24-1 Kuhonji, Chuo-ku Kumamoto, Kumamoto 862-0976, JapanTel +81 96 373 5462Fax +81 96 373 5462Email omorih@gpo.kumamoto-u.ac.jpIntroduction: This study aimed to assess the association between airflow limitation (AL) severity and reduced bone mineral density (BMD) in Japanese men.Subjects and methods: This cross-sectional study included 290 subjects aged over 40 years (mean age 72.0, SD 11.6), who underwent a comprehensive health examination, including spirometry and measurement of BMD at the left femoral neck using dual-energy X-ray absorptiometry (DXA), between 2016 and 2017 at Japanese Red Cross Kumamoto Health Care Center. AL was defined as forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) of −2.5 SD]), or osteoporosis (YAM ≦ 70% [≦ −2.5 SD]). Reduced BMD was defined as osteopenia, osteoporosis, or medication used for osteoporosis. Logistic regression analysis was used to assess the association between AL severity and the reduced BMD.Results: The prevalence of reduced BMD in subjects with moderate-to-severe AL (76.2%) was significantly higher than in those without AL (47.9%) (p=0.030). In logistic regression models adjusted for age, body mass index, pack-years, physical activity, and alcohol drinking, the risk of reduced BMD (odds ratio: 3.87; 95% confidence interval: 1.20–12.49; p=0.024) was significantly higher in subjects with moderate-to-severe AL than in those with normal pulmonary function.Conclusion: Present results suggest that reduced BMD is associated with AL severity in Japanese men.Keywords: chronic obstructive pulmonary disease, comorbidity, bone mineral density, osteoporosis, airflow limitation, pulmonary function

Masaki Nakamura,1 Satoshi Katagiri,1 Takaaki Hayashi,1,2 Ranko Aoyagi,1 Taiji Hasegawa,3 Akiko Kogure,3 Tomohiro Iida,3 Tadashi Nakano11Department of Ophthalmology, The Jikei University School of Medicine, Tokyo, Japan; 2Department of Ophthalmology, Katsushika Medical Center, The Jikei University School of Medicine, Tokyo, Japan; 3Department of Ophthalmology, Tokyo Women’s Medical University, Tokyo, JapanObjective: To describe longitudinal retinal changes in two cases of isolated paracentral acute middle maculopathy (PAMM).Case series: We reported two cases (64 and 67-year-old men) with isolated PAMM, who were followed-up for over 5 and 2.5 years, respectively. Both cases exhibited similar clinical natural histories. The first examinations took place several days after onset, with funduscopy showing that both cases exhibited paracentral scotoma with good visual acuity and small gray lesions, while optical coherence tomography (OCT) showed the presence of a hyperreflective band that ranged from the inner plexiform layer to the outer plexiform layer (OPL). The lesions became unremarkable within 1 month. The hyperreflective band also became unremarkable and was limited to the inner nuclear layer (INL) within 1 month, with the band disappearing within several months. Subsequently, OCT showed there was a thin and irregular INL and OPL, an excavated change of the inner retinal surface, along with outer nuclear layer (ONL) thickening. After several years, OCT angiography demonstrated normal flow of macular capillaries in the superficial capillary plexus, and decreased flow in the lesion with dilation of the capillaries around the area in the deep capillary plexus (DCP). Focal serous retinal detachment (SRD) occurred in one case after 4–5 years.Conclusion: Our findings indicated that long-term retinal changes in PAMM resulted in excavation of the inner retinal surface, INL thinning, ONL thickening and abnormal vasculature, especially in the DCP. Focal SRD may be a rare complication that can present at 4 years after onset.Keywords: paracentral acute middle maculopathy, optical coherence tomography angiography, serous retinal detachment

Toshinobu Hayashi,1,2 Mototsugu Shimokawa,3 Koichi Matsuo,2 Takanori Miyoshi,4 Yoko Toriyama,4 Chiaki Yokota,5 Jun Taniguchi,6 Kiyonori Hanada,7 Kyouichi Tsumagari,8 Noriko Okubo,9 Yoshimichi Koutake,10 Kohei Sakata,11 Yosei Kawamata,12 Takashi Goto,13 Yasufumi Tsurusaki,14 Makiko Koyabu1 1Department of Pharmacy, Clinical Research Institute, National Kyushu Medical Center, Fukuoka, Japan; 2Department of Pharmaceutical and Health Care Management, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan; 3Cancer Biostatistics Laboratory, Clinical Research Institute, National Kyushu Cancer Center, Fukuoka, Japan; 4Department of Pharmacy, National Hospital Organization Beppu Medical Center, Oita, Japan; 5Department of Pharmacy, National Hospital Organization Nagasaki Medical Center, Nagasaki, Japan; 6Department of Pharmacy, National Hospital Organization Ureshino Medical Center, Saga, Japan; 7Department of Pharmacy, National Hospital Organization Kumamoto Saishunso National Hospital, Kumamoto, Japan; 8Department of Pharmacy, National Hospital Organization Miyakonojo Medical Center, Miyazaki, Japan; 9Department of Pharmacy, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan; 10Department of Pharmacy, National Hospital Organization Fukuoka National Hospital, Japan; 11Department of Pharmacy, National Hospital Organization Kumamoto South National Hospital, Kumamoto, Japan; 12Department of Pharmacy, National Hospital Organization Kagoshima Medical Center, Kagoshima, Japan; 13Department of Pharmacy, National Hospital Organization Kokura Medical Center, Kitakyushu, Japan; 14Department of Pharmacy, National Hospital Organization Saga National Hospital, Saga, Japan Purpose: Improvement in the control of delayed chemotherapy-induced nausea and vomiting (CINV) is needed. There is limited information on antiemetic prophylaxis for patients undergoing low-emetic-risk chemotherapy (LEC), and the optimal antiemetic treatment is not well understood. Therefore, we analyzed the risk factors for delayed CINV to aid in the development of individualized treatments. Patients and methods: This prospective multicenter study was conducted in 13 hospitals and included patients with solid cancers undergoing LEC. A total of 222 patients were enrolled between September 2013 and November 2014. The participants completed a daily diary for 5 days after the commencement of the first cycle of LEC to describe the daily incidence of CINV (yes/no). Furthermore, the participants described the severity of nausea and the amount of food intake with the help of VAS. Results: Two hundred and ten patients provided their data that were analyzed using multivariate logistic regression to examine the risk factors for delayed CINV. History of CINV, Eastern Cooperative Oncology Group performance status score ≥1, acute CINV, and single-day antiemetic prophylaxis were identified as independent risk factors for delayed CINV. Conclusion: The current use of antiemetic prophylaxis according to the recommended guideline appears to effectively control delayed CINV in patients undergoing LEC. Therefore, patients with the abovementioned risk factors should be carefully observed, and their treatment should be adjusted according to their symptoms. The use of multiple-day dexamethasone may be beneficial for those patients who develop acute CINV, especially when it is accompanied by anorexia. Keywords: adverse effects, antiemetics, prophylaxis, quality of life

Tadashi Nakano,1 Takeshi Hayashi,2 Toru Nakagawa,2 Toru Honda,2 Satoshi Owada,3 Hitoshi Endo,3 Masayuki Tatemichi3 1Department of Ophthalmology, The Jikei University School of Medicine, Tokyo, 2Hitachi Health Care Center, Ibaraki, 3Department of Preventive Medicine, Tokai University, School of Medicine, Kanagawa, Japan Purpose: To perform a preliminary evaluation of the applicability of automatic spectral domain optical coherence tomography (ASD-OCT) for glaucoma mass screening in a population-based setting. Methods: Information using ASD-OCT (thicknesses of the macular retinal nerve fiber layer [mRNFL], disc retinal nerve fiber layer [dRNFL], ganglion cell layer [GCL] + inner plexiform layer [IPL]; GCL+, and ganglion cell complex [GCL + IPL + RNFL; GCL++]) was obtained from 245 eyes of 123 glaucomatous subjects and 1,454 eyes of 727 normal subjects. For all four measurements, each grid was scored as follows: 2= within 95% of the normal database; 1= within 5%; and 0= within 1%. The sums of each grid (mRNFLs, dRNFLs, GCL+s, and GCL++s) were used as indicators. The effectiveness was estimated by the area under the receiver operating characteristic curve (AUC-ROC). The appropriate algorithm was then applied to 10,145 eyes of 5,088 subjects from the general population (mean age: 50.1±10.3 years). Results: AUC-ROC of mRNFLs, dRNFLs, GCL+s, and GCL++s was 0.927 (95% confidence interval [CI] =0.903–0.950), 0.919 (95% CI =0.899–0.940), 0.972 (95% CI =0.958–0.986), and 0.972 (95% CI =0.957–0.986), respectively. The discriminant analysis demonstrated that the canonical correlation coefficients of mRNFLs, dRNFLs, GCL+s, and dGCL++s were 0.07, 0.255, 0.661, and 0.207, respectively. AUC-ROC of the discriminant value was 0.971 (95% CI =0.956–0.986). The sensitivity/specificity using GCL+s (cutoff =160) was 81.6%/99.9%. This algorithm was applied to the general population, and 1,658 eyes (16.3%) were found to be positive for glaucoma. Conclusion: In the case–control setting, ASD-OCT showed a relatively high performance, and the thickness of the GCL + IPL was the best predictor. However, further prospective studies are needed, in which the results of this study are compared to the general population, because the false-positive rate of glaucoma seems to be high. Keywords: automatic spectral domain optical coherence tomography, glaucoma mass screening, population based, applicability

Ranko Aoyagi, Takaaki Hayashi, Hiroshi TsuneokaDepartment of Ophthalmology, The Jikei University School of Medicine, Tokyo, JapanObjective: The purpose of this study was to report optical coherence tomography (OCT) and angiographic findings in a patient with pregnancy-induced hypertension (PIH).Case report: A 39-year-old woman, who was diagnosed with PIH, reported blurred and distorted vision at 5 days after an emergency cesarean delivery. OCT revealed a large serous retinal detachment (SRD) that included areas in the macula, along with an increased choroidal thickness noted in both eyes. Indocyanine green angiograms indicated delayed filling of the choroidal circulation in the early phase but choroidal hyperpermeability in the mid-phase. The SRD was gradually resolving without any treatment except for antihypertensive drugs. At 40 days after the initial examination, OCT revealed both the disappearance of the SRD and marked improvement of the choroidal thickening.Conclusion: Ophthalmologists need to be aware that PIH can cause choroidal ischemia, a breakdown of the outer blood–retinal barrier, and lead to the development of SRD.Keywords: pregnancy, hypertension, serous retinal detachment, choroidal thickening

Hiroshi Ikeda,1 Kazuya Ishiguro,1 Tetsuyuki Igarashi,1 Yuka Aoki,1 Toshiaki Hayashi,1 Tadao Ishida,1 Yasushi Sasaki,1,2 Takashi Tokino,2 Yasuhisa Shinomura1 1Department of Gastroenterology, Rheumatology and Clinical Immunology, 2Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan Abstract: A 69-year-old man was diagnosed with IgG λ-type multiple myeloma (MM), Stage II in October 2010. He was treated with one cycle of high-dose dexamethasone. After three cycles of bortezomib, the patient exhibited slow elevations in the free light-chain levels and developed a significant new increase of serum M protein. Bone marrow cytogenetic analysis revealed a complex karyotype characteristic of malignant plasma cells. To better understand the molecular pathogenesis of this patient, we sequenced for mutations in the entire coding regions of 409 cancer-related genes using a semiconductor-based sequencing platform. Sequencing analysis revealed eight nonsynonymous somatic mutations in addition to several copy number variants, including CCND1 and RB1. These alterations may play roles in the pathobiology of this disease. This targeted next-generation sequencing can allow for the prediction of drug resistance and facilitate improvements in the treatment of MM patients. Keywords: multiple myeloma, drug resistance, genome-wide sequencing, semiconductor sequencer, target therapy

Tomohiro Mizuno,1,2 Takahiro Hayashi,3 Sayo Hikosaka,1 Yuka Shimabukuro,1 Maho Murase,1 Kazuo Takahashi,2 Hiroki Hayashi,2 Yukio Yuzawa,2 Tadashi Nagamatsu,1 Shigeki Yamada3 1Department of Analytical Pharmacology, Graduate School of Pharmacy, Meijo University, Nagoya, Japan; 2Department of Nephrology, School of Medicine, Fujita Health University, Toyoake, Japan; 3Department of Clinical Pharmacy, School of Medicine, Fujita Health University, Toyoake, Japan Background: Maintenance of low serum urate levels is important for the management of gout. Achieving the recommended serum urate levels of less than 6.0 mg/dL is difficult in elderly (65 years of age or older) patients with renal impairment. Xanthine oxidase inhibitors allopurinol and febuxostat are used for this purpose. Although febuxostat had been shown to be efficacious in elderly patients, its safety and efficacy in elderly female patients with hyper­uricemia remain unclear.Objective: The aim of this study was to assess the efficacy and safety of febuxostat in elderly female patients.Methods: We studied a retrospective cohort study. The study included elderly Japanese patients (65 years of age or older) who were treated with febuxostat at Fujita Health University Hospital from January 2012 to December 2013. The treatment goal was defined as achievement of serum urate levels of 6.0 mg/dL or lower within 16 weeks; this was the primary endpoint in the present study. Adverse events of febuxostat were defined as more than twofold increases in Common Terminology Criteria for adverse events scores from baseline. Results: We evaluated 82 patients treated with febuxostat during the observation period and classified them into male (n=53) and female (n=29) groups. The mean time to achievement of the treatment goal was significantly shorter in the female group (53 days) than in the male group (71 days). There were no significant differences in adverse events between the 2 groups.Conclusion: Our findings suggest that the efficacy of febuxostat in elderly female patients is superior to that in elderly male patients and that the safety is equivalent. Keywords: febuxostat, elderly female patients, hyperuricemia

Tomohiro Mizuno,1,2,* Takahiro Hayashi,3,* Rina Kato,1 Ayaka Noguchi,1 Hiroki Hayashi,2 Yukio Yuzawa,2 Shigeki Yamada,3 Tadashi Nagamatsu1 1Department of Analytical Pharmacology, Meijo University Faculty of Pharmacy, Nagoya; 2Department of Nephrology, 3Department of Clinical Pharmacy, School of Medicine, Fujita Health University, Toyoake, Japan *These authors contributed equally to this work Background: Patients with end-stage renal disease (ESRD) have symptoms related to severe anemia, edema, and heart failure. Although dialysis improves ESRD syndromes, the optimum timing for initiation of dialysis is unclear. Recent observational studies have suggested that early commencement of dialysis can be harmful. Given that early dialysis may increase the risk of death, avoiding an early start to dialysis is recommended. Patients with diabetic nephropathy (DN) may have risk factors for early dialysis. However, the risk factors for early dialysis are unclear in ESRD patients with DN. The aim of this study was to elucidate the risk factors for early initiation of dialysis in patients with DN and ESRD. Methods: From April 2009 to December 2012, we identified Japanese DN patients with an estimated glomerular filtration rate of less than 15 mL/minute/1.73 m2. The patients were divided into late or early dialysis groups based on the timing of start of dialysis. Results: We evaluated 52 patients who commenced dialysis during the observation period, including 33 in the late dialysis group and 19 in the early dialysis group. There was a significant association between early dialysis and age ≥65 years (odds ratio 4.59). The incidence of pneumonia before starting dialysis was significantly higher in elderly patients than in nonelderly patients. Conclusion: Our findings suggest that elderly patients with DN and ESRD have an increased risk of early initiation of dialysis, and occurrence of pneumonia is also associated with early dialysis. To avoid early commencement of dialysis, booster pneumococcal vaccination could be useful in elderly DN patients with ESRD. Keywords: early dialysis, diabetes mellitus, nephropathy, elderly patients, estimated glomerular filtration rate

Yasuhiro Ohkuma,1 Takaaki Hayashi,1 Tsutomu Sakai,1 Akira Watanabe,1 Hisashi Yamada,2 Masakazu Akahori,3 Takeshi Itabashi,3 Takeshi Iwata,3 Toru Noda,4 Hiroshi Tsuneoka11Department of Ophthalmology, 2Department of Molecular Genetics, Institute of DNA Medicine, The Jikei University School of Medicine, 3Division of Molecular and Cellular Biology, National Institute of Sensory Organs, 4Division of Ophthalmology, National Hospital Organization Tokyo Medical Center, Tokyo, JapanBackground: The purpose of this study was to investigate the association between ARMS2/HTRA1, CFH, and C3 gene polymorphisms and retinal angiomatous proliferation (RAP), an infrequent and severe form of exudative age-related macular degeneration, which is characterized by intraretinal neovascularization.Methods: Diagnosis of RAP was based on fundus photographs, images of fluorescein and indocyanine green angiographies, and optical coherence tomography findings. Six single nucleotide polymorphisms (SNPs), A69S (rs10490924) in ARMS2, rs11200638 in HTRA1, I62V (rs800292) in CFH, Y402H (rs1061170) in CFH, R80G (rs2230199) in C3, and rs2241394 in C3, were genotyped in eight Japanese patients with RAP.Results: The two SNPs in the ARMS2/HTRA1 were in complete linkage disequilibrium. The frequency of the risk T allele in ARMS2 (the risk A allele in HTRA1) was 93.8% in the RAP patients. The frequency of homozygosity for the risk genotype TT of ARMS2 (the risk genotype AA of HTRA1) was 87.5%. The frequency of the non-risk allele (A) of I62V was 100%. The frequencies of risk alleles of Y402H, R80G, and rs2241394 were 12.5%, 0%, and 18.8%, respectively.Conclusion: Our results suggest that the risk alleles of the ARMS2/HTRA1 SNPs may be associated with development of RAP and play a major role in the pathogenesis of intraretinal angiogenesis.Keywords: age-related macular degeneration, retinal angiomatous proliferation, single nucleotide polymorphisms, ARMS2/HTRA1 genes, components of the complement system

Asako Shibata, Yasuhiro Ohkuma, Takaaki Hayashi, Hiroshi Tsuneoka Department of Ophthalmology, The Jikei University School of Medicine, Tokyo, Japan Background: Very few reports have addressed methods of treatment for idiopathic serous (IS) pigment epithelial detachment (PED). Objective: The purpose of this report was to describe clinical courses of two patients with ISPED in whom reduced-fluence photodynamic therapy (RFPDT) was performed. Case reports: Two patients (a 38-year-old woman and a 42-year-old man) were diagnosed with ISPED. In both patients, indocyanine green angiography revealed an area of choroidal vascular hyperpermeability including hyperfluorescent PED, which was evident at the subfoveal area. Both patients underwent RFPDT at an energy of 25 J/cm2. The PED was seen to have resolved 1 month after the treatment and visual acuity was maintained or improved. There was no posttreatment recurrence of PED after 6 months to 1 year, and no treatment-related adverse events were observed. Conclusion: RFPDT may be an effective and safe method of treatment for ISPED with choroidal vascular hyperpermeability. Keywords: pigment epithelial detachment, central serous chorioretinopathy, reduced-fluence photodynamic therapy

Koichi Sugimoto,1 Takahiro Akiyama,2 Nobutaka Shimizu,3 Naoki Matsumura,1 Taiji Hayashi,1 Tsukasa Nishioka,1 Hirotsugu Uemura3 1Department of Urology, Sakai Hospital, Kinki University Faculty of Medicine, Sakai, Osaka, Japan; 2Department of Urology, Sakai-Onshinkai Hospital, Sakai, Osaka, Japan; 3Department of Urology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan Aim: To investigate the clinical efficacy of acotiamide hydrochloride hydrate in patients with detrusor underactivity. Methods: We measured the post-void residual urinary volume in 19 patients with underactive bladders. All these patients had been under treatment with distigmine bromide and were prescribed acotiamide hydrochloride hydrate at a dose of 100 mg three times daily for 2 weeks. Results: Compared with the post-void residual urinary volume value at baseline (161.4±90.0 mL) a statistically significant reduction was observed at the end of treatment (116.3±63.1 mL) (P=0.006). The drug was generally well tolerated by the majority of patients. Conclusion: Maybe, acotiamide hydrochloride hydrate showed clinical efficacy in patients with underactive bladders and may, therefore, be used alternatively in patients who do not respond sufficiently to distigmine bromide. Keywords: acotiamide hydrochloride hydrate, distigmine bromide, underactive bladder, detrusor underactive

Masaomi Kubota, Takaaki Hayashi, Kota Arai, Hiroshi TsuneokaDepartment of Ophthalmology, The Jikei University School of Medicine, Tokyo, JapanBackground: Patients with angioid streaks are prone to develop a subretinal hemorrhage after ocular injury, due to fragility of Bruch's membrane.Objective: The purpose of this study was to report a patient with angioid streaks in whom subfoveal choroidal neovascularization (CNV) developed after blunt ocular trauma.Case report: A 60-year-old man was accidentally struck in the left eye with a crowbar handle while engaged in the demolition of wooden building materials in May 2011 and was initially evaluated at our hospital. Corrected visual acuity was 0.3 in the right and 1.2 in the left eye, and relative afferent pupillary defect was negative. Funduscopy revealed choroidal atrophy around the optic papillae and angioid streaks radiating from around the optic discs in both eyes. In the right eye, there was macular atrophy. In the left eye, there was a subretinal hemorrhage around the macular region. Fluorescein angiography of the left eye showed a blockage due to subretinal hemorrhage and increasing hyperfluorescent spots superior to the fovea, suggestive of extrafoveal CNV. Spectral-domain optical coherence tomography showed macular thinning in the right eye and no obvious abnormalities near the subfoveal region in the left eye. Two months later, the patient noticed decreased visual acuity in the left eye and was reevaluated. Visual acuity had decreased to 0.7, and well-defined CNV, one disc diameter in size, was presenting slightly superior to the macula, including the subfoveal region. Two weeks later, anti-vascular endothelial growth factor (anti-VEGF) antibody (bevacizumab) was injected intravitreally; the CNV then regressed, and visual acuity improved to 1.2.Conclusion: Marked improvement in visual acuity with early treatment has not been reported in angioid streaks with subfoveal CNV after ocular injury. Intravitreal injection of an anti-VEGF antibody should be considered early after the diagnosis of CNV.Keywords: pseudoxanthoma elasticum, subretinal hemorrhage, anti-VEGF therapy

Nobutaka Shimizu,1 Masahiro Nozawa,1 Koichi Sugimoto,2 Yutaka Yamamoto,1 Takafumi Minami,1 Taiji Hayashi,1 Kazuhiro Yoshimura,1 Tokumi Ishii,1 Hirotsugu Uemura11Department of Urology, Faculty of Medicine, Kinki University, Osaka, 2Department of Urology, Sakai Hospital, Faculty of Medicine, Kinki University, Osaka, JapanObjectives: This study was conducted to examine the therapeutic efficacy and anti-inflammatory effect of ramelteon in elderly patients with insomnia associated with lower urinary tract symptoms (LUTS), who visited our urology department.Methods: The study included 115 patients (102 men, 13 women) who scored ≥4 on the Athens Insomnia Scale and who wished to receive treatment. The assessment scales for therapeutic efficacy included the International Prostate Symptom Score (IPSS) for LUTS and the Insomnia Severity Index (ISI) for sleep disorders. The high-sensitivity C-reactive protein (hs-CRP) test was used to an objective assessment. The patients were treated with ramelteon (8 mg/day) for an average of 10 weeks and were then reexamined using the questionnaires and hs-CRP test to evaluate therapeutic efficacy.Results: IPSS total scores declined significantly from 11.39 ± 8.78 to 9.4 ± 7.72. ISI total scores improved significantly from 11.6 ± 5.2 to 9.2 ± 5.3 (P < 0.0001). The levels of hs-CRP decreased significantly from 0.082 (standard deviation [SD] upper limit, 0.222; SD lower limit, −0.059) to 0.06 (SD upper limit, 0.152; SD lower limit, −0.032). The ISI scores ≥ 10 (n = 51) showed a weak correlation with the hs-CRP levels.Conclusion: Ramelteon had a systemic anti-inflammatory effect and improved sleep disorders and LUTS, suggesting that it may be a useful treatment for patients with LUTS-associated insomnia.Keywords: sleep disorders, inflammation, lower urinary tract symptoms, ramelteon

Nobutaka Shimizu,1 Yasuharu Nagai,1 Yutaka Yamamoto,1 Takafumi Minami,1 Taiji Hayashi,1 Hidenori Tsuji,1 Masahiro Nozawa,1 Kazuhiro Yoshimura,1 Tokumi Ishii,1 Hirotsugu Uemura,1 Takashi Oki,2 Koichi Sugimoto,2 Kazuhiro Nose,2 Tsukasa Nishioka21Department of Urology, Kinki University Faculty of Medicine, Osaka, Japan; 2Department of Urology, Sakai Hospital, Kinki University Faculty of Medicine, Osaka, JapanObjectives: This study examined the association between sleep disorders and lower urinary tract symptoms in patients who had visited urology departments.Methods: This was an independent cross-sectional, observational study. Outpatients who had visited the urology departments at the Kinki University School of Medicine or the Sakai Hospital, Kinki University School of Medicine, between August 2011 and January 2012 were assessed using the Athens Insomnia Scale and the International Prostate Symptom Score.Results: In total, 1174 patients (mean age, 65.7 ± 13.7 years), with 895 men (67.1 ± 13.2 years old) and 279 women (61.4 ± 14.6 years old), were included in the study. Approximately half of these patients were suspected of having a sleep disorder. With regard to the International Prostate Symptom Score subscores, a significant increase in the risk for suspected sleep disorders was observed among patients with a post-micturition symptom (the feeling of incomplete emptying) subscore of ≥1 (a 2.3-fold increase), a storage symptom (daytime frequency + urgency + nocturia) subscore of ≥5 (a 2.7-fold increase), a voiding symptom (intermittency + slow stream + hesitancy) subscore of ≥2 (a 2.6-fold increase), and a nocturia subscore of ≥2 (a 1.9-fold increase).Conclusion: The results demonstrated that the risk factors for sleep disorders could also include voiding, post-micturition, and storage symptoms, in addition to nocturia.Keywords: lower urinary tract symptoms, sleep disturbance, urological disease

Electrochemical measurements of the solid-oxide galvanic cell of the type Mo/Mo + MoO2/ZrO2 (MgO)/Fe + {Na2O-Al2O3-SiO2-FexO} slag/Ag/Fe were conducted at 1673 K in order to obtain the activities of FexO in Na2O-Al2O3-SiO2-FexO system. The iso-activity curves for FexO at 1673 K were determined for Na2O-(Al2O3 + SiO2)-FexO pseudo-ternary slags with an Al2O3/SiO2 molar ratio of 33/67.

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