Search

Tomokazu Yamaguchi,1,2,* Ryo Ozawa,2,3,* Takafumi Minato,2 Midori Hoshizaki,4 Yutaro Kammura,1,5 Kazuma Okawara,1,6 Yousef A Khalil,1 Masafumi Nakamura,6 Ken Yamaura,5 Masayuki Fukuda,3 Yumiko Imai,4 Keiji Kuba1,2 1Department of Pharmacology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; 2Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, Akita, Japan; 3Department of Dentistry and Oral Surgery, Akita University Graduate School of Medicine, Akita, Japan; 4National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Ibaraki, Japan; 5Department of Anesthesiology and Critical Care Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; 6Department of Surgery and Oncology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan*These authors contributed equally to this workCorrespondence: Keiji Kuba, Department of Pharmacology, Kyushu University Graduate School of Medical Sciences, Maidashi 3-1-1, Higashi-ku, Fukuoka, 813-0016, Japan, Email kuba.keiji.815@m.kyushu-u.ac.jpBackground: Acute lung injury (ALI) is caused by a variety of illnesses, including aspiration pneumonia and sepsis. The CCR4-NOT complex is a large multimeric protein complex that degrades mRNA through poly(A) tail shortening, whereas it also contributes to regulation of transcription and translation. Cnot3 is a scaffold component of the CCR4-NOT complex and is essential for the integrity of the complex; loss of Cnot3 leads to depletion of whole complex. While the significance of cytokine mRNA degradation in limiting inflammation has been established, the roles of CCR4-NOT complex-mediated in ALI remain elusive.Methods: The effects of Cnot3 haploinsufficiency in the pathology and cytokine expression were analyzed in the mouse lungs of acid aspiration-induced acute lung injury. The decay rate and transcription activity of cytokine mRNAs under Cnot3 heterozygous deletion were analyzed in lipopolysaccharide (LPS) -stimulated mouse embryonic fibroblasts (MEFs).Results: Tamoxifen-induced heterozygous deletion of Cnot3 in adult mice (Cnot3 Hetz) did not show body weight loss or any apparent abnormality. Under acid aspiration-induced acute lung injury, Cnot3 Hetz mice exhibited increased pulmonary edema, worse lung pathologies and more severe inflammation compared with wild type mice. mRNA expression of pro-inflammatory genes Il1b and Nos2 were significantly upregulated in the lungs of Cnot3 Hetz mice. Consistently, mRNA expression of Il1b and Nos2 was upregulated in LPS-stimulated Cnot3 Hetz MEFs. Mechanistically, while heterozygous depletion of Cnot3 stabilized both Il1b and Nos2 mRNAs, the nascent pre-mRNA level of Il1b was upregulated in Cnot3 Hetz MEFs, implicating Cnot3-mediated transcriptional repression of Il1b expression in addition to destabilization of Il1b and Nos2 mRNAs. PU.1 (Spi1) was identified as a causative transcription factor to promote Il1b expression under Cnot3 haploinsufficient conditions.Conclusion: CNOT3 plays a protective role in ALI by suppressing expression of pro-inflammatory genes Il1b and Nos2 through both post-transcriptional and transcriptional mechanisms, including mRNA stability control of Spi1.Keywords: acute lung injury, ALI, ARDS, CNOT3, CCR4-NOT complex, deadenylation

Timo A Auer,1,2 Keitaro Sofue,3 Eisuke Ueshima,3 Nina Rauer,1 Takeru Yamaguchi,3 Bernhard Gebauer,1 Bernd Hamm,1 Takamichi Murakami,3 Christian E Althoff1 1Department of Radiology, Charité - University Medicine Berlin, Berlin, Germany; 2Berlin Institute of Health (BIH), Berlin, Germany; 3Department of Radiology, Kobe University Graduate School of Medicine, Kobe, JapanCorrespondence: Timo A Auer, Department of Radiology, Campus Virchow-Klinikum, Charité – Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, 13353, Germany, Tel +49-30-450-557001, Fax +49-30-450-557901, Email timo-alexander.auer@charite.deObjective: The purpose of this study was to investigate outcomes of transarterial chemoembolization (TACE) in treating hepatocellular carcinoma (HCC) comparing the different approaches used in Germany and Japan.Methods: This binational IRB-approved retrospective dual-center study included a total of 94 HCC patients subdivided in a German and a Japanese cohort. For each patient, liver and tumor volumetry was performed using computed tomography (CT) and magnetic resonance imaging (MRI). Furthermore, a comprehensive risk profile, including body constitution and liver and kidney function was established. Primary endpoints were progression-free and overall survival (PFS/OS).Results: PFS in the German cohort was 168 vs 224d in the Japanese cohort (p=0.640). When subdivided by BCLC stage, no significant differences were reported (p=0.160– 0.429). OS was significantly longer in the Japanese cohort with 856 vs. 303d (p< 0.001). OS for BCLC A was significantly longer in the Japanese cohort (1960 vs. 428d; p< 0.001), while survival rates did not differ significantly in BCLC B (785 vs 330d; p=0.067) and C-stages (208 vs 302d; p=0.186). Older age (p=0.034), poorer liver/kidney function (p=0.025-0-035), and a higher liver/tumor ratio (p< 0.001) were found to correlate with shorter survival. ECOG scores were significantly higher in the German cohort (p=0.002).Conclusion: While OS is longer in TACE-treated patients in the Japanese cohort compared to the German cohort, the two approaches seem to be equally effective as PFS does not differ significantly. The different survival rates may be caused by the different clinical performance status of the selected collectives. In very early and early stage HCC, TACE in Japan seems to be an effective treatment option while in Germany for patients in those stages TACE remains a second-line option for patients not available for surgery or ablation.Keywords: HCC, TACE, liver, hepatocellular carcinoma, interventional oncology

Shunsuke Takagi,1 Hikaru Hori,2 Tatsuya Yamaguchi,3,4 Shinichiro Ochi,5 Masaki Nishida,6 Takashi Maruo,1 Hidehiko Takahashi1 1Department of Psychiatry and Behavioral Neurosciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan; 2Department of Psychiatry, School of Medicine, Fukuoka University, Fukuoka, 814-0180, Japan; 3Institute for Integrated Sports Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, 160-8582, Japan; 4Department of Neuropsychiatry, Keio University School of Medicine, Shinjuku-ku, Tokyo, 160-8582, Japan; 5Department of Neuropsychiatry, Molecules and Function, Ehime University Graduate School of Medicine, Shitsukawa, Ehime, 791-0295, Japan; 6Faculty of Sport Science, Waseda University Tokorozawa, Saitama, 359-1192, JapanCorrespondence: Shunsuke Takagi, Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan, Tel +81-3-5803-5238, Fax +81-3-5803-0135, Email stakagi.psyc@tmd.ac.jpBackground: The development of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASDs) has various influences on physical abilities. Identification of specific physical abilities of people with ADHD/ASDs as biomarkers for diagnosing these conditions is necessary. Therefore, in the present review, we aimed firstly to extract the difference in physical abilities of people with ADHD or ASDs compared to those of normal individuals. Secondly, we aimed to extract the specific physical ability characteristics for identifying potential diagnostic biomarkers in people with ADHD/ASDs.Methods: A systematic literature review was performed. The databases were searched for relevant articles on motor function deficits and characteristics of ADHD or ASD.Results: Forty-one cross-sectional studies and three randomized controlled trials were identified, comprising 33 studies of ADHD, 10 studies of ASDs, and 1 study of both ADHD and ASDs. The quality of studies varied. Three types of physical activities/exercises were identified, including coordinated movement, resistance-type sports, and aerobic-type sports. People with ADHD/ASDs generally exhibited poorer physical abilities for all types of activities, possibly because of low levels of physical activity. Specifically, we found temporal discoordination of movement in ADHD and integration or synchronization of separate movements in ASDs.Conclusion: Specific deficits in physical ability may be attributed to ADHD/ASDs. However, there is not enough research on the physical abilities of people with ADHD and ASDs to clarify the specific deficits. Investigation of specific motor functions that characterize ADHD/ASDs should be facilitated.Keywords: motor function, neurodevelopmental disorders, sports, coordination, neural deficits

Daiji Nagayama,1,2 Kentaro Fujishiro,3 Keijiro Nakamura,4 Yasuhiro Watanabe,2 Takashi Yamaguchi,2 Kenji Suzuki,3 Kazuhiro Shimizu,5 Atsuhito Saiki,2 Kohji Shirai6 1Department of Internal Medicine, Nagayama Clinic, Tochigi, Japan; 2Center of Diabetes, Endocrinology and Metabolism, Toho University, Sakura Medical Center, Chiba, Japan; 3Japan Health Promotion Foundation, Tokyo, Japan; 4Division of Cardiovascular Medicine, Toho University, Ohashi Medical Center, Tokyo, Japan; 5Division of Cardiovascular Medicine, Toho University, Sakura Medical Center, Chiba, Japan; 6Department of Internal Medicine, Mihama Hospital, Chiba, JapanCorrespondence: Daiji NagayamaNagayama Clinic, 2-12-22, Tenjin-Cho, Oyama-City, Tochigi, 323-0032, Japan, Tel/Fax +81-285-22-0219, Email deverlast96071@gmail.comAim: Physiological tests to assess systemic vascular function are not included in the risk score for atrial fibrillation (AF). We aimed to examine whether cardio-ankle vascular index (CAVI), a systemic arterial stiffness parameter, is associated with the presence of AF in Japanese general population.Methods: A cross-sectional study (N = 47,687) and a cohort study (N = 5418, four consecutive years) in Japanese urban residents who participated in annual health screening were conducted.Results: A total of 164 subjects (0.34%) had AF in the cross-sectional data. After propensity score matching for age and gender, logistic regression analysis revealed that CAVI is independently associated with AF, as are body mass index and estimated glomerular filtration rate. In a 4-year cohort study, 22 subjects (0.41%) with new-appearance of AF showed higher CAVI at baseline than those without. In the receiver-operating-characteristic curve analysis, the area under the curve, which is a measure of predictability, of CAVI for the new-appearance of AF was 0.747, and the cut-off value of CAVI was 8.0. Kaplan–Meier analysis revealed that the cumulative incidence of new-appearance of AF was higher in subjects with CAVI ≥ 8.0 compared to those with CAVI < 8.0. In Cox-proportional hazards analysis, CAVI ≥ 8.0 as well as gender were identified as independent predictors for the new-appearance of AF, whereas age ≥ 65 years was not.Conclusion: Increased CAVI may represent a major modifiable risk factor for the development of AF. Studies are needed to confirm that CAVI is a predictor of AF independent of various AF risk factors and that CAVI-lowering interventions can prevent new-appearance or recurrence of AF.Keywords: atrial fibrillation, cardio-ankle vascular index, CAVI, arterial stiffness, health screening

Yusuke Hanioka,1 Ryo Morita,2 Keiko Yamagami,1 Shuhei Yao,1 Ryota Nakamura,1 Tomoyuki Nakamura,1 Katsushu Shimizu,3 Toshimasa Yamaguchi,3 Hitoshi Goto1 1Department of Internal Medicine, Osaka City General Hospital, Osaka, Japan; 2Department of Infectious Diseases, Osaka City General Hospital, Osaka, Japan; 3Department of Primary Care and Advanced Triage Section, Osaka City General Hospital, Osaka, JapanCorrespondence: Yusuke HaniokaDepartment of Internal Medicine, Osaka City General Hospital, 2-13-22 Miyakojima-Hondori, Miyakojima-ku, Osaka, 534-0021, JapanTel +81-6-6929-1221Fax +81-6-6929-2041Email y-hanioka@med.osakacity-hp.or.jpPurpose: It is important to understand how COVID-19 is affecting general outpatient services, since hospitals see a wide variety of patients. This study aimed to evaluate the incidence and clinical picture of COVID-19 in general outpatient services. Currently, the diagnosis of COVID-19 depends strongly on the results of polymerase chain reaction (PCR) assays. However, since the sensitivity of PCR tests for SARS-CoV-2 is not high enough to assure confidence. On the other hand, the SARS-CoV-2 antibody (Ab) test is highly sensitive after 2 weeks of symptom onset, and might complement the PCR test. Therefore, we measured Ab in addition to PCR to obtain a more accurate clinical profile of COVID-19, which might be helpful in building future practice strategies.Patients: The study patients were those who visited our department for the first time between November 2020 and March 2021 and fulfilled the enrolment criteria.Methods: All patients underwent total SARS-CoV-2 Ab testing, and PCR tests were performed in only some of them; patients were classified according to the performance of PCR tests for comparisons.Results: Ninety-four patients who underwent Ab testing during the study period were eligible for study enrolment, and the PCR test was performed in 40 of them. Only one patient was diagnosed with acute stage COVID-19 based on a positive PCR test. Antibodies were positive in six (6.4%) of the 94 patients. Five of the six Ab-positive patients were negative for PCR, and the test was not performed in the sixth patient. All the six patients had prior symptoms suggestive of infection, and respiratory symptoms were more noticeable than fever. The Ab positivity rate was significantly higher than published data.Conclusion: COVID-19 is not rare in general outpatient services and can be missed based on PCR tests alone. The diagnosis should be made from a comprehensive perspective.Keywords: COVID-19, SARS-CoV-2 antibody, outpatient service, fever

Takumi Yamaguchi,1,2 Akio Yamamoto,2,3 Yutaro Oki,2 Hideki Sakai,1 Shogo Misu,1,4 Yusuke Iwata,2 Masahiro Kaneko,5 Kaku Sawada,6 Yukari Oki,2 Yuji Mitani,2 Kumiko Ono,2 Akira Ishikawa2 1Department of Rehabilitation, Kobe City Hospital Organization, Kobe City Medical Center West Hospital, Kobe, Hyogo, 653-0013, Japan; 2Kobe University Graduate School of Health Sciences, Kobe, Hyogo, 654-0142, Japan; 3Department of Faculty of Nursing, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, 569-0095, Japan; 4Department of Physical Therapy, Faculty of Nursing and Rehabilitation, Konan Women’s University, Kobe, Hyogo, 658-0001, Japan; 5Department of Respiratory Medicine, Kobe City Hospital Organization Kobe City Medical Center West Hospital, Kobe, Hyogo, 653-0013, Japan; 6Department of Internal Medicine, Keiwakai Nishioka hospital, Sapporo, Hokkaido, 062-0034, JapanCorrespondence: Takumi YamaguchiDepartment of Rehabilitation, Kobe City Hospital Organization, Kobe City Medical Center, West Hospital, 2-4, Ichibancho, Nagata-Ku, Kobe, 653-0013, Hyogo, JapanTel +81-78-576-5251Fax +81-78-576-5358Email taato8327@gmail.comPurpose: Japan has only a few respiratory disease-specific activity of daily living scales that are accepted outside of Japan, and they are not widely used. The Barthel Index dyspnea (BI-d), an improved version of the Barthel Index (BI), may be popular in Japan. The purpose of this study was to develop the Japanese version of BI-d (J-BI-d) and investigate its reliability and validity.Patients and Methods: The J-BI-d was developed using the basic guidelines for scale translation. The study included patients with chronic respiratory disease, receiving outpatient care at two centers between January 2019 and February 2020. Scores on the J-BI-d, modified Medical Research Council scale (mMRC scale), BI, respiratory function tests, and 6-minute walk distance (6MWD) test were measured. To verify the test–retest reliability, the J-BI-d was re-administered, and the intraclass correlation coefficient (ICC) was obtained. Internal consistency was verified by Cronbach’s alpha reliability coefficient, and criterion-related validity was verified through a correlation analysis of the J-BI-d with mMRC scale and 6MWD test. Divergent validity was verified through correlation analysis between the J-BI-d and BI.Results: Data for 57 participants (mean age 74.4 ± 8.3 years) were analyzed, and reliability testing was performed with 42 of them. The mean time to retest was 8.1 ± 3.0 days, and the ICC (2, 1) was 0.76 (95% CI: 0.62– 0.85), indicating high reliability. Cronbach’s alpha reliability coefficient was 0.81, indicating high internal consistency. Correlation coefficients of the J-BI-d with 6MWD test (r = − 0.46, p < 0.01) and mMRC scale (ρ = 0.76, p < 0.01) indicated high criterion-related validity. The J-BI-d and BI had a weak negative correlation (r = − 0.29, p < 0.05), indicating high divergent validity.Conclusion: The results of this study demonstrate high reliability and appropriate validity of the J-BI-d in patients with chronic respiratory disease.Keywords: activities of daily living, dyspnea, chronic obstructive pulmonary disease, interstitial lung disease, Japanese, reliability and validity

Kanako Azuma,1 Takashi Kawaguchi,2 Takuhiro Yamaguchi,3 Sayuri Motegi,1 Kimito Yamada,4 Kenji Onda,5 Satoru Iwase,6 Sakae Unezaki,2 Hironori Takeuchi1 1Department of Pharmacy, Tokyo Medical University Hospital, Tokyo, Japan; 2Department of Practical Pharmacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan; 3Division of Biostatistics, Tohoku University Graduate School of Medicine, Miyagi, Japan; 4Department of Breast Surgery, Tokyo Medical University Hospital, Tokyo, Japan; 5Department of Clinical Pharmacology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan; 6Department of Emergency & Palliative Medicine, Faculty of Medicine, Saitama Medical University, Saitama, JapanCorrespondence: Takashi Kawaguchi Email tkawa@toyaku.ac.jpPurpose: The importance of shared decision-making (SDM) between physicians and patients is increasingly recognized. In Japan, patients have shown more willingness to participate in treatment if medical professionals provide sufficient information; however, relationships between physicians and patients have traditionally been asymmetric, with patients accepting information from physicians without discussion. To explore the benefits of SDM in cancer treatment, including confidence in treatment decisions, satisfaction with treatment, and trust in healthcare providers, this study developed Japanese versions of the Control Preference Scale (CPS) and Information Needs Questionnaire (INQ).Patients and Methods: Reliability and validity of the CPS and INQ were tested with 49 breast cancer patients.Results: The CPS showed good test–retest reliability (kappa coefficient: 0.61, weighted kappa coefficient: 0.61, Kendall’s tau coefficient: 0.61) and acceptable criterion validity. The INQ showed adequate consistency; the mean number of circular triads and coefficient of consistency were 3 (range 0– 19) and 0.9 (range 0.37– 1), respectively. Using the CPS and INQ to identify patients’ roles in decision-making and information needs, results further suggested that breast cancer patients in Japan want to participate in SDM. Medical issues, including disease spread and cure, were found to be of high interest, while social and psychological issues, including sexual attractiveness, genetic risk, and family impact, tended to be low.Conclusion: The Japanese CPS and INQ can be used to assess patients’ needs to improve care. Further, as patients’ information needs change along the care trajectory, these tools should be used throughout treatment.Keywords: shared decision-making, breast cancer, treatment option, control preference scale, information needs questionnaire

Ryuji Kawahara,1 Takahiro Yamaguchi,1 Yoshimasa Yamamoto2,3 1Division of Microbiology, Osaka Institute of Public Health, Osaka, Japan; 2Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan; 3Life Science Research Center, Gifu University, Gifu, JapanCorrespondence: Yoshimasa YamamotoLife Science Research Center, Gifu University, 1-1 Yanagido, Gifu, 501-1194, JapanTel/Fax +81-58-230-6239Email yyamamot@gifu-u.ac.jpBackground: Emergence and dissemination of colistin-resistant bacteria that harbor mobile colistin resistance (mcr) genes pose a dire challenge for the treatment of intractable infections caused by multidrug-resistant bacteria. Current findings on colistin-resistant bacteria in both humans and livestock of the same households highlight the need to identify the dissemination mechanisms of colistin-resistant bacteria.Methods: In this study, a comparative genome analysis of colistin-resistant Escherichia coli isolates from livestock and humans of the same household was performed to clarify the possible dissemination mechanism of mcr genes among bacteria. Pulsed-field gel electrophoresis and whole-genome sequencing followed by sequence typing of the isolates were performed for assessment of the samples.Results: The study revealed that two colistin-resistant E. coli isolates, one each from a pig and a chicken, were phylogenetically similar but not identical to the human isolates obtained from the same household. The comparative genome analysis revealed that the chicken isolate and a human isolate shared the same IncHl2 plasmid harboring the mcr transposon (mcr-1-PAP2). The pig isolate and the other human isolate retained the mcr-1 transposon on the chromosome, with the pig isolate carrying the complete mcr transposon (ISApl1-mcr-1-PAP2-ISApl1) and the human isolate carrying the incomplete mcr transposon (ISApl1-mcr-1-PAP2).Conclusion: The results of the study confirm the distribution of colistin-resistant bacteria and subsequent transmission of the resistance gene-carrying transposon between livestock and humans of the same household. To the best of our knowledge, this is the first report on genomic analysis of colistin-resistant E. coli isolates obtained from livestock and residents of the same household.Keywords: colistin-resistance, multidrug resistance, comparative genome analysis, whole-genome sequencing, mcr

Experimental determination of the cross sections of proton capture on radioactive nuclei is extremely difficult. Therefore, it is of substantial interest for the understanding of the production of the p-nuclei. For the first time, a direct measurement of proton-capture cross sections on stored, radioactive ions became possible in an energy range of interest for nuclear astrophysics. The experiment was performed at the Experimental Storage Ring (ESR) at GSI by making use of a sensitive method to measure (p,γ) and (p,n) reactions in inverse kinematics. These reaction channels are of high relevance for the nucleosyn-thesis processes in supernovae, which are among the most violent explosions in the universe and are not yet well understood. The cross section of the 118Te(p,γ) reaction has been measured at energies of 6 MeV/u and 7 MeV/u. The heavy ions interacted with a hydrogen gas jet target. The radiative recombination process of the fully stripped 118Te ions and electrons from the hydrogen target was used as a luminosity monitor. An overview of the experimental method and preliminary results from the ongoing analysis will be presented.

Katsura Hayakawa,1 Tetsuo Yamaguchi,2 Daisuke Ono,2 Hajime Suzuki,1 Jiro Kamiyama,1 Shigemasa Taguchi,1 Kazuya Kiyota1 1Department of Emergency and Critical Care Medicine, Saitama Red Cross Hospital, Saitama, Japan; 2Department of Microbiology and Infection Diseases, Toho University School of Medicine, Tokyo, JapanCorrespondence: Katsura Hayakawa Department of Emergency and Critical Care Medicine, Saitama Red Cross Hospital, 1-5 Shintoshin, Chu-o-Ku, Saitama City 330-8553, JapanTel +81-48-852-1111Fax +81-48-852-3120Email gene1982jp@gmail.comIntroduction: Staphylococcus aureus produces numerous toxins, such as toxic shock syndrome toxin 1 (TSST-1) and Panton–Valentine leukocidin (PVL). We isolated community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) strains producing both TSST-1 and PVL isolated from severe necrotizing pneumonia cases in a Nepali family. Detection of these CA-MRSA strains is rare in the world, and infection with these strains can take a rapidly progressive and lethal course. In this study, we traced the clinical course of this case and conducted a genetic analysis of the isolated strains.Case Report: We described 2 familial cases (a 20-year-old male and 61-year-old female) of severe necrotizing pneumonia caused by CA-MRSA with the TSST-1 and PVL genes. A 20-year-old Nepalese male was admitted to our hospital after a 3-day history of high fever and coughing. Despite resuscitation efforts, he died of multiple organ failure. A 61-year-old Nepalese female was admitted to our hospital with a complaint of high fever and dyspnea for 1 day. She was the grandmother of the male subject and mostly stayed at his residence in Japan. We administered intravenous antibiotics, including anti-MRSA antibiotics, and she improved in 2 weeks. The sequence type of the isolates was ST22/SCCmec type IVa, and the spa type was t005. The virulence genes detected were as follows: PVL gene (lukSF-pv), TSST-1 gene (tst-1), sec, seg, sei, sel, sem, sen, seo, and seu. ST22 was not the dominant CA-MRSA clone type in Japan. Some of the reports demonstrated that PVL-/TSST-1-positive ST22-MRSA strains are prevalent in Nepal. Therefore, the MRSA strains were thought to be acquired from Nepal.Conclusion: These cases highlight the emergence of TSST-1- and PVL-positive CA-MRSA infection and its association with life-threatening community-acquired necrotizing pneumonia. Clinicians should note the possibility of introducing MRSA strains from abroad and be aware of this illness to initiate appropriate treatment.Keywords: community-acquired methicillin-resistant Staphylococcus aureus, CA-MRSA, toxic shock syndrome toxin 1, TSST-1, Panton–Valentine leukocidin, PVL, necrotizing pneumonia

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

Daiji Nagayama,1,* Haruki Imamura,2,* Kei Endo,3 Atsuhito Saiki,2 Yuta Sato,2 Takashi Yamaguchi,2 Yasuhiro Watanabe,2 Masahiro Ohira,2 Kohji Shirai,4 Ichiro Tatsuno2 1Nagayama Clinic, Tochigi, Japan; 2Center of Diabetes, Endocrinology and Metabolism, Toho University, Sakura Medical Center, Chiba, Japan; 3Endo Clinic, Chiba, Japan; 4Department of Internal Medicine, Mihama Hospital, Chiba, Japan*These authors contributed equally to this workCorrespondence: Daiji NagayamaNagayama Clinic, 2-12-22, Tenjin-Cho, Oyama-City, Tochigi 323-0032, JapanTel +81-285-22-0219Fax +81-285-22-0219Email deverlast96071@gmail.comIntroduction: The main pathophysiology of sepsis is considered to be circulation crisis with an imbalance of vasodilation and vasoconstriction mechanisms, which contributes to multiple organ failure. However, sepsis-induced hemodynamic changes have not been fully validated by novel arterial stiffness parameter. The aim of this study was to clarify the acute vascular alteration and hemodynamic change in sepsis using cardio-ankle-vascular index (CAVI).Methods: Twenty-one Japanese patients (14 males and 7 females, age 62.8 ± 19.0 years) with sepsis were recruited. CAVI was measured before and 1-week after sepsis treatment.Results: The leading underlying cause of sepsis was pyelonephritis, followed by pneumonia, lung abscess, hepatic abscess and cholecystitis. All subjects recovered from sepsis. Analysis of all subjects showed a significant increase in CAVI after 1-week treatment (7.9 ± 2.4 to 9.6 ± 1.8, P < 0.001), but no significant change in blood pressure (BP) was observed. Significant correlations were observed for all combinations among the change in CAVI, systolic BP and ln[procalcitonin (PCT)], respectively. Additionally, in subjects with PCT at presentation ≥2.0 ng/mL, the increase in CAVI after treatment was significantly greater compared to those with PCT < 2.0 ng/mL (2.4 ± 1.6 vs 1.1 ± 0.9, P = 0.037).Discussion: CAVI may reflect sepsis-induced vascular alteration which is not indicated by BP change, and is associated with sepsis severity. These findings suggest the usefulness of CAVI in the management of circulatory failure in sepsis patients.Keywords: SIRS, circulation crisis, procalcitonin, arterial stiffness

Takashi Uchino,1,2 Takahiro Nemoto,1 Taiju Yamaguchi,1 Naoyuki Katagiri,1 Naohisa Tsujino,1 Yoshitaka Murakami,3 Kuniaki Tanaka,2 Masafumi Mizuno1 1Department of Neuropsychiatry, Toho University Graduate School of Medicine, Tokyo 143-8540, Japan; 2Tokyo Adachi Hospital, Tokyo 121-0064, Japan; 3Department of Medical Statistics, Toho University School of Medicine, Tokyo 143-8540, JapanCorrespondence: Takahiro NemotoDepartment of Neuropsychiatry, Toho University Graduate School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540, JapanTel +81 3 37624151Fax +81 3 54715774Email takahiro.nemoto@med.toho-u.ac.jpObjective: Functional capacity, which indicates one’s ability to perform everyday living tasks, contributes to real-world functional performance in patients with schizophrenia. However, functional capacity is sometimes not comparable with functional performance in clinical settings. We hypothesized that specific personality traits are related to this capacity-performance discrepancy of functional outcome.Methods: The measures in this study were the UCSD Performance-based Skills Assessment Brief (UPSA-B) for functional capacity, the Social Functioning Scale (SFS) for functional performance, and the Temperament and Character Inventory-140 (TCI-140) for personality traits. A total of 94 stable outpatients with schizophrenia were divided into four groups based on combinations of their UPSA-B and SFS cut-off points, as follows: a high capacity and high performance (HH) group, a high capacity but low performance (HL) group, a low capacity but high performance (LH) group, and a low capacity and low performance (LL) group.Results: There were no significant differences in demographics among the four groups. The LH group showed a significantly lower harm avoidance level than the LL group. The HL group showed a significantly lower persistence level than the HH group.Conclusion: Lower harm avoidance may enhance functional performance, and lower persistence can limit functional performance, regardless of the primary levels of functional capacity in patients with schizophrenia. Novel and individualized psychosocial treatments considering the individual’s personality traits seem to be helpful for maximizing their functional performance in the community.Keywords: functional capacity, performance-based assessment, real-world functioning, social functioning, Temperament and Character Inventory

Ryuji Kawahara,1,* Diep Thi Khong,2,* Ha Viet Le,2 Quang Ngoc Phan,2 Thang Nam Nguyen,2 Takahiro Yamaguchi,1 Yuko Kumeda,3 Yoshimasa Yamamoto4,5 1Department of Microbiology, Osaka Institute of Public Health, Osaka, Japan; 2Center of Medical, Pharmaceutical Science and Technology Services, Thai Binh University of Medicine and Pharmacy, Thai Binh, Vietnam; 3Research Center for the 21st Century, Osaka Prefecture University, Osaka, Japan; 4Life Science Research Center, Gifu University, Gifu, Japan; 5Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan*These authors contributed equally to this workCorrespondence: Yoshimasa YamamotoLife Science Research Center, Gifu University, 1-1 Yanagido, Gifu 501-1194, JapanTel/fax +81 58 230 6239Email yyamamot@sahs.med.osaka-u.ac.jpPurpose: The dissemination of colistin-resistant bacteria harboring the colistin-resistance gene mcr-1 in developing countries has recently entered the spotlight as an emerging public health threat, which is attributed to the abuse of colistin use in these countries. However, the prevalence of these bacteria in developing countries has not been extensively investigated. Therefore, in the present study, we examined the prevalence of cefotaxime-resistant commensal Escherichia coli harboring mcr-1 among residents of a representative Vietnamese village and assessed the characteristics of these isolates.Materials and methods: The stool samples, one stool sample per resident, of 612 residents were cultured on MacConkey agar with cefotaxime. Resulting E. coli-like colonies were isolated and examined further for the presence of colistin-resistant extended-spectrum β-lactamase (ESBL)-producing E. coli with mcr-1. Antibiotic susceptibility tests were performed, and clonal relationship among colistin-resistant isolates was assessed.Results: Thirty-one of the 451 cefotaxime-resistant E. coli isolates were resistant to colistin and the majority possessed mcr-1, blaCTX-M, and/or blaTEM, except for two isolates that produced the AmpC β-lactamase. All mcr-1 ESBL-producing E. coli isolates were multidrug-resistant (5–11 antibiotics). The isolates contained various plasmid replicon types, including the most prevalent types IncHI2 (54.8%), IncFIB (48.4%), and IncN (41.9%). In addition, 83.9% of the mcr-1 ESBL-E. coli isolates possessed a transposon ISApl1-mcr-1 segment. Furthermore, 77.4% of the mcr-1 ESBL-E. coli isolates belonged to phylogenetic group A. Pulsed-field gel electrophoresis analysis indicated limited clonal expansion of a specific strain.Conclusion: These results demonstrate the wide dissemination of colistin-resistant ESBL-E. coli harboring mcr-1 among commensal bacteria of rural residents in Vietnam, suggesting possible mobilization of the mcr-1 gene among ESBL-producing microbiota, which is a great public health concern.Keywords: mcr-1, residents, stool specimens, commensal bacteria, Vietnam

Tetsuo Yamaguchi,1,2 Rina Ando,2 Tetsuya Matsumoto,2 Yoshikazu Ishii,1 Kazuhiro Tateda11Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Tokyo, Japan; 2Department of Microbiology, Tokyo Medical University, Tokyo, JapanObjectives: We investigated the association between the rate of cell growth and vancomycin (VAN) resistance by comparing the genomic and phenotypic characteristics of different sized colonies isolated from a single origin.Methods: Vancomycin-intermediate Staphylococcus aureus (VISA) strain TMUS2136 was isolated from the pus of a patient with a brain abscess and a chronic subdural abscess. This strain grew slowly and formed colonies poorly on agar plates within 24 h of incubation. However, variously sized colonies were observed after 48 h of incubation. We isolated five strains from different sized colonies and compared their VAN susceptibility and genomic sequences using next-generation sequencing.Results: The five strains showed different rates of growth and susceptibilities to VAN (range of MIC after 48 h of incubation; 3–5 mg/L), and slower growing strains tended to be more VAN resistant. Deletion of the spdC gene and SNPs in the sarA gene was confirmed in all five strains and six SNPs in other genes (including mreC, hssS, prs, SA2339, sun, and SA1132) were confirmed when comparing the five strains.Conclusions: Deletion of the spdC gene, a novel virulence factor of S. aureus, and SNPs in the sarA gene may be associated with VAN resistance. It was hypothesized that any of the six genes in which SNPs were detected could affect cell growth rate and VAN resistance in slow-VISA strains.Keywords: next generation sequencing, MRSA, VISA, vancomycin

Jumpei Fujisawa,1 Tomokazu Mutoh,1 Kengo Kawamura,1 Nami Sawada,2 Daisuke Ono,3 Tetsuo Yamaguchi,3 Ichiro Morioka1 1Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan; 2Department of Acute Medicine, Nihon University School of Medicine, Tokyo, Japan; 3Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Tokyo, Japan Abstract: Haemophilus influenzae was the main causative organism for acute epiglottitis in the pre-Haemophilus influenzae type b (Hib) vaccine era. However, with current widespread Hib vaccination, the causative organisms may have changed. Here, we report the case of a healthy infant with acute epiglottitis caused by community-acquired methicillin-resistant Staphylococcus aureus (MRSA). The patient was a healthy 17-day-old male infant without a family history of immunodeficiency syndrome. He had not been started on any vaccines. On the third day of illness, he was diagnosed with acute pharyngitis with exudation on the back of the larynx. Although treatment using cefotaxime was initiated, he showed stridor, difficulty in pronunciation, and cyanosis upon crying on the fourth day. On the fifth day, he was diagnosed with acute epiglottitis by laryngoscopy, which showed a downward spread of the exudation and laryngeal edema. He was intubated and started on artificial respiration. Due to the detection of MRSA from a pharyngeal swab culture, he was treated with vancomycin. His fever disappeared on the first day after admission, and he was extubated on the eighth day after admission. MRSA genome analysis of the patient sample revealed negative Panton–Valentine leukocidin, positive toxic shock syndrome toxin 1, and type IV clone of staphylococcal cassette chromosome mec. This is a first case of acute epiglottitis caused by MRSA with a Panton–Valentine leukocidin-negative and toxic shock syndrome toxin 1-positive staphylococcal cassette chromosome mec type IV clone, which is known as a community-acquired MRSA in Japan. Community-acquired MRSA may be considered a causative organism for acute epiglottitis in the post-Hib vaccine era. Keywords: pre-Haemophilus influenzae type b vaccine era, type IV clone of staphylococcal cassette chromosome mec, Panton-Valentine leucocidin, toxic shock syndrome toxin 1, exudate

Sachio Fushida,1 Jun Kinoshita,1 Katsunobu Oyama,1 Takashi Fujimura,2 Tomoya Tsukada,3 Takahisa Yamaguchi,1 Itasu Ninomiya,1 Tetsuo Ohta1 1Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan; 2Department of Surgery, Toyama City Hospital, Toyama, Japan; 3Department of Surgery, Toyama Prefectural Central Hospital, Toyama, Japan Background: Scirrhous gastric cancer (SGC) is highly invasive and metastatic because of its interactions with stromal cells, such as fibroblasts and macrophages, and extracellular matrix, leading to a higher incidence of peritoneal metastasis (PM) than other gastric cancers (GCs). Taxane-based intraperitoneal chemotherapy (IPC) is a promising therapy for PM. We retrospectively analyzed outcomes of multidisciplinary therapies that included IPC for SGC. Patients and therapy: Of 1,679 GC patients treated between 1990 and 2012, we analyzed 119 patients who underwent multidisciplinary therapy for SGC. Patients without PM received gastrectomy with lymphadenectomy and resection of involved adjacent organs followed by intraoperative IPC using cisplatin. Patients with PM received chemotherapy using fluorouracil, with or without methotrexate plus IPC using cisplatin before 2000, and S-1 plus IPC using paclitaxel or docetaxel since 2000. Results: Of the 119 patients, 73 (61%) had PM and 63 (53%) had positive peritoneal lavage cytology. Of the 89 gastrectomy patients, 30 (34%) had macroscopic residual tumors (R2). Of the patients treated since 2000, 66 (100%) received S-1 plus taxanes and 44 patients (67%) received taxane-based IPC. Median survival time was significantly longer in the post-2000 group (22.8 months) than in the pre-2000 group (9.5 months). In univariate analysis, lavage cytology, PM, taxane-based IPC, gastrectomy, and R2 resection were significant prognostic factors. However, only R2 resection was an independent prognostic factor in multivariate analysis (hazard ratio: 5.53, 95% CI: 2.05–14.93). Conclusion: As use of taxane-based IPC is not an independent prognostic factor, new multidisciplinary therapies are necessary to avoid R2 resections. Keywords: peritoneal metastasis, intraperitoneal chemotherapy, taxanes

Toru Kurata, Sachio Fushida, Jun Kinoshita, Katsunobu Oyama, Takahisa Yamaguchi, Mitsuyoshi Okazaki, Tomoharu Miyashita, Hidehiro Tajima, Itasu Ninomiya, Tetsuo Ohta Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan Background: Characterized by aggressive proliferation, extensive stromal fibrosis, and resulting drug resistance, peritoneal dissemination in gastric cancer remains associated with poor prognosis. Interaction between cancer and stromal cells accelerates tumor progression via epithelial–mesenchymal transition (EMT), which is one of the major causes of tissue fibrosis, and human peritoneal mesothelial cells (HPMCs) play important roles as cancer stroma in peritoneal dissemination. Transforming growth factor-β (TGF-β) has a pivotal function in the progression of EMT, and Smad proteins play an important role in the TGF-β signaling pathway. Eribulin mesylate (eribulin), a nontaxane microtubule dynamics inhibitor used for the treatment of advanced breast cancer, inhibits EMT changes in triple-negative breast cancer cells. We examined its ability to inhibit tumor progression and EMT changes resulting from the interaction between gastric cancer cells and HPMCs and to act synergistically with 5-fluorouracil (5-FU), a key drug for gastric cancer. Materials and methods: Proliferation of gastric cancer cells and HPMCs isolated from healthy omentum was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Following gastric cancer cell/HPMC coculture, EMT markers were detected by immunofluorescence, immunohistochemistry, and Western blotting; invasion assays were performed; and TGF-β and Smad phosphorylation were assessed by Western blotting and enzyme-linked immunosorbent assay. A mouse fibrotic tumor xenograft model was established using gastric cancer cell/HPMC cocultures. The effect of eribulin and/or 5-FU was tested in each case. Results: Eribulin significantly suppressed gastric cancer cell proliferation and EMT changes in MKN-45 gastric cancer cells and HPMCs induced by their interaction in vitro. Eribulin inhibited EMT at much lower concentrations (≥0.5 nM for MKN-45 and ≥0.1 nM for HPMCs) than its half maximal inhibitory concentrations (2.2 nM for MKN-45 and 8.1 nM for HPMCs), and this resulted, at least partly, from the downregulation of TGF-β/Smad signaling. Eribulin administration of ≥0.1 mg/kg suppressed tumor progression (0.1 mg/kg, p=0.02), and fibrosis was inhibited by lower dose (0.05 mg/kg, p=0.008) in the xenograft model. Furthermore, 0.05 mg/kg administration with 5-FU brought about synergistic antitumor effects (p=0.006). Conclusion: Low-dose eribulin combined with 5-FU might be a promising therapy for peritoneal dissemination in gastric cancer. Keywords: peritoneal dissemination, cancer–stromal interaction, human peritoneal mesothelial cell, TGF-β, Smad, synergism

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

Tatsuya Nakayama,1,2 Yuko Kumeda,3 Ryuji Kawahara,4 Takahiro Yamaguchi,4,5 Yoshimasa Yamamoto5 1Center for Global Initiatives, Osaka University, Suita, Osaka, Japan; 2Division of Biomedical Food Research, National Institute of Health Science, Kawasaki, Kanagawa, Japan; 3Center for Microorganism Control, Osaka Prefecture University, Sakai, Osaka, Japan; 4Division of Microbiology, Osaka Institute of Public Health, Osaka, Japan; 5Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan Background: Due to increasing colistin usage, the dissemination of the colistin-resistant gene mcr-1 has been increasingly investigated. The aim of this study was to determine whether a traveler on a short-term international trip to a developing country could bring mcr-1 back to their home country. Materials and methods: Thirty-four travel events from Japan to Vietnam encompassing 19 travelers were assessed. A fecal specimen was collected from each traveler before and after each travel event and was inoculated on CHROMagar containing cefotaxime (CTX). Three to seven colonies exhibiting the characteristics of Escherichia coli were collected. Susceptibility to antibiotics and extended-spectrum β-lactamase (ESBL) production were determined by the disk diffusion method and the double-disk synergy test, respectively. ESBL-encoding genes were genotyped, and phylogenetic groupings were determined by multiplex polymerase chain reaction (PCR). The presence of mcr-1 was also confirmed by PCR and sequencing. Results: A total of 175 ESBL-producing E. coli isolated before and up to 2 weeks after traveling to Vietnam were analyzed. Genotyping of ESBL-producing isolates showed that blaCTX-M-1/blaTEM (27.7%) and blaCTX-M-9 (45.9%) were the most prevalent genotypes, while the most frequently detected phylogenetic group was D (41.9%) followed by B2 (23.0%). In a significant number of travel events, travelers brought ESBL-producing E. coli back to Japan and three events by three travelers carried mcr-1. ESBL-producing E. coli isolates harboring mcr-1 were identified as those carrying both blaCTX-M-14 or blaCTX-M-55 and mcr-1. Conclusion: Using Vietnam as an example, we have shown that even a short-term trip to some countries may result in ESBL-producing mcr-1-positive E. coli carriage by international travelers. Keywords: traveler, ESBL-producing E. coli, mcr-1, Vietnam, Japan

Yukari Fujimoto,1 Yutaro Oki,1 Masahiro Kaneko,2 Hideki Sakai,3 Shogo Misu,1,3 Takumi Yamaguchi,1,3 Yuji Mitani,1,4 Hisafumi Yasuda,1 Akira Ishikawa1 1Department of Community Health Sciences, Kobe University Graduate School of Health Sciences, Kobe, Hyogo, Japan; 2Department of Respiratory Medicine, Kobe City Medical Center West Hospital, Kobe, Hyogo, Japan; 3Department of Rehabilitation, Kobe City Medical Center West Hospital, Kobe, Hyogo, Japan; 4Department of Rehabilitation, Sapporo Nishimaruyama Hospital, Sapporo, Hokkaido, Japan Purpose: A straightforward, noninvasive method is needed to assess emphysema and pulmonary hypertension (PH) in COPD patients. The desaturation–distance ratio (DDR) is an index derived from the distance traveled and level of desaturation during a six-minute walk test (6MWT); it has previously been shown to be associated with percentage of forced expiratory volume in the first second of expiration (%FEV1.0) and percentage of diffusion capacity of the lung for carbon monoxide (%DLCO). The aim of this study was to examine the associations between DDR and emphysema and PH.Patients and methods: We collected the following data for 74 stable COPD outpatients: lung function tests (%FEV1.0 and %DLCO), 6MWT distance and desaturation, and area of emphysema on computed tomography (percentage of low attenuation area). Enlargement of the pulmonary artery (PA) was assessed by the ratio of the diameter of the PA to that of the aorta (PA:A ratio) as an index of PH. DDR was calculated by the distance traveled and the degree of desaturation reached during a 6MWT. The relationships between study outcomes were assessed with Spearman’s rank-correlation analysis. Receiver operating characteristic (ROC) curves were used to determine the threshold values with the optimum cutoff points for predicting severe or very severe airway obstruction, pulmonary diffusing capacity disorder, moderate or severe emphysema, and enlargement of the PA.Results: DDR correlated significantly with %FEV1.0, %DLCO, %LAA, and PA:A ratio. DDR showed high accuracy (area under the ROC curve >0.7) for predicting severe or very severe airway obstruction, pulmonary diffusing capacity disorder, moderate or severe emphysema, and enlargement of the PA.Conclusion: The results suggest that DDR is a good index of emphysema and PH in COPD patients. The 6MWT is widely used to assess COPD, and DDR could help with the early diagnosis of COPD. Keywords: six-minute walk test, COPD, desaturation–distance ratio, exercise-induced oxygen desaturation, emphysema, pulmonary hypertension

Tetsuya Muto,1 Tomoharu Nishimura,1 Takefumi Yamaguchi,2 Makoto Chikuda,1 Shigeki Machida1 1Department of Ophthalmology, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Japan; 2Department of Ophthalmology, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan Purpose: Cataract progression after lens-sparing vitrectomy might differ according to original posterior segment diseases. Our objective was to analyze the refractive values after lens-sparing vitrectomy for macular hole (MH) and epiretinal membrane (ERM). Materials and methods: We reviewed the medical records of 25 MH patients (25 eyes) and 23 ERM patients (23 eyes) who underwent lens-sparing vitrectomy. Refractive changes in both groups were compared. All patients underwent 20-gauge three-port pars plana vitrectomy. Fluid–air exchange was performed during vitrectomy only in the MH group. The results were analyzed using the unpaired t-test, chi-square test, or Fisher exact probability test, and multivariate analysis. Results: There were no significant differences in the patient’s age (P=0.45). The myopia progression rate (D/month) was higher in the MH group after surgery than that in the ERM group (P=0.035). MH group had more females (P=0.043), longer surgical time (P

Suguru Miyagawa,1,2 Hisashi Fukuyama,3 Masakazu Hirota,1 Tatsuo Yamaguchi,4 Kazuo Kitamura,4 Takao Endo,3 Hiroyuki Kanda,1 Takeshi Morimoto,1 Takashi Fujikado1 1Department of Applied Visual Science, Osaka University Graduate School of Medicine, Suita, Osaka, 2Technology Development Department Research and Development Section, Topcon Corporation, Itabashi, Tokyo, 3Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, 4Eye Care Technology Development Department, Product Technology Section, Topcon Corporation, Itabashi, Tokyo, Japan Purpose: The purpose of this study was to develop an algorithm based on region-based segmentation for automated calculations of human cone photoreceptor density of en face images obtained by an adaptive optics scanning laser ophthalmoscope (AOSLO). Subjects and methods: Cone mosaics of 15 eyes of 15 healthy subjects were photographed by a custom-built AOSLO. The cone density was calculated at 0.5, 1.0, and 1.5 mm temporal from the fovea using a region-based segmentation method (RSM) developed in our laboratory. The cone density was also determined by a manual identification method (MIM) and a conventional spatial filtering method (SFM). The cone densities of three eyes of three patients with retinal degeneration were calculated by the three methods and compared to the results from normal eyes. Results: The cone densities in healthy retinas determined by the RSM at 0.5, 1.0, and 1.5 mm temporal from the fovea were 28,436, 21,233, and 13,620 cells/mm2, respectively. These densities were in good agreement with a histological study and with in vivo AOSLO studies. The cone densities determined by RSM were different from those determined by MIM with a difference of 5% in healthy eyes. In eyes with retinal degeneration, with the appropriate threshold-level settings or spatial frequency bandwidth, the cone density measured by MIM was significantly closer to that measured by RSM than by SFM. Conclusion: These results suggest that our method is more stable than conventional methods in cases of non-periodical photoreceptor structures such as the affected retinal area. Our method can be used in the longitudinal follow-up of retinal degenerative diseases and to determine the effect of therapy. Keywords: AOSLO, adaptive optics, cone photoreceptor, photoreceptor density, retinal imaging, image processing

Daiji Nagayama,1,2 Haruki Imamura,2 Yuta Sato,2 Takashi Yamaguchi,2 Noriko Ban,2 Hidetoshi Kawana,2 Masahiro Ohira,2 Atsuhito Saiki,2 Kohji Shirai,3 Ichiro Tatsuno2 1Center of Endocrinology and Metabolism, Shin-Oyama City Hospital, Oyama-City, 2Center of Diabetes, Endocrinology and Metabolism, 3Department of Vascular Function, Sakura Medical Center, Toho University, Sakura-City, Japan Objective: The objective of this study is to investigate the association of body mass index (BMI) with arterial stiffness assessed by cardioankle vascular index (CAVI). Subjects and methods: A retrospective cross-sectional study was conducted in 23,257 healthy Japanese subjects (12,729 men and 10,528 women, aged 47.1 ± 12.5 years, BMI 22.9 ± 3.4 kg/m2) who underwent health screening between 2004 and 2006 in Japan. Exclusion criteria were current medication use and a past history of cardiovascular disease, hypertension, stroke, diabetes, and nephritis. Results: Male subjects showed significantly higher BMI, CAVI, and triglycerides and lower high-density lipoprotein (HDL)-cholesterol compared with female subjects. Next, the subjects were divided into tertiles of BMI: lower, middle, and upper, in a gender-specific manner. After adjusting for confounders including age, systolic blood pressure, and HDL-cholesterol identified by multiple regression analysis, the mean CAVI decreased progressively as BMI tertile increased in both genders. Furthermore, a negative inverse relationship between BMI and adjusted CAVI was observed throughout the BMI distribution. Multivariate logistic regression model for contributors of high CAVI (≥90th percentile) identified obesity (odds ratios (95% confidence interval): 0.804 (0.720–0.899)], older age [15.6 (14.0–17.4)], male gender [2.26 (2.03–2.51)], hypertension [2.28 (2.06–2.54)], impaired fasting glucose [1.17 (1.01–1.37)], and low HDL-cholesterol [0.843 (0.669–1.06)] as independent factors. Conclusion: We demonstrated an inverse relationship between CAVI and BMI in healthy Japanese subjects, suggesting that systemic accumulation of adipose tissue per se may lead to a linear decrease of arterial stiffness in nonobese and obese subjects without metabolic disorders. Keywords: BMI, cardioankle vascular index, arterial stiffness

Yutaro Oki,1,2 Masahiro Kaneko,3 Yukari Fujimoto,1 Hideki Sakai,2 Shogo Misu,1,2 Yuji Mitani,1,4 Takumi Yamaguchi,1,2 Hisafumi Yasuda,1 Akira Ishikawa1 1Department of Community Health Sciences, Kobe University Graduate School of Health Sciences, 2Department of Rehabilitation, 3Department of Respiratory Medicine, Kobe City Medical Center West Hospital, Kobe, 4Department of Rehabilitation, Sapporo Nishimaruyama Hospital, Sapporo, Japan Purpose: Pulmonary hypertension and exercise-induced oxygen desaturation (EID) influence acute exacerbation of COPD. Computed tomography (CT)-detected pulmonary artery (PA) enlargement is independently associated with acute COPD exacerbations. Associations between PA to aorta (PA:A) ratio and EID in patients with COPD have not been reported. We hypothesized that the PA:A ratio correlated with EID and that results of the 6-minute walk test (6MWT) would be useful for predicting the risk associated with PA:A >1.Patients and methods: We retrospectively measured lung function, 6MWT, emphysema area, and PA enlargement on CT in 64 patients with COPD. The patients were classified into groups with PA:A ≤1 and >1. Receiver-operating characteristic curves were used to determine the threshold values with the best cutoff points to predict patients with PA:A >1.Results: The PA:A >1 group had lower forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1:FVC ratio, diffusion capacity of lung carbon monoxide, 6MW distance, and baseline peripheral oxygen saturation (SpO2), lowest SpO2, highest modified Borg scale results, percentage low-attenuation area, and history of acute COPD exacerbations ≤1 year, and worse BODE (Body mass index, airflow Obstruction, Dyspnea, and Exercise) index results (P1 was determined for SpO2 during 6MWT (best cutoff point 89%, area under the curve 0.94, 95% confidence interval 0.88–1). SpO2

Emi Mashima, Akiha Inoue, Yumiko Sakuragi, Takashi Yamaguchi, Natsuko Sasaki, Yoko Hara, Daisuke Omoto, Shun Ohmori, Sanehito Haruyama, Yu Sawada, Manabu Yoshioka, Daisuke Nishio, Motonobu Nakamura Department of Dermatology, University of Occupational and Environmental Health, Kitakyushu, Japan Abstract: Nivolumab was developed as a monoclonal antibody against programmed death receptor-1, an immune checkpoint inhibitor which negatively regulates T-cell proliferation and activation. Intravenous administration of nivolumab was approved for the treatment of unresectable malignant melanoma in 2014 in Japan. When advanced melanoma patients were treated with nivolumab, median overall survival became longer. Overall survival rate was significantly better in nivolumab-treated melanoma patients than dacarbazine-treated melanoma patients. Nivolumab had an acceptable long-term tolerability profile, with 22% of patients experiencing grade 3 or 4 adverse events related to the drug. Therefore, nivolumab can become an alternative therapy for advanced malignant melanoma. Keywords: monoclonal antibody, PD-1, PD-L1

Mitsukuni Suenaga,1 Nobuyuki Mizunuma,1 Satoshi Matsusaka,1 Eiji Shinozaki,1 Masato Ozaka,1 Mariko Ogura,1 Toshiharu Yamaguchi21Department of Gastroenterology, 2Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, JapanBackground: The effectiveness of reintroducing oxaliplatin in patients with metastatic colorectal cancer refractory to standard chemotherapy has not been verified. We performed a single-arm, open-label, Phase II study to evaluate the safety and efficacy of reintroducing oxaliplatin. Methods: Eligible patients had received prior chemotherapy including oxaliplatin and irinotecan that achieved a response or stable disease followed by confirmed disease progression ≥6 months previously during prior oxaliplatin-based therapy. The primary endpoint was the disease control rate (DCR) after 12 weeks of treatment starting. The DCR was defined as the sum of patients with complete response, partial response, and stable disease. Results: Thirty-three patients were enrolled. The median age was 62 (range: 35–77) years and the male/female ratio was 19/14. Eastern Cooperative Oncology Group performance status was 0 in 84.8%. Fourteen primary tumors were in the colon and 19 were in the rectum. All patients received modified FOLFOX6 as the protocol treatment. After 12 weeks of treatment starting, the DCR was 39.4% (95% confidence interval 21.8–57.0) and the response rate (complete response and partial response) was 6.1%. The median number of chemotherapy cycles was five and the median total dose of oxaliplatin was 425 mg/m2. Median progression-free survival time was 98 days and median overall survival was 300 days. The incidence of grade ≥1 and grade ≥3 allergic reactions was 28.1% and 3.1%, respectively. The incidence of grade ≥1 and grade ≥3 peripheral sensory neuropathy was 53.1% and 0%, respectively. There were no other severe adverse events and no treatment-related deaths.Conclusion: Reintroducing oxaliplatin can be both safe and effective. This may be a salvage option for patients with metastatic colorectal cancer who achieved a response or stable disease with prior oxaliplatin-based therapy followed by disease progression ≥6 months previously during prior oxaliplatin-based therapy.Keywords: reintroduction, oxaliplatin, FOLFOX, advanced colorectal cancer, salvage-line

Mitsukuni Suenaga,1 Yoshiya Fujimoto,2 Satoshi Matsusaka,1 Eiji Shinozaki,1 Takashi Akiyoshi,2 Satoshi Nagayama,2 Yosuke Fukunaga,2 Masatoshi Oya,2 Masashi Ueno,2 Nobuyuki Mizunuma,1 Toshiharu Yamaguchi21Department of Gastroenterology, 2Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, JapanBackground: Perioperative chemotherapy combined with surgery for liver metastases is considered an active strategy in metastatic colorectal cancer (CRC). However, its impact on initially unresectable, previously untreated advanced CRC, regardless of concurrent metastases, remains to be clarified.Methods: A Phase II study was conducted to evaluate the safety and efficacy of perioperative FOLFOX4 plus bevacizumab for initially unresectable advanced CRC. Patients with previously untreated advanced colon or rectal cancer initially diagnosed as unresectable advanced CRC (TNM stage IIIb, IIIc, or IV) but potentially resectable after neoadjuvant chemotherapy (NAC) were studied. Preoperatively, patients received six cycles of NAC (five cycles of neoadjuvant FOLFOX4 plus bevacizumab followed by one cycle of FOLFOX4 alone). The interval between the last dose of bevacizumab and surgery was at least 5 weeks. Six cycles of adjuvant FOLFOX4 plus bevacizumab were given after surgery. The completion rate of NAC and feasibility of curative surgery were the primary endpoints.Results: An interim analysis was performed at the end of NAC in the 12th patient to assess the completion rate of NAC. The median follow-up time was 56 months. The characteristics of the patients were as follows: sex, eight males and four females; tumor location, sigmoid colon in three, ascending colon in one, and rectum (above the peritoneal reflection) in eight; stage, III in eight and IV in four (liver or lymph nodes). All patients completed six cycles of NAC. There were no treatment-related severe adverse events or deaths. An objective response to NAC was achieved in nine patients (75%), and no disease progression was observed. Eleven patients underwent curative tumor resection, including metastatic lesions. In December 2012, this Phase II study was terminated because of slow registration.Conclusion: Perioperative FOLFOX4 plus bevacizumab is well tolerated and has a promising response rate leading to curative surgery, which offers a survival benefit in initially unresectable advanced CRC with concurrent metastatic lesions.Keywords: bevacizumab, metastatic colorectal cancer, FOLFOX4, perioperative treatment

Kazuyoshi Kawakami,1 Eri Nakamoto,1 Takashi Yokokawa,1 Kazuo Sugita,1 Yutarou Mae,1 Akane Hagino,1 Mitsukuni Suenaga,2 Nobuyuki Mizunuma,2 Sayaka Oniyama,3 Yoshiaki Machida,3 Toshiharu Yamaguchi,2 Toshihiro Hama1 1Department of Pharmacy, 2Gastroenterology Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3Section for Practical Education, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan Background: Capecitabine plus oxaliplatin (XELOX) has been established as a first-line treatment for metastatic colorectal cancer. Adherence is particularly important with capecitabine to maintain appropriate curative effect. In this study, we monitored the adherence to capecitabine on XELOX treatment and investigated which factors might decrease compliance.Methods: The study included 242 consecutive patients who received XELOX treatment for metastatic colorectal cancer between October 2009 and March 2012. Adherence to capecitabine was checked by pharmacists with a patient-reported treatment diary at a pharmaceutical outpatient clinic. Adherence rate was defined as the number of times that a patient took capecitabine in a 14-day cycle/28 prescribed doses. We retrospectively surveyed median relative dose intensities of capecitabine and the factors deteriorating adherence across eight cycles from electronic patient records and examined differences in compliance rates according to age. Results: The study included 144 male and 98 female patients. The overadherence rate was 1.5% (n=23). The median adherence rate was 93.5% (n=242) in the first cycle of XELOX treatment, which gradually rose to 96.1% (n=148) in the eighth cycle. The median relative dose intensity of capecitabine was 79.2%. The main factors contributing to decreased adherence to capecitabine were diarrhea (22.5%, 352 instances) and nausea/vomiting (13.8%, 215 instances). The rate of missed dose was 12.1%. Analysis of adherence issues in relation to patient age showed a trend toward worse adherence to capecitabine therapy in the group of patients aged ≥80 years (hazard ratio =3.83; 95% confidence interval 2.48–5.91, P

Yoshihito Ohhara,1,2 Mitsukuni Suenaga,1 Satoshi Matsusaka,1 Eiji Shinozaki,1 Nobuyuki Mizunuma,1 Toshiharu Yamaguchi3 1Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan; 2Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan; 3Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan Background: A previous pivotal Phase III study (NO16966) demonstrated the benefit of the addition of bevacizumab (BV) to oxaliplatin-based regimens in metastatic colorectal cancer (MCRC). Our study evaluated the safety and efficacy of three oxaliplatin-based chemotherapy regimens (FOLFOX4 [intravenous twice-bolus and twice-infusional 5-fluorouracil/folinic acid plus oxaliplatin], mFOLFOX6 [intravenous once-bolus and once-infusional 5-fluorouracil/folinic acid plus oxaliplatin], and XELOX [capecitabine plus oxaliplatin]) plus BV in the first-line treatment of MCRC patients.Methods: Patients with MCRC who started treatment between June 2007 and September 2010 were evaluated in this retrospective cohort study. We also evaluated early objective tumor response (EOTR) within 12 weeks, which was defined as a relative change of ≥30% in the sum of the longest diameters of target lesions when compared with baseline. The primary study endpoints were progression-free survival (PFS) and response rate.Results: A total of 185 patients received the following chemotherapy: FOLFOX4 + BV (FF4 arm, n=85), mFOLFOX6 + BV (FF6 arm, n=40), and XELOX + BV (XELOX arm, n=60). The overall response rates were 61.2%, 72.5%, and 75.0% (95% confidence interval: 50.6%–71.8%, 58.0%–87.0%, and 63.7%–86.3%). Median PFS was 18.0, 15.5, and 13.7 months, respectively (log-rank: P=0.254; data cut-off: May 2013). Patients with EOTR (n=117) had significantly better PFS than those without-EOTR (n=68) (17.5 versus 12.7 months, P=0.004).Conclusion: This study suggests that these three BV plus oxaliplatin-based treatments might have comparable benefit in terms of tumor response and PFS. Moreover, EOTR may be a predictive factor for PFS in patients with MCRC. Keywords: bevacizumab, early tumor objective response, oxaliplatin, colorectal cancer

Mitsukuni Suenaga,1 Nobuyuki Mizunuma,1 Satoshi Matsusaka,1 Eiji Shinozaki,1 Masato Ozaka,1 Mariko Ogura,1 Keisho Chin,1 Toshiharu Yamaguchi2 1Department of Gastroenterology, 2Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Ariake, Koto-ku, Tokyo, Japan Background: Triweekly capecitabine plus irinotecan (XELIRI) is not completely regarded as a valid substitute for fluorouracil, leucovorin, and irinotecan (FOLFIRI) in metastatic colorectal cancer (mCRC) because of the potential for greater toxicity. We conducted a phase I/II study to assess the efficacy and safety of biweekly XELIRI plus bevacizumab (BV) as second-line chemotherapy for mCRC.Methods: Patients with mCRC who had received prior chemotherapy including oxaliplatin and BV and had a UGT1A1 genotype of wild-type or heterozygous for UGT1A1*6 or *28 were eligible for this study. Treatment comprised capecitabine 1,000 mg/m2 twice daily from the evening of day 1 to the morning of day 8, intravenous irinotecan on day 1, and BV 5 mg/kg on day 1 every 2 weeks. The phase I study consisted of two steps (irinotecan 150 and 180 mg/m2), and dose-limiting toxicity was assessed during the first treatment cycle. The primary endpoint of the phase II study was progression-free survival (PFS). Results: The recommended dose of irinotecan was determined to be 180 mg/m2 in the phase I study. Between November 2010 and August 2013, 44 patients were enrolled in phase II. The patients’ characteristics were as follows (N=44): median age, 60 years (range 32–80); male/female, 21/23; and UGT1A1 wild-type/heterozygous, 29/15. The median PFS was 6.8 months (95% confidence interval, 5.3–8.2 months), and the primary endpoint was met. Median overall survival was 18.3 months. The response rate was 22.7%. There was no significant difference in PFS or overall survival according to UGT1A1 status. Grade 3 or higher adverse events were mainly neutropenia in six patients and diarrhea in five patients. There were no other severe adverse events or treatment-related deaths.Conclusion: In mCRC patients with wild-type or heterozygous UGT1A1*6 or *28 genotype, biweekly XELIRI + BV is effective and feasible as second-line chemotherapy. Biweekly XELIRI + BV is considered a valid substitute for FOLFIRI + BV in mCRC. Keywords: XELIRI, bevacizumab, metastatic colorectal cancer, UGT1A1

Toshiyuki Yokoyama, Koki Kanbayashi, Tamaki YamaguchiDepartment of Ophthalmology, Juntendo University Nerima Hospital, Tokyo, JapanPurpose: To assess the treatment of pediatric patients with rhegmatogenous retinal detachment (RRD) by scleral buckling with chandelier illumination.Methods: Three eyes were treated in three patients, healthy boys aged 7 years, 12 years, and 11 years, with RRD, macular involvement, and small retinal holes, of which two were preoperatively undetectable. Conventional scleral buckling with cryoretinopexy was performed under the contact lens for vitreous surgery or noncontact wide-angle viewing system using 27-gauge twin chandelier illumination.Results: The only known predisposing factor for retinal detachment was myopia stronger than 3 D with lattice retinal degeneration in two of the three patients. Retinal reattachment was achieved in all cases without intra- or postoperative complications. However, visual recovery was limited in one of the three patients.Conclusion: Scleral buckling with chandelier illumination is effective for pediatric RRD, especially if the retinal hole is difficult to detect preoperatively. However, visual recovery was sometimes limited because of macular involvement due to late diagnosis, which is one of the characteristic features of pediatric RRD.Keywords: pediatric rhegmatogenous retinal detachment, chandelier illumination, scleral buckling

Mitsukuni Suenaga, Nobuyuki Mizunuma, Eiji Shinozaki, Satoshi Matsusaka, Masato Ozaka, Mariko Ogura, Keisho Chin, Toshiharu Yamaguchi Department of Gastroenterology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan Background: Doppler ultrasound imaging is useful for management of venous thromboembolism associated with a subclavicular implantable central venous access system in patients receiving bevacizumab (Bev). We investigated the efficacy and safety of our anticoagulant regimen based on Doppler findings.Methods: Patients aged ≤75 years with metastatic colorectal cancer, no history of thromboembolism, and no prior use of Bev received chemotherapy plus Bev. Doppler ultrasound imaging of the deep venous system to detect thrombosis was performed after the first course of Bev and repeated after the third course in patients with asymptomatic thrombosis. Indications for anticoagulant therapy in patients with asymptomatic thrombosis were as follows: enlarging thrombus (E), thrombus >40 mm in diameter (S), thrombus involving the superior vena cava (C), and decreased blood flow (V).Results: Among 79 patients enrolled in this study, asymptomatic thrombosis was detected in 56 patients (70.9%) by Doppler ultrasound imaging after the first course of Bev and there was no thrombus in 23 patients (29.1%). Of these 56 patients, 11 (19.6%) received anticoagulant therapy with warfarin, including eight after the first course and three after follow-up imaging. S + V was observed in four of 11 patients (36.4%), as well as V in two (18.2%), S + V + C in one (9.1%), E + S + V in one (9.1%), E + C in one (9.1%), E in one (9.1%), and C in one (9.1%). All patients resumed chemotherapy, including seven who resumed Bev. Improvement or stabilization of thrombi was achieved in ten patients (90.9%). Only one patient had symptomatic thromboembolism. Mild bleeding due to anticoagulant therapy occurred in six patients (54.5%), but there were no treatment-related severe adverse events or deaths. Severe thromboembolism was not observed in the other 68 patients.Conclusion: Our anticoagulant protocol for asymptomatic thrombosis detected by Doppler ultrasound imaging was effective at preventing severe thromboembolism during continued treatment with Bev. Keywords: venous thromboembolism, Bev, anticoagulant therapy, colorectal cancer

Noriaki Matsuki,1 Takuji Ishikawa,2 Shingo Ichiba,3 Naoki Shiba,3 Yoshihito Ujike,3 Takami Yamaguchi4 1Department of Biomedical Engineering, Graduate School of Engineering, Okayama University of Science, Okayama, 2Department of Bioengineering and Robotics, Graduate School of Engineering, Tohoku University, Sendai, 3Department of Emergency and Critical Care Medicine, Okayama University Hospital, Okayama, 4Graduate School of Biomedical Engineering, Tohoku University, Sendai, JapanAbstract: Microbubbles show peculiar properties, such as shrinking collapse, long lifetime, high gas solubility, negative electric charge, and free radical production. Fluids supersaturated with various gases can be easily generated using microbubbles. Oxygen microbubble fluid can be very useful for oxygen delivery to hypoxic tissues. However, there have been no reports of comparative investigations into adding fluids containing oxygen fine micro/nanobubbles (OFMNBs) to common infusion solutions in daily medical care. In this study, it was demonstrated that OFMNBs can generate oxygen-supersaturated fluids, and they may be sufficiently small to infuse safely into blood vessels. It was found that normal saline solution is preferable for generating an oxygen-rich infusion fluid, which is best administered as a 30-minute intravenous infusion. It was also concluded that dextran solution is suitable for drug delivery substances packing oxygen gas over a 1-hour intravenous infusion. In addition, normal saline solution containing OFMNBs was effective for improving blood oxygenation. Thus, the use of OFMNB-containing fluids is a potentially effective novel method for improving blood oxygenation in cases involving hypoxia, ischemic diseases, infection control, and anticancer chemoradiation therapies.Keywords: microbubble, fine micro/nanobubble, nanobubble, oxygenation, fluid oxygenation

Masahiro Ohira,1 Takashi Yamaguchi,1 Atsuhito Saiki,1 Noriko Ban,1 Hidetoshi Kawana,1 Ayako Nagumo,1 Takeyoshi Murano,2 Kohji Shirai,3 Ichiro Tatsuno1 1Center for Diabetes, Endocrinology and Metabolism, 2Department of Clinical Laboratory Medicine, 3Department of Vascular Function, Sakura Hospital, Toho University Medical Center, Chiba, Japan Background: Type 2 diabetes is known to be associated with elevated cardiovascular mortality. Pioglitazone improves blood pressure (BP) and pulse wave velocity (PWV), which is an arterial stiffness parameter. Arterial stiffness is closely associated with cardiovascular disease. However, PWV is correlated with BP. The cardio-ankle vascular index (CAVI) reflects arterial stiffness independent of BP. Pioglitazone improves PWV but reduces blood pressure. The aim of this study was to re-evaluate the effect of pioglitazone on arterial stiffness with CAVI. Methods: Sixty patients with type 2 diabetes mellitus and already on 500 mg/day of metformin received add-on therapy of pioglitazone 15 mg/day or glimepiride 1 mg/day for 6 months, during which time changes in their metabolic parameters and CAVI were observed. Results: After 6 months of treatment, both pioglitazone (n=30) and glimepiride (n=30) improved fasting blood glucose and glycated hemoglobin. The changes in fasting blood glucose and glycated hemoglobin between the two groups were greater in the pioglitazone group. Systolic and diastolic BP was decreased in both groups, with no significant between-group differences. Only pioglitazone increased serum adiponectin levels, and the change in adiponectin between the pioglitazone and glimepiride groups was significantly different. CAVI was decreased significantly by pioglitazone but remained unchanged after treatment with glimepiride. The change in CAVI between the two groups was significantly different. Conclusion: These results suggest that pioglitazone improves CAVI, a BP-independent arterial stiffness parameter, in patients with type 2 diabetes mellitus treated with metformin. Keywords: biguanide, thiazolidinediones, sulfonylurea, blood pressure, cardiovascular disease, arterial stiffness

Motofumi Kawai, Toru Yamaguchi, Seigo Nakabayashi, Akitoshi Yoshida Department of Ophthalmology, Asahikawa Medical University, Asahikawa, JapanBackground: In patients with severe optic nerve damage, it is crucial to prevent the hypertensive phase that can develop after Baerveldt glaucoma drainage implant (BGI) surgery. We describe the combination of BGI surgery with surgical bleb revision to prevent the postoperative hypertensive phase.Case reports: We report two patients who underwent BGI surgery combined with surgical bleb revision. The combined surgery was performed in a 62-year-old man with open-angle glaucoma (patient 1) and a 37-year-old man with neovascular glaucoma (patient 2) at Asahikawa Medical University in 2013. Each patient had undergone a previous failed trabeculectomy and another trabeculectomy was expected to be unsuccessful. In patient 1, the early postoperative intraocular pressure (IOP) was well controlled due to a well-functioning bleb, despite development of a small amount of hyphema. In contrast, in patient 2 the postoperative IOP was higher with poor bleb formation; however, after bleb needling, the IOP was well controlled. Thus, the usual techniques used after trabeculectomy were also applicable in this combined surgery. For comparison, we also report the case of a 54-year-old woman with secondary glaucoma who underwent BGI surgery alone (patient 3). The postoperative IOP remained relatively high compared to patients 1 and 2.Conclusion: Combining BGI surgery with surgical bleb revision might be effective to prevent the hypertensive phase that can occur after BGI surgery.Keywords: Baerveldt glaucoma drainage implant, surgical bleb revision, intraocular pressure

Keiichi Onoda,1 Tsuyoshi Hamano,2 Yoko Nabika,1 Atsuo Aoyama,1 Hiroyuki Takayoshi,1 Tomonori Nakagawa,1 Masaki Ishihara,1 Shingo Mitaki,1 Takuya Yamaguchi,1 Hiroaki Oguro,1 Kuninori Shiwaku,3 Shuhei Yamaguchi1 1Department of Neurology, 2Center for Community-Based Health Research and Education, Shimane University, Izumo, 3Shimane University, Matsue, Shimane, Japan Background: We have developed a new screening test for dementia that runs on an iPad and can be used for mass screening, known as the Cognitive Assessment for Dementia, iPad version (CADi). The CADi consists of items involving immediate recognition memory for three words, semantic memory, categorization of six objects, subtraction, backward repetition of digits, cube rotation, pyramid rotation, trail making A, trail making B, and delayed recognition memory for three words. The present study examined the reliability and validity of the CADi. Methods: CADi evaluations were conducted for patients with dementia, healthy subjects selected from a brain checkup system, and community-dwelling elderly people participating in health checkups. Results: CADi scores were lower for dementia patients than for healthy elderly individuals and correlated significantly with Mini-Mental State Examination scores. Cronbach’s alpha values for the CADi were acceptable (over 0.7), and test–retest reliability was confirmed via a significant correlation between scores separated by a one-year interval. Conclusion: These results suggest that the CADi is a useful tool for mass screening of dementia in Japanese populations. Keywords: dementia, mass screening, early detection, iPad

Takefumi Yamaguchi1,2, Kazuno Negishi1, Kazuhiko Ohnuma3, Kazuo Tsubota11Department of Ophthalmology, Keio University School of Medicine, Tokyo; 2Department of Ophthalmology, Ichikawa General Hospital, Tokyo Dental College, Chiba; 3Department of Medical System Engineering, Faculty of Engineering, Chiba University, Chiba, JapanBackground: The purpose of this study was to evaluate the correlation between contrast sensitivity and calculated higher-order aberrations based on individual natural pupil diameter after cataract surgery.Methods: This prospective study included 120 eyes from 92 patients who were randomized to receive one of four lenses, including three aspheric lenses (Acrysof SN60WF, Tecnis ZA9000, and Hoya Py60AD) and one spherical lens (Acrysof SN60AT). Contrast sensitivity, higher-order aberrations of the whole eye, and pupil diameter under photopic and mesopic conditions were measured 1 month postoperatively. Higher-order aberrations were decomposed into Zernike coefficients, calculated according to individual pupil diameter. The correlation between higher-order aberrations and contrast sensitivity was evaluated.Results: There were no significant differences in contrast sensitivity function between the four types of lenses under photopic conditions. However, the contrast sensitivity function and area under log contrast sensitivity function in the aspheric lenses were significantly better than in the spherical lens under mesopic conditions. Under mesopic conditions, spherical aberration in eyes with aspheric lenses was significantly lower than in eyes with spherical lenses (P < 0.05). Under photopic conditions, coma aberration had a significant negative correlation with contrast sensitivity at 12 cycles/degree. Under mesopic conditions, spherical aberration had a significant negative correlation with contrast sensitivity at 3, 6, and 12 cycles/degree with glare, and with contrast sensitivity at 6 and 18 cycles/degree without glare.Conclusion: In terms of influence on visual function, coma aberration may be more significant under photopic conditions and spherical aberration under mesopic conditions.Keywords: mesopic conditions, spherical aberration, wavefront, photopic and mesopic conditions

Seigo Nakabayashi, Motofumi Kawai, Toru Yamaguchi, Akitoshi Yoshida Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan Abstract: We report the case of a patient with recurrent acute angle-closure glaucoma who had undergone a previous laser iridotomy. Because the initial iridotomy was small, patency could not be determined by slit-lamp examination. Therefore, anterior-segment optical coherence tomography was used to evaluate the patency. Cross-sectional images showed the presence of a membrane with an anterior bowing configuration at the base of the iridotomy, suggesting that recurrent pupillary block was the causative mechanism. A repeat laser iridotomy was performed, with a resultant decrease in the intraocular pressure and widening of the anterior chamber angle. Anterior-segment optical coherence tomography may be helpful to confirm the status of a laser iridotomy, especially when the iridotomy is small. Keywords: anterior-segment optical coherence tomography, laser iridotomy, acute angle-closure glaucoma