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Toshihiro Kita,1 Yoshikazu Kaji,2 Kazuo Kitamura1 1Division of Circulatory and Body Fluid Regulation, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; 2Souseikai Hakata Clinic, Fukuoka, JapanCorrespondence: Toshihiro KitaDivision of Circulatory and Body Fluid Regulation, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Miyazaki 889-1692, JapanTel +81-985-85-0872Fax +81-985-85-6596Email toshihiro_kita@med.miyazaki-u.ac.jpBackground: Adrenomedullin (AM), an endogenous vasodilative peptide, has immunomodulative effects and acts as an accelerator of mucosal regeneration in the digestive tract. AM has shown beneficial effects in rodent models of inflammatory bowel disease and patients with ulcerative colitis. The present study aimed to evaluate the pharmacodynamic properties and safety of AM in healthy male adults in a phase 1 clinical trial.Methods: This phase 1, randomized, double-blind, single-center study was conducted on healthy males aged 20–65 years. Subjects received either a placebo, 3 ng/kg/min AM, 9 ng/kg/min AM, or 15 ng/kg/min AM via continuous 12-h intravenous infusion. Other subjects received either placebo or 15 ng/kg/min AM for 8 h per day for 7 days. Adverse events (AEs), vital signs, physical examinations, laboratory tests, electrocardiograms (ECG), and pharmacokinetics were assessed.Findings: All 24 subjects in the single-dose test completed the study. Of the 12 subjects in multiple dosing test, one from the AM group withdrew owing to a headache. No serious AEs were reported. Hemodynamic parameters were well maintained in all subjects. Slight ECG abnormalities were observed in the single-dose test. The plasma concentration of AM progressively increased in a dose-dependent manner and reached Cmax at the end of administration. Plasma AM rapidly returned to baseline concentrations after termination, with a T1/2 of under 60 min.Interpretation: This is the first phase 1 trial in healthy men evaluating the safety of AM. Our results demonstrate the safety and tolerability of AM for subsequent Phase 2 trials.Keywords: adrenomedullin, Phase 1 clinical trial, clinical pharmacology, inflammatory bowel disease

Akemi Takahashi,1 Kaori Kitamura,2 Yumi Watanabe,2 Ryosaku Kobayashi,3 Toshiko Saito,4 Ribeka Takachi,5 Keiko Kabasawa,6 Rieko Oshiki,1 Shoichiro Tsugane,7 Masayuki Iki,8 Ayako Sasaki,9 Osamu Yamazaki,10 Kazutoshi Nakamura2 1Department of Rehabilitation, Niigata University of Rehabilitation, Niigata, Japan; 2Division of Preventive Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; 3Department of Physical Therapy, Niigata University of Health and Welfare, Niigata, Japan; 4Department of Health and Nutrition, Niigata University of Health and Welfare, Niigata, Japan; 5Department of Food Science and Nutrition, Nara Women’s University Graduate School of Humanities and Sciences, Nara, Japan; 6Department of Health Promotion Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; 7Center for Public Health Sciences, National Cancer Center, Tokyo, Japan; 8Department of Public Health, Kindai University Faculty of Medicine, Osaka, Japan; 9Murakami Public Health Center, Niigata, Japan; 10Niigata Prefectural Office, Niigata, Japan Purpose: Epidemiological profiles of chronic low back and knee pain have not been studied extensively. This study aimed to determine the prevalence of and potential risk factors associated with chronic low back and knee pain in middle-aged and elderly Japanese. Methods: This cross-sectional study involved 14,217 community-dwelling individuals aged 40–74 years living in the Murakami area of Japan. A self-administered questionnaire was used to obtain information regarding marital status, education level, occupation, household income, and body size. Participants also reported current chronic pain, if any, by site and degree of severity, using the verbal rating scale of the Short Form 36. Results: The prevalence of moderate–very severe chronic pain was 9.7% in the low back, 6.7% in the knee, 13.9% in either the low back or knee, and 2.6% in both the low back and knee. Multivariate analysis revealed that lower education level, lower income, and manual occupation in men and older age and higher body mass index in women were significantly associated with a higher prevalence of chronic low back pain. In both sexes, older age, lower education level, and higher body mass index were significantly associated with a higher prevalence of knee pain. Regarding sex differences, adjusted ORs of chronic pain of the low back and knee for women were 0.85 (95% CI 0.75–0.97) and 1.27 (95% CI 1.09–1.49), respectively. Conclusion: Nearly 14% of middle-aged and elderly individuals had moderate–very severe chronic pain of the low back or knee, and this pain was associated with many demographic factors, including sex, age, education level, household income, occupation, and body size. Keywords: body mass index, chronic pain, demography, knee pain, low back pain, prevalence

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