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Natsuki Sugimura,1,2 Koji Aso,1 Hiroyuki Wada,1 Masashi Izumi,1 Masahiko Ikeuchi1 1Department of Orthopedic Surgery, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan; 2Department of Orthopedic Surgery, Hata Prefectural Hospital, Sukumo, Kochi, 788-0785, JapanCorrespondence: Natsuki Sugimura, Department of Orthopedic Surgery, Kochi Medical School, Kochi University, 185-1 Oko-cho Kohasu, Nankoku, Kochi, 783-8505, Japan, Tel +81-88-880-2386, Fax +81-88-880-2388, Email sugimura.n@kochi-u.ac.jpPurpose: Some patients experience chronic postsurgical pain (CPSP) after total knee arthroplasty (TKA) despite the absence of clinical or radiographic abnormalities. Postoperative synovitis as a cause of CPSP after TKA has received limited research attention. This study aimed to investigate the relationship between synovitis after TKA and CPSP.Patients and Methods: A total of 111 knees of 85 patients, with at least 1-year post-TKA follow-up, were assessed retrospectively and cross-sectionally. Power Doppler (PD) ultrasonography was used to detect the synovial hypervascularity associated with synovitis. The knee joint was divided into 15 areas, and PD signals were graded semi-quantitatively (0– 3) in each area, the sum of which was defined as the total PD score. Clinical information regarding CPSP, including the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscales, was recorded. The relationship between pain and PD ultrasonography findings was accessed. Patients were divided into two groups (CPSP+ and CPSP− groups) based on pain severity. Clinical information, including PD ultrasonography findings and other possible causes, was compared between the groups.Results: The WOMAC pain subscale was significantly correlated with the total PD score and maximum PD grade (r=0.3977, p< 0.0001; r=0.2797, p=0.0029; respectively). The CPSP+ group had a significantly higher maximum PD grade and total PD score than the CPSP− group (median [interquartile range]: 2 [1, 2] vs 1 [1, 2], p=0.0001; 6 [2, 11] vs 2 [1, 4], p=0.0002; respectively). Multiple and logistic regression analyses showed that the total PD score was an independent factor for the WOMAC pain subscale (β=0.3822, 95% confidence interval [CI]=0.1460, 0.6184, p=0.00176) and CPSP (odds ratio=1.19, 95% CI=1.01, 1.41, p=0.0424).Conclusion: This study indicated a possible association between the total PD score and chronic pain after TKA; however, further studies are needed to corroborate these findings.Keywords: chronic postsurgical pain, synovitis, ultrasonography

Naoyuki Akashi,1 Tomio Umemoto,1 Hodaka Yamada,2 Takayuki Fujiwara,3 Kei Yamamoto,1 Yousuke Taniguchi,1 Kenichi Sakakura,1 Hiroshi Wada,1 Shin-ichi Momomura,1 Hideo Fujita1 1Division of Cardiovascular Medicine, Jichi Medical University Saitama Medical Center, Saitama, Japan; 2Division of Endocrinology and Metabolism, Jichi Medical University Saitama Medical Center, Saitama, Japan; 3Department of Cardiovascular Medicine, The University of Tokyo Hospital, Tokyo, JapanCorrespondence: Tomio Umemoto, Division of Cardiovascular Medicine, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan, Tel +81-48-647-2111, Fax +81-48-648-5188, Email to-ume@omiya.jichi.ac.jpPurpose: Dipeptidyl peptidase-4 (DPP-4) inhibitors increase endothelial progenitor cells (EPCs) in peripheral blood circulation. However, the underlying mechanisms and effects on vascular endothelial function remain unclear. We evaluated whether the DPP-4 inhibitor teneligliptin increases circulating EPCs by inhibiting stromal-derived factor-1α (SDF-1α) and improves flow-mediated vascular dilatation (FMD) in type 2 diabetes mellitus patients with acute coronary syndrome (ACS) or its risk factors.Patients and Methods: This single-center, open-label, prospective, randomized controlled trial evaluated 17 patients (hemoglobin A1c ≤ 7.5% and peak creatinine phosphokinase < 2000 IU/mL) with ACS or a history of ACS or multiple cardiovascular risk factors. Metabolic variables of glucose and lipids, circulating EPCs, plasma DPP-4 activity, and SDF-1α levels, and FMD were evaluated at baseline and 28 ± 4 weeks after enrollment. Patients were randomly assigned to either the teneligliptin (n = 8) or control (n = 9) groups.Results: The DPP-4 activity (∆− 509.5 ± 105.7 vs ∆32.8 ± 53.4 μU/mL) and SDF-1α levels (∆− 695.6 ± 443.2 vs ∆11.1 ± 193.7 pg/mL) were significantly decreased after 28 weeks in the teneligliptin group than those in the control group. The number of EPCs showed an increasing trend in the teneligliptin treated group; albeit this did not reach statistical significance. Glucose and lipid levels were not significantly different between the groups before and after 28 weeks. However, FMD was significantly improved in the teneligliptin group when compared to the control group (∆3.8% ± 2.1% vs ∆− 0.3% ± 2.9%, P=0.006).Conclusion: Teneligliptin improved FMD through a mechanism other than increasing the number of circulating EPCs.Keywords: endothelial progenitor cell, teneligliptin, DPP-4 inhibitor, flow-mediated dilation, type 2 diabetes mellitus

Naoki Aoyama, Masashi Izumi, Toru Morimoto, Hiroyuki Wada, Junpei Dan, Yusuke Kasai, Yoshinori Satake, Koji Aso, Masahiko Ikeuchi Department of Orthopedic Surgery, Kochi Medical School, Kochi University, Nankoku, JapanCorrespondence: Masashi Izumi, Department of Orthopedic Surgery, Kochi Medical School, Kochi University, 185-1 Oko-cho Kohasu, Nankoku, 783-8505, Japan, Tel +81-88-880-2386, Fax +81-88-880-2388, Email izumim@kochi-u.ac.jpPurpose: The mechanisms underlying chronic postsurgical pain after joint replacement (JR) are complex, and it has been suggested that chronic postsurgical pain can develop as a result of inadequate acute pain management. Few studies have addressed acute pain after JR using specific animal models. This study aimed to develop a novel JR model focused on postsurgical pain assessment and the time course of pain recovery.Materials and Methods: Rats were allocated to the following three groups: sham (joint exposure), joint destruction (JD; resection of the femoral head), and JR (femoral head replacement using an originally developed implant). The time course of postsurgical pain behavior was measured using a dynamic weight-bearing apparatus, along with radiological assessments. The expression of calcitonin gene-related peptide-immunoreactive (CGRP-IR) neurons in the dorsal root ganglion (DRG) was evaluated by immunohistochemistry on days 28 and 42.Results: The ratio of weight-bearing distribution in the JR group gradually recovered from day 14 and reached the same level as that in the sham group on day 42, which was significantly greater than that in the JD group after day 7 (p< 0.05). Radiologically, no significant issues were found, except for transient central migration of the implant in the JR group. The percentage of CGRP-IR DRG neurons in the JR group was significantly lower than that in the JD group on day 28 (mean, 37.4 vs 58.1%, p< 0.05) and day 42 (mean, 32.3 vs 50.0%, p< 0.05).Conclusion: Our novel JR model presented acute postsurgical pain behavior that was successfully recovered to the baseline level at day 42 after surgery. Difference of the pain manifestation between the JR and JD groups could be supported by the expression of CGRP-IR in DRG neurons. This model is the first step toward understanding detailed mechanisms of post-JR pain.Keywords: joint replacement, postsurgical pain, dynamic weight bearing, CGRP

Yusuke Kasai, Koji Aso, Masashi Izumi, Hiroyuki Wada, Junpei Dan, Yoshinori Satake, Toru Morimoto, Masahiko Ikeuchi Department of Orthopedic Surgery, Kochi Medical School, Kochi University, Nankoku, 783-8505, JapanCorrespondence: Koji AsoDepartment of Orthopedic Surgery, Kochi Medical School, Kochi University, 185-1 Oko-cho Kohasu, Nankoku, 783-8505, JapanTel +81-88-880-2386Fax +81-88-880-2388Email koji.aso@gmail.comPurpose: Nonunion bone fracture can be a cause of persistent pain, but the pathophysiology remains largely unknown. The objective of this study was to identify how nonunion affect persistent pain after fracture. Specifically, we evaluated the association of neuropeptide change in dorsal root ganglia (DRG) and nerve proliferation at fracture sites with pain.Methods: Rat union and nonunion fracture models were created. A piece of latex glove was placed at the fracture site to create a nonunion model. At 6 weeks after surgery, bone healing was assessed using radiography. In addition, the presence of calcitonin gene-related peptide-immunoreactive (CGRP-IR) DRG at the level of L3 and anti-growth associated protein 43-immunoreactive (GAP43-IR) nerve fibers in the scar tissue between the bone fragments were evaluated. Pain-related behavior was assessed using forced treadmill running.Results: In radiological images at 6 weeks after surgery, callus formation was formed continuously between bone fragments in the union models. On the one hand, a clear gap was detected between fragments in nonunion models. The percentage of CGRP-IR DRG cells and the density of GAP43-IR nerve fibers in the scar tissue between the bone fragments in nonunion models was significantly higher than that in union models (p < 0.05). An increase in inflammatory cell infiltrate was observed in scar tissues in the nonunion models. During forced treadmill running, rats in the union model could run significantly longer than those in the nonunion models.Conclusion: Increased CGRP expression in DRG cells and abnormal nerve proliferation secondary to prolonged inflammation could lead to persistent pain after bone fracture. In clinical practice, early achievement of bone union may minimize the development of persistent pain after fractures.Keywords: fracture pain, nerve proliferation, nonunion of fractures

Masafumi Funamoto,1,2 Yoichi Sunagawa,1–3 Yasufumi Katanasaka,1–3 Yusuke Miyazaki,1,2 Atsushi Imaizumi,4 Hideaki Kakeya,5 Hajime Yamakage,2 Noriko Satoh-Asahara,2 Maki Komiyama,2 Hiromichi Wada,2 Koji Hasegawa,2 Tatsuya Morimoto1–3 1Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 2Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, 3Shizuoka General Hospital, Shizuoka, 4Theravalues Corporation, Kioicho, Tokyo, 5Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan Purpose: COPD is mainly caused by tobacco smoking and is associated with a high frequency of coronary artery disease. There is growing recognition that the inflammation in COPD is not only confined to the lungs but also involves the systemic circulation and can impact nonpulmonary organs, including blood vessels. α1-antitrypsin–low-density lipoprotein (AT-LDL) complex is an oxidatively modified LDL that accelerates atherosclerosis. Curcumin, one of the best-investigated natural products, is a powerful antioxidant. However, the effects of curcumin on AT-LDL remain unknown. We hypothesized that Theracurmin®, a highly absorptive curcumin with improved bioavailability using a drug delivery system, ameliorates the inflammatory status in subjects with mild COPD.Patients and methods: This is a randomized, double-blind, parallel-group study. Subjects with stages I–II COPD according to the Japanese Respiratory Society criteria were randomly assigned to receive 90 mg Theracurmin® or placebo twice a day for 24 weeks, and changes in inflammatory parameters were evaluated.Results: There were no differences between the Theracurmin® and placebo groups in terms of age, male/female ratio, or body mass index in 39 evaluable subjects. The percent changes in blood pressure and hemoglobin A1c and LDL-cholesterol, triglyceride, or high-density lipoprotein-cholesterol levels after treatment were similar for the two groups. However, the percent change in the AT-LDL level was significantly (P=0.020) lower in the Theracurmin® group compared with the placebo group.Conclusion: Theracurmin® reduced levels of atherosclerotic AT-LDL, which may lead to the prevention of future cardiovascular events in mild COPD subjects. Keywords: curcumin, AT-LDL, COPD, atherosclerosis

We review the works done by our collaboration (Scalar collaboration) for the scalar mesons in the lattice QCD. We present the preliminary results and the plan for simulation of the sigma meson and the kappa meson.