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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

Yoshinori Satake,1 Masashi Izumi,1 Koji Aso,1 Yoichi Igarashi,2 Nao Sasaki,3 Masahiko Ikeuchi1 1Department of Orthopaedic Surgery, Kochi Medical School, Kochi University, Kochi, Japan; 2Department of Orthopaedic Surgery, Tosa Municipal Hospital, Kochi, Japan; 3Medicines Development Unit Japan, Eli Lilly Japan K.K., Hyogo, JapanCorrespondence: Yoshinori SatakeDepartment of Orthopaedic Surgery, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku-shi, Kochi 783-8505, JapanTel +81 88 880 2387Fax +81 88 880 2388Email y-satake@kochi-u.ac.jpPurpose: Patients with knee osteoarthritis (OA) complain of various types of pain, divided into two main categories: pain on movement and pain at rest. A thorough understanding of pain is essential for managing knee OA; however, few studies have investigated the mechanisms underlying the two different types of pain. This study aimed to clarify the predisposing factors for pain in patients with knee OA with a focus on differences between pain on walking and pain at rest.Patients and Methods: This study involved 93 patients, aged 44– 90 years, with knee OA, including 74 women. We assessed demographic variables (sex, age, body mass index [BMI], side), visual analogue scale (VAS) score on walking, VAS score at rest, Kellgren and Lawrence (KL) grade on radiograph, synovitis score and bone marrow lesion (BML) score on magnetic resonance imaging, and pressure pain threshold (PPT), and used univariate and multiple regression analyses to investigate factors predisposing patients to pain at rest or pain on walking.Results: In the univariate analyses, we found significant correlations between VAS score on walking and BMI (r=0.31, p< 0.01), KL grade (r=0.40, p< 0.01), synovitis score (r=0.26, p=0.01), and BML score (r=0.36, p< 0.01), whereas VAS score at rest correlated with PPT (r=− 0.23, p=0.02) and BMI (r= 0.26, p=0.01). Multiple regression analysis showed that significant explanatory factors for VAS score on walking were BMI (β=0.22, p=0.03) and KL grade (β=0.27, p=0.03). By contrast, PPT was the only significant explanatory factor for VAS score at rest (β=− 0.27, p=0.01).Conclusion: Predisposing factors were significantly different between pain on walking and pain at rest, indicating that different pain mechanisms exist in the two types of pain. Pain on walking was more strongly associated with mechanical and structural factors, while pain at rest was associated with mechanical hyperalgesia of the knee.Clinical Registration: University Hospital Medical Information Network Clinical Trials Registration number; 000041190.Keywords: knee osteoarthritis, pain at rest, hyperalgesia

Chest computed tomography (CT) showed a 30 mm × 10 mm mass in the trachea at the thyroid gland-level causing airway stenosis (Figure 1b and c). Learning points for clinicians Airway tumours, including tracheal leiomyoma, should be considered in patients being treated for asthma who present with symptoms atypical of asthma, such as dyspnoea with position changes and stridor on inspiration, or who do not respond to conventional therapy. In summary, clinicians should consider airway tumours, such as leiomyomas, in patients being treated for asthma and presenting with atypical asthma symptoms. [Extracted from the article]

RNA-binding proteins and microRNAs are potent post-transcriptional regulators of gene expression. Human transformer 2β (Tra2β) is a serine/arginine-rich-like protein splicing factor and is now implicated to have wide-ranging roles in gene expression as an RNA-binding protein. RNA immunoprecipitation (RIP) with an anti-Tra2β antibody and microarray analysis identified a subset of Tra2β-associated mRNAs in HCT116 human colon cancer cells, many of which encoded cell death-related proteins including Bcl-2 (B-cell CLL/lymphoma 2). Tra2β knockdown in HCT116 cells decreased Bcl-2 expression and induced apoptosis. Tra2β knockdown accelerated the decay of BCL2α mRNA that encodes Bcl-2 and full-length 3′ UTR, while it did not affect the stability of BCL2β mRNA having a short, alternatively spliced 3′ UTR different from BCL2α 3′ UTR. RIP assays with anti-Tra2β and anti-Argonaute 2 antibodies, respectively, showed that Tra2β bound to BCL2α 3′ UTR, and that Tra2β knockdown facilitated association of miR-204 with BCL2α 3′ UTR. The consensus sequence (GAA) for Tra2β-binding lies within the miR-204-binding site of BCL2 3′ UTR. Mutation of the consensus sequence canceled the binding of Tra2β to BCL2 3′ UTR without disrupting miR-204-binding to BCL2 3′ UTR. Transfection of an anti-miR-204 or introduction of three-point mutations into the miR-204-binding site increased BCL2 mRNA and Bcl-2 protein levels. Inversely, transfection of precursor miR-204 reduced their levels. Experiments with Tra2β-silenced or overexpressed cells revealed that Tra2β antagonized the effects of miR-204 and upregulated Bcl-2 expression. Furthermore, TRA2β mRNA expression was significantly upregulated in 22 colon cancer tissues compared with paired normal tissues and positively correlated with BCL2 mRNA expression. Tra2β knockdown in human lung adenocarcinoma cells (A549) increased their sensitivity to anticancer drugs. Taken together, our findings suggest that Tra2β regulates apoptosis by modulating Bcl-2 expression through its competition with miR-204. This novel function may have a crucial role in tumor growth. [ABSTRACT FROM AUTHOR]