Yoshihiro Sakuma

Chiba University, Tiba, Chiba, Japan

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Publications (40)61.66 Total impact

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    ABSTRACT: Transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated nonselective cation channel, which can be activated by capsaicin and other noxious stimuli. Recently, an association between bone pain and TRPV1 has been reported. However, the influence of osteoporosis on TRPV1 in the sensory system innervating the femur has not been reported.
    Yonsei medical journal. 11/2014; 55(6):1600-5.
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    ABSTRACT: Opioids improve pain from knee and hip osteoarthritis (OA) and decrease the functional impairment of patients. However, there is a possibility that opioids induce analgesia and suppress the physiological pain of OA in patients, thereby inducing the progression of OA changes in these patients. The purpose of the current study was to investigate the possibility of progressive changes in OA among patients using opioids.
    Yonsei medical journal. 09/2014; 55(5):1379-85.
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    Asian spine journal 06/2014; 8(3):260-6.
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    ABSTRACT: Study Design. Quantitative and immunohistological analysis of the efficacy of an IκB kinase-β (IKKβ) inhibitor in an injured intervertebral disc (IVD) model.Objective. To elucidate the efficacy of an IKKβ inhibitor on inflammatory cytokine levels in injured IVDs or on neuropeptide levels in the dorsal root ganglia (DRG) neurons innervating injured IVDs in rats.Summary of Background Data. Multiple studies have suggested that upregulation of inflammatory cytokines in damaged IVDs causes discogenic low back pain. The efficacy of blocking individual inflammatory cytokines is limited; however, inflammatory cytokine stimuli often require IKKβ to activate nuclear factor-k B.Methods. Sprague-Dawley rats were divided into 3 groups: sham, saline (disc-injury plus saline), and IKKβ (disc-injury plus anti-IKKβ). To induce injury, IVDs were repeatedly punctured.Experiment 1: 4, 7 and 14 days post-injury, coccygeal (Co) 5/6, Co6/7, and Co7/8 IVDs were resected and tumor necrosis factor (TNF)-alpha, interleukin (IL)-1β, and IL-6 levels were quantified by ELISA. Experiment 2: The neurotracer Fluorogold (FG) was injected into injured L5/6 IVDs and uninjured sham group IVDs to detect DRG neurons. One week post-surgery, L1-L6 DRGs were immunolabeled with the neuropeptide CGRP. The proportions of FG-labeled CGRP-immunoreactive DRG neurons were assessed.Results. Experiment 1: IVD levels of TNF-alpha (through 2 weeks), IL-1β (at 4 days), and IL-6 (at 4 days) were significantly higher in the saline group than in the sham group, and significantly lower in the IKKβ group than in the saline group (p<0.05). Experiment 2: The percentage of CGRP-immunoreactive FG-labeled DRG neurons was significantly higher in the saline group than in the sham group, and significantly lower in the IKKβ group than in the saline group (p<0.05).Conclusion. Injury-induced upregulation of inflammatory cytokines within IVDs and increased levels of neuropeptides within DRG neurons can be suppressed by inhibiting IKKβ.
    Spine 05/2014; · 2.16 Impact Factor
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    ABSTRACT: To examine the effects of conservative and surgical treatments for nocturnal leg cramps in patients with lumbar spinal stenosis (LSS). Nocturnal leg cramps is frequently observed in patients with peripheral neuropathy. However, there have been few reports on the relationship between nocturnal leg cramps and LSS, and it remains unknown whether conservative or surgical intervention has an impact on leg cramps in patients with LSS. The subjects were 130 LSS patients with low back and leg pain. Conservative treatment such as exercise, medication, and epidural block was used in 66 patients and surgical treatment such as decompression or decompression and fusion was performed in 64 patients. Pain scores and frequency of nocturnal leg cramps were evaluated based on self-reported questionnaires completed before and 3 months after treatment. The severity of low back and leg pain was higher and the incidence of nocturnal leg cramps was significantly higher before treatment in the surgically treated group compared with the conservatively treated group. Pain scores improved in both groups after the intervention. The incidence of nocturnal leg cramps was significantly improved by surgical treatment (p=0.027), but not by conservative treatment (p=0.122). The findings of this prospective study indicate that the prevalence of nocturnal leg cramps is associated with LSS and severity of symptoms. Pain symptoms were improved by conservative or surgical treatment, but only surgery improved nocturnal leg cramps in patients with LSS. Thus, these results indicate that the prevalence of nocturnal leg cramps is associated with spinal nerve compression by LSS.
    Yonsei medical journal 05/2014; 55(3):779-84. · 0.77 Impact Factor
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    ABSTRACT: Study Design. Immunohistological analysis of the cervical dorsal root ganglia (DRG).Objective. To investigate immunohistologically in rats whether intradiscal administration of anti-nerve growth factor (NGF) antibody in injured cervical intervertebral discs (IVDs) suppresses pain-related peptide expression in DRG neurons.Summary of Background Data. Neck pain can involve the entire neck and become chronic and intractable. Cervical disc degeneration is a primary cause of neck pain, and pain-related mediators, such as NGF, have been correlated with discogenic pain.Methods. We examined Sprague-Dawley rats that received 10 punctures in the C5/6 IVD, and were treated with saline (puncture group) or an anti-NGF antibody (anti-NGF group). The retrograde neurotracer Fluoro-Gold (FG) was then injected into the C5/6 IVD. In addition, we examined a sham group that did not receive punctures (disc non-puncture). The C2-C7 DRG were harvested 1 week after surgery and immunostained for calcitonin gene-related peptide (CGRP), a marker for peptide-containing neurons. We determined for each group the percentages of FG-labeled DRG neurons that were CGRP-immunoreactive (CGRP-ir).Results. FG-labeled neurons innervating the C5/6 IVD were found in all C2-C7 DRG examined. The percentage of FG-labeled CGRP-ir DRG neurons in the puncture group was significantly higher than that observed in the sham (p < 0.001) and anti-NGF groups (p < 0.001), but there was no significant difference between the sham and anti-NGF groups (p > 0.05). Therefore, intradiscal administration of anti-NGF antibody suppressed CGRP expression the cervical DRG.Conclusion. Neurons located in the C2-C7 DRG innervated the C5/6 IVD. These findings indicate that neck pain may be derived from degenerated IVDs. Furthermore, intradiscal administration of anti-NGF antibody suppressed CGRP expression in the cervical DRG innervating the injured IVD. Therefore, inhibiting NGF upregulation in the cervical IVD may be an efficient treatment for discogenic neck pain.
    Spine 04/2014; · 2.16 Impact Factor
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    ABSTRACT: Purpose: Bupivacaine is commonly used for the treatment of back pain and the diagnosis of its origin. Nonunion is sometimes observed after spinal fusion surgery; however, whether the nonunion causes pain is controversial. In the current study, we aimed to detect painful nonunion by injecting bupivacaine into the disc space of patients with nonunion after anterior lumbar interbody fusion (ALIF) surgery for discogenic low back pain. Materials and Methods: From 52 patients with low back pain, we selected 42 who showed disc degeneration at only one level (L4-L5 or L5-S1) on magnetic resonance imaging and were diagnosed by pain provocation on discography and pain relief by discoblock (the injection of bupivacaine). They underwent ALIF surgery. If the patients showed low back pain and nonunion 2 years after surgery, we injected bupivacaine into the nonunion disc space. Patients showing pain relief after injection of bupivacaine underwent additional posterior fixation using pedicle screws. These patients were followed up 2 years after the revision surgery. Results: Of the 42 patient subjects, 7 showed nonunion. Four of them did not show low back pain; whereas 3 showed moderate or severe low back pain. These 3 patients showed pain reduction after injection of bupivacaine into their nonunion disc space and underwent additional posterior fixation. They showed bony union and pain relief 2 years after the revision surgery. Conclusion: Injection of bupivacaine into the nonunion disc space after ALIF surgery for discogenic low back pain is useful for diagnosis of the origin of pain.
    Yonsei medical journal 03/2014; 55(2):487-92. · 0.77 Impact Factor
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    ABSTRACT: Study Design. Animal study.Objective. To investigate pain-related expression of NaV1.7 in dorsal root ganglia (DRG) innervating intervertebral discs.Summary of Background Data. The pathophysiology of discogenic low back pain is not fully understood. Prostaglandins and cytokines produced by degenerated discs can cause pain, but non-steroidal anti-inflammatory and steroid medications are often ineffective at pain reduction. Tetrodotoxin-sensitive voltage-gated sodium (NaV) channels are associated with sensory transmission in primary sensory nerves, and the NaV1.7 channel has emerged as an attractive analgesic target. The purpose of this study was to investigate pain-related expression of NaV1.7 in DRG innervating intervertebral discs.Methods. Using a rodent model of disc puncture, we labeled DRG neurons innervating L5/6 discs with FluoroGold neurotracer (n = 20). Half of the rats (n = 10) underwent intervertebral disc puncture using a 23-gauge needle (puncture group), and the other half underwent non-puncture sham surgery (non-puncture group). Seven and fourteen days after surgery, DRGs from the L1 to L6 levels were harvested, sectioned, and immunostained for NaV1.7, and the proportion of NaV1.7- immunoreactive DRG neurons was evaluated.Results. NaV1.7 was expressed in DRG neurons innervating intervertebral discs from L1 to L5. The ratio of NaV1.7-expressing DRG neurons to total FG-labeled neurons was 7.2% and 7.6% at 1 and 2 weeks after surgery, respectively, in the non-puncture group and 16.2% and 16.3% at 1 and 2 weeks, respectively, in the puncture group. The up-regulation of NaV1.7 after puncture was significant at both 1 and 2 weeks after surgery (P < 0.01).Conclusion. We found that disc injury increases NaV1.7 expression in DRG neurons innervating injured discs. NaV1.7 may be a therapeutic target for pain control in patients with lumbar disc degeneration.
    Spine 01/2014; · 2.16 Impact Factor
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    ABSTRACT: Purpose: Pain from vertebral or femoral neck fractures is a particularly important problem in clinical orthopaedics. Transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated nonselective cation channel, and there are recent reports on an association between bone pain and TRPV1. However, an increase in TRPV1 activity has not been reported following femoral fracture. Materials and Methods: We applied a neurotracer [Fluoro-gold (FG)] onto femur to detect dorsal root ganglia (DRGs) innervating the cortex of the femur in 30 Sprague Dawley rats. Seven days after application, a closed mid-diaphyseal fracture of the femur was performed. FG labeled TRPV1-immunoreactive (ir) DRGs innervating the femur were examined in nonfractured controls, and 3 days, 1 week, 2 weeks, and 4 weeks after fracture. We evaluated bone healing of the femur and compared the ratio of TRPV1-ir DRG neurons innervating the femur at the time points. Results: Four weeks after fracture, complete bone union was observed. There was no significant difference in the ratio of FG labeled DRG neurons to total DRG neurons at each time point. The percentages of TRPV1-ir neurons in DRGs innervating the femur at 3 days and 1 week after fracture were significantly higher than those in control, 2 weeks, and 4 weeks after fracture (p<0.05). Conclusion: Fracture induced an increase of TRPV1-ir neurons in DRGs innervating the fractured femur within 3 days, and decreased during bone healing over 4 weeks. These findings show that TRPV1 may play a role in sensory sensation of bone fracture pain.
    Yonsei medical journal 01/2014; 55(1):185-90. · 0.77 Impact Factor
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    ABSTRACT: Study Design. Animal studyObjective. To evaluate pain behavior and neuropeptide changes in the spinal dorsal horn after sciatic nerve compression and application of nucleus pulposus (NP) in rats.Summary of Background Data. The pathomechanisms of lumbar-disc herniation pain have not been fully elucidated. Pain-associated neuropeptides, including Substance P and calcitonin gene-related peptide (CGRP), are produced in DRG neurons and transported to spinal dorsal horn nerve terminals where they function in pain transmission. However, changes in CGRP-immunoreactive (IR) sensory nerve terminals have not been reported in models of disc herniation. This study evaluated pain-related behavior and changes in CGRP-IR terminals in the spinal dorsal horn after combined sciatic nerve compression and nucleus pulposus (NP) application.Methods. Five groups of rats underwent either sciatic nerve compression with NP (n = 20), application of NP only (n = 20), nerve compression only (n = 20), sham operation with neither compression nor NP (n = 20), or no operation (controls, n = 20). Mechanical hyperalgesia was measured every second day for three weeks. CGRP-IR terminals in each spinal dorsal horn lamina were examined 7 and 14 days post-surgery. Pain behavior and CGRP immunoreactivity were compared among the five groups.Results. Mechanical hyperalgesia was found in the NP only, nerve compression only, and the NP ± nerve compression groups (P ≤ 0.05). CGRP-IR nerve terminals in the superficial laminae (I and II) and the deep laminae (III-VI) significantly increased in the NP only, nerve compression only, and NP ± nerve compression groups compared to control and sham groups (P ≤ 0.05). Significant mechanical hyperalgesia and increased CGRP-IR nerve terminals were found in the NP ± nerve compression group compared with the NP only and nerve compression only groups (P ≤ 0.05).Conclusion. Our results indicate that nerve compression plus NP application produces the most pain-related behavior. CGRP-IR nerve terminals increased in laminae I and II which transmit pain and in laminae III-VI which transmit proprioception. Findings suggest that nerve compression plus NP application induce changes in CGRP expression in the superficial and deep laminae, and these changes are partly responsible for disc herniation pain.
    Spine 12/2013; · 2.16 Impact Factor
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    ABSTRACT: The pathomechanisms of pain resulting from lumbar disc herniation have not been fully elucidated. Prostaglandins and cytokines generated at the inflammatory site produce associated pain; however, non-steroidal anti-inflammatory drugs and steroids are sometimes ineffective in patients. Tetrodotoxin-sensitive voltage-gated sodium (NaV) channels are related to sensory transmission in primary sensory nerves. The sodium channel NaV1.7 has emerged as an attractive analgesic target. The purpose of this study was to evaluate pain-related behavior and expression of NaV1.7 in dorsal root ganglia (DRG) after combined sciatic nerve compression and nucleus pulposus (NP) application in rats. Rats were divided into three groups and underwent either sciatic nerve compression with NP for 2 s using forceps (n = 20), sham operation with neither compression nor NP (n = 20), or no operation (controls, n = 20). Mechanical hyperalgesia was measured every second day for three weeks using von Frey filaments. NaV1.7 expression in L5 DRG was examined 7 and 14 days after surgery using immunohistochemistry. The number of neurons immunoreactive for NaV1.7 was compared among the three groups. Mechanical hyperalgesia was found over the 14-day observation in the nerve compression plus NP application group, but not in the sham-operated or control groups (P < 0.05). NaV1.7 expression in L5 DRG was up-regulated in the nerve compression plus NP application group, compared with sham-operated and control rats (P < 0.01). Our results indicate that nerve compression plus NP application produces pain-related behavior. We conclude that NaV1.7 expression in DRG neurons may play an important role in mediating pain from sciatic nerves after compression injury and exposure to NP.
    European Spine Journal 11/2013; · 2.47 Impact Factor
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    ABSTRACT: Basic pain study using osteoporotic rodent models. To examine alterations in distribution of pain-related neuropeptides after compressive force on osteoporotic vertebrae and their chronic pain-related properties. We previously reported significantly increased production of calcitonin gene-related peptide (CGRP), a marker of inflammatory pain, in the dorsal root ganglia (DRG) of vertebrae in osteoporosis-model ovariectomized (OVX) rats. Here, we hypothesized that longitudinal compressive force on vertebrae can affect osteoporotic pain properties, which has not been examined yet. OVX rats were used as the osteoporosis model. Female Sprague-Dawley rats were prepared and Fluoro-Gold (FG) neurotracer was applied to the periosteal surface of the Co5 vertebra. After FG labeling, the animals were divided into 4 groups: Control, Control + compression, OVX, and OVX + compression. The Control groups were not ovariectomized. In the compression groups, K-wires were stabbed transversely through Co4 and Co6 with Co5 compressed longitudinally by rubber bands bridged between the 2. One, 2, 4, and 8 weeks after surgery, bilateral S1 to S3 DRGs were excised for immunofluorescence assays. Expression of CGRP and activating transcription factor 3, a marker of neuronal injury, were compared among the 4 groups. Sustained upregulation of CGRP in DRG neurons was observed after compression of the Co5 vertebra, and Co5 compression caused significant increase in CGRP production in DRG neurons, whereas a greater level of activating transcription factor 3 upregulation was observed in DRGs in OVX rats after dynamic vertebral compression 8 weeks after surgery, implying potential neuropathic pain. There was sustained upregulation of CGRP and activating transcription factor 3 in DRGs in osteoporotic model rats compared with controls, and levels were further enhanced by dynamic vertebral compression. These findings imply that dynamic compression stress on vertebrae can exacerbate osteoporotic pain by inducing both inflammatory and neuropathic pain mediators.Level of Evidence: N/A.
    Spine 11/2013; 38(24):2085-91. · 2.16 Impact Factor
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    ABSTRACT: Study Design. Basic pain study using osteoporotic rodent models.Objective. To examine alterations in distribution of pain-related neuropeptides following compressive force on osteoporotic vertebrae and their chronic pain-related properties.Summary of Background Data. We previously reported significantly increased production of calcitonin gene-related peptide (CGRP), a marker of inflammatory pain, in the dorsal root ganglia (DRG) of vertebrae in osteoporosis-model ovariectomized (OVX) rats. Here, we hypothesized that longitudinal compressive force on vertebrae can affect osteoporotic pain properties, which has not been examined yet.Methods. OVX rats were used as the osteoporosis model. Female Sprague Dawley rats were prepared and Fluoro-Gold (FG) neurotracer was applied to the periosteal surface of the Co5 vertebra. After FG-labeling, the animals were divided into 4 groups: Control, Control + compression, OVX, and OVX + compression. The Control groups were not ovariectomized. In the compression groups, K-wires were stabbed transversely through Co4 and Co6 with Co5 compressed longitudinally by rubber bands bridged between the two. One, 2, 4, and 8 weeks after surgery, bilateral S1 to S3 DRGs were excised for immunofluorescence assays. Expression of CGRP and activating transcription factor 3 (ATF-3), a marker of neuronal injury, were compared among the 4 groups.Results. Sustained upregulation of CGRP in DRG neurons was observed following compression of the Co5 vertebra, and Co5 compression caused significant increase in CGRP production in DRG neurons, while a greater level of ATF-3 upregulation was observed in DRGs in OVX rats following dynamic vertebral compression 8 weeks after surgery, implying potential neuropathic pain.Conclusion: There was sustained upregulation of CGRP and ATF3 in DRGs in osteoporotic model rats compared with controls, and levels were further enhanced by dynamic vertebral compression. These findings imply that dynamic compression stress on vertebrae can exacerbate osteoporotic pain by inducing both inflammatory and neuropathic pain mediators.
    Spine 09/2013; · 2.16 Impact Factor
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    ABSTRACT: Purpose: Osteoarthritic pain is largely considered to be inflammatory pain. Sensory nerve fibers innervating the knee have been shown to be significantly damaged in rat models of knee osteoarthritis (OA) in which the subchondral bone junction is destroyed, and this induces neuropathic pain (NP). Pregabalin was developed as a pain killer for NP; however, there are no reports on pregabalin use in OA patients. The purpose of this study was to investigate the efficacy of pregabalin for pain in OA patients. Materials and Methods: Eighty-nine knee OA patients were evaluated in this randomized prospective study. Patients were divided into meloxicam, pregabalin, and meloxicam+pregabalin groups. Pain scores were evaluated before and 4 weeks after drug application using a visual analogue scale (VAS), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Pain scales among groups were compared using a Kruskal-Wallis test. Results: Before drug application, there was no significant difference in VAS and WOMAC scores among the three groups (p>0.05). Significant pain relief was seen in the meloxicam+pregabalin group in VAS at 1, 2, and 4 weeks, and WOMAC score at 4 weeks, compared with the other groups (p<0.05). No significant pain relief was seen in the meloxicam only group in VAS during 4 weeks and WOMAC score at 4 weeks compared with the pregabalin only group (p>0.05). Conclusion: Meloxicam+pregabalin was effective for pain in OA patients. This finding suggests that OA pain is a combination of inflammatory and NP.
    Yonsei medical journal 09/2013; 54(5):1253-8. · 0.77 Impact Factor
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    ABSTRACT: Prospective study of changes in intervertebral disc degeneration after injection of bupivacaine. To examine whether injection of bupivacaine into human intervertebral discs accelerates their degeneration. Bupivacaine is commonly used for therapy and diagnosis of discogenic low back pain. However, several in vitro studies have reported toxic effects of bupivacaine to disc cells. We sought to evaluate whether this finding is clinically relevant. We selected 46 patients with low back pain who showed disc degeneration at only one level (L4-L5 or L5-S1) on magnetic resonance imaging (MRI) (discography group, n=18), discoblock group (injection of bupivacaine, n=18), and a control group, n=10). There were no significant differences in baseline characteristics across the 3 groups. The two experimental groups underwent either discography or anesthetic discoblock, respectively. All three groups were followed up 5 years after the examination. At 5 years follow-up, there was no significant difference in the rate of disc degeneration among the 3 groups (p>0.1). Moreover, X-ray images showed that there was no significant difference in disc height, range of motion, or translation between flex and extension position (p>0.1). In conclusion, radiologic and MRI findings did not show acceleration of intervertebral disc degeneration at 5 years after a single injection of bupivacaine into human discs.
    Asian spine journal 09/2013; 7(3):212-7.
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    ABSTRACT: Study Design. Animal study.Objective. To determine the existence of dichotomizing sensory nerve fibers innervating both the lumbar vertebral body and the area surrounding the iliac crest.Summary of background data. Elderly patients with osteoporosis sometimes experience lumbar vertebral fracture and may feel diffuse nonlocalized pain in the back, the lateral portion of the trunk, and the area surrounding the iliac crest (ASIC). The pattern of sensory innervation of vertebral bodies remains unclear. DRG neurons with dichotomizing axons have been reported and are thought to be related to referred pain. The purpose of this study was to investigate the existence of dichotomizing axons to the lumbar vertebral bodies and the ASIC in rats.Methods: Two kinds of neurotracers [1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) and fluoro-gold (FG)] were used. DiI crystals were placed in the left ASIC, and FG was applied into the L2 vertebral body in 10 rats. Four weeks later, left DRGs from L1 to L6 were resected, sectioned and observed under a fluorescence microscope.Results: DiI-labeled DRG neurons innervating the ASIC and FG-labeled DRG neurons innervating the vertebral L2 body were distributed from L1 to L6. The ratio of total double-labeled per total DiI-labeled DRG neurons was 10.2%, and that of total double-labeled per total FG-labeled DRG neurons was 14.7%. These double-labeled DRG neurons innervating the L2 vertebral body had other axons that extended to the ASIC.Conclusions: This finding provides a possible neuroanatomical explanation for referred pain in the ASIC from vertebral bodies.
    Spine 08/2013; · 2.16 Impact Factor
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    ABSTRACT: Previous studies reported that the publication rate of abstracts presented at overseas meetings was around 50 %. The study objectives were to determine the rate of publication in English-language journals and the impact factor (IF) for all papers presented at the Annual Meeting of the Japanese Orthopaedic Association (JOA) and Annual Research Meeting of the Japanese Orthopaedic Association (JOAR), and to compare the publication rates and IFs from abstracts accepted for oral versus poster presentations. Titles and first authors were identified for 1,676 abstracts of free papers accepted for presentation to the JOA in 2006 and 2007, and 1,529 abstracts to the JOAR from 2006 to 2008. We identified the associated journal publications by searching PubMed, and IFs were determined using the journal citation reports. The publication rates and IFs for papers accepted for oral versus poster presentations were compared using statistical analysis. The overall publication rate was 25.5 % from the JOA and 50 % from the JOAR. There were no significant differences in yearly publication rates, or between oral and poster presentations for each year. The average IFs for all publications from the JOA was 2.45 and that from the JOAR was 3.5. There were no significant differences in yearly IFs, or between oral and poster presentations for each year (P > 0.05). The rate from JOAR was similar to publication rates for abstracts presented at overseas orthopedic meetings, however, the rate from JOA was half that of publication rates for abstracts presented at overseas orthopedic meetings, indicating that JOA may provide a below average contribution of new medical data to the international scientific community. No significant difference in publication rates between oral and poster presentations were found, and this suggests a need for improvement of the review system for the annual meeting and that review scores at the meetings did not predict the publication fate of abstracts.
    Journal of Orthopaedic Science 07/2013; · 0.96 Impact Factor
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    ABSTRACT: Our purpose was to examine platelet-rich plasma (PRP) for its effect on bone formation and to follow the immunohistochemical changes in calcitonin gene-related peptide (CGRP) in dorsal root ganglion neurons innervating the discs as a possible index of nociceptive nerve transmission in a rat model. A total of seventy rats were used. Ten constituted a non-punctured disc sham group, while another ten rats constituted a group that underwent puncture of the L4-L5 discs. Forty rats were in experimental groups in which the L4-L5 discs were punctured; posterolateral lumbar arthrodesis was performed with PRP (the PRP group) or without the use of PRP (the normal arthrodesis group), with twenty rats in each group. The remaining ten rats were used as blood donors. Four and eight weeks after surgery, microcomputed tomography examinations were done to evaluate the amount of bone and the L4-L5 spines were harvested to evaluate bone union, followed by resection of dorsal root ganglion neurons. The percentages of Fluoro-Gold-labeled and CGRP-immunoreactive neurons were calculated. The platelet count and the concentration of growth factors in PRP were higher than those in blood (p < 0.05). The bone volumes observed in the PRP group were significantly greater than those of the normal arthrodesis group at four and eight weeks (p < 0.05). Three (30%; 95% confidence interval [CI], 6% to 65%) of ten rats in the normal arthrodesis group and eight (80%; 95% CI, 44% to 98%) of ten rats in the PRP group were considered to have bone fusion four weeks after surgery (p < 0.05). At eight weeks, seven (70%; 95% CI, 34% to 94%) of ten rats in the normal arthrodesis group and nine (90%; 95% CI, 55% to 99%) of ten rats in the PRP group were considered to have bone fusion (p = 0.27). The proportion of CGRP-immunoreactive neurons was significantly greater in the punctured group than in the other groups. There were no significant differences between the normal arthrodesis group and the PRP group. PRP appears to promote bone formation in rats and has a tendency to shorten the period of bone union in this rat model of posterolateral lumbar arthrodesis, but it did not influence the proportion of CGRP-immunoreactive neurons, a likely indicator of inflammatory pain originating from the degenerative intervertebral disc. The ability of PRP in this model suggests that it may be able to shorten the period of union and lead to an early return to social activities after treatment.
    The Journal of Bone and Joint Surgery 06/2013; 95(12):1109-16. · 3.23 Impact Factor
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    ABSTRACT: Study Design: Pain behavior and immunohistological analysis in intervertebral disk (IVD) injury model.Objective: To investigate pain behavior in a rat model of IVD injury using the CatWalk system.Summary of Background Data: There are few reports examining low back pain behavior in animal models. The CatWalk is a computer-assisted gait analysis system that provides an automated way to assess gait function and pain-related alterations of this behavior.Methods: In the IVD injury group, L5/6 IVDs were injured with a 24-gauge needle. Simultaneously, the neurotracer Fluoro-Gold (FG) was injected into the L5/6 IVDs. In the sham group, FG was injected into the L5/6 IVDs only. Animals in control group received no operation. One, 2, 3, and 4 weeks after surgery, the gait of rats in the three groups was investigated using the CatWalk system. One, 2, and 4 weeks after surgery, in IVD injury and sham groups, DRGs from the L1 to L6 levels were resected. DRGs were immunostained for CGRP.Results: In the IVD injury group, the mean stands of hind paws and the mean duty cycle of front paws at some time points were significantly higher compared with the sham group. Furthermore, the mean stride length of the front and hind paws and the mean swing speed of the front and hind paws at some time points were significantly shorter compared with the sham group. The proportion of CGRP-immunoreactive, FG-labeled neurons among all FG-labeled DRG neurons in the IVD injury group was significantly higher than the corresponding proportion in the sham group.Conclusions: These results suggest that IVD injury produced significant changes in rat gait, including longer stance phases and shorter strides. In the future, we may be able to apply the CatWalk system to the evaluation of behavior associated with pain in models of low back pain.
    Spine 05/2013; · 2.16 Impact Factor
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    ABSTRACT: BACKGROUND: Neuropathic pain is difficult to control and patient response to current treatment is often inadequate. Opioids have been widely used to treat a variety of pain states, but have several side effects. Endogenous opioids are clinically safe, but are not used for treatment because of rapid metabolism. However, in-vivo transfection of endogenous opioid genes could have a powerful and safe analgesic effect. The purpose of this study was to investigate the efficacy of proopiomelanocortin (POMC, a precursor of the endogenous opioid peptide β-endorphin) gene transfer by use of radial shock waves (RSWs) in a rat neuropathic pain model. METHODS: As a neuropathic pain model, we used the Bennett chronic constriction injury (CCI) method. Immediately after CCI induction, POMC plasmid was injected into the rats' gastrocnemius muscle followed by exposure to RSW. Mechanical allodynia was measured for 4 weeks and dorsal root ganglion (DRG) neurons were sectioned and immunostained. RESULTS: β-Endorphin blood levels and the number of β-endorphin-immunoreactive (IR) muscle fibers increased over 28 days. β-Endorphin overexpression caused a decrease in the number of calcitonin gene-related peptide (CGRP)-IR DRG neurons and suppressed neuropathic pain induced by CCI without causing adverse side effects. The size-distribution pattern of CGRP-IR DRG neurons shifted from small to large cells in the CCI group; however, the number of both small and large CGRP-IR cells decreased in the POMC group. CONCLUSION: POMC gene transfection alleviated allodynia and reduced CGRP expression in DRG neurons without adverse effects. CGRP is not produced in large neurons under physiologic conditions; however, in this study CGRP expression was shifted to large neurons after nerve injury. This change in cell-size distribution suggests that CGRP expression in large neurons is related to neuropathic pain. These findings suggest that POMC gene transfection using RSWs is a safe and effective treatment for neuropathic pain.
    Journal of Orthopaedic Science 04/2013; · 0.96 Impact Factor