研究者詳細 - 中村　雅也

論文 - 中村　雅也

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Generation and characterization of a novel shoulder contracture mouse model

Oki Satoshi, Shirasawa Hideyuki, Yoda Masaki, Matsumura Noboru, Tohmonda Takahide, Yuasa Kazuki, Nakamura Masaya, Matsumoto Morio, Horiuchi Keisuke

Journal of Orthopaedic Research 33 （ 11 ） 1732 - 1738 2015年11月

ISSN 0736-0266

Frozen shoulder is a relatively common disorder that leads to severe pain and stiffness in the shoulder joint. Although this disorder is self-limiting in nature, the symptoms often persist for years, resulting in severe disability. Recent studies using human specimens and animal models have shown distinct changes in the gene expression patterns in frozen shoulder tissue, indicating that novel therapeutic intervention could be achieved by controlling the genes that are potentially involved in the development of frozen shoulder. To achieve this goal, it is imperative to develop a reliable animal joint contracture model in which gene expression can be manipulated by gene targeting and transgenic technologies. Here, we describe a novel shoulder contracture mouse model. We found that this model mimics the clinical presentation of human frozen shoulder and recapitulates the changes in the gene expression pattern and the histology of frozen shoulder and joint contracture in humans and other larger animal models. The model is highly reproducible, without any major complications. Therefore, the present model may serve as a useful tool for investigating frozen shoulder etiology and for identifying its potential target genes.

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A Novel Percutaneous Guide Wire (S-Wire) for Percutaneous Pedicle Screw Insertion

Ishii Ken, Kaneko Yasuhito, Funao Haruki, Ishihara Shinichi, Shinohara Akira, Nakanishi Kazuo, Hikata Tomohiro, Fujita Nobuyuki, Iwanami Akio, Hosogane Naobumi, Watanabe Kota, Nagura Takeo, Nakamura Masaya, Toyama Yoshiaki, Matsumoto Morio

Surgical Innovation 22 （ 5 ） 469 - 473 2015年10月

ISSN 1553-3506

Purpose. Minimally invasive spine stabilization (MISt) procedures, including MIS-transforaminal lumbar interbody fusion (MIS-TLIF), rely on precise placement of percutaneous pedicle screws (PPS). Serious intraoperative complications associated with PPS placement include great vessel and bowel injuries due to the guide-wire's anterior migration and penetration through the anterior aspect of the vertebral body. To address this issue, we developed a novel percutaneous guide wire (S-wire) and compared the biomechanical characteristics of S-wire and conventional wire in cadaveric spines, and to evaluate the S-wire's efficacy and safety in a clinical trial. Methods. The S-wire is hollow, with braided wires extending at one tip. We compared the push-out and penetration forces of the S-wire and conventional wire in fresh cadaveric lumbar spines, from L1 to L5. Results. Push-out forces caused the braided tip of the S-wire to bend or spread, and thus to resist anterior migration. The mean push-out forces for the S-wire and conventional wire were 15.5 ± 1.9 and 5.7 ± 0.8 N, respectively (P <.0001); the mean penetration forces were 69.1 ± 4.2 and 37.1± 4.8 N, respectively (P <.0005). There was no wire breakage or anterior-wall penetration in a clinical trial of 922 S-wires; interestingly, the pull-out force increased in 780 (84.6%) S-wires after placement. Conclusions. The mean push-out and penetration forces for the S-wire were approximately 3 and 2 times greater than those of conventional wire, respectively. The S-wire effectively prevented guide-wire anterior migration and penetration of the anterior vertebral-body wall. The S-wire device should effectively improve the safety of MISt procedures, including MIS-TLIF and percutaneous kyphoplasty in selected patient with osteoporosis.

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Histological and electrophysiological analysis of the corticospinal pathway to forelimb motoneurons in common marmosets

Kondo Takahiro, Yoshihara Yamato, Yoshino-Saito Kimika, Sekiguchi Tomofumi, Kosugi Akito, Miyazaki Yuta, Nishimura Yukio, Okano Hirotaka J., Nakamura Masaya, Okano Hideyuki, Isa Tadashi, Ushiba Junichi

Neuroscience Research 98 35 - 44 2015年09月

ISSN 0168-0102

Using histological and electrophysiological methods, we identified the neuroanatomical properties of the common marmoset corticospinal tract (CST), which underlies hand/arm motor control. Biotinylated dextran amine (BDA) was injected into the primary motor cortex to anterogradely label CST axons in the cervical segments, revealing that most CST axons descend in the contralateral dorsolateral funiculus (DLF; 85.0%), and some in the ipsilateral DLF (10.7%). Terminal buttons were mainly found in the contralateral lamina VII of the gray matter, but projection to lamina IX, where forelimb motoneurons are located, was rare. Bilateral projections were more abundant than found in the rat CST, resembling the CST organization of other primates. Intracellular recordings were made from 57 forelimb motoneurons on the contralateral side to stimulation, which revealed no monosynaptic excitatory postsynaptic potentials (EPSPs), but di- or polysynaptic EPSPs and inhibitory synaptic potentials were commonly found. Local field potentials showed monosynaptic excitation mainly in laminae VII, where abundant BDA-labeled CST terminals were observed. These results suggest that direct corticomotoneuronal projection is absent in common marmosets but di- or oligosynaptic effects would be mediated by spinal interneurons.

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BDNF Induced by Treadmill Training Contributes to the Suppression of Spasticity and Allodynia After Spinal Cord Injury via Upregulation of KCC2

Tashiro Syoichi, Shinozaki Munehisa, Mukaino Masahiko, Renault-Mihara François, Toyama Yoshiaki, Liu Meigen, Nakamura Masaya, Okano Hideyuki

Neurorehabilitation and Neural Repair 29 （ 7 ） 677 - 689 2015年08月

ISSN 1545-9683

Background. Spasticity and allodynia are major sequelae that affect the quality of life and daily activities of spinal cord injury (SCI) patients. Although rehabilitation ameliorates spasticity and allodynia, the molecular mechanisms involved in these processes remain elusive. Objective. To investigate the molecular mechanisms by which rehabilitation ameliorates spasticity and allodynia after SCI in rats. Methods. The expression levels of brain-derived neurotrophic factor (BDNF) and potassium-chloride cotransporter-2 (KCC2), as well as the localization of KCC2, were examined in the lumbar enlargements of untrained and treadmill-trained thoracic SCI model rats. Spasticity and allodynia were determined via behavioral and electrophysiological analyses. The effects of BDNF on spasticity, allodynia, and KCC2 activation were determined by inhibition of BDNF signaling via intrathecal administration of TrkB-IgG. The effects of SCI and training on the expression levels of functional phospholipase C-γ in the lumbar enlargement were also examined. Results. Treadmill training after SCI upregulated endogenous BDNF expression and posttranslational modification of KCC2 in the lumbar enlargement significantly. There were also significant correlations between increased KCC2 expression and ameliorated spasticity and allodynia. Administration of TrkB-IgG abrogated the training-induced upregulation of KCC2 and beneficial effects on spasticity and allodynia. The expression level of functional phospholipase C-γ was reduced significantly after SCI, which may have contributed to the change in the function of BDNF, whereby it did not trigger short-term downregulation or induce long-term upregulation of KCC2 expression secondary to training. Conclusions. BDNF-mediated restoration of KCC2 expression underlies the suppression of spasticity and allodynia caused by rehabilitation.

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Migration and differentiation of transplanted enteric neural crest-derived cells in murine model of Hirschsprung’s disease

Nishikawa Ryuhei, Hotta Ryo, Shimojima Naoki, Shibata Shinsuke, Nagoshi Narihito, Nakamura Masaya, Matsuzaki Yumi, Okano Hirotaka J., Kuroda Tatsuo, Okano Hideyuki, Morikawa Yasuhide

Cytotechnology 67 （ 4 ） 661 - 670 2015年08月

ISSN 0920-9069

Stem cell therapy offers the potential of rebuilding the enteric nervous system (ENS) in the aganglionic bowel of patients with Hirschsprung’s disease. P0-Cre/Floxed-EGFP mice in which neural crest-derived cells express EGFP were used to obtain ENS stem/progenitor cells. ENS stem/progenitor cells were transplanted into the bowel of Ret−/− mouse, an animal model of Hirschsprung’s disease. Immunohistochemical analysis was performed to determine whether grafted cells gave rise to neurons in the recipient bowel. EGFP expressing neural crest-derived cells accounted for 7.01 ± 2.52 % of total cells of gastrointestinal tract. ENS stem/progenitor cells were isolated using flow cytometry and expanded as neurosphere-like bodies (NLBs) in a serum-free culture condition. Some cells in NLBs expressed neural crest markers, p75 and Sox10 and neural stem/progenitor cells markers, Nestin and Musashi1. Multipotency of isolated ENS stem/progenitor cells was determined as they differentiated into neurons, glial cells, and myofibloblasts in culture. When co-cultured with explants of hindgut of Ret−/− mice, ENS stem/progenitor cells migrated into the aganglionic bowel and gave rise to neurons. ENS stem/progenitor cells used in this study appear to be clinically relevant donor cells in cell therapy to treat Hirschsprung’s disease capable of colonizing the affected bowel and giving rise to neurons.

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Effects of femoral bone tunnel characteristics on graft-bending angle in double-bundle anterior cruciate ligament reconstruction

Niki Yasuo, Nagai Katsuya, Harato Kengo, Suda Yasunori, Nakamura Masaya, Matsumoto Morio

Knee Surgery, Sports Traumatology, Arthroscopy 2015年08月

ISSN 0942-2056

Purpose: Bone tunnel creation techniques influence the 3-dimensional (3D) position of bone tunnels and graft-bending angle in anterior cruciate ligament (ACL) reconstruction. This study assessed graft-bending angle and 3D characteristics of femoral bone tunnels and compared them between outside-in (OI) and transportal (TP) techniques. Methods: Participants comprised 64 patients who underwent anatomic double-bundle ACL reconstruction, allocated to OI and TP groups (n = 32 each). The graft orientation plane exhibiting the largest graft-bending angle at the femoral tunnel aperture with the knee in extension was reconstructed from CT data using 3D imaging software. In this plane, graft-bending angle was compared between the OI and TP techniques. Results: Although positionings of the intra-articular apertures of the femoral and tibial bone tunnels were similar, several spatial parameters of bone tunnels differed between techniques. Graft-bending angles of both anteromedial and posterolateral bundles were significantly more acute with the OI technique than with the TP technique. On coronal-plane CT, angle of the bone tunnel axis relative to the distal condylar axis correlated negatively with graft-bending angle, while in the axial plane, angle of the bone tunnel axis relative to the posterior condylar axis correlated positively with graft-bending angle. Lysholm score, pivot shift test, and anteroposterior laxity at >2.5-year follow-up demonstrated no significant differences between techniques. Discussion: Different bone tunnel directions in OI and TP techniques substantially affected graft-bending angle, despite similar positionings of the intra-articular apertures. Graft-bending angle with the OI technique was acute, but risk of posterior blowout of the lateral femoral condyle was decreased. Surgeons should create the femoral tunnel while considering an obtuse graft-bending angle without increasing the risk of posterior blowout. Level of evidence: III.

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Comparison of surgical treatments for triple extensor tendon ruptures in rheumatoid hands

Suzuki Taku, Iwamoto Takuji, Ikegami Hiroyasu, Sakuma Y., Ikari Katsunori, Matsumura Noboru, Ochi Kensuke, Sato Kazuki, Nakamura Masaya, Matsumoto Morio, Momohara Shigeki

Modern Rheumatology 2015年08月

ISSN 1439-7595

Objective. This retrospective study was designed to evaluate the outcomes of four different surgical reconstructions for extensor tendon ruptures in ulnar three fingers in 48 patients with rheumatoid arthritis. Methods. The following four techniques were performed; palmaris longus tendon grafting (PL group; n = 9), extensor indicis proprius (EIP) tendon transfers (EIP group; n = 8), end-to-side transfers with tension-reduced early mobilization (End-to-side group; n = 16), and a combination of end-to-side and EIP transfers (Combination group; n = 15). Loss of extension was evaluated to determine the mean postoperative range of motion of the metacarpophalangeal (MP) joint and clinical outcomes were categorized using modified Geldmacher criteria. Results. Combination group demonstrated the best mean MP joint extension (− 3°), followed by End-to-side group (− 12°), EIP group (− 16°), and PL group (− 21°). Combination group yielded the best clinical outcomes with all cases showing good results. Conclusions. The combination of end-to-side and EIP transfer was an effective surgical reconstruction procedure for triple fingers extension loss.

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IRE1α/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis

Tohmonda Takahide, Yoda Masaki, Iwawaki Takao, Matsumoto Morio, Nakamura Masaya, Mikoshiba Katsuhiko, Toyama Yoshiaki, Horiuchi Keisuke

Journal of Clinical Investigation 125 （ 8 ） 3269 - 3279 2015年08月

ISSN 0021-9738

The unfolded protein response (UPR) is a cellular adaptive mechanism that is activated in response to the accumulation of unfolded proteins in the endoplasmic reticulum. The inositol-requiring protein-1α/X-box-binding protein-mediated (IRE1α/ XBP1-mediated) branch of the UPR is highly conserved and has also been shown to regulate various cell-fate decisions. Herein, we have demonstrated a crucial role for the IREα/XBP1-mediated arm of the UPR in osteoclast differentiation. Using murine models, we found that the conditional abrogation of IRE1α in bone marrow cells increases bone mass as the result of defective osteoclastic bone resorption. In osteoclast precursors, IRE1α was transiently activated during osteoclastogenesis, and suppression of the IRE1α/XBP1 pathway in these cells substantially inhibited the formation of multinucleated osteoclasts in vitro. We determined that XBP1 directly binds the promoter and induces transcription of the gene encoding the master regulator of osteoclastogenesis nuclear factor of activated T cells cytoplasmic 1 (NFATc1). Moreover, activation of IRE1α was partially dependent on Ca2+ oscillation mediated by inositol 1,4,5-trisphosphate receptors 2 and 3 (ITPR2 and ITPR3) in the endoplasmic reticulum, as pharmacological inhibition or deletion of these receptors markedly decreased Xbp1 mRNA processing. The present study thus reveals an intracellular pathway that integrates the UPR and osteoclast differentiation through activation of the IRE1α/XBP1 pathway.

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Control of the survival and growth of human glioblastoma grafted into the spinal cord of mice by taking advantage of immunorejection

Itakura Go, Kobayashi Yoshiomi, Nishimura Soraya, Iwai Hiroki, Takano Morito, Iwanami Akio, Toyama Yoshiaki, Okano Hideyuki, Nakamura Masaya

Cell Transplantation 24 （ 7 ） 1299 - 1311 2015年07月

ISSN 0963-6897

Recent studies have demonstrated that transplantation of induced pluripotent stem cell-derived neurospheres can promote functional recovery after spinal cord injury in rodents, as well as in nonhuman primates. However, the potential tumorigenicity of the transplanted cells remains a matter of apprehension prior to clinical applications. As a first step to overcome this concern, this study established a glioblastoma multiforme xenograft model mouse. The feasibility of controlling immune suppression to ablate the grafted cells was then investigated. The human glioblastoma multiforme cell line U251 MG was transplanted into the intact spinal cords of immunodeficient NOD/SCID mice or into those of immunocompetent C57BL/6J H-2kb mice treated with or without immunosuppressants [FK506 plus anticluster of differentiation (CD) 4 antibody (Ab), or FK506 alone]. In vivo bioluminescent imaging was used to evaluate the chronological survival of the transplanted cells. The graft survival rate was 100% (n = 9/9) in NOD/SCID mice, 0% (n = 6/6) in C57BL/6J mice without immunosuppressant treatment, and 100% (n = 37/37) in C57BL6/J mice with immunosuppressant treatment. After confirming the growth of the grafted cells in the C57/BL6J mice treated with immunosuppressants, immune suppression was discontinued. The grafted cells were subsequently rejected within 3 days in C57BL/6J mice treated with FK506 alone, as opposed to 26 days in C57BL/6J mice treated with FK506 plus anti-CD4 Ab. Histological evaluation confirmed the ablation of the grafted cells. Although this work describes a xenograft setting, the results suggest that this immunomodulatory strategy could provide a safety lock against tumor formation stemming from transplanted cells.

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Hyperglycemia promotes Schwann cell de-differentiation and de-myelination via sorbitol accumulation and Igf1 protein down-regulation

Hao Wu, Tashiro Syoichi, Hasegawa Tomoka, Sato Yuiko, Kobayashi Tami, Tando Toshimi, Katsuyama Eri, Fujie Atsuhiro, Watanabe Ryuichi, Morita Mayu, Miyamoto Kana, Morioka Hideo, Nakamura Masaya, Matsumoto Morio, Amizuka Norio, Toyama Yoshiaki, Miyamoto Takeshi

Journal of Biological Chemistry 290 （ 28 ） 17106 - 17115 2015年07月

ISSN 0021-9258

Diabetes mellitus (DM) is frequently accompanied by complications, such as peripheral nerve neuropathy. Schwann cells play a pivotal role in regulating peripheral nerve function and conduction velocity; however, changes in Schwann cell differentiation status in DM are not fully understood. Here, we report that Schwann cells de-differentiate into immature cells under hyperglycemic conditions as a result of sorbitol accumulation and decreased Igf1 expression in those cells. We found that dedifferentiated Schwann cells could be re-differentiated in vitro into mature cells by treatment with an aldose reductase inhibitor, to reduce sorbitol levels, or with vitaminD<inf>3</inf>, to elevate Igf1 expression. In vivo DM models exhibited significantly reduced nerve function and conduction, Schwann cell de-differentiation, peripheral nerve de-myelination,andall conditionsweresignificantly rescued by aldose reductase inhibitor or vitamin D<inf>3</inf> administration. These findings reveal mechanisms underlying pathological changes in Schwann cells seen in DM and suggest ways to treat neurological conditions associated with this condition.

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Allogeneic neural stem/progenitor cells derived from embryonic stem cells promote functional recovery after transplantation into injured spinal cord of nonhuman primates

Iwai Hiroki, Shimada Hiroko, Nishimura Soraya, Kobayashi Yoshiomi, Itakura Go, Hori Keiko, Hikishima Keigo, Ebise Hayao, Negishi Naoko, Shibata Shinsuke, Habu Sonoko, Toyama Yoshiaki, Nakamura Masaya, Okano Hideyuki

Stem Cells Translational Medicine 4 （ 7 ） 708 - 719 2015年07月

ISSN 2157-6564

Previous studies have demonstrated that neural stem/progenitor cells (NS/PCs) promote functional recovery in rodent animal models of spinal cord injury (SCI). Because distinct differences exist in the neuroanatomy and immunological responses between rodents and primates, it is critical to determine the effectiveness and safety of allografted embryonic stem cell (ESC)-derived NS/PCs (ESC-NS/PCs) in a nonhuman primate SCI model. In the present study, common marmoset ESC-NS/PCs were grafted into the lesion epicenter 14 days after contusive SCI in adult marmosets (transplantation group). In the control group, phosphate-buffered saline was injected instead of cells. In the presence of a low-dose of tacrolimus, several grafted cells survived without tumorigenicity and differentiated into neurons, astrocytes, or oligodendrocytes. Significant differences were found in the transverse areas of luxol fast blue-positive myelin sheaths, neurofilament-positive axons, corticospinal tract fibers, and platelet endothelial cell adhesion molecule-1-positive vessels at the lesion epicenter between the transplantation and control groups. Immunoelectron microscopic examination demonstrated that the grafted ESC-NS/PC-derived oligodendrocytes contributed to the remyelination of demyelinated axons. In addition, some grafted neurons formed synaptic connections with host cells, and some transplanted neurons were myelinated by host cells. Eventually, motor functional recovery significantly improved in the transplantation group compared with the control group. In addition, a mixedlymphocyte reaction assay indicated that ESC-NS/PCs modulated the allogeneic immune rejection. Taken together, our results indicate that allogeneic transplantation of ESC-NS/PCs from a nonhuman primate promoted functional recovery after SCI without tumorigenicity.

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Synergistic antiproliferative effect of imatinib and adriamycin in platelet-derived growth factor receptor-expressing osteosarcoma cells

Yamaguchi Sayaka I., Ueki Arisa, Sugihara Eiji, Onishi Nobuyuki, Yaguchi Tomonori, Kawakami Yutaka, Horiuchi Keisuke, Morioka Hideo, Matsumoto Morio, Nakamura Masaya, Muto Akihiro, Toyama Yoshiaki, Saya Hideyuki, Shimizu Takatsune

Cancer Science 106 （ 7 ） 875 - 882 2015年07月

ISSN 1347-9032

Osteosarcoma (OS) is the most frequent primary solid malignant tumor of bone. Its prognosis remains poor in the substantial proportion of patients who do not respond to chemotherapy and novel therapeutic options are therefore needed. We previously established a mouse model that mimics the aggressive behavior of human OS. Enzyme-linked immunosorbent assay-based screening of such mouse tumor lysates identified platelet-derived growth factor-BB (PDGF-BB) as an abundant soluble factor, the gene for which was expressed dominantly in surrounding non-malignant cells of the tumor, whereas that for the cognate receptor (PDGF receptor β) was highly expressed in OS cells. Platelet-derived growth factor-BB induced activation of both MEK-ERK and phosphatidylinositol 3-kinase-protein kinase B signaling pathways and promoted survival in OS cells deprived of serum, and these effects were blocked by the PDGF receptor inhibitor imatinib. However, these actions of PDGF-BB and imatinib were mostly masked in the presence of serum. Whereas imatinib alone did not manifest an antitumor effect in mice harboring OS tumors, combined treatment with imatinib and adriamycin exerted a synergistic antiproliferative effect on OS cells in vivo. These results suggest that treatment of OS with imatinib is effective only when cell survival is dependent on PDGF signaling or when imatinib is combined with another therapeutic intervention that renders the tumor cells susceptible to imatinib action, such as by inducing cellular stress.

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Long-term safety issues of iPSC-based cell therapy in a spinal cord injury model

Nori Satoshi, Okada Yohei, Nishimura Soraya, Sasaki Takashi, Itakura Go, Kobayashi Yoshiomi, Renault-Mihara Francois, Shimizu Atsushi, Koya Ikuko, Yoshida Rei, Kudoh Jun, Koike Masato, Uchiyama Yasuo, Ikeda Eiji, Toyama Yoshiaki, Nakamura Masaya, Okano Hideyuki

Stem Cell Reports 4 （ 3 ） 360 - 373 2015年03月

ISSN 2213-6711

Previously, we described the safety and therapeutic potential of neurospheres (NSs) derived from a human induced pluripotent stem cell (iPSC) clone, 201B7, in a spinal cord injury (SCI) mouse model. However, several safety issues concerning iPSC-based cell therapy remain unresolved. Here, we investigated another iPSC clone, 253G1, that we established by transducing OCT4, SOX2, and KLF4 into adult human dermal fibroblasts collected from the same donor who provided the 201B7 clone. The grafted 253G1-NSs survived, differentiated into three neural lineages, and promoted functional recovery accompanied by stimulated synapse formation 47 days after transplantation. However, long-term observation (for up to 103 days) revealed deteriorated motor function accompanied by tumor formation. The tumors consisted of Nestin⁺ undifferentiated neural cells and exhibited activation of the OCT4 transgene. Transcriptome analysis revealed that a heightened mesenchymal transition may have contributed to the progression of tumors derived from grafted cells.

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Breast carcinoma metastasis to meningioma in the thoracic spine

Okada Eijiro, Nakamura Masaya, Koshida Yoshitomo, Mukai Kiyoshi, Toyama Yoshiaki, Matsumoto Morio

Journal of Spinal Cord Medicine 38 （ 2 ） 231 - 235 2015年03月

ISSN 1079-0268

Context: Systemic metastasis to a primary tumor of the central nervous system is uncommon. Breast carcinomas metastasizing to a possibly preexisting meningioma in the spine are reported very rarely. Study design: Case report. Findings: A 69-year-old female was referred to us with progressive gait disturbance. She had undergone a total mastectomy for carcinoma of the right breast 11 years previously. A magnetic resonance imaging of the thoracic spine showed an intra- and extradural spinal cord tumor. The patient underwent resection of the tumor via laminectomy from T2 to T4. After the operation, the patient's neurological status improved significantly, and she was able to walk without assistance. Histological examination showed the tumor to be a fibrous-type meningioma within a metastatic breast cancer tumor. The patient underwent 40 Gy radiation treatment for local control of the tumor. However, the tumor recurred locally 7 months after the surgery. The patient died of carcinomatous pleurisy 13 months after the surgery. Conclusion: This case illustrates that a primary meningioma in the thoracic spine can be a recipient of breast cancer metastasis, which may alter the treatment strategy.

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Controlling immune rejection is a fail-safe system against potential tumorigenicity after human iPSC-derived neural stem cell transplantation

Itakura Go, Kobayashi Yoshiomi, Nishimura Soraya, Iwai Hiroki, Takano Morito, Iwanami Akio, Toyama Yoshiaki, Okano Hideyuki, Nakamura Masaya

PLoS ONE 10 （ 2 ） 2015年02月

Our previous work reported functional recovery after transplantation of mouse and human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) into rodent models of spinal cord injury (SCI). Although hiPSC-NS/PCs proved useful for the treatment of SCI, the tumorigenicity of the transplanted cells must be resolved before they can be used in clinical applications. The current study sought to determine the feasibility of ablation of the tumors formed after hiPSC-NS/PC transplantation through immunoregulation. Tumorigenic hiPSC-NS/PCs were transplanted into the intact spinal cords of immunocompetent BALB/cA mice with or without immunosuppressant treatment. In vivo bioluminescence imaging was used to evaluate the chronological survival and growth of the transplanted cells. The graft survival rate was 0% in the group without immunosuppressants versus 100% in the group with immunosuppressants. Most of the mice that received immunosuppressants exhibited hindlimb paralysis owing to tumor growth at 3 months after iPSC-NS/PC transplantation. Histological analysis showed that the tumors shared certain characteristics with low-grade gliomas rather than with teratomas. After confirming the progression of the tumors in immunosuppressed mice, the immunosuppressant agents were discontinued, resulting in the complete rejection of iPSC-NS/PC-derived masses within 42 days after drug cessation. In accordance with the tumor rejection, hind-limb motor function was recovered in all of the mice. Moreover, infiltration of microglia and lymphocytes was observed during the course of tumor rejection, along with apoptosis of iPSC-NS/PC-generated cells. Thus, immune rejection can be used as a fail-safe system against potential tumorigenicity after transplantation of iPSC-NS/PCs to treat SCI.

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Effects of Reduction Osteotomy on Gap Balancing During Total Knee Arthroplasty for Severe Varus Deformity

Niki Yasuo, Harato Kengo, Nagai Katsuya, Suda Yasunori, Nakamura Masaya, Matsumoto Morio

Journal of Arthroplasty 2015年01月

ISSN 0883-5403

This study aimed to assess the effects of down-sizing and lateralizing of the tibial component (reduction osteotomy) on gap balancing in TKA, and the clinical feasibility of an uncemented modular trabecular metal tibial tray in this technique. Reduction osteotomy was performed for 39 knees of 36 patients with knee OA with a mean tibiofemoral angle of 21° varus. In 20 knees, appropriate gap balance was achieved by release of the deep medial collateral ligament alone. Flexion gap imbalance could be reduced by approximately 1.7° and 2.8° for 4-mm osteotomy and 8-mm osteotomy, respectively. Within the first postoperative year, clinically-stable tibial component subsidence was observed in 9 knees, but it was not progressive, and the clinical results were excellent at a mean follow-up of 3.3years.

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Neural stem/progenitor cell-laden microfibers promote transplant survival in a mouse transected spinal cord injury model

Sugai Keiko, Nishimura Soraya, Kato-Negishi Midori, Onoe Hiroaki, Iwanaga Shintaroh, Toyama Yoshiaki, Matsumoto Morio, Takeuchi Shoji, Okano Hideyuki, Nakamura Masaya

Journal of Neuroscience Research 2015年

ISSN 0360-4012

Previous studies have demonstrated that transplantation of neural stem/progenitor cells (NS/PCs) into the lesioned spinal cord can promote functional recovery following incomplete spinal cord injury (SCI) in animal models. However, this strategy is insufficient following complete SCI because of the gap at the lesion epicenter. To obtain functional recovery in a mouse model of complete SCI, this study uses a novel collagen-based microfiber as a scaffold for engrafted NS/PCs. We hypothesized that the NS/PC-microfiber combination would facilitate lesion closure as well as transplant survival in the transected spinal cord. NS/PCs were seeded inside the novel microfibers, where they maintained their capacity to differentiate and proliferate. After transplantation, the stumps of the transected spinal cord were successfully bridged by the NS/PC-laden microfibers. Moreover, the transplanted cells migrated into the host spinal cord and differentiated into three neural lineages (astrocytes, neurons, and oligodendrocytes). However, the NS/PC-laden scaffold could not achieve a neural connection between the rostral end of the injury and the intact caudal area of the spinal cord, nor could it achieve recovery of motor function. To obtain optimal functional recovery, a microfiber design with a modified composition may be useful. Furthermore, combinatorial therapy with rehabilitation and/or medications should also be considered for practical success of biomaterial/cell transplantation-based approaches to regenerative medicine.

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Reply to letter to the editor by Toda

Nakamura Masaya, Ushida Takahiro, Toyama Yoshiaki

Journal of Orthopaedic Science 19 （ 6 ） 1057 2014年11月

ISSN 0949-2658

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Regeneration of the damaged central nervous system through reprogramming technology

Matsui Takeshi, Akamatsu Wado, Nakamura Masaya, Okano Hideyuki

Experimental Neurology 260 12 - 18 2014年10月

ISSN 0014-4886

Neural stem cell (NSC) transplantation provides a new approach for the repair of damage to the central nervous system (CNS), including that resulting from cerebral infarction and spinal cord injury (SCI). In the past, there were no reputable means of converting non-neural somatic cells into neural cells. This status was overturned by the establishment of induced pluripotent stem (iPS) cells, which have pluripotency akin to that of embryonic stem (ES) cells and can differentiate into most cells of the three germ layers. If differentiated somatic cells could be reprogrammed into iPS cells, and if these iPS cells could be induced to differentiate once again, it would be theoretically possible to obtain a large number of neural cells. However, this is not yet feasible due to the limitations of existing stem cell technology. Induction of neural cells from iPS cells is currently hindered by two distinct problems: 1) the preparation of specific types of targeted neural cells requires extensive cell culture, and 2) tumors are likely to form due to the presence of residual undifferentiated cells following transplantation of the induced cells. By contrast, direct induction methods permit the generation of target cells from somatic cells without the transitional iPS cell stage. This review outlines the present-day status of research surrounding the direct induction of NSCs from somatic cells, as well as the perspectives for the future clinical application of this technique for cell replacement therapy following CNS injury.

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Focal transplantation of human iPSC-derived glial-rich neural progenitors improves lifespan of ALS mice

Kondo Takayuki, Funayama Misato, Tsukita Kayoko, Hotta Akitsu, Yasuda Akimasa, Nori Satoshi, Kaneko Shinjiro, Nakamura Masaya, Takahashi Ryosuke, Okano Hideyuki, Yamanaka Shinya, Inoue Haruhisa

Stem Cell Reports 3 （ 2 ） 242 - 249 2014年08月

ISSN 2213-6711

Transplantation of glial-rich neural progenitors has been demonstrated to attenuate motor neuron degeneration and disease progression in rodent models of mutant superoxide dismutase 1 (SOD1)-mediated amyotrophic lateral sclerosis (ALS). However, translation of these results into a clinical setting requires a renewable human cell source. Here, we derived glial-rich neural progenitors from human iPSCs and transplanted them into the lumbar spinal cord of ALS mouse models. The transplanted cells differentiated into astrocytes, and the treated mouse group showed prolonged lifespan. Our data suggest a potential therapeutic mechanism via activation of AKT signal. The results demonstrated the efficacy of cell therapy for ALS by the use of human iPSCs as cell source. © 2014 The Authors.

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Major complications and sequelae after total en bloc spondylectomy for malignant spinal tumors

Matsumoto Morio, Hikata Tomohiro, Iwanami Akio, Hosogane Naobumi, Watanabe Kota, Ishii Ken, Nakamura Masaya, Toyama Yoshiaki

Neurosurgery Quarterly 2014年07月

ISSN 1050-6438

This retrospective study looked at 33 consecutive patients with malignant, aggressive tumors in the thoracic and lumbar spine who underwent TES (24 men and 9 women; mean age 49.9 years; mean follow-up 3.6 years; 14 primary tumors and 19 metastatic tumors). TES was performed by a posterior-only approach in 15 patients and by a combined anterior and posterior approach in 18 patients. We classified complications as intraoperative, early (within 1 month after surgery), or late (>1 month after surgery), and examined the relationships between major complications and potentially related factors. Ten died of disease at 22.3 months after TES. Local recurrence was observed in 8 patients (24%) at an average of 15.4 months. Thirty-one major complications occurred in 24 patients (72.7%). There were 3 intraoperative, 17 early, and 11 late complications. Intraoperative complications included injury to the segmental artery, to the aorta, and to the spinal cord in 1 patient each. Early complications included prolonged chest tube drainage, cerebrospinal fluid leakage, and monoplegia due to the severing of nerve roots in 3 patients each, and pulmonary embolism, recurrent nerve palsy, pneumonia, endplate fracture, implant dislodgement, gastric ulcer, and ileus in 1 patient each. Late complications included implant failures in 8 patients and infection in 3 patients. Major complications were significantly associated with major blood loss (P=0.047). TES was frequently associated with major intraoperative, early, and late postoperative complications; most complications were managed successfully.

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Intramedullary cervicothoracic subependymoma

Wu Zhiwei, Iwanami Akio, Yasuda Akimasa, Mikami Shuji, Toyama Yoshiaki, Nakamura Masaya

Journal of Orthopaedic Science 20 （ 5 ） 927 - 934 2014年05月

ISSN 0949-2658

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Surgeons' exposure to radiation in single- and multi- level minimally invasive transforaminal lumbar interbody fusion; a prospective study

Funao Haruki, Ishii Ken, Momoshima Suketaka, Iwanami Akio, Hosogane Naobumi, Watanabe Kota, Nakamura Masaya, Toyama Yoshiaki, Matsumoto Morio

PLoS ONE 9 （ 4 ） 2014年04月

Although minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) has widely been developed in patients with lumbar diseases, surgeons risk exposure to fluoroscopic radiation. However, to date, there is no studies quantifying the effective dose during MIS-TLIF procedure, and the radiation dose distribution is still unclear. In this study, the surgeons' radiation doses at 5 places on the bodies were measured and the effective doses were assessed during 31 consecutive 1- to 3-level MIS-TLIF surgeries. The operating surgeon, assisting surgeon, and radiological technologist wore thermoluminescent dosimeter on the unshielded thyroid, chest, genitals, right middle finger, and on the chest beneath a lead apron. The doses at the lens and the effective doses were also calculated. Mean fluoroscopy times were 38.7, 53.1, and 58.5 seconds for 1, 2, or 3 fusion levels, respectively. The operating surgeon's mean exposures at the lens, thyroid, chest, genitals, finger, and the chest beneath the shield, respectively, were 0.07, 0.07, 0.09, 0.14, 0.32, and 0.05 mSv in 1-level MIS-TLIF; 0.07, 0.08, 0.09, 0.18, 0.34, and 0.05 mSv in 2-level; 0.08, 0.09, 0.14, 0.15, 0.36, and 0.06 mSv in 3-level; and 0.07, 0.08, 0.10, 0.15, 0.33, and 0.05 mSv in all cases. Mean dose at the operating surgeon's right finger was significantly higher than other measurements parts (P,0.001). The operating surgeon's effective doses (0.06, 0.06, and 0.07 mSv for 1, 2, and 3 fusion levels) were low, and didn't differ significantly from those of the assisting surgeon or radiological technologist. Revision MIS-TLIF was not associated with higher surgeons' radiation doses compared to primary MIS-TLIF. There were significantly higher surgeons' radiation doses in over-weight than in normal-weight patients. The surgeons' radiation exposure during MIS-TLIF was within the safe level by the International Commission on Radiological Protection's guidelines. The accumulated radiation exposure, especially to surgeon's hands, should be carefully monitored. © 2014 Funao et al.

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Rewiring of regenerated axons by combining treadmill training with semaphorin3A inhibition

Zhang Liang, Kaneko Shinjiro, Kikuchi Kaoru, Sano Akihiko, Maeda Miho, Kishino Akiyoshi, Shibata Shinsuke, Mukaino Masahiko, Toyama Yoshiaki, Liu Meigen, Kimura Toru, Okano Hideyuki, Nakamura Masaya

Molecular Brain 7 （ 1 ） 2014年03月

Background: Rats exhibit extremely limited motor function recovery after total transection of the spinal cord (SCT). We previously reported that SM-216289, a semaphorin3A inhibitor, enhanced axon regeneration and motor function recovery in SCT adult rats. However, these effects were limited because most regenerated axons likely do not connect to the right targets. Thus, rebuilding the appropriate connections for regenerated axons may enhance recovery. In this study, we combined semaphorin3A inhibitor treatment with extensive treadmill training to determine whether combined treatment would further enhance the "rewiring" of regenerated axons. In this study, which aimed for clinical applicability, we administered a newly developed, potent semaphorin3A inhibitor, SM-345431 (Vinaxanthone), using a novel drug delivery system that enables continuous drug delivery over the period of the experiment. Results: Treatment with SM-345431 using this delivery system enhanced axon regeneration and produced significant, but limited, hindlimb motor function recovery. Although extensive treadmill training combined with SM-345431 administration did not further improve axon regeneration, hindlimb motor performance was restored, as evidenced by the significant improvement in the execution of plantar steps on a treadmill. In contrast, control SCT rats could not execute plantar steps at any point during the experimental period. Further analyses suggested that this strategy reinforced the wiring of central pattern generators in lumbar spinal circuits, which, in turn, led to enhanced motor function recovery (especially in extensor muscles). Conclusions: This study highlights the importance of combining treatments that promote axon regeneration with specific and appropriate rehabilitations that promote rewiring for the treatment of spinal cord injury. © 2014 Zhang et al.; licensee BioMed Central Ltd.

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Inflammatory cascades mediate synapse elimination in spinal cord compression

Takano Morito, Kawabata Soya, Komaki Yuji, Shibata Shinsuke, Hikishima Keigo, Toyama Yoshiaki, Okano Hideyuki, Nakamura Masaya

Journal of Neuroinflammation 11 2014年03月

Background: Cervical compressive myelopathy (CCM) is caused by chronic spinal cord compression due to spondylosis, a degenerative disc disease, and ossification of the ligaments. Tip-toe walking Yoshimura (twy) mice are reported to be an ideal animal model for CCM-related neuronal dysfunction, because they develop spontaneous spinal cord compression without any artificial manipulation. Previous histological studies showed that neurons are lost due to apoptosis in CCM, but the mechanism underlying this neurodegeneration was not fully elucidated. The purpose of this study was to investigate the pathophysiology of CCM by evaluating the global gene expression of the compressed spinal cord and comparing the transcriptome analysis with the physical and histological findings in twy mice. Methods: Twenty-week-old twy mice were divided into two groups according to the magnetic resonance imaging (MRI) findings: a severe compression (S) group and a mild compression (M) group. The transcriptome was analyzed by microarray and RT-PCR. The cellular pathophysiology was examined by immunohistological analysis and immuno-electron microscopy. Motor function was assessed by Rotarod treadmill latency and stride-length tests. Results: Severe cervical calcification caused spinal canal stenosis and low functional capacity in twy mice. The microarray analysis revealed 215 genes that showed significantly different expression levels between the S and the M groups. Pathway analysis revealed that genes expressed at higher levels in the S group were enriched for terms related to the regulation of inflammation in the compressed spinal cord. M1 macrophage-dominant inflammation was present in the S group, and cysteine-rich protein 61 (Cyr61), an inducer of M1 macrophages, was markedly upregulated in these spinal cords. Furthermore, C1q, which initiates the classical complement cascade, was more upregulated in the S group than in the M group. The confocal and electron microscopy observations indicated that classically activated microglia/macrophages had migrated to the compressed spinal cord and eliminated synaptic terminals. Conclusions: We revealed the detailed pathophysiology of the inflammatory response in an animal model of chronic spinal cord compression. Our findings suggest that complement-mediated synapse elimination is a central mechanism underlying the neurodegeneration in CCM. © 2014 Takano et al.; licensee BioMed Central Ltd.

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Distinct roles of endogenous vascular endothelial factor receptor 1 and 2 in neural protection after spinal cord injury

Shinozaki Munehisa, Nakamura Masaya, Konomi Tsunehiko, Kobayashi Yoshiomi, Takano Morito, Saito Nobuhito, Toyama Yoshiaki, Okano Hideyuki

Neuroscience Research 78 （ 1 ） 55 - 64 2014年01月

ISSN 0168-0102

Secondary degeneration after spinal cord injury (SCI) is caused by increased vascular permeability, infiltration of inflammatory cells, and subsequent focal edema. Therapeutic interventions using neurotrophic factors have focused on the prevention of such reactions to reduce cell death and promote tissue regeneration. Vascular endothelial growth factor (VEGF) is a potent angiogenic and vascular permeability factor. However, the effect of VEGF on SCI remains controversial. VEGF signaling is primarily regulated through two primary receptors, VEGF receptor 1 (VEGF-R1) and VEGF receptor 2 (VEGF-R2). The purpose of this study was to examine the effects of intraperitoneal administration of VEGF-R1- and VEGF-R2-neutralizing antibodies on a mouse model of SCI. VEGF-R1 blockade, but not VEGF-R2 blockade, decreased the permeability and infiltration of inflammatory cells, and VEGF-R2 blockade caused a significant increase in neuronal apoptosis in the acute phase of SCI. VEGF-R2 blockade decreased the residual tissue area and the number of neural fibers in the chronic phase of SCI. VEGF-R2 blockade worsened the functional recovery and prolonged the latency of motor evoked potentials. These data suggest that endogenous VEGF-R2 plays a crucial role in neuronal protection after SCI. © 2013 Elsevier Ireland Ltd and the Japan Neuroscience Society.

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Perioperative factors affecting the occurrence of acute complex regional pain syndrome following limb bone fracture surgery

Sumitani Masahiko, Yasunaga Hideo, Uchida Kanji, Horiguchi Hiromasa, Nakamura Masaya, Ohe Kazuhiko, Fushimi Kiyohide, Matsuda Shinya, Yamada Yoshitsugu

Rheumatology (United Kingdom) 53 （ 7 ） 1186 - 1193 2014年

ISSN 1462-0324

Objective: Complex regional pain syndrome (CRPS) describes a broad spectrum of symptoms that predominantly localize to the extremities. Although limb fracture is one of the most frequently reported triggering events, few large-scale studies have shown the occurrence of and factors associated with CRPS following limb fracture. This study aimed to show the occurrence and identify of those factors. Methods: Using the Japanese Diagnosis Procedure Combination database, we identified 39 patients diagnosed with CRPS immediately after open reduction and internal fixation (ORIF) for limb fracture from a cohort of 185 378 inpatients treated with ORIF between 1 July and 31 December of each year between 2007 and 2010. Patient and clinical characteristics such as age, gender, fracture site, duration of anaesthesia and use of regional anaesthesia were investigated by logistic regression analyses to examine associations between these factors and the in-hospital occurrence of CRPS after ORIF. Results: The occurrence of CRPS was relatively high in fractures of the distal forearm, but low in fractures of the lower limb and in patients with multiple fractures. Generally females are considered to be at high risk of CRPS; however, we found a comparable number of male and female patients suffering from CRPS after ORIF for limb fracture. In terms of perioperative factors, a longer duration of anaesthesia, but not regional anaesthesia, was significantly associated with a higher incidence of CRPS. Conclusion: Although a limited number of CRPS patients were analysed in this study, reduced operative time might help to prevent the development of acute CRPS following limb fracture. © The Author 2013. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.

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Pediatric myxopapillary ependymoma treated with subtotal resection and radiation therapy

Shirasawa H., Ishii K., Iwanami A., Mikami S., Toyama Y., Matsumoto M., Nakamura M.

Spinal Cord 52 （ SUPPL. 2 ） 2014年

ISSN 1362-4393

Study design:Case report and review of the literature.Objectives: Myxopapillary ependymoma (MPE) is a relatively rare glioma that develops from the spinal part of the filum terminale, usually in adulthood. While it is generally benign, MPE can disseminate intraspinally, and this malignant behavior requires a multidisciplinary response with surgery and radiotherapy. We report here a case of MPE occurring in the lumbosacral spine area of an 8-year-old boy.Setting:Japan, Tokyo.Methods:We report here a case of MPE, treated with subtotal surgical resection followed by craniospinal irradiation (CSI), in an 8-year-old boy. The patient was referred to our hospital with a 6-month history of severe pain in the lower back and legs, paralysis of the legs and dysuria. Magnetic resonance imaging images showed a large tumor that filled the entire spinal canal below L1. After subtotal resection of the tumor, the pathological findings established a diagnosis of MPE. Since the tumor had perforated its capsule, increasing the risk of intraspinal dissemination, the patient underwent radiotherapy and CSI after surgery.Results:Magnetic resonance images obtained 3 years after the surgery did not show any recurrence of MPE.Conclusion:Although tumor resection followed by CSI can be considered an effective strategy for treating a child with MPE, long-term follow-up is necessary to ensure early detection of any local recurrence or dissemination of the tumor, or of post-radiotherapy scoliosis. © 2014 International Spinal Cord Society All rights reserved.

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Prevalence and characteristics of chronic musculoskeletal pain in Japan

Nakamura Masaya, Nishiwaki Yuji, Ushida Takahiro, Toyama Yoshiaki

Journal of Orthopaedic Science 19 （ 2 ） 339 - 350 2014年

ISSN 0949-2658

Background: An epidemiological survey conducted in Japan in fiscal year 2010 revealed a high prevalence of chronic musculoskeletal pain, low patient satisfaction with treatment, a high incidence of protracted treatment lasting a year or more, and reduced quality of life. To improve the current system for treating chronic musculoskeletal pain, it is important to identify risk factors, including patient characteristics, for developing chronic pain. Thus, we sought to determine the incidence of new chronic pain in the Japanese population, as well as the persistence rate, associated factors, and current state of treatment of chronic pain, by repeating a postal survey in a nationwide representative sample group first surveyed in 2010. Methods: Among 11,507 participants in the 2010 epidemiological survey, 1,717 reported chronic pain and 6,283 reported no chronic pain. A repeat questionnaire, mailed to subjects in these 2 groups in fiscal year 2011, received replies from 85 % of those who reported pain and 76 % of those without pain in 2010. Results: The incidence of new chronic pain was 11.1 %. Risk factors for developing chronic pain included working in a professional, managerial, or clerical/specialist occupation, being female, having a BMI ≥25; currently using alcohol or cigarettes; and having completed an education level of vocational school or higher. Persistent chronic pain was reported by 45.2 % of respondents. Those with severe (VAS score ≥7) and constant lower-back pain lasting more than 5 years had the highest risk of the pain persisting. More than 80 % respondents with persistent chronic pain had a history of treatment, and while about 30 % were still receiving treatment at the time of the survey, the other 50 % had discontinued treatment despite the persistence of pain because of a low degree of satisfaction with treatment. Discussion: We identified risk factors related to the development of new chronic pain and the persistence of chronic pain. Countermeasures to prevent chronic pain could be especially important for the high-risk populations for understanding the pathology of chronic pain. © 2014 The Author(s).

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Factors contributing to improvement of syringomyelia after foramen magnum decompression for Chiari type I malformation

Nagoshi Narihito, Iwanami Akio, Toyama Yoshiaki, Nakamura Masaya

Journal of Orthopaedic Science 19 （ 3 ） 418 - 423 2014年

ISSN 0949-2658

Background: Although various surgical approaches have been proposed for treating syringomyelia associated with Chiari type I malformation, a standard method has yet to be established. we prospectively investigated the results of our surgical method: foramen magnum decompression combined with C1 laminectomy and excision of the outer layer of the dura mater. Methods: Twenty patients underwent surgery between 2000 and 2010 at our hospital. After surgery, the size of the syrinx decreased in 11 patients (decreased group) but remained unchanged in nine patients (unchanged group). The following parameters were compared: age at the time of surgery, duration of morbidity, improvement of preoperative symptoms, morphological type and length of the syrinx, presence or absence of scoliosis, cervical alignment, basal and clivo-axial angles, and postoperative subarachnoid space at the foramen magnum level. Results: Preoperative symptoms improved in all patients in the decreased group but in only one patient in the unchanged group. The average duration of morbidity was significantly shorter in the decreased group. Morphological examination revealed that the size of all central-type syrinxes decreased after surgery, whereas in all cases of deviated-type syrinx, size was unchanged. The average length of preoperative syrinx was significantly shorter in the decreased group. The postoperative subarachnoid space at the foramen magnum was enlarged in the entire decreased group, whereas residual narrowing of the space was observed in 44 % of patients in the unchanged group. No significant intergroup differences were observed in the other factors. Conclusions: In patients with syringomyelia, a longer and deviated type of syrinx, a longer duration of morbidity, and postoperative residual narrowing of the subarachnoid space are associated with a poor prognosis after the surgical procedure. The pathogenesis of syringomyelia is inconsistent, and the choice of surgical technique for each pathological condition is important. © 2014 The Japanese Orthopaedic Association.

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Investigation of chronic musculoskeletal pain (third report)

Nakamura Masaya, Nishiwaki Yuji, Sumitani Masahiko, Ushida Takahiro, Yamashita Toshihiko, Konno Shinichi, Taguchi Toshihiko, Toyama Yoshiaki

Journal of Orthopaedic Science 19 （ 4 ） 667 - 675 2014年

ISSN 0949-2658

Background: The previous epidemiological surveys conducted in Japan revealed that once the vicious cycle of chronic musculoskeletal pain begins, it is difficult to disrupt the cycle. This finding suggests the existence of problems with the conventional approaches to treatment of chronic musculoskeletal pain. The purpose of this study was to investigate the characteristics of patients with chronic musculoskeletal pain focusing on neuropathic and psychogenic pain. Methods: The questionnaire was sent again to the 660 subjects found to have persistent chronic pain in the epidemiological surveys conducted in 2011. Responses were collected from 588 subjects (response rate 90 %). Results: Of the 588 responders, 365 (62 %) complained of persistent chronic pain. Among them, 128 (35 %) were still receiving treatment and 193 (53 %) had discontinued treatment. The degree of satisfaction with the treatment was low, and 66 % of the patients had switched the medical facility that they visited to receive treatment. The cited reasons for the change in the medical facility visited and discontinuation of treatment were "treatment was ineffective," "I did not have sufficient time," "I thought I could take care of it myself," and "Treatment seemed to be unnecessary". Involvement of neuropathic pain was suggested in 20 % of all the patients with chronic pain. As the PainDETECT Score rose, the Visual Analog Scale (VAS) score became higher and the change of medical facility for treatment also increased. The Pain Catastrophizing Scale score was correlated positively with the VAS score. The Hospital Anxiety and Depression Scale score was significantly correlated with the VAS score and the duration of pain. Discussion: The results of this survey indicated that the chronic course of musculoskeletal pain may be attributable to the following factors: (1) lack of appropriate treatment of neuropathic pain and psychogenic pain, and (2) insufficient awareness/knowledge among patients about chronic musculoskeletal pain. © 2014 The Author(s).

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Dumbbell mesenchymal chondrosarcoma

Iida Tsuyoshi, Nakamura Masaya, Tsuji Osahiko, Iwanami Akio, Mikami Shuji, Toyama Yoshiaki, Chiba Kazuhiro, Matsumoto Morio

Journal of Orthopaedic Science 19 （ 1 ） 190 - 193 2014年

ISSN 0949-2658

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Global gene expression analysis following spinal cord injury in non-human primates

Nishimura Soraya, Sasaki Takashi, Shimizu Atsushi, Yoshida Kenji, Iwai Hiroki, Koya Ikuko, Kobayashi Yoshiomi, Itakura Go, Shibata Shinsuke, Ebise Hayao, Horiuchi Keisuke, Kudoh Jun, Toyama Yoshiaki, Anderson Aileen J., Okano Hideyuki, Nakamura Masaya

Experimental Neurology 261 171 - 179 2014年

ISSN 0014-4886

Spinal cord injury (SCI) is a devastating condition with no established treatment. To better understand the pathology and develop a treatment modality for SCI, an understanding of the physiological changes following SCI at the molecular level is essential. However, studies on SCI have primarily used rodent models, and few studies have examined SCI in non-human primates. In this study, we analyzed the temporal changes in gene expression patterns following SCI in common marmosets (Callithrix jacchus) using microarray analysis and mRNA deep sequencing. This analysis revealed that, although the sequence of events is comparable between primates and rodents, the inflammatory response following SCI is significantly prolonged and the onset of glial scar formation is temporally delayed in primates compared with rodents. These observations indicate that the optimal time window to treat SCI significantly differs among different species. This study provides the first extensive analysis of gene expression following SCI in non-human primates and will serve as a valuable resource in understanding the pathology of SCI. © 2014 Elsevier Inc.

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High preoperative hemoglobin A1c is a risk factor for surgical site infection after posterior thoracic and lumbar spinal instrumentation surgery

Hikata Tomohiro, Iwanami Akio, Hosogane Naobumi, Watanabe Kota, Ishii Ken, Nakamura Masaya, Kamata Michihiro, Toyama Yoshiaki, Matsumoto Morio

Journal of Orthopaedic Science 19 （ 2 ） 223 - 228 2014年

ISSN 0949-2658

Background: Diabetes mellitus (DM) is reported to be a risk factor for surgical site infection (SSI), which is a serious complication after spinal surgery. The effect of DM on SSI after instrumented spinal surgery remains to be clarified. The aim was to elucidate perioperative risk factors for infection at the surgical site after posterior thoracic and lumbar spinal arthrodesis with instrumentation in patients with DM. Methods: Consecutive patients who underwent posterior instrumented thoracic and lumbar spinal arthrodesis during the years 2005-2011, who could be followed for at least 1 year after surgery, were included. These included 36 patients with DM (19 males and 17 females; mean age 64.3 years). The patients' medical records were retrospectively reviewed to determine the SSI rate. The characteristics of the DM patients were examined in detail, including the levels of serum glucose and HbA1c, which indicate the level of diabetes control. Results: Patients with DM had a higher rate of SSI (6 of 36 patients, 16.7 %) than patients without DM (10 of 309 patients, 3.2 %). Although the perioperative serum glucose level did not differ between DM patients that did or did not develop SSI, the preoperative HbA1c value was significantly higher in the patients who developed SSI (7.6 %) than in those who did not (6.9 %). SSI developed in 0.0 % of the patients with controlled diabetes (HbA1c <7.0 %) and in 35.3 % of the patients with uncontrolled diabetes (HbA1c ≥7.0 %). Conclusions: DM patients whose blood glucose levels were poorly controlled before surgery were at high risk for SSI. To prevent SSI in DM patients, we recommend lowering the HbA1c to <7.0 % before performing surgery. © 2013 The Japanese Orthopaedic Association.

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C1 posterior arch screw as an auxiliary anchor in posterior reconstruction for atlantoaxial dislocation associated with type II odontoid fracture

Nagoshi Narihito, Suda Kota, Morita Tomonori, Matsumoto Satoko, Iimoto Seiji, Yasui Keigo, Komatsu Miki, Kobayashi Yosuke, Minami Akio, Toyama Yoshiaki, Matsumoto Morio, Nakamura Masaya

SpringerPlus 3 （ 1 ） 2014年

Introduction: Although pedicle or lateral mass screws are usually chosen to fix atlantoaxial (C1-C2) instability, there is an increased risk for vertebral artery (VA) injury when used in patients with bone or arterial anomalies or osteoporotic bone. Here we report the C1 posterior arch screw as a new technique for upper cervical fixation.Case description: A 90-year-old man complained of upper cervical pain after falling in his house. The initial computed tomography (CT) scan showed C1-C2 posterior dislocation with a type II odontoid fracture. The patient underwent C2 fracture reduction and posterior C1-C2 fixation. On the right side of C1, because lateral mass screw placement could cause injury to the dominant VA considering a risk in oldest-old osteoporotic patients, a posterior arch screw was chosen instead as an auxiliary anchor. An intralaminar screw was placed on the right side of C2 because a high-riding VA was observed. A lateral mass screw and a pars interarticularis screw were placed on the left side of C1 and C2, respectively. Ten months later, the odontoid fracture had healed, with normal anatomical alignment. Although the patient experienced slight weakness when spreading his bilateral fingers, his overall condition was good.Discussion and evaluation: We have presented a novel technique using C1 posterior arch screws for the fixation of a C1-C2 dislocation. Such a screw is an alternative to the C1 lateral mass screw in patients who are at risk for a VA injury because of anomalous bone and arterial structures or poor bone quality.Conclusions: Although there have been few comparable studies, and the long-term outcome is unknown, fixation with a posterior arch screw could be a beneficial choice for surgeries involving the upper cervical region.

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Transplantation of neural stem/progenitor cells at different locations in mice with spinal cord injury

Iwai Hiroki, Nori Satoshi, Nishimura Soraya, Yasuda Akimasa, Takano Morito, Tsuji Osahiko, Fujiyoshi Kanehiro, Toyama Yoshiaki, Okano Hideyuki, Nakamura Masaya

Cell Transplantation 23 （ 11 ） 1415 - 1464 2014年

ISSN 0963-6897

Transplantation of neural stem/progenitor cells (NS/PCs) promotes functional recovery after spinal cord injury (SCI); however, few studies have examined the optimal site of NS/PC transplantation in the spinal cord. The purpose of this study was to determine the optimal transplantation site of NS/PCs for the treatment of SCI. Wild-type mice were generated with contusive SCI at the T10 level, and NS/PCs were derived from fetal transgenic mice. These NS/PCs ubiquitously expressed ffLuc-cp156 protein (Venus and luciferase fusion protein) and so could be detected by in vivo bioluminescence imaging 9 days postinjury. NS/PCs (low: 250,000 cells per mouse; high: 1 million cells per mouse) were grafted into the spinal cord at the lesion epicenter (E) or at rostral and caudal (RC) sites. Phosphate-buffered saline was injected into E as a control. Motor functional recovery was better in each of the transplantation groups (E-Low, E-High, RC-Low, and RC-High) than in the control group. The photon counts of the grafted NS/PCs were similar in each of the four transplantation groups, suggesting that the survival of NS/PCs was fairly uniform when more than a certain threshold number of cells were transplanted. Quantitative RT-PCR analyses demonstrated that brain-derived neurotropic factor expression was higher in the RC segment than in the E segment, and this may underlie why NS/PCs more readily differentiated into neurons than into astrocytes in the RC group. The location of the transplantation site did not affect the area of spared fibers, angiogenesis, or the expression of any other mediators. These findings indicated that the microenvironments of the E and RC sites are able to support NS/PCs transplanted during the subacute phase of SCI similarly. Optimally, a certain threshold number of NS/PCs should be grafted into the E segment to avoid damaging sites adjacent to the lesion during the injection procedure.

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Surgeons' exposure to radiation in single- and multi-level minimally invasive transforaminal lumbar interbody fusion; a prospective study

Funao Haruki, Ishii Ken, Momoshima Suketaka, Iwanami Akio, Hosogane Naobumi, Watanabe Kota, Nakamura Masaya, Toyama Yoshiaki, Matsumoto Morio

PLoS ONE 9 （ 4 ） e95233 2014年

Although minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) has widely been developed in patients with lumbar diseases, surgeons risk exposure to fluoroscopic radiation. However, to date, there is no studies quantifying the effective dose during MIS-TLIF procedure, and the radiation dose distribution is still unclear. In this study, the surgeons' radiation doses at 5 places on the bodies were measured and the effective doses were assessed during 31 consecutive 1- to 3-level MIS-TLIF surgeries. The operating surgeon, assisting surgeon, and radiological technologist wore thermoluminescent dosimeter on the unshielded thyroid, chest, genitals, right middle finger, and on the chest beneath a lead apron. The doses at the lens and the effective doses were also calculated. Mean fluoroscopy times were 38.7, 53.1, and 58.5 seconds for 1, 2, or 3 fusion levels, respectively. The operating surgeon's mean exposures at the lens, thyroid, chest, genitals, finger, and the chest beneath the shield, respectively, were 0.07, 0.07, 0.09, 0.14, 0.32, and 0.05 mSv in 1-level MIS-TLIF; 0.07, 0.08, 0.09, 0.18, 0.34, and 0.05 mSv in 2-level; 0.08, 0.09, 0.14, 0.15, 0.36, and 0.06 mSv in 3-level; and 0.07, 0.08, 0.10, 0.15, 0.33, and 0.05 mSv in all cases. Mean dose at the operating surgeon's right finger was significantly higher than other measurements parts (P<0.001). The operating surgeon's effective doses (0.06, 0.06, and 0.07 mSv for 1, 2, and 3 fusion levels) were low, and didn't differ significantly from those of the assisting surgeon or radiological technologist. Revision MIS-TLIF was not associated with higher surgeons' radiation doses compared to primary MIS-TLIF. There were significantly higher surgeons' radiation doses in over-weight than in normal-weight patients. The surgeons' radiation exposure during MIS-TLIF was within the safe level by the International Commission on Radiological Protection's guidelines. The accumulated radiation exposure, especially to surgeon's hands, should be carefully monitored.

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FOXC2 mutations in familial and sporadic spinal extradural arachnoid cyst

Ogura Yoji, Yabuki Shoji, Iida Aritoshi, Kou Ikuyo, Nakajima Masahiro, Kano Hiroki, Shiina Masaaki, Kikuchi Shinichi, Toyama Yoshiaki, Ogata Kazuhiro, Nakamura Masaya, Matsumoto Morio, Ikegawa Shiro

PLoS ONE 8 （ 11 ） 2013年11月

Spinal extradural arachnoid cyst (SEDAC) is a cyst in the spinal canal that protrudes into the epidural space from a defect in the dura mater. Most cases are sporadic; however, three familial SEDAC cases have been reported, suggesting genetic etiological factors. All familial cases are associated with lymphedema-distichiasis syndrome (LDS), whose causal gene is FOXC2. However, FOXC2 mutation analysis has been performed in only 1 family, and no mutation analysis has been performed on sporadic (non-familial) SEDACs. We recruited 17 SEDAC subjects consisting of 2 familial and 7 sporadic cases and examined FOXC2 mutations by Sanger sequencing and structural abnormalities by TaqMan copy number assay. We identified 2 novel FOXC2 mutations in 2 familial cases. Incomplete LDS penetrance was noted in both families. Four subjects presented with SEDACs only. Thus, SEDAC caused by the heterozygous FOXC2 loss-of-function mutation should be considered a feature of LDS, although it often manifests as the sole symptom. Seven sporadic SEDAC subjects had no FOXC2 mutations, no symptoms of LDS, and showed differing clinical characteristics from those who had FOXC2 mutations, suggesting that other gene(s) besides FOXC2 are likely to be involved in SEDAC. © 2013 Ogura et al.

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In vivo tracing of neural tracts in tiptoe-walking yoshimura mice by diffusion tensor tractography

Takano Morito, Komaki Yuji, Hikishima Keigo, Konomi Tsunehiko, Fujiyoshi Kanehiro, Tsuji Osahiko, Okano Hideyuki, Toyama Yoshiaki, Nakamura Masaya

107 - 117 2013年11月

In ossification of the posterior longitudinal ligaments (OPLL), axonal disruption results in motor and sensory function impairment. Twy (tiptoe-walking Yoshimura) mice develop spontaneous calcification in the cervical ligaments, thereby causing chronic compression of the spinal cords. To determine whether in vivo diffusion tensor tractography (DTT) can evaluate the axonal disruption of the chronic compressive spinal cords in twy mice, 6-, 15-, and 20-week-old twy mice were chronologically subjected to DTT. MRI was performed using a 7.0-Tesla magnet with a surface coil (CryoProbe). Diffusion tensor images were analyzed using TrackVis (Massachusetts General Hospital, MA, USA). We succeeded in depicting in vivo high-resolution DTT of the twy mice. The progress of the ligamentous calcification was observed at C2-3 level in each twy mouse, and the number of RT-97 or SMI31 positive fibers was decreased depending on the severity of the compression of the spinal cord. Quantitative analysis of sequential DTT enabled to detect subtle damage of the compressed spinal cord prior to the deterioration of neurological function in twy mice. Thus, in a clinical setting, DTT could be a new effective imaging modality in patients with cervical OPLL.

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Regenerative medicine for spinal cord injury utilizing iPS cells

Tsuji Osahiko, Nori Satoshi, Kobayashi Yoshiomi, Fujiyoshi Kanehiro, Okano Hideyuki, Toyama Yoshiaki, Nakamura Masaya

229 - 245 2013年11月

Reports of functional recovery from spinal cord injury (SCI) after the transplantation of rat-fetus-derived neural stem/precursor cells (NS/PCs) and murine embryonic stem cells (ES cells) have raised great expectations for the successful clinical trial of stem cell transplantation therapy. However, the ethical issues concerning about destroying human embryos or fertilized oocytes to obtain such stem cells have been a major impediment to developing clinically useful stem cell sources and to use them in clinical applications. Recently, induced pluripotent stem cells (iPS cells), which can serve as a source of autologous cell transplantation, have been attracting a lot of attention as a clinically practical alternative to stem cells obtained directly from tissues. In this chapter, we outline the neural induction of murine and human iPS cells, their therapeutic efficacy in mouse and primate SCI models, and their safety in vivo.

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Recombinant human hepatocyte growth factor promotes functional recovery after spinal cord injury

Kitamura Kazuya, Iwanami Akio, Fujiyoshi Kanehiro, Yamane Jun Ichi, Hikishima Keigo, Funakoshi Hiroshi, Nakamura Toshikazu, Aoki Masashi, Toyama Yoshiaki, Okano Hideyuki, Nakamura Masaya

147 - 167 2013年11月

Hepatocyte growth factor (HGF), which is a potent mitogen for mature hepatocytes and a mediator of the inflammatory responses to tissue injury, was recently highlighted as a potent neurotrophic factor in the central nervous system. We revealed that introducing exogenous HGF into the injured rat spinal cord using a herpes simplex virus-1 vector significantly reduces the area of damaged tissue and promotes functional recovery. However, this rat study did not examine the therapeutic effects of administering HGF after injury, which is the most critical issue for clinical application. To translate this strategy to human treatment, we induced a contusive cervical SCI in the common marmoset, a primate, and then administered recombinant human HGF (rhHGF) intrathecally. Motor function was assessed using an original open-field scoring system focusing on manual function, including reach-and-grasp performance and hand placement in walking. The intrathecal rhHGF preserved the corticospinal fibers and myelinated areas, thereby promoting functional recovery. This study demonstrates the therapeutic effects, safety, and clinical efficacy of intrathecal rhHGF treatment for SCI in adult nonhuman primates and the possibility that this novel therapy may be suitable for clinical application.

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Assessment of injured spinal cord using diffusion tensor tractography

Fujiyoshi Kanehiro, Konomi Tsunehiko, Tsuji Osahiko, Yamada Masayuki, Hikishima Keigo, Momoshima Suketaka, Okano Hideyuki, Toyama Yoshiaki, Nakamura Masaya

345 - 365 2013年11月

In spinal cord injury (SCI), the evaluation of axonal fibers is important to assess the severity of injury and efficacy of any treatment protocol, but conventional methods such as tracer injection in the brain parenchyma are highly invasive and require histological evaluation, precluding clinical applications. Magnetic resonance imaging (MRI) is essential for predicting prognosis and planning treatment of patients with SCI noninvasively. However, the information provided by conventional T1- and T2-weighted MRI of the spinal cord is essentially limited to the differentiation of the white matter from the gray matter. By contrast, diffusion-weighted magnetic resonance imaging (DWI) provides much information about biological structures. In particular, diffusion tensor imaging (DTI) and diffusion tensor tractography (DTT) are powerful tools for evaluating white matter fibers in the central nervous system. We previously established a reproducible SCI model in adult common marmosets and demonstrated that DTT could be used to trace the neural tracts in the intact and injured spinal cord of these animals in vivo. Recently, many reports using DTT to analyze the spinal cord area have been published. Based on the findings from our experimental studies, we are now routinely performing DTT of the human spinal cord clinically. In this chapter, we outline the basic principles of DTT and describe the characteristics, limitations, and clinical application of DTT in the spinal cord.

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Neuroprotection and regeneration of the spinal cord

Uchida Kenzo, Ozawa Hiroshi, Toyama Yoshiaki, Nakamura Masaya, Katoh Shinsuke

2013年11月

Neuroprotection and Regeneration of the Spinal Cord comprehensively covers the most recent research in the field of spinal cord injury. The first part of this book focuses on the latest animal models and clinically oriented work, providing extensive information on morphological factors and, biomechanical analysis, in addition to the mechanism of functional recovery. The book goes on to provide information on clinical relevance introducing analysis of spinal cord injuries using MRI and PET. Edited by renowned experts in the field, this book will provide clinical physicians, basic researchers, and postgraduate students with valuable insight into the cutting-edge research and progress in the field of spinal cord injury, treatment, and repair.

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Blockade of interleukin-6 effects on cytokine profiles and macrophage activation after spinal cord injury in mice

Guerrero Alexander Rodriguez, Uchida Kenzo, Nakajima Hideaki, Watanabe Shuji, Nakamura Masaya, Okada Seiji, Johnson William E B, Baba Hisatoshi

203 - 212 2013年11月

The objective of this study was to clarify the effects of a temporal blockade of IL-6/IL-6 receptor (IL-6R) engagement, using an anti-mouse IL-6R monoclonal antibody (MR16-1), on macrophage activation and the inflammatory response in the acute phase after spinal cord injury (SCI) in mice. MR16-1 antibodies versus isotype control antibodies or saline alone was administered immediately after thoracic SCI in mice. MR16-1-treated group samples showed increased neuronal regeneration and locomotor recovery compared with controls. Immunoblot analysis of the MR16-1-treated samples identified downregulation of Th1 and upregulation of Th2 cytokines. MR16-1 treatment promoted arginase-1-positive, CD206-positive M2 macrophages, with preferential localization of these cells at the injury site and enhanced positivity for Mac-2 and Mac-3, suggestive of increased phagocytic behavior. The results suggest that temporal blockade of IL-6 signaling after SCI abrogates damaging inflammatory activity and promotes functional recovery by promoting the formation of alternatively activated M2 macrophages.

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Spinal kyphosis causes demyelination and neuronal loss in the spinal cord

Nakamura Masaya, Shimizu Kentaro, Toyama Yoshiaki

129 - 138 2013年11月

The spinal cord has remarkable ability to resist chronic compression; however, delayed paralysis is sometimes seen following the development of spinal kyphosis. In the past, no animal model to clarify the mechanism of spinal cord damage due to spinal kyphotic deformity has been available. We developed a new experimental model of chronic spinal cord compression using a bird, to evaluate the effects of chronic compression associated with kyphotic deformity of the cervical spine on the spinal cord. As kyphosis progressed, the spinal cord flattening became more marked, causing histopathological changes, including demyelination and neuronal loss. Demyelination of the axons progressed in the order of the anterior, lateral, and then posterior funiculus. Furthermore, microangiography suggested that vascular disturbance in addition to mechanical compression may have contributed to the development of histological changes. In conclusion, progressive kyphosis of the cervical spine resulted in demyelination of nerve fibers in the funiculi and neuronal loss in the anterior horn due to chronic compression of the spinal cord. These histological changes seem to be associated with both continuous mechanical compression and vascular changes in the spinal cord.

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Microenvironment within the injured spinal cord focusing on IL-6

Nakamura Masaya

11 - 18 2013年11月

In recent years, a variety of studies have been conducted towards the goal of achieving regeneration of the central nervous system using neural stem cells. However, various complex factors are involved in the regulation of neural stem cell differentiation, and many unresolved questions remain. It has been reported that after spinal cord injury, the intrinsic neural stem cells do not differentiate into neurons but into astrocytes, resulting in the formation of glial scars. Based on reports that the expression of IL-6 and the IL-6 receptor is sharply increased in the acute stages after spinal cord injury and that IL-6 may serve as a factor strongly inducing the differentiation of neural stem cells into astrocytes, we examined the effects of an antibody to the IL-6 receptor in cases of spinal cord injury and found that the antibody indeed suppressed secondary injury (caused by inflammatory reactions) and glial scar formation, facilitating functional recovery. In this paper, we present the data from this investigation and discuss the relationship between IL-6 signals and spinal cord injury.

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A rare case of dumbbell meningioma of the upper cervical spinal cord

Ozaki Masahiro, Nakamura Masaya, Tsuji Osahiko, Iwanami Akio, Toyama Yoshiaki, Chiba Kazuhiro, Matsumoto Morio

Journal of Orthopaedic Science 18 （ 6 ） 1042 - 1045 2013年11月

ISSN 0949-2658

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Spinal coronal profiles and proximal femur bone mineral density in adolescent idiopathic scoliosis

Chen Rui Qiang, Watanabe Kota, Hosogane Naobumi, Hikata Tomohiro, Iwanami Akio, Ishii Ken, Nakamura Masaya, Toyama Yoshiaki, Matsumoto Morio

European Spine Journal 22 （ 11 ） 2433 - 2437 2013年11月

ISSN 0940-6719

Purpose: Although the occurrence and progression of AIS has been linked to low bone mineral density (BMD), the relationships between spinal curvature and bilateral differences in proximal femur BMD are controversial. Few correlation studies have stratified patients by curve type. The purpose of this study was to evaluate the relationships between spinal coronal profile and bilateral differences in proximal femur BMD in patients with adolescent idiopathic scoliosis (AIS). Methods: This study included 67 patients with AIS who underwent posterior correction and fusion surgery between January 2009 and October 2011. The mean age at the time of surgery was 17.4 ± 4.1 years. Bilateral proximal femur BMD was measured before surgery by dual-energy X-ray absorptiometry. We compared the proximal femur BMDs by determining the bilateral BMD ratio (left proximal femur BMD divided by that of the right). We evaluated correlations between coronal parameters, obtained from preoperative radiographs, and the BMD ratio using Pearson's correlation analysis. Results: Patients with Lenke type 1 curve (48; all with a right convex curve) had a mean bilateral proximal femur BMD ratio of 1.00 ± 0.04. Patients with Lenke type 5 curve (19; all with a left convex curve) had a mean bilateral proximal femur BMD ratio of 0.94 ± 0.04, indicating that the BMD in the proximal femur on the right side (concave) was greater than that in the left (convex). Coronal balance was significantly correlated with the BMD ratio in both the Lenke type 1 and type 5 groups, with a correlation coefficient of 0.46 and 0.50, respectively. Conclusions: The bilateral proximal femur BMD ratio was significantly correlated with the coronal balance in AIS patients. When the C7 plumb line was shifted toward one side, the BMD was greater in the contralateral proximal femur. © 2013 Springer-Verlag Berlin Heidelberg.

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[110th Scientific Meeting of the Japanese Society of Internal Medicine

Nakamura Masaya, Okano Hideyuki, Toyama Yoshiaki

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 102 （ 9 ） 2247 - 2253 2013年09月

ISSN 0021-5384

Nondura-based clear cell meningioma of the cauda equina in an adult

Kobayashi Yoshiomi, Nakamura Masaya, Tsuji Osahiko, Iwanami Akio, Ishii Ken, Watanabe Kota, Hosogane Naobumi, Tsuji Takashi, Kameyama Kaori, Toyama Yoshiaki, Chiba Kazuhiro, Matsumoto Morio

Journal of Orthopaedic Science 18 （ 5 ） 861 - 865 2013年09月

ISSN 0949-2658

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Total en bloc spondylectomy for spinal metastasis of differentiated thyroid cancers

Matsumoto Morio, Tsuji Takashi, Iwanami Akio, Watanabe Kota, Hosogane Naobumi, Ishii Ken, Nakamura Masaya, Morioka Hideo, Toyama Yoshiaki

Journal of Spinal Disorders and Techniques 26 （ 4 ） 2013年06月

ISSN 1536-0652

Study Design: A retrospective case series. Objective: To evaluate the long-term effectiveness and problems of total en bloc spondylectomy (TES) for treating metastatic thyroid cancer of the spine. Summary of Background Data: Although TES is indicated for low-grade malignant spinal tumors, its efficacy in treating thyroid cancer metastases in the spine is uncertain. Methods: This study followed 8 patients who underwent TES for spinal metastasis of thyroid cancer (5 males, 3 females; mean age, 55.3 y; mean follow-up period, 6.4 y), 6 with follicular carcinomas and 2 with papillary carcinomas. In 6 patients without a marked paravertebral tumor extension, TES was performed using a posterior approach. Two patients had prominent anterior or anterolateral tumor extension into the thoracic and retroperitoneal cavities, and a combined anterior and posterior approach was used. We evaluated the patients' clinical symptoms, operative procedures, complications, and prognoses. Results: Before surgery, the patients' neurological status was evaluated by the Frankel classification (grade C, 4 patients; grade D, 1 patient; grade E, 3 patients) and Tokuhashi scores (9, 1 patient; 11, 2 patients; 13 and 14, 1 patient each; 15, 3 patients). One year after surgery, all the patients had improved by at least a Frankel grade, and 4 patients classified as grade C before surgery had become ambulatory. At the final follow-up (average of 6.4 y), 5 patients had a grade E Frankel classification and 1 had grade D, but 2 patients had suffered neurological deterioration, because of tumor recurrence, at the same level as the TES in one patient and at an adjacent level in the other. At follow-up, all patients were alive; 5 showed no evidence of disease. Two patients experienced rod breakage, at 2.8 and at 3.3 years after TES, and 1 patient suffered an endplate fracture 6 months after TES; this patient developed a late infection, 7 years after TES. Conclusions: TES was effective in controlling spinal thyroid cancer metastasis locally and in preserving the ability to walk. However, instrumentation failure and other late complications arose during the patients' long survival times after TES. Copyright © 2012 by Lippincott Williams & Wilkins.

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Health Survey of Numbness/Pain and Its Associated Factors in Kotohira, Japan

Inoue Shinsuke, Ikeuchi Masahiko, Okumura Keiko, Nakamura Masaya, Kawakami Chihiro, Ikemoto Tatsunori, Kawasaki Motohiro, Tani Toshikazu, Ushida Takahiro

PLoS ONE 8 （ 4 ） 2013年04月

We conducted a survey of adults in Kotohira, a town of about 10,000 people located in the Nakatado District of Kagawa Prefecture, Japan. The survey was distributed to 8184 individuals, and effective responses were received from 3863 persons (response rate, 47.2%) during the survey period. Results regarding numbness and pain showed numbness alone in 7.7%, pain alone in 7.2%, both numbness and pain in 6.0%, and neither numbness nor pain in 79.6%. Spine and spinal cord damage was reported present by 5.4%, and absent by 94.6%. Analysis using the Short-Form Health Survey questionnaire, with comparison between subjects reporting both numbness and pain in the extremities and subjects with either numbness or pain alone, showed lower scores for in Short-Form Health Survey subscales (physical functioning, role [physical, emotional], bodily pain, vitality, and mental health). Subjects with numbness alone generally reported no disability in daily life. In a secondary survey, analysis of neurological findings by specialists identified 6 cases of "pain following spinal cord damage" in which spinal cord-related pain developed in the hands or feet. This represented 0.15% of the survey population starting from the primary survey. © 2013 Inoue et al.

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Diffusion tensor imaging and tractography of the spinal cord

Fujiyoshi Kanehiro, Konomi Tsunehiko, Yamada Masayuki, Hikishima Keigo, Tsuji Osahiko, Komaki Yuji, Momoshima Suketaka, Toyama Yoshiaki, Nakamura Masaya, Okano Hideyuki

Experimental Neurology 242 74 - 82 2013年04月

ISSN 0014-4886

Diffusion-weighted magnetic resonance imaging provides detailed information about biological structures. In particular, diffusion tensor imaging and diffusion tensor tractography (DTT) are powerful tools for evaluating white matter fibers in the central nervous system. We previously established a reproducible spinal cord injury model in adult common marmosets and showed that DTT could be used to trace the neural tracts in the intact and injured spinal cord of these animals in vivo. Recently, many reports using DTT to analyze the spinal cord area have been published. Based on the findings from our experimental studies, we are now routinely performing DTT of the human spinal cord in the clinic. In this review we outline the basic principles of DTT, and describe the characteristics, limitations, and future uses of DTT to examine the spinal cord. © 2012.

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PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies

Iwanami Akio, Gini Beatrice, Zanca Ciro, Matsutani Tomoo, Assuncao Alvaro, Nael Ali, Dang Julie, Yang Huijun, Zhu Shaojun, Kohyama Jun, Kitabayashi Issay, Cavenee Webster K., Cloughesy Timothy F., Furnari Frank B., Nakamura Masaya, Toyam Yoshiaki, Okano Hideyuki, Mischel Paul S.

Proceedings of the National Academy of Sciences of the United States of America 110 （ 11 ） 4339 - 4344 2013年03月

ISSN 0027-8424

Despite their nearly universal activation of mammalian target of rapamycin (mTOR) signaling, glioblastomas (GBMs) are strikingly resistant to mTOR-targeted therapy. We analyzed GBM cell lines, patient-derived tumor cell cultures, and clinical samples from patients in phase 1 clinical trials, and find that the promyelocytic leukemia (PML) gene mediates resistance to mTOR-targeted therapies. Direct mTOR inhibitors and EGF receptor (EGFR) inhibitors that block downstreammTOR signaling promote nuclear PML expression in GBMs, and genetic overexpression and knockdown approaches demonstrate that PML prevents mTOR and EGFR inhibitor-dependent cell death. Low doses of the PML inhibitor, arsenic trioxide, abrogate PML expression and reverse mTOR kinase inhibitor resistance in vivo, thus markedly inhibiting tumor growth and promoting tumor cell death in mice. These results identify a unique role for PML in mTOR and EGFR inhibitor resistance and provide a strong rationale for a combination therapeutic strategy to overcome it.

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Epigenetic transcriptional activation of monocyte chemotactic protein 3 contributes to long-lasting neuropathic pain

Imai Satoshi, Narita Minoru, Ikegami Daigo, Yamashita Akira, Shimizu Toshikazu, Narita Michiko, Niikura Keiichi, Furuya Masaharu, Kobayashi Yasuhisa, Miyashita Kazuhiko, Okutsu Daiki, Kato Akira, Nakamura Atsushi, Araki Akiko, Omi Kazuo, Nakamura Masaya, James Okano Hirotaka, Okano Hideyuki, Ando Takayuki, Takeshima Hideyuki, Ushijima Toshikazu, Kuzumaki Naoko, Suzuki Tsutomu

Brain 136 （ 3 ） 828 - 843 2013年03月

ISSN 0006-8950

A multiplex analysis for profiling the expression of candidate genes along with epigenetic modification may lead to a better understanding of the complex machinery of neuropathic pain. In the present study, we found that partial sciatic nerve ligation most remarkably increased the expression of monocyte chemotactic protein 3 (MCP-3, known as CCL7) a total of 33 541 genes in the spinal cord, which lasted for 4 weeks. This increase in MCP-3 gene transcription was accompanied by the decreased trimethylation of histone H3 at Lys27 at the MCP-3 promoter. The increased MCP-3 expression associated with its epigenetic modification observed in the spinal cord was almost abolished in interleukin 6 knockout mice with partial sciatic nerve ligation. Consistent with these findings, a single intrathecal injection of recombinant proteins of interleukin 6 significantly increased MCP-3 messenger RNA with a decrease in the level of Lys27 trimethylation of histone H3 at the MCP-3 promoter in the spinal cord of mice. Furthermore, deletion of the C-C chemokine receptor type 2 (CCR2) gene, which encodes a receptor for MCP-3, failed to affect the acceleration of MCP-3 expression in the spinal cord after partial sciatic nerve ligation. A robust increase in MCP-3 protein, which lasted for up to 2 weeks after surgery, in the dorsal horn of the spinal cord of mice with partial sciatic nerve ligation was seen mostly in astrocytes, but not microglia or neurons. On the other hand, the increases in both microglia and astrocytes in the spinal cord by partial sciatic nerve ligation were mostly abolished in interleukin 6 knockout mice. Moreover, this increase in microglia was almost abolished by CCR2 gene deletion, whereas the increase in astrocytes was not affected in nerve-ligated mice that lacked the CCR2 gene. We also found that either in vivo or in vitro treatment with MCP-3 caused robust microglia activation. Under these conditions, intrathecal administration of MCP-3 antibody suppressed the increase in microglia within the mouse spinal cord and neuropathic pain-like behaviours after nerve injury. With the use of a functional magnetic resonance imaging analysis, we demonstrated that a single intrathecal injection of MCP-3 induced dramatic increases in signal intensity in pain-related brain regions. These findings suggest that increased MCP-3 expression associated with interleukin 6 dependent epigenetic modification at the MCP-3 promoter after nerve injury, mostly in spinal astrocytes, may serve to facilitate astrocyte-microglia interaction in the spinal cord and could play a critical role in the neuropathic pain-like state. © 2013 The Author (2013). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

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Cervical intramedullary ependymoma masquerading as cervical spondylotic myelopathy on MRI analysis

Tsuji Osahiko, Nakamura Masaya, Fujiyoshi Kanehiro, Ishii Ken, Watanabe Kota, Hosogane Naobumi, Tsuji Takashi, Momoshima Suketaka, Toyama Yoshiaki, Chiba Kazuhiro, Matsumoto Morio

Journal of Orthopaedic Science 18 （ 2 ） 355 - 358 2013年03月

ISSN 0949-2658

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Surgical correction of severe cervical kyphosis in patients with neurofibromatosis Type 1

Kawabata Soya, Watanabe Kota, Hosogane Naobumi, Ishii Ken, Nakamura Masaya, Toyama Yoshiaki, Matsumoto Morio

Journal of Neurosurgery: Spine 18 （ 3 ） 274 - 279 2013年03月

ISSN 1547-5654

Severe cervical kyphosis requiring surgical treatment is rare in patients with neurofibromatosis Type 1 (NF1). When it occurs, however, dystrophic changes in the vertebrae make surgical correction and fusion of the deformity extremely difficult. The authors report on 3 cases of severe cervical kyphosis associated with NF1 that were successfully treated with combined anterior and posterior correction and fusion. All patients underwent halo-gravity traction for approximately 1 month prior to surgery to correct the deformity gradually. Posterior correction and fusion were performed with segmental spinal instrumentation consisting of lateral mass screws, lamina screws, pedicle screws, and polyethylene tape for sublaminar wiring. Anterior spinal fusion was performed using a fibula strut to induce solid bone fusion. All patients used a halo vest for postoperative external fixation. Preoperative CT scans showed dystrophic cervical spine changes, and MR images demonstrated extensive neurofibromas outside the cervical spine in all 3 patients. The preoperative kyphotic angles were as follows: Case 1, 140°; Case 2, 81°; and Case 3, 72°; after halo-gravity traction, the kyphosis angles improved to 50°, 55°, and 51°, respectively; and after surgery, they were 50°, 15°, and 27°, respectively. Solid bone union was observed in all patients at the latest follow-up. All three patients experienced postoperative complications consisting of superficial infection, severe pneumonia, and partial dislocation of the distal fibula graft after removing the halo vest, in one patient each. Although dystrophic cervical vertebral changes in these patients with NF1 complicated the correction of severe cervical kyphosis, the use of preoperative halo-gravity traction, a combination of spinal instrumentations, an anterior strut bone graft, and postoperative halo-vest fixation made it possible to correct the kyphosis, maintain the correction, and achieve solid bone fusion. © 2013 AANS.

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Steps toward safe cell therapy using induced pluripotent stem cells

Okano Hideyuki, Nakamura Masaya, Yoshida Kenji, Okada Yohei, Tsuji Osahiko, Nori Satoshi, Ikeda Eiji, Yamanaka Shinya, Miura Kyoko

Circulation Research 112 （ 3 ） 523 - 533 2013年02月

ISSN 0009-7330

The enthusiasm for producing patient-specific human embryonic stem cells using somatic nuclear transfer has somewhat abated in recent years because of ethical, technical, and political concerns. However, the interest in generating induced pluripotent stem cells (iPSCs), in which pluripotency can be obtained by transcription factor transduction of various somatic cells, has rapidly increased. Human iPSCs are anticipated to open enormous opportunities in the biomedical sciences in terms of cell therapies for regenerative medicine and stem cell modeling of human disease. On the other hand, recent reports have emphasized the pitfalls of iPSC technology, including the potential for genetic and epigenetic abnormalities, tumorigenicity, and immunogenicity of transplanted cells. These constitute serious safety-related concerns for iPSC-based cell therapy. However, preclinical data supporting the safety and efficacy of iPSCs are also accumulating. In this Review, recent achievements and future tasks for safe iPSC-based cell therapy are summarized, using regenerative medicine for repair strategies in the damaged central nervous system (CNS) as a model. Insights on safety and preclinical use of iPSCs in cardiovascular repair model are also discussed. © 2013 American Heart Association, Inc.

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[Reconstruction for spinal cord injury].

Hori Keiko, Nakamura Masaya, Okano Hideyuki

Nihon Jibiinkoka Gakkai kaiho 116 （ 2 ） 53 - 59 2013年02月

ISSN 0030-6622

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Minimally invasive endoscopic resection of a solitary bone cyst of the lumbar vertebrae

Matsubayashi Kohei, Tsuji Osahiko, Watanabe Kota, Hosogane Naobumi, Tsuji Takashi, Ishii Ken, Nakamura Masaya, Toyama Yoshiaki, Chiba Kazuhiro, Matsumoto Morio

Neurosurgery Quarterly 23 （ 1 ） 66 - 69 2013年02月

ISSN 1050-6438

Solitary bone cysts of the lumbar vertebrae are extremely rare. We report a 20-year-old man, who presented with a 5-year history of persistent low back pain. Radiographic examination, magnetic resonance imaging, and subsequent computed tomography revealed a well-circumscribed osteolytic and cystic lesion at the right pedicle of the L3 vertebra. On the basis of the radiologic findings, a simple bone cyst was considered the most probable diagnosis. The patient underwent a minimally invasive operation with the assistance of an endoscope. The gross total curettage resection of the lesion including the cyst walls was accomplished, followed by a combined graft consisting of granulated β-tricalcium phosphate and autologous iliac crest cancellous bone. At the 1-year follow-up, the patient's symptoms were resolved, bone union at the lesion site had been achieved, and he had returned to his previous level of physical activity. Copyright © 2013 by Lippincott Williams & Wilkins.

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In vivo tracing of neural tracts in tiptoe walking yoshimura mice by diffusion tensor tractography

Takano Morito, Komaki Yuji, Hikishima Keigo, Konomi Tsunehiko, Fujiyoshi Kanehiro, Tsuji Osahiko, Toyama Yoshiaki, Okano Hideyuki, Nakamura Masaya

Spine 38 （ 2 ） 2013年01月

ISSN 0362-2436

STUDY DESIGN.: Basic imaging experiment. OBJECTIVE.: To determine whether in vivo diffusion tensor tractography (DTT) can be used to evaluate the axonal disruption of the chronically compressed spinal cord in tiptoe walking Yoshimura (twy) mice. SUMMARY OF BACKGROUND DATA.: In cervical ossification of the posterior longitudinal ligament, axonal disruption results in motor and sensory functional impairment. Twy mice develop spontaneous calcification in the cervical ligaments, which causes chronic compression of the spinal cord. DTT is emerging as a powerful tool for tracing axonal fibers in vivo. METHODS.: Five twy mice were subjected to DTT at 6, 15, and 20 weeks of age. Magnetic resonance imaging was performed using a 7.0-Tesla magnet (Biospec 70/16; Billerica, MA) with a CryoProbe. Diffusion tensor images were analyzed using TrackVis (Massachusetts General Hospital, MA). Motor performance was evaluated by Rotarod treadmill test and Digigait analysis. Histological analysis was performed by hematoxylin-eosin staining and immunostaining for RT-97 and SMI-31. RESULTS.: High resolution DTT of twy mice in vivo was successful. A lower number of RT-97- or SMI-31-positive fibers were associated with more severe spinal cord compression, which was determined by observing the ligamentous calcification at the C2-C3 level in each twy mouse. The severity of canal stenosis based on magnetic resonance images was strongly correlated with the axial area of the spinal cord. The tract fiber (TF) ratio (the number of TFs at the C2-C3 level/the number of TFs at the C0-C1 level) was strongly correlated with the RT-97/SMI-31-positive area and with motor function (rotarod latency, stride length). Furthermore, a two-part linear regression analysis showed that canal stenosis around 50% to 60% caused a sharp decrease in the TF ratio before the deterioration of motor function. CONCLUSION.: We conclude that DTT could be useful for detecting the early changes associated with the compressed spinal cord in cervical ossification of the posterior longitudinal ligament. Copyright © 2013 Lippincott Williams & Wilkins.

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Cell transplantation therapies for spinal cord injury focusing on induced pluripotent stem cells

Nakamura Masaya, Okano Hideyuki

Cell Research 23 （ 1 ） 70 - 80 2013年01月

ISSN 1001-0602

Stimulated by the 2012 Nobel Prize in Physiology or Medicine awarded for Shinya Yamanaka and Sir John Gurdon, there is an increasing interest in the induced pluripotent stem (iPS) cells and reprograming technologies in medical science. While iPS cells are expected to open a new era providing enormous opportunities in biomedical sciences in terms of cell therapies and regenerative medicine, safety-related concerns for iPS cell-based cell therapy should be resolved prior to the clinical application of iPS cells. In this review, the pre-clinical investigations of cell therapy for spinal cord injury (SCI) using neural stem/progenitor cells derived from iPS cells, and their safety issues in vivo, are outlined. We also wish to discuss the strategy for the first human trails of iPS cell-based cell therapy for SCI patients. © 2013 IBCB, SIBS, CAS All rights reserved.

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Long-term surgical outcomes of cervical dumbbell neurinomas

Nakamura Masaya, Iwanami Akio, Tsuji Osahiko, Hosogane Naobumi, Watanabe Kota, Tsuji Takashi, Ishii Ken, Toyama Yoshiaki, Chiba Kazuhiro, Matsumoto Morio

Journal of Orthopaedic Science 18 （ 1 ） 8 - 13 2013年01月

ISSN 0949-2658

Study design: Retrospective case series. Objective: To evaluate our treatment strategy for cervical dumbbell neurinoma. Summary of background data: In treating cervical dumbbell neurinoma, possible difficulties include reoperation due to recurrent tumor, denervation due to nerve root resection, and postoperative spinal deformity due to extensive bony removal. Methods: We reviewed 75 cases of cervical dumbbell neurinoma that were treated surgically between 1985 and 2006. Postoperative neurological deficits, effects of surgical margins on tumor recurrence, and surgical complications were investigated retrospectively. Results: Sensory and motor deficits due to resection of specific nerve roots appeared temporarily in 33 and 23 % of all cases, and persisted in 8 and 8 % at final evaluation, respectively. Total, subtotal, and partial resection was performed in 57, 13, and 5 cases, respectively. The total resection rate was low in the tumors that had large extraforaminal components. Of the subtotally resected 13 cases, only two cases of high tumor-growth rate required re-operation or showed tumor growth. Among the five partially resected cases, re-operation was necessary in two cases 13 and 15 years later because of aggravated neurological symptoms due to tumor growth. Two patients who underwent C2 laminectomy developed kyphosis, and three patients who underwent facet joint resection and curettage of vertebral body lesions developed scoliosis. Conclusion: Total resection should be attempted for cervical dumbbell tumors. In cases where total resection was potentially of high risk, however, subtotal resection (within the capsule) was found to be a practical choice yielding favorable long-term outcome when the tumor growth rate (MIB-1 index) was low. © 2012 The Japanese Orthopaedic Association.

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Novel method for analyzing locomotor ability after spinal cord injury in rats

Shinozaki Munehisa, Yasuda Akimasa, Nori Satoshi, Saito Nobuhito, Toyama Yoshiaki, Okano Hideyuki, Nakamura Masaya

Neurologia Medico-Chirurgica 53 （ 12 ） 907 - 913 2013年

ISSN 0470-8105

In the research for the treatment of spinal cord injury (SCI), the evaluation of motor function in model rats must be as objective, noninvasive, and ethical as possible. The maximum speed and acceleration of a mouse measured using a SCANET system were previously reported to vary significantly according to severity of SCI. In the present study, the motor performance of SCI model rats was examined with SCANET and assessed for Basso-Beattie-Bresnahan (BBB) score to determine the usefulness of the SCANET system in evaluating functional recovery after SCI. Maximum speed and acceleration within the measurement period correlated significantly with BBB scores. Furthermore, among several phased kinematic factors used in BBB scores, the capability of "plantar stepping" was associated with a drastic increase in maximum speed and acceleration after SCI. Therefore, evaluation of maximum speed and acceleration using a SCANET system is a useful method for rat models of SCI and can complement open field scoring scales. © 2013 by The Japan Neurosurgical Society.

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Current status and perspective on regenerative medicine for spinal cord injury using iPS cell

Nakamura Masaya, Toyama Yoshiaki, Okano Hideyuki

Clinical Neurology 53 （ 11 ） 1013 - 1016 2013年

ISSN 0009-918X

Stimulated by the 2012 Nobel Prize in Physiology or Medicine awarded for Shinya Yamanaka and Sir John Gurdon, there is an increasing interest in the iPS cells and reprogramming technologies in medical science. While iPS cells are expected to open new era providing enormous opportunities in the biomedical sciences in terms of cell therapies for regenerative medicine, safety-related concerns for iPS cell-based cell therapy should be resolved prior to the clinical application of iPS cells. In this symposium, the pre-clinical investigations of cell therapy for SCI using neural stem/progenitor cells derived from iPS cells, and their safety issues in vivo are outlined.

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Classification of the pain nature of CRPS type 1, based on patient complaints, into neuropathic pain and nociceptive/inflammatory pain, using the McGill Pain Questionnaire

Sumitani Masahiko, Kogure Takamichi, Nakamura Masaya, Shibata Masahiko, Arito Yozu, Otake Yuko, Yamada Yoshitsugu

Journal of Anesthesia and Clinical Research 4 （ 8 ） 2013年

Objectives: The precise causes of Complex Regional Pain Syndrome (CRPS) are as yet not well known. Some consider CRPS type 1 without apparent nerve injury to arise due to a prolonged inflammatory state after initial trauma and its underlying pathophysiology indicates Nociceptive/Inflammatory Pain (NocP) components. Yet others have shown clear direct evidence of nerve injury in CRPS type 1-affected limbs, and they consider CRPS type 1to be Neuropathic Pain (NeP). The McGill Pain Questionnaire (MPQ) has the potential to diagnose pain disorders as well as suggest the underlying pathophysiology. Methods: We investigated pain characteristics of 165 NeP and 66 NocP patients, by using the 78 words of the MPQ, and thereby developed a discriminant function which efficiently discriminates NocP from NeP. We then applied this function to 36 CRPS type 1 patients' complaints and classified their pain into either NocP or NeP. Results: The discriminant probability of the function was 81.0% (chi-square, p=0.24) and this function revealed 47.2% of CRPS type 1 patients' complaints were classified as NocP and 52.8% as NeP. These subgroups showed almost comparable demographic data. Considerations: Our results indicate that CRPS type 1 cannot be classified as NeP or NocP dichotomously according to pain descriptions. This raises the possibility that CRPS type 1 represents a "mixed" pain mechanism comprised of both NeP and NocP. © 2013 Sumitani M, et al.

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Recurrence of lumbar disc herniation after microendoscopic discectomy

Matsumoto Morio, Watanabe Kota, Hosogane Naobumi, Tsuji Takashi, Ishii Ken, Nakamura Masaya, Chiba Kazuhiro, Toyama Yoshiaki

Journal of Neurological Surgery, Part A: Central European Neurosurgery 74 （ 4 ） 222 - 227 2013年

ISSN 2193-6315

Background Although microendoscopic discectomy (MED) is a minimally invasive surgical method for lumbar disc herniation (LDH), early postoperative recurrence may outweigh that advantage. The purpose of the present study was to retrospectively investigate the recurrence rate after MED for LDH and to determine the risk factors for recurrence in patients treated by a single surgeon. Materials and Methods The study included 344 patients who underwent MED (213 males and 131 females; mean age, 39.3 years; age range, 11-82 years; mean follow-up, 3.6 years; follow-up range, 2.0-6.5 years). The clinical outcomes were evaluated using the Japanese Orthopedic Association Score for Low Back Pain (JOA score). Recurrence factors investigated by logistic regression analysis included age; sex; level, laterality, and classified type of LDH; occupation; sports activity; and learning curve of the surgeon. Results LDH recurrence was observed in 37 patients (10.8%). It was observed at the same level in the ipsilateral side as the original LDH in 30 patients, in the contralateral side in three patients, and at a level adjacent to the original level in four patients. The mean time interval between MED and the recurrence was 16.6 months (range, 0.5-52 months). Twenty patients (54.1%) developed recurrence within 1 year after MED. Twenty-two patients (59.5%) were treated by revision surgery (MED in 20 patients and microdiscectomy in two patients), and 15 patients (40.5%) were treated conservatively. The mean JOA score of all the patients was 14.7 ± 3.5 before surgery and 26.5 ± 2.2 at the final follow-up, yielding an average recovery rate of 82.3 ± 15.7%. The recovery rate was 83.1 ± 14.8% in patients without recurrence and 75.7 ± 20.4% in patients with recurrence (p = 0.006). By logistic regression analysis, we identified migration of LDH as a significant factor related to recurrence. The patients with caudal migration of LDH had recurrence more frequently (19.0%) than those with rostral migration (12.5%) or without migration (10.2%) (p = 0.04; odds ratio, 2.0; 95% confidence interval, 1.0-3.8). Conclusion The recurrence rate and reoperation rate for LDH after MED were comparable to those of conventional discectomy. More than half of the cases of recurrence occurred at an early postoperative phase, and patients with caudally migrated LDH experienced recurrence significantly more often than those with rostrally migrated or nonmigrated LDH. ©2013 Georg Thieme Verlag KG Stuttgart, New York.

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Time-dependent changes in the microenvironment of injured spinal cord affects the therapeutic potential of neural stem cell transplantation for spinal cord injury

Nishimura Soraya, Yasuda Akimasa, Iwai Hiroki, Takano Morito, Kobayashi Yoshiomi, Nori Satoshi, Tsuji Osahiko, Fujiyoshi Kanehiro, Ebise Hayao, Toyama Yoshiaki, Okano Hideyuki, Nakamura Masaya

Molecular Brain 6 （ 1 ） 2013年

Background: The transplantation of neural stem/progenitor cells (NS/PCs) at the sub-acute phase of spinal cord injury, but not at the chronic phase, can promote functional recovery. However, the reasons for this difference and whether it involves the survival and/or fate of grafted cells under these two conditions remain unclear. To address this question, NS/PC transplantation was performed after contusive spinal cord injury in adult mice at the sub-acute and chronic phases. Results: Quantitative analyses using bio-imaging, which can noninvasively detect surviving grafted cells in living animals, revealed no significant difference in the survival rate of grafted cells between the sub-acute and chronic transplantation groups. Additionally, immunohistology revealed no significant difference in the differentiation phenotypes of grafted cells between the two groups. Microarray analysis revealed no significant differences in the expression of genes encoding inflammatory cytokines or growth factors, which affect the survival and/or fate of grafted cells, in the injured spinal cord between the sub-acute and chronic phases. By contrast, the distribution of chronically grafted NS/PCs was restricted compared to NS/PCs grafted at the sub-acute phase because a more prominent glial scar located around the lesion epicenter enclosed the grafted cells. Furthermore, microarray and histological analysis revealed that the infiltration of macrophages, especially M2 macrophages, which have anti-inflammatory role, was significantly higher at the sub-acute phase than the chronic phase. Ultimately, NS/PCs that were transplanted in the sub-acute phase, but not the chronic phase, promoted functional recovery compared with the vehicle control group. Conclusions: The extent of glial scar formation and the characteristics of inflammation is the most remarkable difference in the injured spinal cord microenvironment between the sub-acute and chronic phases. To achieve functional recovery by NS/PC transplantation in cases at the chronic phase, modification of the microenvironment of the injured spinal cord focusing on glial scar formation and inflammatory phenotype should be considered. © 2013 Nishimura et al.; licensee BioMed Central Ltd.

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Chondroitin sulphate N-acetylgalactosaminyl-transferase-1 inhibits recovery from neural injury

Takeuchi Kosei, Yoshioka Nozomu, Higa Onaga Susumu, Watanabe Yumi, Miyata Shinji, Wada Yoshino, Kudo Chika, Okada Masayasu, Ohko Kentaro, Oda Kanako, Sato Toshiya, Yokoyama Minesuke, Matsushita Natsuki, Nakamura Masaya, Okano Hideyuki, Sakimura Kenji, Kawano Hitoshi, Kitagawa Hiroshi, Igarashi Michihiro

Nature Communications 4 2013年

Extracellular factors that inhibit axon growth and intrinsic factors that promote it affect neural regeneration. Therapies targeting any single gene have not yet simultaneously optimized both types of factors. Chondroitin sulphate (CS), a glycosaminoglycan, is the most abundant extracellular inhibitor of axon growth. Here we show that mice carrying a gene knockout for CS N-acetylgalactosaminyltransferase-1 (T1), a key enzyme in CS biosynthesis, recover more completely from spinal cord injury than wild-type mice and even chondroitinase ABC-treated mice. Notably, synthesis of heparan sulphate (HS), a glycosaminoglycan promoting axonal growth, is also upregulated in TI knockout mice because HS-synthesis enzymes are induced in the mutant neurons. Moreover, chondroitinase ABC treatment never induces HS upregulation. Taken together, our results indicate that regulation of a single gene, T1, mediates excellent recovery from spinal cord injury by optimizing counteracting effectors of axon regeneration - an extracellular inhibitor of CS and intrinsic promoters, namely, HS-synthesis enzymes. © 2013 Macmillan Publishers Limited. All rights reserved.

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Human induced pluripotent stem (iPS) cells-derived neural stem cell bundle covered with growth factor-encapsulated amphiphilic chitosan

Kato-Negishi Midori, Onoe Hiroaki, Iwanaga Shintaroh, Kobayashi Yoshiomi, Nakamura Masaya, Okano Hideyuki, Takeuchi Shoji

1054 - 1056 2013年

This paper describes human induced pluripotent stem (iPS) cell-derived neural stem cell (hiPSC-NSC) bundles covered with growth factor-encapsulated amphiphilic chitosan. The hiPSC-NSC bundle is formed by 4-12 hiPSC-NSC microfibers that are made by core-shell hydrogel microfibers encapsulating hiPSC-NSCs. The hiPSC-NSC microfibers can be cultured for over two weeks and induced to differentiate into neurons predominantly. We modified the coating material to make bundle structures that have growth factor enrichment capability (Figure 1). The coating material, amphiphilic chitosan, can release growth factors slowly for a long time, allowing hiPSC-NSCs to survive, grow and differentiate into neural lineages in the bundle structure. We believe that our hiPSC-NSC bundle would be an extremely effective tool for neural transplantation in neurodegenerative diseases such as stroke, spinal cord injury and peripheral nerve injury, because hiPSC-NSCs in the bundle structure have long-term survival ability in vivo.

Pre-Evaluated Safe Human iPSC-Derived Neural Stem Cells Promote Functional Recovery after Spinal Cord Injury in Common Marmoset without Tumorigenicity

Kobayashi Yoshiomi, Okada Yohei, Itakura Go, Iwai Hiroki, Nishimura Soraya, Yasuda Akimasa, Nori Satoshi, Hikishima Keigo, Konomi Tsunehiko, Fujiyoshi Kanehiro, Tsuji Osahiko, Toyama Yoshiaki, Yamanaka Shinya, Nakamura Masaya, Okano Hideyuki

PLoS ONE 7 （ 12 ） 2012年12月

Murine and human iPSC-NS/PCs (induced pluripotent stem cell-derived neural stem/progenitor cells) promote functional recovery following transplantation into the injured spinal cord in rodents. However, for clinical applicability, it is critical to obtain proof of the concept regarding the efficacy of grafted human iPSC-NS/PCs (hiPSC-NS/PCs) for the repair of spinal cord injury (SCI) in a non-human primate model. This study used a pre-evaluated "safe" hiPSC-NS/PC clone and an adult common marmoset (Callithrix jacchus) model of contusive SCI. SCI was induced at the fifth cervical level (C5), followed by transplantation of hiPSC-NS/PCs at 9 days after injury. Behavioral analyses were performed from the time of the initial injury until 12 weeks after SCI. Grafted hiPSC-NS/PCs survived and differentiated into all three neural lineages. Furthermore, transplantation of hiPSC-NS/PCs enhanced axonal sparing/regrowth and angiogenesis, and prevented the demyelination after SCI compared with that in vehicle control animals. Notably, no tumor formation occurred for at least 12 weeks after transplantation. Quantitative RT-PCR showed that mRNA expression levels of human neurotrophic factors were significantly higher in cultured hiPSC-NS/PCs than in human dermal fibroblasts (hDFs). Finally, behavioral tests showed that hiPSC-NS/PCs promoted functional recovery after SCI in the common marmoset. Taken together, these results indicate that pre-evaluated safe hiPSC-NS/PCs are a potential source of cells for the treatment of SCI in the clinic. © 2012 Kobayashi et al.

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MRI Characterization of Paranodal Junction Failure and Related Spinal Cord Changes in Mice

Takano Morito, Hikishima Keigo, Fujiyoshi Kanehiro, Shibata Shinsuke, Yasuda Akimasa, Konomi Tsunehiko, Hayashi Akiko, Baba Hiroko, Honke Koichi, Toyama Yoshiaki, Okano Hideyuki, Nakamura Masaya

PLoS ONE 7 （ 12 ） 2012年12月

The paranodal junction is a specialized axon-glia contact zone that is important for normal neuronal activity and behavioral locomotor function in the central nervous system (CNS). Histological examination has been the only method for detecting pathological paranodal junction conditions. Recently, diffusion tensor MRI (DTI) has been used to detect microstructural changes in various CNS diseases. This study was conducted to determine whether MRI and DTI could detect structural changes in the paranodal junctions of the spinal cord in cerebroside sulfotransferase knock-out (CST-KO) mice. Here, we showed that high-resolution MRI and DTI characteristics can reflect paranodal junction failure in CST-KO mice. We found significantly lower T1 times and significantly higher T2 times in the spinal cord MRIs of CST-KO mice as compared to wild-type (WT) mice. Spinal cord DTI showed significantly lower axial diffusivity and significantly higher radial diffusivity in CST-KO mice as compared to WT mice. In contrast, the histological differences in the paranodal junctions of WT and CST-KO mice were so subtle that electron microscopy or immunohistological analyses were necessary to detect them. We also measured gait disturbance in the CST-KO mice, and determined the conduction latency by electrophysiology. These findings demonstrate the potential of using MRI and DTI to evaluate white matter disorders that involve paranodal junction failure. © 2012 Takano et al.

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Novel In Vivo Imaging Analysis of an Inner Ear Drug Delivery System in Mice

Kanzaki Sho, Fujioka Masato, Yasuda Akimasa, Shibata Shinsuke, Nakamura Masaya, Okano Hirotaka James, Ogawa Kaoru, Okano Hideyuki

PLoS ONE 7 （ 12 ） 2012年12月

Objective: Systemic steroid injections are used to treat idiopathic sudden-onset sensorineural hearing loss (ISSHL) and some inner ear disorders. Recent studies show that transtympanic (TT) steroid injections are effective for treating ISSHL. As in vivo monitoring of drug delivery dynamics for inner ear is lacking, its time course and dispersion of drugs is unknown. Here, we used a new in vivo imaging system to monitor drug delivery in live mice and to compare drug concentrations over time after TT and systemic injections. Methods: Luciferin delivered into the inner ears of GFAP-Luc transgenic mice reacted with luciferase in GFAP-expressing cells in the cochlear spiral ganglion, resulting in photon bioluminescence. We used the Xenogen IVIS® imaging system to measure how long photons continued to be emitted in the inner ear after TT or systemic injections of luciferin, and then compared the associated drug dynamics. Results: The response to TT and IP injections differed significantly. Photons were detected five minutes after TT injection, peaking at ~20 minutes. By contrast, photons were first detected 30 minutes after i.p. injection. TT and i.p. drug delivery time differed considerably. With TT injections, photons were detected earlier than with IP injections. Photon bioluminescence also disappeared sooner. Delivery time varied with TT injections. Conclusions: We speculate that the drug might enter the Eustachian tube from the middle ear. We conclude that inner-ear drug concentration can be maintained longer if the two injection routes are combined. As the size of luciferin differs from that of therapeutics like dexamethasone, combining drugs with luciferin may advance our understanding of in vivo drug delivery dynamics in the inner ear. © 2012 Kanzaki et al.

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Conditions for quantitative evaluation of injured spinal cord by in vivo diffusion tensor imaging and tractography

Konomi Tsunehiko, Fujiyoshi Kanehiro, Hikishima Keigo, Komaki Yuji, Tsuji Osahiko, Okano Hirotaka James, Toyama Yoshiaki, Okano Hideyuki, Nakamura Masaya

NeuroImage 63 （ 4 ） 1841 - 1853 2012年12月

ISSN 1053-8119

Conventional magnetic resonance imaging (MRI) can detect hemorrhage, edema, syrinx, and spinal cord atrophy, but not axonal disruption after spinal cord injury (SCI). We previously demonstrated that diffusion tensor tractography (DTT) could depict axonal disruption after hemisection SCI in common marmosets. In the present study, to determine the relationship between DTT results and functional recovery after contusive SCI, we performed longitudinal DTT, behavioral, and histological analyses before and after contusive SCI in common marmosets. By comparing the tract fiber estimate depicted by DTT with neuronal fibers labeled with RT97 and SMI-31, anti-neurofilament antibodies, we determined the optimal fractional anisotropy (FA) threshold for fiber tracking to be 0.40. The ratio of the number of tract fiber estimates at the lesion site to the number before SCI, determined by DTT, was significantly correlated with the functional recovery after SCI. Moreover, comparison of the longitudinal pre- and post-SCI FA and axial diffusivity (λ_||) values revealed that they decreased after injury at the sites caudal to the lesion epicenter in the corticospinal tract and rostral to the lesion epicenter in the dorsal column. The FA values, then, showed partial recovery in the dorsal column. FA-value-oriented color DTT was used to represent axonal sparing or regeneration of the different tracts. These findings indicated that DTT analysis might be a versatile non-invasive tool for evaluating the axonal disruption after SCI. © 2012 Elsevier Inc.

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Efficient Derivation of Multipotent Neural Stem/Progenitor Cells from Non-Human Primate Embryonic Stem Cells

Shimada Hiroko, Okada Yohei, Ibata Keiji, Ebise Hayao, Ota Shin ichi, Tomioka Ikuo, Nomura Toshihiro, Maeda Takuji, Kohda Kazuhisa, Yuzaki Michisuke, Sasaki Erika, Nakamura Masaya, Okano Hideyuki

PLoS ONE 7 （ 11 ） 2012年11月

The common marmoset (Callithrix jacchus) is a small New World primate that has been used as a non-human primate model for various biomedical studies. We previously demonstrated that transplantation of neural stem/progenitor cells (NS/PCs) derived from mouse and human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) promote functional locomotor recovery of mouse spinal cord injury models. However, for the clinical application of such a therapeutic approach, we need to evaluate the efficacy and safety of pluripotent stem cell-derived NS/PCs not only by xenotransplantation, but also allotransplantation using non-human primate models to assess immunological rejection and tumorigenicity. In the present study, we established a culture method to efficiently derive NS/PCs as neurospheres from common marmoset ESCs. Marmoset ESC-derived neurospheres could be passaged repeatedly and showed sequential generation of neurons and astrocytes, similar to that of mouse ESC-derived NS/PCs, and gave rise to functional neurons as indicated by calcium imaging. Although marmoset ESC-derived NS/PCs could not differentiate into oligodendrocytes under default culture conditions, these cells could abundantly generate oligodendrocytes by incorporating additional signals that recapitulate in vivo neural development. Moreover, principal component analysis of microarray data demonstrated that marmoset ESC-derived NS/PCs acquired similar gene expression profiles to those of fetal brain-derived NS/PCs by repeated passaging. Therefore, marmoset ESC-derived NS/PCs may be useful not only for accurate evaluation by allotransplantation of NS/PCs into non-human primate models, but are also applicable to analysis of iPSCs established from transgenic disease model marmosets. © 2012 Shimada et al.

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Comparative study of spinopelvic sagittal alignment between patients with and without degenerative spondylolisthesis

Funao Haruki, Tsuji Takashi, Hosogane Naobumi, Watanabe Kota, Ishii Ken, Nakamura Masaya, Chiba Kazuhiro, Toyama Yoshiaki, Matsumoto Morio

European Spine Journal 21 （ 11 ） 2181 - 2187 2012年11月

ISSN 0940-6719

Abstract Introduction To date, few studies have focused on spinopelvic sagittal alignment as a predisposing factor for the development of degenerative spondylolisthesis (DS). The objectives of this study were to compare differences in spinopelvic sagittal alignment between patients with or without DS and to elucidate factors related to spinopelvic sagittal alignment. Materials and methods A total of 100 patients with or without DS who underwent surgery for lumbar spinal canal stenosis were assessed in this study. Fifty patients with DS (DS group) and 50 age- and gender-matched patients without DS (non-DS group) were enrolled. Spinopelvic parameters including pelvic incidence (PI), sacral slope (SS), pelvic tilt (PT), L4 slope, L5 slope, thoracic kyphosis (TK), lumbar lordosis (LL) and sagittal balance were compared between the two groups. In the DS group, the percentage of vertebral slip (% slip) was also measured. Results Several spinopelvic parameters, PI, SS, L4 slope, L5 slope, TK and LL, in the DS group were significantly greater than those in the non-DS group, and PI had positive correlation with % slip (r = 0.35, p0.05). Degrees of correlations among spinopelvic parameters differed between the two groups. In the DS group, PI was more strongly correlated with SS (r = 0.82, p0.001) than with PT (r = 0.41, p0.01). In the non-DS group, PI was more strongly correlated with PT (r = 0.73, p0.001) than with SS (r = 0.38, p0.01). Conclusions Greater PI may lead to the development and the progression of vertebral slip. Different compensatory mechanisms may contribute to the maintenance of spinopelvic sagittal alignment in DS and non-DS patients. © 2012 Springer-Verlag.

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Sustained bFGF-release tubes for peripheral nerve regeneration

Takagi Takehiko, Kimura Yu, Shibata Shinsuke, Saito Harukazu, Ishii Ken, Okano Hirotaka J., Toyama Yoshiaki, Okano Hideyuki, Tabata Yasuhiko, Nakamura Masaya

Plastic and Reconstructive Surgery 130 （ 4 ） 866 - 876 2012年10月

ISSN 0032-1052

BACKGROUND: Despite numerous articles on the use of artificial nerve conduits, autologous nerve transplants remain the most effective for nerve repair. To improve this technique, the authors examined conduits containing gelatin hydrogel as a carrier enabling the sustained release of basic fibroblast growth factor (bFGF). METHODS: To confirm sustained bFGF release in vivo, nerve-guide tubes containing iodine-125-labeled bFGF with or without gelatin hydrogel were implanted under the skin of mice, and the remaining radioactivity was measured. Next, a 15-mm segment of the sciatic nerve was resected and repaired with autologous nerve (group 1), a tube with gelatin hydrogel and bFGF (group 2), a tube with bFGF alone (group 3), or a tube only (group 4). Histologic and functional analyses were performed for 16 weeks after surgery. RESULTS: The radioactivity from iodine-125-labeled bFGF incorporated into gelatin hydrogel decreased more slowly than iodine-125-labeled bFGF alone. Four weeks after surgery, significantly more regenerating axons were detected in group 2 than in groups 3 and 4, but the axonal density in group 2 was lower than in group 1. Similarly, the animals in group 2 showed significantly better motor performance than those in groups 3 and 4, but worse than those in group 1. The animals in groups 1 and 2 showed significantly better sensory recovery than those in groups 3 and 4. CONCLUSIONS: The nerve-guide tube containing gelatin hydrogel and bFGF promoted axonal regeneration after peripheral nerve injury, but not as well as autologous transplants. Understanding the limitations of this technique will facilitate its improvement for clinical applications. Copyright © 2012 by the American Society of Plastic Surgeons.

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A novel multi-kinase inhibitor pazopanib suppresses growth of synovial sarcoma cells through inhibition of the PI3K-AKT pathway

Hosaka Seiichi, Horiuchi Keisuke, Yoda Masaki, Nakayama Robert, Tohmonda Takahide, Susa Michiro, Nakamura Masaya, Chiba Kazuhiro, Toyama Yoshiaki, Morioka Hideo

Journal of Orthopaedic Research 30 （ 9 ） 1493 - 1498 2012年09月

ISSN 0736-0266

Synovial sarcoma is an aggressive soft tissue sarcoma with only a modest response to conventional cytotoxic agents. In the present study, we evaluated the potential antitumor effects of a novel anti-angiogenesis agent, pazopanib, against synovial sarcoma cells. We found that pazopanib directly inhibited the growth of synovial sarcoma cells by inducing G1 arrest. Multiplex analyses revealed that the PI3K-AKT pathway was highly suppressed in pazopanib-sensitive synovial sarcoma cells. Furthermore, administration of pazopanib highly suppressed the tumor growth in a xenograft model. Taken together, these results suggest pazopanib as a possible agent against synovial sarcoma and may warrant further clinical studies. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

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Serum cartilage metabolites as biomarkers of degenerative lumbar scoliosis

Hosogane Naobumi, Watanabe Kota, Tsuji Takashi, Miyamoto Takeshi, Ishii Ken, Niki Yasuo, Nakamura Masaya, Toyama Yoshiaki, Chiba Kazuhiro, Matsumoto Morio

Journal of Orthopaedic Research 30 （ 8 ） 1249 - 1253 2012年08月

ISSN 0736-0266

Several biomarkers have been used to evaluate osteoarthritis of the limb joints. Here we evaluated the use of serum cartilage metabolites as biomarkers for degenerative lumbar scoliosis (DLS). Fifty-two DLS patients with Cobb angle>10° were compared with 19 control patients. Serum levels of hyaluronic acid (HA), keratan sulfate (KS), cartilage oligomeric matrix protein (COMP), collagen type II cleavage (C2C), and procollagen type II C-propeptide (CPII) were measured. Serum levels of KS (DLS 1.20±0.44μg/ml vs. control 0.98±0.33μg/ml), CPII (DLS 1905.1±948.2ng/ml vs. control 1223.6±884.4ng/ml), and C2C (DLS 219.1±59.2ng/ml vs. control 177.7±71.7ng/ml) were significantly higher in DLS. There were no significant differences in the levels of HA or COMP. There was a significant positive correlation between the Cobb angle and CPII in DLS. This is the first study to evaluate the cartilage biomarkers in DLS. The results suggest DLS patients have higher levels of type II collagen synthesis and degradation, indicated by elevated serum CPII and C2C, respectively. As type II collagen is a major component of collagens in the nucleus pulposus and facet joint cartilages, its enhanced turnover may be related to the development and progression of DLS. Copyright © 2012 Orthopaedic Research Society.

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Surgical treatment of spinal extradural arachnoid cysts in the thoracolumbar spine

Funao Haruki, Nakamura Masaya, Hosogane Naobumi, Watanabe Kota, Tsuji Takashi, Ishii Ken, Kamata Michihiro, Toyama Yoshiaki, Chiba Kazuhiro, Matsumoto Morio

Neurosurgery 71 （ 2 ） 278 - 284 2012年08月

ISSN 0148-396X

BACKGROUND: Because an idiopathic spinal extradural arachnoid cyst (SEAC) is rare, its optimal surgical treatment remains controversial. OBJECTIVE: To evaluate the results of surgical treatments for SEACs and to clarify features of the disease associated with poor outcomes. METHODS: Twelve patients with SEACs who underwent surgery at our hospital between 1988 and 2008 were examined retrospectively. The mean follow-up period was 4.7 years. Total resection of the cyst was performed in 7 patients and closure of the dural defect without cyst resection in 5 patients. Surgical outcomes were evaluated with regard to the duration of symptoms, the size of the cyst, and the surgical procedure used. RESULTS: Neurological recovery was observed in all patients, and there was no recurrence. Poor outcomes were observed in patients with a long duration of symptoms (>1 year, P < .01) and large cyst size (>5 vertebrae, P < .05). The surgical procedure had no significant association with the postoperative neurological recovery. However, there was a significant difference in the degree of the mean postoperative kyphotic angle between the patients treated by total resection of the cyst (9.7 degrees) and those treated by closure of the dural defect without cyst resection through selective laminectomy (2.2 degrees) (P < .01). CONCLUSION: There was no significant difference in postoperative neurological recovery between the 2 surgical procedures. However, closure of the dural defect without cyst resection was less invasive, preventing postoperative kyphotic deformity of the thoracolumbar spine. Copyright © 2012 by the Congress of Neurological Surgeons.

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Clinical significance of diffusion tensor tractography as a predictor of functional recovery after laminoplasty in patients with cervical compressive myelopathy

Nakamura Masaya, Fujiyoshi Kanehiro, Tsuji Osahiko, Konomi Tsunehiko, Hosogane Naobumi, Watanabe Kota, Tsuji Takashi, Ishii Ken, Momoshima Suketaka, Toyama Yoshiaki, Chiba Kazuhiro, Matsumoto Morio

Journal of Neurosurgery: Spine 17 （ 2 ） 147 - 152 2012年08月

ISSN 1547-5654

Object. This study was conducted to determine whether postoperative changes in the fractional anisotropy (FA) value and diffusion tensor imaging of the cervical spinal cord can predict functional outcome for patients with cervical compressive myelopathy (CCM). Methods. Twenty patients with CCM were treated by laminoplasty from 2008 to 2009. Both T2-weighted MRI and diffusion tensor imaging were performed before and after surgery. The FA values were analyzed and fiber tracking was performed. The fiber tract (FT) ratio was calculated according to the following formula: (number of fibers at the compressed level)/(number of fibers at the C-2 level) x 100%. The Japanese Orthopaedic Association scoring system for cervical myelopathy was used to determine pre- and postoperative neurological status of the patients, and the Hirabayashi method was used to calculate the recovery rate. Results. There was no significant difference in recovery rates between patients with and those without intramedullary high signal intensity on preoperative T2-weighted images. Substantial differences in FA value among spinal cord, bone, and CSF made it difficult to obtain a precise FA value for the compressed spinal cord. There was a significant correlation between the preoperative FT ratio and the recovery rate (p = 0.0006). A poor outcome (recovery rate < 40%) could be anticipated for CCM patients with preoperative FT ratios below 60%. Conclusions. The preoperative FT ratio correlated significantly with the recovery rates in CCM patients. Preoperative diffusion tensor tractography can be a new prognostic predictor for neurological recovery in CCM patients after laminoplasty.

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Impact of lamina closure on long-term outcomes of open-door laminoplasty in patients with cervical myelopathy

Matsumoto Morio, Watanabe Kota, Hosogane Naobumi, Tsuji Takashi, Ishii Ken, Nakamura Masaya, Chiba Kazuhiro, Toyama Yoshiaki

Spine 37 （ 15 ） 1288 - 1291 2012年07月

ISSN 0362-2436

Study Design: A prospective follow-up study. Objective: To elucidate the impact of lamina closure on long-term outcomes after open-door laminoplasty. Summary of Background Data: In a previous study, we did not find significant associations between lamina closure and short-term outcomes. Methods: Of the original cohort of 82 patients who underwent open-door laminoplasty, 69 were included in this study (52 men, 17 women; mean age, 60.9 yr; mean follow-up, 6.2 yr; 56 with spondylosis or disc herniation, 13 with ossification of posterior longitudinal ligament). Lamina closure was previously observed in 23 of these patients (closure group) but not in 46 (nonclosure group). The Japanese Orthopaedic Association (JOA) scores and Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire were recorded. Results: The JOA score was 9.9 ± 3.2 in the closure group and 11.2 ± 2.3 in the nonclosure group before surgery (P = 0.1), 13.8 ± 2.3 and 13.8 ± 2.2 at 1.8 years (P = 0.99), and 13.6 ± 2.2 and 14.2 ± 2.7 at final follow-up (P = 0.29). The recovery rate of the JOA scores was 56.7 ± 30.0% and 46.7 ± 29.2% at 1.8 years (P = 0.22) and 51.0 ± 32.5 and 57.6 ± 31.1 at the final follow-up (P = 0.42). The subdomains assessed by the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire at follow-up were cervical spine function, 68.7 ± 27.5 in the closure group and 67.7 ± 30.0 in the nonclosure group (P = 0.93); upper extremity function, 78.6 ± 24.3 and 87.6 ± 15.4 (P = 0.40); lower extremity function, 69.9 ± 26.0 and 73.9 ± 22.5 (P = 0.68); bladder function, 74.6 ± 22.6 and 84.9 ± 29.2 (P = 0.18); and quality of life, 53.9 ± 25.3 and 56.2 ± 18.1 (P = 0.96). Conclusion: Lamina closure did not significantly impact the long-term surgical outcomes of laminoplasty for cervical myelopathy. Although not statistically significant, the recovery rate tended to decline in the closure group compared with the nonclosure group during the long-term follow-up period, and the utilization of a laminar retention device to prevent the laminar closure should be considered. Copyright © 2012 Lippincott Williams & Wilkins.

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Cell transplantation for spinal cord injury focusing on iPSCs

Nakamura Masaya, Tsuji Osahiko, Nori Satoshi, Toyama Yoshiaki, Okano Hideyuki

Expert Opinion on Biological Therapy 12 （ 7 ） 811 - 821 2012年07月

ISSN 1471-2598

Introduction: Reports of functional recovery from spinal cord injury (SCI) after the transplantation of neural stem cells (NSCs) derived from fetus/embryonic stem cells (ESCs), has raised great expectations for the successful clinical use of stem cell transplantation therapy. However, the ethical issues involved in destroying human embryos or fertilized oocytes to obtain NSCs have been a major obstacle to developing clinically useful stem cell sources, and the transplantation of stem cells isolated from other human embryonic tissues has not yet been developed for use in clinical applications. Areas covered: Recently, induced pluripotent stem cells (iPSCs), which can serve as a source of cells for autologous transplantation, have been attracting a great deal of attention as a clinically viable alternative to stem cells obtained directly from tissues. In this review, the authors outline the neural induction of ESC/iPSC, their therapeutic efficacy in SCI and their safety in vivo. Expert opinion: Although iPSCs offer great promise as the cell source for autologous transplantation for SCI, safety issues including tumorigenicity should be determined prior to the clinical trial. © 2012 Informa UK, Ltd.

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Central neuropathic pain after surgical resection in patients with spinal intramedullary tumor

Nakamura Masaya, Tsuji Osahiko, Iwanami Akio, Tsuji Takashi, Ishii Ken, Toyama Yoshiaki, Chiba Kazuhiro, Matsumoto Morio

Journal of Orthopaedic Science 17 （ 4 ） 352 - 357 2012年07月

ISSN 0949-2658

Study design Retrospective case series. Objective To examine central neuropathic pain after surgical resection of intramedullary spinal cord tumor (IMSCT). Summary of background data Because of the rarity of IMSCT, there is little information about postoperative neuropathic pain after surgical resection. Methods Eighty-five of 105 patients treated surgically for IMSCT at our hospital between 2000 and 2008 completed the Neuropathic Pain Symptom Inventory (NPSI) and the short form (SF)-36 health inventory. The NPSI score was analyzed against the tumor type and the postoperative Japanese Orthopaedic Association (JOA) score for neurological symptoms. Results The mean NPSI score of the patients was 13.5. The subscore for paresthesia/dysesthesia was significantly higher than the other subscores. Analysis of the NPSI scores by tumor type revealed no significant differences among patients with ependymoma, astrocytoma, and vascular tumors. The postoperative JOA score showed a weak negative correlation with the NPSI score in patients with thoracic spinal cord tumor, and no correlation in those with cervical tumor. In the 11 patients with hemangioblastoma, intense pain was reported at the level of the tumor, although postoperative paralysis was mild. All the postoperative SF-36 subscores of our study patients were significantly lower than the national average, and a significant negative correlation was observed between the SF-36 and the NPSI subscores. Conclusion Neuropathic pain after surgical resection reduces the QOL of patients with IMSCTs, and pain severity varies with the tumor's location and histological features, the severity of paralysis, and the location of pain relative to the tumor. © The Japanese Orthopaedic Association 2012.

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Neural stem cells directly differentiated from partially reprogrammed fibroblasts rapidly acquire gliogenic competency

Matsui Takeshi, Takano Morito, Yoshida Kenji, Ono Soichiro, Fujisaki Chikako, Matsuzaki Yumi, Toyama Yoshiaki, Nakamura Masaya, Okano Hideyuki, Akamatsu Wado

Stem Cells 30 （ 6 ） 1109 - 1119 2012年06月

ISSN 1066-5099

Neural stem cells (NSCs) were directly induced from mouse fibroblasts using four reprogramming factors (Oct4, Sox2, Klf4, and cMyc) without the clonal isolation of induced pluripotent stem cells (iPSCs). These NSCs gave rise to both neurons and glial cells even at early passages, while early NSCs derived from clonal embryonic stem cells (ESCs)/iPSCs differentiated mainly into neurons. Epidermal growth factor-dependent neurosphere cultivation efficiently propagated these gliogenic NSCs and eliminated residual pluripotent cells that could form teratomas in vivo. We concluded that these directly induced NSCs were derived from partially reprogrammed cells, because dissociated ESCs/iPSCs did not form neurospheres in this culture condition. These NSCs differentiated into both neurons and glial cells in vivo after being transplanted intracranially into mouse striatum. NSCs could also be directly induced from adult human fibroblasts. The direct differentiation of partially reprogrammed cells may be useful for rapidly preparing NSCs with a strongly reduced propensity for tumorigenesis. © AlphaMed Press.

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Loss of apical vertebral derotation in adolescent idiopathic scoliosis

Cui Guanyu, Watanabe Kota, Nishiwaki Yuji, Hosogane Naobumi, Tsuji Takashi, Ishii Ken, Nakamura Masaya, Toyama Yoshiaki, Chiba Kazuhiro, Matsumoto Morio

European Spine Journal 21 （ 6 ） 1111 - 1120 2012年06月

ISSN 0940-6719

Purpose: The objective of this study was to evaluate 2 years post-surgical loss of three-dimensional correction in adolescent idiopathic scoliosis (AIS) patients using multi-planar reconstruction computed tomography (CT). Methods: Twenty-seven AIS patients treated by segmental pedicle screw (PS) constructs were included in this study. Correction in the axial plane was evaluated using the "relative apical vertebral rotation angle" (rAVR), defined as the difference between the axial rotation angles of the upper instrumented vertebra and the apical vertebra on reconstructed axial CT images. The Cobb angle of the main curve and apical vertebral translation was measured to evaluate the coronal correction. Thoracic kyphosis was also measured for the evaluation of sagittal profile. Measurements were performed before surgery, and 1 week and 2 years after surgery. The relationships between the correction losses and skeletal maturity, and variety of spinal constructs were also evaluated. Results: The mean preoperative Cobb angle of the major curve was 59.1° ± 11.2° before and 13.0° ± 7.2° immediately after surgery. Two years later, the mean Cobb angle had increased significantly, to 15.5° ± 7.8°, with a mean correction loss of 2.5° ± 1.5° (p<0.001). The mean preoperative rAVR of 28.5° ± 8.4° was corrected to 15.8° ± 7.8° after surgery. It had increased significantly to 18.5 ± 8.4 by 2 years after surgery, with a mean correction loss of 2.7° ± 1.0° (p<0.001). The mean correction losses for both the Cobb angle and rAVR were significantly greater in the skeletally immature patients. The significant correlations were recognized between the correction losses and the proportion of multi-axial screws, and the materials of constructs. Conclusions: Statistically significant loss of correction in the Cobb angle and apical vertebral axial rotation angle (AVR) were recognized 2 years after surgery using PS constructs. The correction losses, especially AVR, were more evident in the skeletally immature patients, and in patients treated with more multi-axial screws and with titanium constructs rather than with stainless constructs. © Springer-Verlag 2012.

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Long-term surgical outcomes of spinal meningiomas

Nakamura Masaya, Tsuji Osahiko, Fujiyoshi Kanehiro, Hosogane Naobumi, Watanabe Kota, Tsuji Takashi, Ishii Ken, Toyama Yoshiaki, Chiba Kazuhiro, Matsumoto Morio

Spine 37 （ 10 ） 2012年05月

ISSN 0362-2436

STUDY DESIGN.: Retrospective case series. OBJECTIVE.: To evaluate the treatment strategies for spinal meningioma. SUMMARY OF BACKGROUND DATA.: Although previous studies have demonstrated favorable surgical outcomes for spinal meningioma, with a low incidence of tumor recurrence, few have examined long-term surgical outcomes. METHODS.: The influence of patient age, surgical margin status (Simpson grade), tumor location, and histological subtype on tumor recurrence were examined retrospectively. In addition, the resected dura mater from Simpson grade I cases was examined for invasive tumor cells and compared with the presence or absence of a dural tail sign on magnetic resonance image. RESULTS.: Complete resection (Simpson grades I and II) was performed in 62 patients. Among them, the tumor recurrence rate was 9.7%, all in patients who underwent grade II resection for ventral spinal lesions. The mean duration to reoperation in these patients was 12.2 ± 5.2 years. Of the 6 patients who underwent incomplete resection (Simpson grade III/IV), all required reoperation for tumor recurrence or regrowth, 5 years later on average. Patients younger than 50 years at the initial surgery had a significantly higher recurrence rate than those aged 50 years or older. Histologic examination of 43 dura mater specimens from Simpson grade I-resection patients revealed tumor cell invasion between the inner and outer layers in 15 patients. This invasion was noted in 8 (29%) of 28 patients who were negative for the dural tail sign on magnetic resonance image, and in 7 (47%) of 15 patients who showed a positive dural tail sign. The MIB-1 index reached about 10% for dumbbell-type meningiomas invading the vertebral body; these were associated with repeated recurrence and unfavorable prognosis. CONCLUSION.: Long-term follow-up after surgery for meningiomas indicated that Simpson grade I resection should be selected whenever practicable when treating younger patients or dumbbell-type meningiomas. Tumors recurred at 12 years, on average, in approximately 30% of patients who underwent grade II resection. Copyright © 2012 Lippincott Williams &Wilkins.

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Morphologic evaluation of the thoracic vertebrae for safe free-hand pedicle screw placement in adolescent idiopathic scoliosis

Cui Guanyu, Watanabe Kota, Hosogane Naobumi, Tsuji Takashi, Ishii Ken, Nakamura Masaya, Toyama Yoshiaki, Chiba Kazuhiro, Lenke Lawrence G., Matsumoto Morio

Surgical and Radiologic Anatomy 34 （ 3 ） 209 - 216 2012年04月

ISSN 0930-1038

Objective To evaluate the morphologic characteristics of the thoracic pedicle with regard to safe free-hand thoracic pedicle screw placement, based on multi-planar reconstruction CT images. Methods Thirty adolescent idiopathic scoliosis (AIS) patients who had undergone posterior corrective surgery for major thoracic curve were included in this study. Reconstructed CT axial images at each thoracic vertebra were used to measure: (1) the shortest distance from an entry point to the ventral cortex of the lamina (critical distance), and (2) the distance from the entry point to the tangent of the spinal canal at the medial wall of the pedicle (safe distance). The critical length was defined as the distance between the critical distance and the safe distance. The distance from the entry point to the medial wall breach site (breach distance) was measured on post-operative CT images. Results The mean critical distance was 9.3 ± 1.1 mm. The critical distance of vertebrae from different levels was relatively constant, between 8.1 and 10.1 mm. The mean safe distance was 15.2 ± 1.3 mm. The safe distance of vertebrae from different levels was also relatively constant, between 14.5 and 16 mm. The mean critical length was 5.9 ± 1.0 mm. The critical length of vertebrae between T3 and T12 was relatively constant, ranging from 5 to 6.5 mm. The mean breach distance was 12.3 ± 1.3 mm and the each breach always recognized between the critical distance and the safe distance. Conclusions The risk of pedicle medial wall perforation increases as the pedicle probe advances beyond the critical distance of 8-10 mm from the entry point, while it decreases entering into the safe distance at 14.5-16 mm. These parameters were relatively constant even in the most rotated vertebrae at T9 or those with the narrowest pedicle at T7 or T4. © Springer-Verlag 2011.

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Sterility of posterior elements of the spine in posterior correction surgery

Shiono Yuta, Watanabe Kota, Hosogane Naobumi, Tsuji Takashi, Ishii Ken, Nakamura Masaya, Toyama Yoshiaki, Chiba Kazuhiro, Matsumoto Morio

Spine 37 （ 6 ） 523 - 526 2012年03月

ISSN 0362-2436

Study Design.: Prospective clinical series. Objective.: To investigate the sterility of the posterior elements of the spine during posterior correction surgery. Summary of Background Data.: Bacterial growth in the operating field is considered one of the causes of surgical-site infection. Methods.: A total of 80 consecutive patients (mean age = 19.5 years) who underwent posterior correction surgery for spinal deformities were included in the study. During surgery, specimens for bacterial culture were obtained by swabs from (1) the skin after cleansing using povidone-iodine scrub solution but before draping, (2) laminae immediately after exposure, (3) laminae immediately after screw placement, (4) laminae immediately before wound closure, (5) a small piece of bone obtained from the spinous process immediately after exposure and placed on a sterile dish during surgery as a control, kept covered, and (6) a similar sample as (5), kept uncovered. The culture was conducted on both blood agar and Gifu anaerobic medium agar plates. Results.: No patient developed surgical-site infection. The culture was positive in specimen (S) 1 in 25 patients (31.3%), S2 in 20 (25%), S3 in 25 (31.3%), S4 in 26 (32.5%), S5 in 6 (7.5%), and S6 in 7 (8.8%). Bacterial species included Propionibacterium acnes in 15 specimens, Propionibacterium species in 9, and others in 10. Of the 25 patients with a positive culture in S1 and 55 patients without, 22 (88%) and 26 (47.3%), respectively, demonstrated a positive culture in specimens obtained during surgery. Conclusion.: The culture was more frequently positive in specimens obtained immediately before wound closure than in those harvested immediately after exposure and isolated from the surgical field. The results suggest that bacterial contamination of the operating field may originate from the skin of the patient during surgery. © 2012 Lippincott Williams and Wilkins.

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Bioluminescent system for dynamic imaging of cell and animal behavior

Hara-Miyauchi Chikako, Tsuji Osahiko, Hanyu Aki, Okada Seiji, Yasuda Akimasa, Fukano Takashi, Akazawa Chihiro, Nakamura Masaya, Imamura Takeshi, Matsuzaki Yumi, Okano Hirotaka James, Miyawaki Atsushi, Okano Hideyuki

Biochemical and Biophysical Research Communications 419 （ 2 ） 188 - 193 2012年03月

ISSN 0006-291X

The current utility of bioluminescence imaging is constrained by a low photon yield that limits temporal sensitivity. Here, we describe an imaging method that uses a chemiluminescent/fluorescent protein, . ffLuc-cp156, which consists of a yellow variant of . Aequorea GFP and firefly luciferase. We report an improvement in photon yield by over three orders of magnitude over current bioluminescent systems. We imaged cellular movement at high resolution including neuronal growth cones and microglial cell protrusions. Transgenic . ffLuc-cp156 mice enabled video-rate bioluminescence imaging of freely moving animals, which may provide a reliable assay for drug distribution in behaving animals for pre-clinical studies. © 2012 Elsevier Inc.

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Management of chronic atlantoaxial rotatory fixation

Ishii Ken, Toyama Yoshiaki, Nakamura Masaya, Chiba Kazuhiro, Matsumoto Morio

Spine 37 （ 5 ） 2012年03月

ISSN 0362-2436

Study Design: Retrospective case series of chronic atlantoaxial rotatory fixation (AARF) treated by a novel closed reduction method (remodeling therapy) and review of the literature. Objective: To describe clinical features of chronic AARF and the rationale of the remodeling therapy. Summary of Background Data: Treatment strategy for chronic recurrent AARF remains controversial. Posterior C1-C2 arthrodesis has been widely used for recurrent unstable AARFs after the closed reduction, and a variety of posterior fusion techniques have been advocated. In contrast, several investigators reported a chronic AARF case treated by a simple traction or closed reduction followed by cervical immobilization. Previously, we have found that a deformity of the superior C2 facet joint (C2 facet deformity) on three dimensional computed tomography (3D CT) reconstructions is a risk factor for recurrent subluxation. In addition, the remodeling of this C2 facet deformity by careful closed manipulation followed by halo fixation (remodeling therapy) could prevent the recurrence of subluxation. Methods: Twelve children with chronic AARF who sustained torticollis for an average of 4.4 months after the onset were referred to our clinic. The mean age at the initial visit was 7.8 years. All patients underwent the remodeling therapy as reported previously. Radiographic findings and clinical courses were retrospectively reviewed. Treatment methodology, pearls, and pitfalls of the remodeling therapy were discussed with review of the literature. Results: 3D CT images before reduction revealed persistent atlantoaxial subluxation and the C2 facet deformity in the dislocated side in all cases. Follow-up 3D CT scans demonstrated the remodeling of the C2 facet deformity at an average of 2.4 months after successful reduction of subluxation. Neither recurrence of symptoms nor subluxation was observed at a mean follow-up of 42 months in any case. The cervical range of motion was 73.9° at the dislocated and 83.5° at the contra-dislocated side from the midline. Conclusion: Chronic irreducible and recurrent unstable AARF should be initially managed by remodeling therapy using the facet deformity sign as a clinical index, if the C1 and C2 have not been osseously fused. Copyright © 2012 Lippincott Williams & Wilkins.

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Blockade of interleukin-6 signaling inhibits the classic pathway and promotes an alternative pathway of macrophage activation after spinal cord injury in mice

Guerrero Alexander R., Uchida Kenzo, Nakajima Hideaki, Watanabe Shuji, Nakamura Masaya, Johnson William E B, Baba Hisatoshi

Journal of Neuroinflammation 9 2012年02月

Background: Recent in vivo and in vitro studies in non-neuronal and neuronal tissues have shown that different pathways of macrophage activation result in cells with different properties. Interleukin (IL)-6 triggers the classically activated inflammatory macrophages (M1 phenotype), whereas the alternatively activated macrophages (M2 phenotype) are anti-inflammatory. The objective of this study was to clarify the effects of a temporal blockade of IL-6/IL-6 receptor (IL-6R) engagement, using an anti-mouse IL-6R monoclonal antibody (MR16-1), on macrophage activation and the inflammatory response in the acute phase after spinal cord injury (SCI) in mice.Methods: MR16-1 antibodies versus isotype control antibodies or saline alone were administered immediately after thoracic SCI in mice. SC tissue repair was compared between the two groups by Luxol fast blue (LFB) staining for myelination and immunoreactivity for the neuronal markers growth-associated protein (GAP)-43 and neurofilament heavy 200 kDa (NF-H) and for locomotor function. The expression of T helper (Th)1 cytokines (interferon (IFN)-γ and tumor necrosis factor-α) and Th2 cytokines (IL-4, IL-13) was determined by immunoblot analysis. The presence of M1 (inducible nitric oxide synthase (iNOS)-positive, CD16/32-positive) and M2 (arginase 1-positive, CD206-positive) macrophages was determined by immunohistology. Using flow cytometry, we also quantified IFN-γ and IL-4 levels in neutrophils, microglia, and macrophages, and Mac-2 (macrophage antigen-2) and Mac-3 in M2 macrophages and microglia.Results: LFB-positive spared myelin was increased in the MR16-1-treated group compared with the controls, and this increase correlated with enhanced positivity for GAP-43 or NF-H, and improved locomotor Basso Mouse Scale scores. Immunoblot analysis of the MR16-1-treated samples identified downregulation of Th1 and upregulation of Th2 cytokines. Whereas iNOS-positive, CD16/32-positive M1 macrophages were the predominant phenotype in the injured SC of non-treated control mice, MR16-1 treatment promoted arginase 1-positive, CD206-positive M2 macrophages, with preferential localization of these cells at the injury site. MR16-1 treatment suppressed the number of IFN-γ-positive neutrophils, and increased the number of microglia present and their positivity for IL-4. Among the arginase 1-positive M2 macrophages, MR16-1 treatment increased positivity for Mac-2 and Mac-3, suggestive of increased phagocytic behavior.Conclusion: The results suggest that temporal blockade of IL-6 signaling after SCI abrogates damaging inflammatory activity and promotes functional recovery by promoting the formation of alternatively activated M2 macrophages. © 2012 Guerrero et al; licensee BioMed Central Ltd.

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Spontaneous regression of soft disc herniation in patients with cervical myelopathy

Matsumoto Morio, Okada Eijiro, Watanabe Kota, Hosogane Naobumi, Tsuji Takashi, Ishii Ken, Nakamura Masaya, Chiba Kazuhiro, Toyama Yoshiaki

Neurosurgery Quarterly 22 （ 1 ） 7 - 11 2012年02月

ISSN 1050-6438

PURPOSE:: To describe patients with cervical myelopathy due to cervical disc herniation (CDH) who showed spontaneous regression, we conducted a retrospective study. METHODS:: A review of clinical records since 1990 identified 19 patients (12 male and 7 female; mean age, 42.4 y) with mild cervical myelopathy due to CDH who exhibited spontaneous CDH regression after conservative treatment. RESULTS:: The mean Japanese Orthopaedic Association scores were 13.7±1.4 before conservative treatment, 14.8±1.2 at 3 months, and 15.9±0.7 at final follow-up. On magnetic resonance imaging (MRI), the CDH regression was observed at 7.5 months on average. Intramedullary high-signal intensity was observed in 15 patients (78.9%) before treatment and 9 patients (47.4%) at follow-up. The mean area of the spinal cord was 58.4±8.3 mm before treatment and 62.4±9.7 mm at follow-up. CONCLUSIONS:: Spontaneous regression of the CDH in 19 patients with mild cervical myelopathy was observed, with improvements in neurological status and in intramedullary high-signal intensity on MRI. © 2012 by Lippincott Williams & Wilkins.

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Therapeutic potential of induced pluripotent stem cells for spinal cord injury

Nori Satoshi, Tsuji Osahiko, Okada Yohei, Toyama Yoshiaki, Okano Hideyuki, Nakamura Masaya

Brain and Nerve 64 （ 1 ） 17 - 27 2012年01月

ISSN 1881-6096

Once the safety issue has been overcome, induced pluripotent stem cells (iPSCs), which do not entail ethical or immunological concerns, may become the preferred cell source for regenerative medicine. Various types of iPSCs have been established by different methods, and each type exhibits different biological properties. Before iPSC-based clinical applications can be initiated, detailed evaluations of the cells, including their differentiation potentials and tumorigenic activities in different contexts, should be investigated to establish their safety and effectiveness for cell transplantation therapies. Recently, we demonstrated the directed neural differentiation of mouse iPSCs and examined their therapeutic potential in a mouse spinal cord injury (SCI) model. Mouse iPSC-derived neural stem/progenitor cells (NS/PCs), which had been pre-evaluated as non-tumorigenic by their transplantation into nonobese diabetic-severe combined immunodeficiency (NOD-scid) mouse brain, were transplanted into the spinal cord 9 days after SCI. Mouse iPSC-derived NS/PCs differentiated into all three neural lineages without forming teratomas or other tumors. They also participated in re-myelination and induced the axonal re-growth, promoting motor functional recovery. Nevertheless, our results constitute only the first step toward clinical application. The safety and effectiveness of human iPSC-derived NS/PCs need to be more intensively investigated in future preclinical studies, for example, using non-human primate SCI models. In particular, human iPSCs established by delivering reprogramming factors using a safer method than retrovirus system, such as an integration-free virus system, virus-free system, or transgene-free system should be evaluated.

Differential diagnosis between intracranial dissemination of spinal cord astrocytoma and paraneoplastic limbic encephalitis

Seki Morinobu, Suzuki Shigeaki, Ishii Ken, Izawa Yoshikane, Takahashi Shinichi, Toyama Yoshiaki, Nakamura Masaya, Suzuki Norihiro

Internal Medicine 51 （ 3 ） 321 - 324 2012年

ISSN 0918-2918

We describe the clinical features of limbic encephalitis that developed after palliative spinal cordotomy in 2 patients with malignant thoracic astrocytoma. Both patients showed short-term memory loss, hallucinations of smells and psychiatric symptoms. Brain MRI on T2-weighted and fluid-attenuated inversion recovery sequences revealed high intensity lesions in bilateral temporal lobe areas. We considered that both patients had paraneoplastic limbic encephalitis associated with astrocytoma because of various clinical and radiological features. But the possibility of intracranial dissemination of astrocytoma could not be fully excluded. The differential diagnosis between intracranial dissemination of spinal cord astrocytoma and paraneoplastic limbic encephalitis may be sometimes difficult. © 2012 The Japanese Society of Internal Medicine.

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Vertebral derotation in adolescent idiopathic scoliosis causes hypokyphosis of the thoracic spine

Watanabe Kota, Nakamura Takayuki, Iwanami Akio, Hosogane Naobumi, Tsuji Takashi, Ishii Ken, Nakamura Masaya, Toyama Yoshiaki, Chiba Kazuhiro, Matsumoto Morio

BMC Musculoskeletal Disorders 13 2012年

Background: The purpose of this study was to test the hypothesis that direct vertebral derotation by pedicle screws (PS) causes hypokyphosis of the thoracic spine in adolescent idiopathic scoliosis (AIS) patients, using computer simulation. Methods: Twenty AIS patients with Lenke type 1 or 2 who underwent posterior correction surgeries using PS were included in this study. Simulated corrections of each patients scoliosis, as determined by the preoperative CT scan data, were performed on segmented 3D models of the whole spine. Two types of simulated extreme correction were performed: 1) complete coronal correction only (C method) and 2) complete coronal correction with complete derotation of vertebral bodies (C + D method). The kyphosis angle (T5-T12) and vertebral rotation angle at the apex were measured before and after the simulated corrections. Results: The mean kyphosis angle after the C + D method was significantly smaller than that after the C method (2.7 ± 10.0° vs. 15.0 ± 7.1°, p<0.01). The mean preoperative apical rotation angle of 15.2 ± 5.5° was completely corrected after the C + D method (0°) and was unchanged after the C method (17.6 ± 4.2°). Conclusions: In the 3D simulation study, kyphosis was reduced after complete correction of the coronal and rotational deformity, but it was maintained after the coronal-only correction. These results proved the hypothesis that the vertebral derotation obtained by PS causes hypokyphosis of the thoracic spine. © 2012 Watanabe et al. licensee BioMed Central Ltd.

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Significance of remyelination by neural stem/progenitor cells transplanted into the injured spinal cord

Yasuda Akimasa, Tsuji Osahiko, Shibata Shinsuke, Nori Satoshi, Takano Morito, Kobayashi Yoshiomi, Takahashi Yuichiro, Fujiyoshi Kanehiro, Hara Chikako Miyauchi, Miyawaki Atsuhi, Okano Hirotaka James, Toyama Yoshiaki, Nakamura Masaya, Okano Hideyuki

Stem Cells 29 （ 12 ） 1983 - 1994 2011年12月

ISSN 1066-5099

Previous reports of functional recovery from spinal cord injury (SCI) in rodents and monkeys after the delayed transplantation of neural stem/progenitor cells (NS/PCs) have raised hopes that stem cell therapy could be used to treat SCI in humans. More research is needed, however, to understand the mechanism of functional recovery. Oligodendrocytes derived from grafted NS/PCs remyelinate spared axons in the injured spinal cord. Here, we studied the extent of this remyelination's contribution to functional recovery following contusive SCI in mice. To isolate the effect of remyelination from other possible regenerative benefits of the grafted cells, NS/PCs obtained from myelin-deficient shiverer mutant mice (shi-NS/PCs) were used in this work alongside wild-type NS/PCs (wt-NS/PCs). shi-NS/PCs behaved like wt-NS/PCs in vitro and in vivo, with the exception of their myelinating potential. shi-NS/PC-derived oligodendrocytes did not express myelin basic protein in vitro and formed much thinner myelin sheaths in vivo compared with wt-NS/PC-derived oligodendrocytes. The transplantation of shi-NS/PCs promoted some locomotor and electrophysiological functional recovery but significantly less than that afforded by wt-NS/PCs. These findings establish the biological importance of remyelination by graft-derived cells for functional recovery after the transplantation of NS/PCs into the injured spinal cord. © AlphaMed Press.

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Human hepatocyte growth factor promotes functional recovery in primates after spinal cord injury

Kitamura Kazuya, Fujiyoshi Kanehiro, Yamane Jun ichi, Toyota Fumika, Hikishima Keigo, Nomura Tatsuji, Funakoshi Hiroshi, Nakamura Toshikazu, Aoki Masashi, Toyama Yoshiaki, Okano Hideyuki, Nakamura Masaya

PLoS ONE 6 （ 11 ） 2011年11月

Many therapeutic interventions for spinal cord injury (SCI) using neurotrophic factors have focused on reducing the area damaged by secondary, post-injury degeneration, to promote functional recovery. Hepatocyte growth factor (HGF), which is a potent mitogen for mature hepatocytes and a mediator of the inflammatory responses to tissue injury, was recently highlighted as a potent neurotrophic factor in the central nervous system. We previously reported that introducing exogenous HGF into the injured rodent spinal cord using a herpes simplex virus-1 vector significantly reduces the area of damaged tissue and promotes functional recovery. However, that study did not examine the therapeutic effects of administering HGF after injury, which is the most critical issue for clinical application. To translate this strategy to human treatment, we induced a contusive cervical SCI in the common marmoset, a primate, and then administered recombinant human HGF (rhHGF) intrathecally. Motor function was assessed using an original open field scoring system focusing on manual function, including reach-and-grasp performance and hand placement in walking. The intrathecal rhHGF preserved the corticospinal fibers and myelinated areas, thereby promoting functional recovery. In vivo magnetic resonance imaging showed significant preservation of the intact spinal cord parenchyma. rhHGF-treatment did not give rise to an abnormal outgrowth of calcitonin gene related peptide positive fibers compared to the control group, indicating that this treatment did not induce or exacerbate allodynia. This is the first study to report the efficacy of rhHGF for treating SCI in non-human primates. In addition, this is the first presentation of a novel scale for assessing neurological motor performance in non-human primates after contusive cervical SCI. © 2011 Kitamura et al.

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Matrix metalloproteinase 13 in the ligamentum flavum from lumbar spinal canal stenosis patients with and without diabetes mellitus

Cui Guanyu, Watanabe Kota, Miyauchi Yoshiteru, Hosogane Naobumi, Tsuji Takashi, Ishii Ken, Nakamura Masaya, Toyama Yoshiaki, Chiba Kazuhiro, Miyamoto Takeshi, Matsumoto Morio

Journal of Orthopaedic Science 16 （ 6 ） 785 - 790 2011年11月

ISSN 0949-2658

Background: Lumbar spinal canal stenosis (LSCS) is one of the most common spinal disorders in the elderly, and ligamentum flavum (LF) hypertrophy is an important cause of LSCS. Matrix metalloproteinase 13 (MMP13) can degrade fibrillar collagens and elastic microfibrils, and is involved in inflammation and fibrosis. The purpose of this study was to compare the expression of MMP13 in the LF from LSCS patients with diabetes mellitus [DM (+)] with that in the LF from patients without DM [DM (-)] and to analyze the relationship among DM, MMP13 expression, and LF hypertrophy. Methods: LFs from 11 DM (+) and 24 DM (-) LSCS patients were analyzed in this study. Histology analysis using hematoxylin and eosin and Masson's trichrome stain was performed for each LF. The expression of MMP13 was analyzed by quantitative real-time PCR. The thickness of LF was measured by CT. Results: In the LF from DM (+) LSCS patients, the elastic fibers were more disorganized and had lower volumes than in the LF from DM (-) LSCS patients, while more fibrotic tissue was observed in the LF from DM (+) than from DM (-) LSCS patients. MMP13 expression was significantly higher in the LF from DM (+) LSCS patients (0.46 ± 0.61 vs. 0.05 ± 0.09, P = 0.002). The LF from the DM (+) LSCS patients was significantly thicker than that from the DM (-) LSCS patients (5.0 ± 0.9 vs. 3.1 ± 0.8 mm, P < 0.01), and the thickness was correlated with the expression of MMP13 (correlation coefficient = 0.43, P = 0.01, Pearson's correlation test). Conclusion: DM-related MMP13 expression can be one of the factors contributing to fibrosis and hypertrophy of the LF. Further research on the mechanism of this process may lead to new therapies for LF hypertrophy. © 2011 The Japanese Orthopaedic Association.

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Beneficial compaction of spinal cord lesion by migrating astrocytes through glycogen synthase kinase-3 inhibition

Renault-Mihara Francois, Katoh Hiroyuki, Ikegami Takeshi, Iwanami Akio, Mukaino Masahiko, Yasuda Akimasa, Nori Satoshi, Mabuchi Yo, Tada Hirobumi, Shibata Shinsuke, Saito Ken, Matsushita Masayuki, Kaibuchi Kozo, Okada Seiji, Toyama Yoshiaki, Nakamura Masaya, Okano Hideyuki

EMBO Molecular Medicine 3 （ 11 ） 682 - 696 2011年11月

ISSN 1757-4676

The migratory response of astrocytes is essential for restricting inflammation and preserving tissue function after spinal cord injury (SCI), but the mechanisms involved are poorly understood. Here, we observed stimulation of in vitro astrocyte migration by the new potent glycogen synthase kinase-3 (GSK-3) inhibitor Ro3303544 and investigated the effect of Ro3303544 administration for 5 days following SCI in mice. This treatment resulted in accelerated migration of reactive astrocytes to sequester inflammatory cells that spared myelinated fibres and significantly promoted functional recovery. Moreover, the decreased extent of chondroitin sulphate proteoglycans and collagen IV demonstrated that scarring was reduced in Ro3303544-treated mice. A variety of in vitro and in vivo experiments further suggested that GSK-3 inhibition stimulated astrocyte migration by decreasing adhesive activity via reduced surface expression of β1-integrin. Our results reveal a novel benefit of GSK-3 inhibition for SCI and suggest that the stimulation of astrocyte migration is a feasible therapeutic strategy for traumatic injury in the central nervous system. © 2011 EMBO Molecular Medicine.

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Grafted human-induced pluripotent stem-cell-derived neurospheres promote motor functional recovery after spinal cord injury in mice

Nori Satoshi, Okada Yohei, Yasuda Akimasa, Tsuji Osahiko, Takahashi Yuichiro, Kobayashi Yoshiomi, Fujiyoshi Kanehiro, Koike Masato, Uchiyama Yasuo, Ikeda Eiji, Toyama Yoshiaki, Yamanaka Shinya, Nakamura Masaya, Okano Hideyuki

Proceedings of the National Academy of Sciences of the United States of America 108 （ 40 ） 16825 - 16830 2011年10月

ISSN 0027-8424

Once their safety is confirmed, human-induced pluripotent stem cells (hiPSCs), which do not entail ethical concerns, may become a preferred cell source for regenerative medicine. Here, we investigated the therapeutic potential of transplanting hiPSC-derived neurospheres (hiPSC-NSs) into nonobese diabetic (NOD)-severe combined immunodeficient (SCID) mice to treat spinal cord injury (SCI). For this, we used a hiPSC clone (201B7), established by transducing four reprogramming factors (Oct3/4, Sox2, Klf4, and c-Myc) into adult human fibroblasts. Grafted hiPSC-NSs survived, migrated, and differentiated into the three major neural lineages (neurons, astrocytes, and oligodendrocytes) within the injured spinal cord. They showed both cell-autonomous and noncellautonomous (trophic) effects, including synapse formation between hiPSC-NS-derived neurons and host mouse neurons, expression of neurotrophic factors, angiogenesis, axonal regrowth, and increased amounts of myelin in the injured area. These positive effects resulted in significantly better functional recovery compared with vehicle-treated control animals, and the recovery persisted through the end of the observation period, 112 d post-SCI. No tumor formation was observed in the hiPSC-NS-grafted mice. These findings suggest that hiPSCs give rise to neural stem/progenitor cells that support improved function post-SCI and are a promising cell source for its treatment.

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Cell Therapy for Spinal Cord Injury by Neural Stem/Progenitor Cells Derived from iPS/ES Cells

Tsuji Osahiko, Miura Kyoko, Fujiyoshi Kanehiro, Momoshima Suketaka, Nakamura Masaya, Okano Hideyuki

Neurotherapeutics 8 （ 4 ） 668 - 676 2011年10月

ISSN 1933-7213

Reports of functional recovery from spinal cord injury after the transplantation of rat fetus-derived neural stem cells and embryonic stem cells has raised great expectations for the successful clinical use of stem cell transplantation therapy. However, the ethical issues involved in destroying human embryos or fertilized oocytes to obtain stem cells have been a major obstacle to developing clinically useful stem cell sources, and the transplantation of stem cells isolated from other human embryonic tissues has not yet been developed for use in clinical applications. Recently, induced pluripotent stem cells, which can serve as a source of cells for autologous transplantation, have been attracting a great deal of attention as a clinically viable alternative to stem cells obtained directly from tissues. In this review, we outline the neural induction of mouse embryonic stem cells and induced pluripotent stem cells, their therapeutic efficacy in spinal cord injury, and their safety in vivo. © 2011 The American Society for Experimental NeuroTherapeutics, Inc.

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Late instrumentation failure after total en bloc spondylectomy

Matsumoto Morio, Watanabe Kota, Tsuji Takashi, Ishii Ken, Nakamura Masaya, Chiba Kazuhiro, Toyama Yoshiaki

Journal of Neurosurgery: Spine 15 （ 3 ） 320 - 327 2011年09月

ISSN 1547-5654

Object. The object of this study was to investigate failures after spinal reconstruction following total en bloc spondylectomy (TES), related factors, and sequelae arising from such failures in patients with malignant spinal tumors. Methods. Fifteen patients (12 males and 3 females, with a mean age of 46.5 years) with malignant spinal tumors who underwent TES and survived for more than 1 year were included in this analysis (mean follow-up 41.5 months). Seven patients had primary tumors, including giant cell tumors in 4 patients, chordoma in 2, and Ewing sarcoma in 1. Eight patients had metastatic tumors, including thyroid cancer in 6 and renal cell cancer and malignant fibrous histiocytoma in 1 patient each. Seven patients without prominent paravertebral extension of the tumor were treated using a posterior approach alone, and 8 patients who exhibited prominent anterior or anterolateral extension of the tumors into the thoracic or abdominal cavity were treated using a combined anterior and posterior approach. Spinal reconstruction after tumor resection was performed using a combination of anterior structural support and posterior instrumentation. The relationship between instrumentation failure and clinical and radiographic factors, including age, sex, history of previous surgery, preoperative radiotherapy, tumor histology, tumor level, surgical approach, number of resected vertebrae, rod diameter, number of instrumented vertebrae, and cage subsidence, was investigated. Results. Six patients (40%) with spinal instrumentation failure were identified: rod breakage occurred in 3 patients, and breakage of both the rod and the cage, combined cage breakage and screw back-out, and endplate fracture arising from cage subsidence occurred in 1 patient each. All of these patients experienced acute or chronic back pain, but only 1 patient with a tumor recurrence experienced neurological deterioration upon instrumentation failure. Cage subsidence (≥ 5 mm), preoperative irradiation, and the number of instrumented vertebrae (≤ 4 vertebrae) were significantly related to late instrumentation failure. Conclusions. Late instrumentation failure was a frequent complication after TES. Although patients with instrumentation failure experienced back pain, the neurological sequelae were not catastrophic. For prevention, meticulous preparation of the graft site and a longer posterior fixation should be considered.

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Spatiotemporal and anatomical analyses of P2X receptor-mediated neuronal and glial processing of sensory signals in the rat dorsal horn

Aoyama Ryoma, Okada Yasumasa, Yokota Shigefumi, Yasui Yutaka, Fukuda Kentaro, Shinozaki Yoshio, Yoshida Hideaki, Nakamura Masaya, Chiba Kazuhiro, Yasui Yukihiko, Kato Fusao, Toyama Yoshiaki

Pain 152 （ 9 ） 2085 - 2097 2011年09月

ISSN 0304-3959

Extracellularly released adenosine triphosphate (ATP) modulates sensory signaling in the spinal cord. We analyzed the spatiotemporal profiles of P2X receptor-mediated neuronal and glial processing of sensory signals and the distribution of P2X receptor subunits in the rat dorsal horn. Voltage imaging of spinal cord slices revealed that extracellularly applied ATP (5-500 μM), which was degraded to adenosine and acting on P1 receptors, inhibited depolarizing signals and that it also enhanced long-lasting slow depolarization, which was potentiated after ATP was washed out. This post-ATP rebound potentiation was mediated by P2X receptors and was more prominent in the deep than in the superficial layer. Patch clamp recording of neurons in the superficial layer revealed long-lasting enhancement of depolarization by ATP through P2X receptors during the slow repolarization phase at a single neuron level. This depolarization pattern was different from that in voltage imaging, which reflects both neuronal and glial activities. By immunohistochemistry, P2X ₁ and P2X ₃ subunits were detected in neuropils in the superficial layer. The P2X ₅ subunit was found in neuronal somata. The P2X ₆ subunit was widely expressed in neuropils in the whole gray matter except for the dorsal superficial layer. Astrocytes expressed the P2X ₇ subunit. These findings indicate that extracellular ATP is degraded into adenosine and prevents overexcitation of the sensory system, and that ATP acts on pre- and partly on postsynaptic neuronal P2X receptors and enhances synaptic transmission, predominantly in the deep layer. Astrocytes are involved in sensitization of sensory network activity more importantly in the superficial than in the deep layer. © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

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Prevalence and characteristics of chronic musculoskeletal pain in Japan

Nakamura Masaya, Nishiwaki Yuji, Ushida Takahiro, Toyama Yoshiaki

Journal of Orthopaedic Science 16 （ 4 ） 424 - 432 2011年07月

ISSN 0949-2658

Background: This cross-sectional study was conducted to obtain epidemiologic data on chronic musculoskeletal pain in the Japanese people, and with it a better understanding of the actual conditions and problems involved. Methods: A questionnaire covering basic information, chronic musculoskeletal pain, daily life, quality of life, and social loss was prepared and mailed to 11507 individuals aged 18 years or older. Subjects were selected randomly nationwide in accordance with the demographic composition of Japan. Results: The prevalence of chronic musculoskeletal pain was 15.4%. The prevalence was highest in people in their 30s to 50s. Pain occurred most frequently in the low back, neck, shoulder, and knee. Among symptomatic subjects, 42% sought treatment, by visiting a medical institution (19%), taking folk remedies (20%), or both (3%). Treatment was generally prolonged, with 70% of those treated reporting treatment durations of more than a year. Although 69% reported that their symptoms had improved, 30% reported unchanged or aggravated symptoms and dissatisfaction with treatment. Among symptomatic subjects, a high percentage of both men and women had lost jobs, left school, been absent from work or school, or had changed jobs. Basic activities of daily living (ADL) were disturbed in men, and the instrumental ADL (IADL) score was low in women. SF-36 scale scores were significantly lower in every area for subjects with chronic pain. Conclusions: Chronic musculoskeletal pain does not necessarily improve even with prolonged treatment. It adversely affects daily life and both physical and mental health. Because those suffering pain often increasingly need assistance in daily activities, people around them are also affected. The therapeutic system and treatment procedures for chronic musculoskeletal pain merit prompt review. © 2011 The Author(s).

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Long-term surgical outcomes of idiopathic spinal cord herniation

Nakamura Masaya, Fujiyoshi Kanehiro, Tsuji Osahiko, Watanabe Kota, Tsuji Takashi, Ishii Ken, Matsumoto Morio, Toyama Yoshiaki, Chiba Kazuhiro

Journal of Orthopaedic Science 16 （ 4 ） 347 - 351 2011年07月

ISSN 0949-2658

Background: Because of the lack of long-term postoperative follow-up studies of idiopathic spinal cord herniation (ISCH), there is little information about the long-term effectiveness and complications of the dural defect enlargement in patients with ISCH. The purpose of this study is to determine the long-term effectiveness of this procedure. Methods: Sixteen patients with ISCH were treated surgically by enlargement of the dural defect. The patient's neurological status and surgical outcome were evaluated by the JOA scores for thoracic myelopathy and the recovery rate (mean follow-up period 9.6 years). Correlations between the surgical outcomes and patients' age and duration of disease were assessed retrospectively. The patients were also divided into two groups based on the location of the dural defect: the ventro-lateral (VL) group and the ventral (V) group. The difference in the duration of disease, preoperative JOA score, and the recovery rate were compared between the two groups. Results: There was no recurrence of ISCH after surgery. The mean recovery rate was 42.6%. There was a significant correlation between the patient's age and the recovery rate, and between the duration of disease and the recovery rate. The median recovery rate was significantly lower in the V group than in the VL group. There were no complications related to CSF leakage after surgery. Conclusions: Long-term surgical outcomes of enlargement of the dural defect for ISCH were stable and favorable without recurrences or any complications. This procedure should be considered for patients with ISCH before their neurological deficit worsens, especially for the patients in whom the dural defect is located at the ventral part of the dural canal. © 2011 The Author(s).

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The IRE1α-XBP1 pathway is essential for osteoblast differentiation through promoting transcription of Osterix

Tohmonda Takahide, Miyauchi Yoshiteru, Ghosh Rajarshi, Yoda Masaki, Uchikawa Shinichi, Takito Jiro, Morioka Hideo, Nakamura Masaya, Iwawaki Takao, Chiba Kazuhiro, Toyama Yoshiaki, Urano Fumihiko, Horiuchi Keisuke

EMBO Reports 12 （ 5 ） 451 - 457 2011年05月

ISSN 1469-221X

During skeletal development, osteoblasts produce large amounts of extracellular matrix proteins and must therefore increase their secretory machinery to handle the deposition. The accumulation of unfolded protein in the endoplasmic reticulum induces an adoptive mechanism called the unfolded protein response (UPR). We show that one of the most crucial UPR mediators, inositol-requiring protein 1α (IRE1α), and its target transcription factor X-box binding protein 1 (XBP1), are essential for bone morphogenic protein 2-induced osteoblast differentiation. Furthermore, we identify Osterix (Osx, a transcription factor that is indispensible for bone formation) as a target gene of XBP1. The promoter region of the Osx gene encodes two potential binding motifs for XBP1, and we show that XBP1 binds to these regions. Thus, the IRE1α-XBP1 pathway is involved in osteoblast differentiation through promoting Osx transcription. © 2011 European Molecular Biology Organization.

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Schwann cell plasticity after spinal cord injury shown by neural crest lineage tracing

Nagoshi Narihito, Shibata Shinsuke, Hamanoue Makoto, Mabuchi Yo, Matsuzaki Yumi, Toyama Yoshiaki, Nakamura Masaya, Okano Hideyuki

GLIA 59 （ 5 ） 771 - 784 2011年05月

ISSN 0894-1491

After spinal cord injury (SCI), various cell types are recruited to the lesion site, including Schwann cells, which originate in the neural crest and normally myelinate axons in the peripheral nervous system. Here, we investigated the differentiation states, migration patterns, and roles of neural crest derivatives following SCI, using two transgenic mouse lines carrying neural crest-specific reporters, P0-Cre/Floxed-EGFP and Wnt1-Cre/Floxed-EGFP. In these mice, EGFP is expressed only in the neural crest cell lineage. Immunohistochemical analysis revealed that most of the EGFP⁺ cells that infiltrated the lesion site after SCI were Schwann cells. Seven days after SCI, the P0-positive, mature Schwann cells residing at the nerve roots had dedifferentiated into P0^-/p75⁺ immature Schwann cells, which proliferated and began migrating into the lesion site. The dedifferentiation of the Schwann cells was corroborated by their expression of phosphorylated c-Jun, which promotes dedifferentiation and inhibits the expression of myelin-associated genes in the peripheral nerves. Thereafter, the number of EGFP⁺/p75⁺ immature Schwann cells decreased and that of EGFP⁺/P0⁺ mature cells increased gradually, indicating that the cells redifferentiated into mature Schwann cells within the lesion site. This study draws on the advantages offered by transgenic mouse lines bearing a genetic cell-lineage marker and extends previous work by describing the origins and behavior of the neural crest-derived cells that contribute to endogenous repair after SCI. This process, involving Schwann cell plasticity, is a novel repair mechanism for the lesioned mammalian spinal cord. © 2011 Wiley-Liss, Inc.

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A rare case of spinal dumbbell tanycytic ependymoma

Ishihama Hiroko, Nakamura Masaya, Funao Hiroki, Ishii Ken, Matsumoto Morio, Toyama Yoshiaki, Chiba Kazuhiro

Spine 36 （ 9 ） 2011年04月

ISSN 0362-2436

Study Design.: Case report. OBJECTIVE:: To report an extremely rare case of spinal dumbbell-type tanycyticependymoma. Summary of Background Data.: Only two previous cases of a dumbbell-type tanycyticependymoma in the spinal cordhave been reported. Methods.: A 40-year-old female presented with low back pain and numbness of the left leg. Magnetic resonance imaging revealed a dumbbell tumor at the Th10-11 level that compressed the spinal cord extensively. The diagnosis of extradural dumbell spinal tumor was made, and a total tumor excision was performed with a thoracic 10-11 laminectomy. Results.: After surgery, the patient's low back pain and numbness disappeared. Detailed immunohistological examinations confirmed the diagnosis of tanycyticependymoma. At 16 months, there was no evidence of tumor recurrence and no further treatment was needed. Conclusion.: A rare case of spinal dumbbell-type tanycyticependy-moma was presented. Detailed histologic examinations are essential to differentiate tanycyticependymoma from other tumors such as schwannoma and pilocyticastrocytoma. © 2011, Lippincott Williams & Wilkins.

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Severe progressive scoliosis due to huge subcutaneous cavernous hemangioma

Ogura Yoji, Watanabe Kota, Hosogane Naobumi, Tsuji Takashi, Ishii Ken, Nakamura Masaya, Toyama Yoshiaki, Chiba Kazuhiro, Matsumoto Morio

Scoliosis 6 （ 1 ） 2011年03月

Cavernous hemangioma consists mainly of congenital vascular malformations present before birth and gradually increasing in size with skeletal growth. A small number of patients with cavernous hemangioma develop scoliosis, and surgical treatment for the scoliosis in such cases has not been reported to date. Here we report a 12-year-old male patient with severe progressive scoliosis due to a huge subcutaneous cavernous hemangioma, who underwent posterior correction and fusion surgery. Upon referral to our department, radiographs revealed a scoliosis of 85° at T6-L1 and a kyphosis of 58° at T4-T10. CT and MR images revealed a huge hemangioma extending from the subcutaneous region to the paraspinal muscles and the retroperitoneal space and invading the spinal canal. Posterior correction and fusion surgery using pedicle screws between T2 and L3 were performed. Massive hemorrhage from the hemangioma occurred during the surgery, with intraoperative blood loss reaching 2800 ml. The scoliosis was corrected to 59°, and the kyphosis to 45° after surgery. Seven hours after surgery, the patient suffered from hypovolemic shock and disseminated intravascular coagulation due to postoperative hemorrhage from the hemangioma. The patient developed sensory and conduction aphasia caused by cerebral hypoxia during the shock on the day of the surgery. At present, two years after the surgery, although the patient has completely recovered from the aphasia. This case illustrates that, in correction surgery for scoliosis due to huge subcutaneous cavernous hemangioma, intraoperative and postoperative intensive care for hemodynamics should be performed, since massive hemorrhage can occur during the postoperative period as well as the intraoperative period.© 2011 Ogura et al; licensee BioMed Central Ltd.

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Surgical treatment for scoliosis in patients with Shprintzen-Goldberg syndrome

Watanabe Kota, Okada Eijiro, Kosaki Kenjiro, Tsuji Takashi, Ishii Ken, Nakamura Masaya, Chiba Kazuhiro, Toyama Yoshiaki, Matsumoto Morio

Journal of Pediatric Orthopaedics 31 （ 2 ） 186 - 193 2011年03月

ISSN 0271-6798

Background: Shprintzen-Goldberg syndrome (SGS) is characterized by craniosynostosis and marfanoid habitus. The clinical findings of SGS include neurological, cardiovascular, connective tissue, and skeletal abnormalities. Among these skeletal findings, developmental scoliosis is recognized in half of all patients with SGS. However, no earlier reports have described the surgical treatment of scoliosis associated with SGS. Methods: Four patients (2 boys and 2 girls; mean age at the time of surgery, 7.3±4.4 y) with SGS who underwent surgical treatment for progressive scoliosis were reviewed. The radiologic findings, operative findings, and perioperative complications were evaluated. Results: The mean preoperative Cobb angle was 102.8±16.9 degrees. The curve patterns were a double curve in 2 cases and a triple curve in 2 cases. Local kyphosis at the thoracolumbar area was recognized in all the cases with a mean kyphosis angle of 49±16 degrees. Growing rod procedures were performed in 2 patients, and posterior correction and fusion were performed in 2 patients. The mean correction rate was 45% in the patients who underwent the growing rod procedures at the time of growing rod placement and 51% in the patients who underwent posterior correction and fusion. Dislodgement of the proximal anchors occurred in 3 of the 4 patients. One patient developed pseudoarthrosis. Two patients developed deep wound infections, and implant removal was necessary in 1 patient. Conclusions: Surgical treatment for scoliosis in patients with SGS was associated with a high incidence of perioperative and postoperative complications including implant dislodgements and deep wound infections attributable to poor bone quality and a thin body habitus, which are characteristic clinical features of this syndrome. Careful preoperative surgical planning and postoperative care are critical for the surgical treatment of scoliosis associated with SGS, especially in infants requiring multiple surgeries. Level of evidence: Level IV. © 2011 by Lippincott Williams & Wilkins.

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Remodeling of C2 facet deformity prevents recurrent subluxation in patients with chronic atlantoaxial rotatory fixation

Ishii Ken, Matsumoto Morio, Momoshima Suketaka, Watanabe Kota, Tsuji Takashi, Takaishi Hironari, Nakamura Masaya, Toyama Yoshiaki, Chiba Kazuhiro

Spine 36 （ 4 ） 2011年02月

ISSN 0362-2436

Study Design. A retrospective case series. Objective. To propose a novel treatment strategy for chronic atlantoaxial rotatory fixation (AARF). Summary Of Background Data. Treatment strategy for chronic or recurrent AARF remains controversial. We have previously reported that a deformity of the superior facet of the axis (C2 facet deformity), which is frequently observed in patients with chronic AARFs, is a risk factor for recurrent dislocation. In this article, we report seven consecutive cases of chronic AARF who underwent closed manipulation followed by external halo fixation and maintained good reduction with the remodeling of the C2 facet deformity. Methods. Seven girls with a chronic AARF who sustained torticollis for an average of 4.6 months after the onset were referred to our clinic. Closed manipulation by careful manipulation under general anesthesia followed by external immobilization with a halo vest was performed in all cases. Radiographic findings and clinical courses were retrospectively reviewed with approvals by the institutional review board. Results. Three-dimensional computed tomography images before reduction revealed persistent atlantoaxial subluxation and the C2 facet deformity in the dislocated side in all cases. Follow-up three-dimensional computed tomographic scans demonstrated the remodeling of the C2 facet deformity at an average of 2.8 months after successful reduction of subluxation. Subsequently, the halo vests were removed and gentle neck range of motion exercise was started in all cases. The normal cervical range of motion was obtained 2 weeks after the removal of halo vests in five cases, whereas the range of motion remained limited in two cases. At a mean follow-up of 17.4 months, neither symptoms nor recurrence of subluxation occurred in all cases. Conclusion. Chronic irreducible and recurrent unstable AARF can be managed successfully by careful closed manipulation followed by halo fixation, if the C1 and C2 have not been osseously fused. The remodeling of the C2 facet deformity detected on follow-up CT scans can be a useful radiographic parameter to determine the appropriate period of halo fixation in this new treatment strategy obviating the need for surgical intervention. Copyright © 2011 Lippincott Williams & Wilkins.

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Intramedullary spinal cord cavernous hemangiomas

Ishii Ken, Nakamura Masaya

Brain and Nerve 63 （ 1 ） 27 - 30 2011年01月

ISSN 1881-6096

Reduced postoperative wound pain after lumbar spinous process-splitting laminectomy for lumbar canal stenosis

Watanabe Kota, Matsumoto Morio, Ikegami Takeshi, Nishiwaki Yuji, Tsuji Takashi, Ishii Ken, Ogawa Yuto, Takaishi Hironari, Nakamura Masaya, Toyama Yoshiaki, Chiba Kazuhiro

Journal of Neurosurgery: Spine 14 （ 1 ） 51 - 58 2011年01月

ISSN 1547-5654

Object. To reduce intraoperative damage to the posterior supporting structures of the lumbar spine during decompressive surgery for lumbar canal stenosis (LCS), lumbar spinous process-splitting laminectomy (LSPSL or split laminectomy) was developed. This prospective, randomized, controlled study was conducted to clarify whether the split laminectomy decreases acute postoperative wound pain compared with conventional laminectomy. Methods. Forty-one patients with LCS were enrolled in this study. The patients were randomly assigned to either the LSPSL group (22 patients) or the conventional laminectomy group (19 patients). Questionnaires regarding wound pain (intensity, depth, and duration) and activities of daily living (ADL) were administered at postoperative days (PODs) 3 and 7. Additionally, the authors evaluated the pre- and postoperative serum levels of C-reactive protein and creatine phosphokinase, the amount of pain analgesics used during a 3-day postoperative period, and the muscle atrophy rate measured on 1-month postsurgical MR images. Results. Data obtained in patients in the LSPSL group and in 16 patients in the conventional laminectomy group were analyzed. The mean visual analog scale for wound pain on POD 7 was significantly lower in the LSPSL group (16 ± 17 mm vs 34 ± 31 mm, respectively; p = 0.04). The mean depth-of-pain scores on POD okinase level was significantly lower in the LSPSL group (126 ± 93 U/L) than in the other group (207 ± 150 U/L) (p = 0.02); on POD 7, the mean serum C-reactive protein level was significantly lower in the LSPSL group (1.1 ± 0.6 mg/dl) than in the conventional laminectomy group (1.9 ± 1.5 mg/dl) (p = 0.04). The number of pain analgesics taken during the 3-day postoperative period was lower in the LSPSL group than in the conventional laminectomy group (1.7 ± 1.3 tablets vs 2.3 ± 2.4 tablets, respectively; p = 0.22). The mean muscle atrophy rate was also significantly lower in the LSPSL group (24% ± 15% vs 43% ± 22%; p = 0.004). Conclusions. Lumbar spinous process-splitting laminectomy for the treatment of LCS reduced acute postoperative wound pain and prevented postoperative muscle atrophy compared with conventional laminectomy, possibly because of minimized damage to the paraspinal muscles.

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Schwann-spheres derived from injured peripheral nerves in adult mice - their in vitro characterization and therapeutic potential

Takagi Takehiko, Ishii Ken, Shibata Shinsuke, Yasuda Akimasa, Sato Momoka, Nagoshi Narihito, Saito Harukazu, Okano Hirotaka J., Toyama Yoshiaki, Okano Hideyuki, Nakamura Masaya

PLoS ONE 6 （ 6 ） 2011年

Multipotent somatic stem cells have been identified in various adult tissues. However, the stem/progenitor cells of the peripheral nerves have been isolated only from fetal tissues. Here, we isolated Schwann-cell precursors/immature Schwann cells from the injured peripheral nerves of adult mice using a floating culture technique that we call "Schwann-spheres." The Schwann-spheres were derived from de-differentiated mature Schwann cells harvested 24 hours to 6 weeks after peripheral nerve injury. They had extensive self-renewal and differentiation capabilities. They strongly expressed the immature-Schwann-cell marker p75, and differentiated only into the Schwann-cell lineage. The spheres showed enhanced myelin formation and neurite growth compared to mature Schwann cells in vitro. Mature Schwann cells have been considered a promising candidate for cell-transplantation therapies to repair the damaged nervous system, whereas these "Schwann-spheres" would provide a more potential autologous cell source for such transplantation. © 2011 Takagi et al.

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Central neuropathic pain after surgical resection in patients with spinal intramedullary tumor

Nakamura Masaya, Tsuji Osahiko, Hosogane Naobumi, Watanabe Kota, Tsuji Takashi, Ishii Ken, Toyama Yoshiaki, Chiba Kazuhiro, Matsumoto Morio

Clinical Neurology 51 （ 11 ） 937 - 938 2011年

ISSN 0009-918X

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Novel concept of motor functional analysis for spinal cord injury in adult mice

Nakamura Masaya, Shinozaki Munehisa, Takahashi Yuichiro, Mukaino Masahiko, Saito Nobuhito, Toyama Yoshiaki, Okano Hideyuki

Journal of Biomedicine and Biotechnology 2011 2011年

ISSN 1110-7243

In basic research on spinal cord injury (SCI), behavioral evaluation of the SCI animal model is critical. However, it is difficult to accurately evaluate function in the mouse SCI model due to the small size of mice. Although the open-field scoring scale is an outstanding appraisal method, supplementary objective tests are required. Using a compact SCANET system, in which a mouse carries out free movement for 5 min, we developed a novel method to detect locomotor ability. A SCANET system samples the horizontal coordinates of a mouse every 0.1 s, and both the speed and acceleration of its motion are calculated at each moment. It was found that the maximum speed and acceleration of motion over 5 min varied by injury severity. Moreover, these values were significantly correlated with open-field scores. The maximum speed and acceleration of SCI model mice using a SCANET system are objective, easy to obtain, and reproducible for evaluating locomotive function. © 2011 Munehisa Shinozaki et al.

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Comparative study of methods for administering neural stem/progenitor cells to treat spinal cord injury in mice

Takahashi Yuichiro, Tsuji Osahiko, Kumagai Gentaro, Hara Chikako Miyauchi, Okano Hirotaka James, Miyawaki Atsushi, Toyama Yoshiaki, Okano Hideyuki, Nakamura Masaya

Cell Transplantation 20 （ 5 ） 727 - 739 2011年

ISSN 0963-6897

To investigate potential cures for spinal cord injury (SCI), several researchers have transplanted neural stem/progenitor cells (NS/PCs) into the injured spinal cord by different procedures, including intralesional (IL), intrathecal (IT), and intravenous (IV) injection. However, there are no reports quantifying or comparing the number of cells successfully transplanted to the lesion site by each procedure in vivo. The purpose of the present study was to determine the optimal method of cell transplantation to the SCI site in terms of grafted cell survival and safety. For this purpose, we developed mouse NS/PCs that expressed a novel Venus-luciferase fusion protein that enabled us to detect a minimum of 1,000 grafted cells in vivo by biolumines-cence imaging (BLI). After inducing contusive SCI at the T10 level in mice, NS/PCs were transplanted into the injured animals three different ways: by IL, IT, or IV injection. Six weeks after the transplantation, BLI analysis showed that in the IL group, the luminescence intensity of the grafted cells had decreased to about 10% of its initial level, and appeared at the site of injury. In the IT group, the luminescence of the grafted cells, which was distributed throughout the entire subarachnoid space immediately after transplantation, was detected at the injured site 1 week later, and by 6 weeks had gradually decreased to about 0.3% of its initial level. In the IV group, no grafted cells were detected at the site of injury, but all of these mice showed luminescence in the bilateral chest, suggesting pulmonary embolism. In addition, one third of these mice died immediately after the IV injection. In terms of grafted cell survival and safety, we conclude that the IL application of NS/PCs is the most effective and feasible method for transplanting NS/PCs into the SCI site.

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Transplantation of human neural stem/progenitor cells overexpressing galectin-1 improves functional recovery from focal brain ischemia in the mongolian gerbil

Yamane Junichi, Ishibashi Satoru, Sakaguchi Masanori, Kuroiwa Toshihiko, Kanemura Yonehiro, Nakamura Masaya, Miyoshi Hiroyuki, Sawamoto Kazunobu, Toyama Yoshiaki, Mizusawa Hidehiro, Okano Hideyuki

Molecular Brain 4 （ 1 ） 2011年

Transplantation of human neural stem/progenitor cells (hNSPCs) is a promising method to regenerate tissue from damage and recover function in various neurological diseases including brain ischemia. Galectin-1(Gal1) is a lectin that is expressed in damaged brain areas after ischemia. Here, we characterized the detailed Gal1 expression pattern in an animal model of brain ischemia. After brain ischemia, Gal1 was expressed in reactive astrocytes within and around the infarcted region, and its expression diminished over time. Previously, we showed that infusion of human Gal1 protein (hGal1) resulted in functional recovery after brain ischemia but failed to reduce the volume of the ischemic region. This prompted us to examine whether the combination of hNSPCs-transplantation and stable delivery of hGal1 around the ischemic region could reduce the ischemic volume and promote better functional recovery after brain ischemia. In this study, we transplanted hNSPCs that stably overexpressed hGal1 (hGal1-hNSPCs) in a model of unilateral focal brain ischemia using Mongolian gerbils. Indeed, we found that transplantation of hGal1-hNSPCs both reduced the ischemic volume and improved deficits in motor function after brain ischemia to a greater extent than the transplantation of hNSPCs alone. This study provides evidence for a potential application of hGal1 with hNSPCs-transplantation in the treatment of brain ischemia. © 2011Yamane et al; licensee BioMed Central Ltd.

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The dual origin of the peripheral olfactory system

Katoh Hiroyuki, Shibata Shinsuke, Fukuda Kimiko, Sato Momoka, Satoh Etsuko, Nagoshi Narihito, Minematsu Takeo, Matsuzaki Yumi, Akazawa Chihiro, Toyama Yoshiaki, Nakamura Masaya, Okano Hideyuki

Molecular Brain 4 （ 1 ） 2011年

Abstract. Background: The olfactory epithelium (OE) has a unique capacity for continuous neurogenesis, extending axons to the olfactory bulb with the assistance of olfactory ensheathing cells (OECs). The OE and OECs have been believed to develop solely from the olfactory placode, while the neural crest (NC) cells have been believed to contribute only the underlying structural elements of the olfactory system. In order to further elucidate the role of NC cells in olfactory development, we examined the olfactory system in the transgenic mice Wnt1-Cre/Floxed-EGFP and P0-Cre/Floxed-EGFP, in which migrating NC cells and its descendents permanently express GFP, and conducted transposon-mediated cell lineage tracing studies in chick embryos. Results: Examination of these transgenic mice revealed GFP-positive cells in the OE, demonstrating that NC-derived cells give rise to OE cells with morphologic and antigenic properties identical to placode-derived cells. OECs were also positive for GFP, confirming their NC origin. Cell lineage tracing studies performed in chick embryos confirmed the migration of NC cells into the OE. Furthermore, spheres cultured from the dissociated cells of the olfactory mucosa demonstrated self-renewal and trilineage differentiation capacities (neurons, glial cells, and myofibroblasts), demonstrating the presence of NC progenitors in the olfactory mucosa. Conclusion: Our data demonstrates that the NC plays a larger role in the development of the olfactory system than previously believed, and suggests that NC-derived cells may in part be responsible for the remarkable capacity of the OE for neurogenesis and regeneration. © 2011Katoh et al; licensee BioMed Central Ltd.

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Mimicking the neurotrophic factor profile of embryonic spinal cord controls the differentiation potential of spinal progenitors into neuronal cells

Nakamura Masaya, Tsuji Osahiko, Bregman Barbara S., Toyama Yoshiaki, Okano Hideyuki

PLoS ONE 6 （ 6 ） 2011年

Recent studies have indicated that the choice of lineage of neural progenitor cells is determined, at least in part, by environmental factors, such as neurotrophic factors. Despite extensive studies using exogenous neurotrophic factors, the effect of endogenous neurotrophic factors on the differentiation of progenitor cells remains obscure. Here we show that embryonic spinal cord derived-progenitor cells express both ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) mRNA before differentiation. BDNF gene expression significantly decreases with their differentiation into the specific lineage, whereas CNTF gene expression significantly increases. The temporal pattern of neurotrophic factor gene expression in progenitor cells is similar to that of the spinal cord during postnatal development. Approximately 50% of spinal progenitor cells differentiated into astrocytes. To determine the effect of endogenous CNTF on their differentiation, we neutralized endogenous CNTF by administration of its polyclonal antibody. Neutralization of endogenous CNTF inhibited the differentiation of progenitor cells into astrocytes, but did not affect the numbers of neurons or oligodendrocytes. Furthermore, to mimic the profile of neurotrophic factors in the spinal cord during embryonic development, we applied BDNF or neurotrophin (NT)-3 exogenously in combination with the anti-CNTF antibody. The exogenous application of BDNF or NT-3 promoted the differentiation of these cells into neurons or oligodendrocytes, respectively. These findings suggest that endogenous CNTF and exogenous BDNF and NT-3 play roles in the differentiation of embryonic spinal cord derived progenitor cells into astrocytes, neurons and oligodendrocytes, respectively. © 2011 Nakamura et al.

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Ball tip technique for thoracic pedicle screw placement in patients with adolescent idiopathic scoliosis

Watanabe Kota, Matsumoto Morio, Takashi Tsuji Ken Ishii, Takaishi Hironari, Nakamura Masaya, Toyama Yoshiaki, Chiba Kazuhiro

Journal of Neurosurgery: Spine 13 （ 2 ） 246 - 252 2010年08月

ISSN 1547-5654

Object. The aim in this study was to evaluate the efficacy of the ball tip technique in placing thoracic pedicle screws (TPSs), as compared with the conventional freehand technique, in both a cadaveric study and a clinical study of patients with adolescent idiopathic scoliosis. Although posterior spinal surgery using TPSs has been widely applied, these screws are associated with the potential risk of vascular, pulmonary, or neurological complications. To further enhance the accuracy and safety of TPS placement, the authors developed the ball tip technique. Methods. After creating an appropriate starting point for probe insertion, a specially designed ball tip probe consisting of a ball-shaped tip with a flexible metal shaft is used to make a guide hole into the pedicle. Holding the probe with the fingertips while using an appropriate amount of pressure or by tapping it gently and continuously with a hammer, one can safely insert the ball tip probe into the cancellous channel in the pedicle. In a cadaveric study, 5 spine fellows with similar levels of experience in placing TPSs applied the ball tip or the conventional technique to place screws in 5 cadavers with no spinal deformities. The incidence of misplaced screws was evaluated by dissecting the spines. In a clinical study, 40 patients with adolescent idiopathic scoliosis underwent posterior surgery with TPS placement via the ball tip or conventional technique (20 patients in each treatment group). The accuracy of the TPS placements was evaluated on postoperative axial CT scanning. Results. In the cadaveric study, 100 TPSs were evaluated, and the incidence of misplaced screws was 14% in the ball tip group and 34% in the conventional group (p = 0.0192). In the clinical study, 574 TPSs were evaluated. One hundred seventy-one intrapedicular screws (67%) were recognized in the conventional group and 288 (90%) in the ball tip group (p < 0.01). In the conventional and ball tip groups, the respective numbers of TPSs with a pedicle breach of ≤ 2 mm were 20 (8%) and 15 (5%), those with a pedicle breach of > 2 mm were 32 (13%) and 9 (3%; p < 0.01), and those located in the costovertebral joints were 32 (13%) and 7 (2%). Conclusions. In both cadaveric and clinical studies the ball tip technique enhanced the accuracy of TPS placement as compared with the conventional freehand technique. Thus, the ball tip technique is useful for the accurate and safe placement of TPSs in deformed spines.

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Anti-IL-6-receptor antibody promotes repair of spinal cord injury by inducing microglia-dominant inflammation

Mukaino Masahiko, Nakamura Masaya, Yamada Osamu, Okada Seiji, Morikawa Satoru, Renault-Mihara Francois, Iwanami Akio, Ikegami Takeshi, Ohsugi Yoshiyuki, Tsuji Osahiko, Katoh Hiroyuki, Matsuzaki Yumi, Toyama Yoshiaki, Liu Meigen, Okano Hideyuki

Experimental Neurology 224 （ 2 ） 403 - 414 2010年08月

ISSN 0014-4886

We previously reported the beneficial effect of administering an anti-mouse IL-6 receptor antibody (MR16-1) immediately after spinal cord injury (SCI). The purpose of our present study was to clarify the mechanism underlying how MR16-1 improves motor function after SCI. Quantitative analyses of inflammatory cells using flow cytometry, and immunohistochemistry with bone marrow-chimeric mice generated by transplanting genetically marked purified hematopoietic stem cells, revealed that MR16-1 dramatically switched the central player in the post-traumatic inflammation, from hematogenous macrophages to resident microglia. This change was accompanied by alterations in the expression of relevant cytokines within the injured spinal cord; the expression of recruiting chemokines including CCL2, CCL5, and CXCL10 was decreased, while that of Granulocyte/Macrophage-Colony Stimulating Factor (GM-CSF), a known mitogen for microglia, was increased. We also showed that the resident microglia expressed higher levels of phagocytic markers than the hematogenous macrophages. Consistent with these findings, we observed significantly decreased tissue damage and reduced levels of myelin debris and Nogo-A, the axonal growth inhibitor, by MR16-1 treatment. Moreover, we observed increased axonal regeneration and/or sprouting in the MR16-1-treated mice. Our findings indicate that the functional improvement elicited by MR16-1 involves microglial functions, and provide new insights into the role of IL-6 signaling in the pathology of SCI. © 2010 Elsevier Inc.

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Risk factors for development of subaxial subluxations following atlantoaxial arthrodesis for atlantoaxial subluxations in rheumatoid arthritis

Ishii Ken, Matsumoto Morio, Takahashi Yuichiro, Okada Eijiro, Watanabe Kota, Tsuji Takashi, Takaishi Hironari, Nakamura Masaya, Toyama Yoshiaki, Chiba Kazuhiro

Spine 35 （ 16 ） 1551 - 1555 2010年07月

ISSN 0362-2436

Study Design: Retrospective radiographic/imaging study. Objective: To evaluate preoperative and sequential postoperative radiographs following C1-C2 arthrodesis for atlantoaxial subluxation in patients with rheumatoid arthritis (RA) to determine risk factors for the development of subaxial subluxations (SAS). Summary of Background Data: The development of SAS has often been observed after C1-C2 arthrodesis. However, there have been no previous reports on the correlation between radiographic parameters and the incidence of postoperative SAS. Methods: The study group comprised of 58 patients with RA who underwent C1-C2 arthrodesis due to atlantoaxial subluxation. There were 5 men and 53 women with a mean age of 55.8 years. The mean follow-up period was 137 months. Nineteen patients with a postoperative SAS after C1-C2 arthrodesis were classified as the SAS+ group. Other 39 pat ents without a postoperative SAS were included in the SAS- group. Clinical outcomes and plain radiographs were reviewed retrospectively and compared between the 2 groups. Results: The difference between pre- and postoperative atlantoaxial (AA) angles in the SAS+ group was significantly greater than those in the SAS- group (P = 0.039). The C2-C7 angles changed significantly between pre- and postoperative periods in the SAS+ group (P = 0.039), but not in the SAS- group (P = 0.897). It was suggested that a large AA angle and a small C2-C7 angle observed at the early postoperative period were the risk factors for the development of SAS. We also demonstrated that a high incidence of the C3-C4 SAS resulted from excessive bone fusion at the C2-C3. Conclusion: Excessive correction of AA angle is likely to cause loss of cervical lordosis, resulting in the development of postoperative SAS. In addition, extensive bony union at C2-C3 following C1-C2 arthrodesis frequently leads to the development of extensive SAS at the C3-C4. © 2010, Lippincott Williams & Wilkins.

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Therapeutic potential of appropriately evaluated safe-induced pluripotent stem cells for spinal cord injury

Tsuji Osahiko, Miura Kyoko, Okada Yohei, Fujiyoshi Kanehiro, Mukaino Masahiko, Nagoshi Narihito, Kitamura Kazuya, Kumagai Gentaro, Nishino Makoto, Tomisato Shuta, Higashi Hisanobu, Nagai Toshihiro, Katoh Hiroyuki, Kohda Kazuhisa, Matsuzaki Yumi, Yuzaki Michisuke, Ikeda Eiji, Toyama Yoshiaki, Nakamura Masaya, Yamanaka Shinya, Okano Hideyuki

Proceedings of the National Academy of Sciences of the United States of America 107 （ 28 ） 12704 - 12709 2010年07月

ISSN 0027-8424

Various types of induced pluripotent stem (iPS) cells have been established by different methods, and each type exhibits different biological properties. Before iPS cell-based clinical applications can be initiated, detailed evaluations of the cells, including their differentiation potentials and tumorigenic activities in different contexts, should be investigated to establish their safety and effectiveness for cell transplantation therapies. Here we show the directed neural differentiation of murine iPS cells and examine their therapeutic potential in amouse spinal cord injury (SCI)model. "Safe" iPS-derived neurospheres, which had been pre-evaluated as nontumorigenic by their transplantation into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse brain, produced electrophysiologically functional neurons, astrocytes, and oligodendrocytes in vitro. Furthermore, when the safe iPS-derived neurospheres were transplanted into the spinal cord 9 d after contusive injury, they differentiated into all three neural lineages without forming teratomas or other tumors. They also participated in remyelination and induced the axonal regrowth of host 5HT⁺ serotonergic fibers, promoting locomotor function recovery. However, the transplantation of iPSderived neurospheres pre-evaluated as "unsafe" showed robust teratoma formation and sudden locomotor functional loss after functional recovery in the SCI model. These findings suggest that preevaluated safe iPS clone-derived neural stem/progenitor cells may be a promising cell source for transplantation therapy for SCI.

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Transplantation of galectin-1-expressing human neural stem cells into the injured spinal cord of adult common marmosets

Yamane Junichi, Nakamura Masaya, Iwanami Akio, Sakaguchi Masanori, Katoh Hiroyuki, Yamada Masayuki, Momoshima Suketaka, Miyao Sachiyo, Ishii Ken, Tamaoki Norikazu, Nomura Tatsuji, Okano Hirotaka James, Kanemura Yonehiro, Toyama Yoshiaki, Okano Hideyuki

Journal of Neuroscience Research 88 （ 7 ） 1394 - 1405 2010年05月

ISSN 0360-4012

Delayed transplantation of neural stem/progenitor cells (NS/PCs) into the injured spinal cord can promote functional recovery in adult rats and monkeys. To enhance the functional recovery after NS/PC transplantation, we focused on galectin-1, a carbohydrate-binding protein with pleiotropic roles in cell growth, differentiation, apoptosis, and neurite outgrowth. Here, to determine the combined therapeutic effect of NS/PC transplantation and galectin-1 on spinal cord injury (SCI), human NS/PCs were transfected by lentivirus with galectin-1 and green fluorescent protein (GFP), (Gal-NS/PCs) or GFP alone (GFP-NS/PCs), expanded in vitro, and then transplanted into the spinal cord of adult common marmosets, 9 days after contusive cervical SCI. The animals' motor function was evaluated by their spontaneous motor activity, bar grip power, and performance on a treadmill test. Histological analyses revealed that the grafted human NS/PCs survived and differentiated into neurons, astrocytes, and oligodendrocytes. There were significant differences in the myelinated area, corticospinal fibers, and serotonergic fibers among the Gal-NS/PC, GFP-NS/PC, vehicle-control, and sham-operated groups. The Gal-NS/PC-grafted animals showed a better performance on all the behavioral tests compared with the other groups. These findings suggest that Gal-NS/PCs have better therapeutic potential than NS/PCs for SCI in nonhuman primates and that human Gal-NS/PC transplantation might be a feasible treatment for human SCI. © 2010 Wiley-Liss, Inc.

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Complicated surgical resection of malignant tumors in the upper cervical spine after failed ion-beam radiation therapy

Matsumoto Morio, Watanabe Kota, Ishii Ken, Tsuji Takashi, Takaishi Hironari, Nakamura Masaya, Toyama Yoshiaki, Chiba Kazuhiro, Imanishi Yorihisa, Kishi Kazuo, Kawana Hiromasa

Spine 35 （ 11 ） 2010年05月

ISSN 0362-2436

STUDY DESIGN.: Case report. OBJECTIVE.: To report 3 cases of malignant tumors in the upper cervical spine that were treated surgically by a combination of posterior tumor resection and stabilization and anterior tumor resection through a mandible-splitting approach after failed ion-beam radiation therapy. SUMMARY OF BACKGROUND DATA.: Few clinical reports have described in detail the postoperative complications associated with transoral surgical resection of tumors in the upper cervical spine after unsuccessful ion-beam radiation therapy. METHODS.: Three patients with malignant tumors in the upper cervical spine who had undergone ion-beam radiotherapy and experienced tumor recurrence were treated by a combination of posterior and anterior surgery through a mandible-splitting approach. One patient (patient 1, a 32-year-old man) had a hemangioendothelioma at the C2 and C3 level, whereas the other 2 patients (patient 2, a 66-year-old woman and patient 3, a 65-year-old man) had a chordoma at the C2 and C3 level. RESULTS.: The intralesional but macroscopic total resection of the tumors was achieved in all 3 patients. However, serious complications developed after surgery, including deep wound infection, cerebrospinal fluid leakage, and meningitis in patient 1, prolonged swallowing difficulty, subsidence of the strut graft, and recurrence in patient 2, and deep wound infection and discitis causing progressive paralysis in patient 3. All patients underwent salvage surgery, including debridement of the wound in patient 1, posterior reinforcement using instrumentation and posterior tumor resection for the recurrent tumor in patient 2, and anterior debridement of the wound with a pedicle flap using the pectoral major muscle in patient 3 to address these problems. Patients 1 and 3 had no signs of recurrence at the time of a follow-up examination. CONCLUSION.: Severe complications, mainly associated with the disturbance in healing of the retropharyngeal wall, were observed in all 3 patients. A preventive method, such as primary repair of the retropharyngeal wall using muscular/musculocutaneous flaps, should be considered for patients undergoing resection through a transoral approach after ion-beam irradiation. © 2010, Lippincott Williams & Wilkins.

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Posterior decompression surgery for extraforaminal entrapment of the fifth lumbar spinal nerve at the lumbosacral junction

Matsumoto Morio, Watanabe Kota, Ishii Ken, Tsuji Takashi, Takaishi Hironari, Nakamura Masaya, Toyama Yoshiaki, Chiba Kazuhiro

Journal of Neurosurgery: Spine 12 （ 1 ） 72 - 81 2010年01月

ISSN 1547-5654

Object. In this paper, the authors' goal was to elucidate the clinical features and results of decompression surgery for extraforaminal stenosis at the lumbosacral junction. Methods. Twenty-eight patients with severe leg pain caused by extraforaminal stenosis at the lumbosacral junction (18 men and 10 women; mean age 68.2 ± 8.9 years) were treated by posterior decompression without fusion using a microendoscope in 19 patients and a surgical microscope or loupe in 9 patients. The decompression procedures consisted of partial resection of the sacral ala, the L-5 transverse process, and the L5-S1 facet joint along the L-5 spinal nerve. The following items were investigated: 1) preoperative neurological findings; 2) preoperative radiological findings, including plain radiographs, CT scans, selective radiculography of L-5; 3) surgical outcome as evaluated using the Japanese Orthopaedic Association scale for low-back pain (JOA score); and 4) need for revision surgery. Results. All patients presented with neurological deficits compatible with a diagnosis of L-5 radiculopathy such as weakness of the extensor hallucis longus muscle and sensory disturbance in the L-5 area together with neurogenic claudication. On plain radiographs, 21 patients (75%) and 17 patients (60.7%) exhibited lumbar scoliosis (? 5° ) and wedging of the L5-S1 intervertebral space (≥ 3 ^o ), respectively. The CT scans demonstrated marked osteophyte formation at the posterolateral margin of the L5-S1 vertebral bodies, and a selective L-5 nerve root block was effective in all patients. All patients reported pain relief immediately after surgery. The mean JOA scores were 11.3 ± 3.8 before surgery and 24.3 ± 3.4 at the time of the final follow-up examination; the recovery rate was 68.6 ± 16.5%. The mean estimated blood loss was 66.6 ± 98.6 ml, and the mean surgical time was 135.3 ± 46.5 minutes. No significant difference in the recovery rate of the JOA scores or in the surgical time and blood loss was observed between the 2 surgical approaches. Four patients underwent revision posterior interbody fusion for the recurrence of radicular pain as a result of intraforaminal stenosis in 3 patients and insufficient decompression of the extraforaminal area in the remaining patient at an average of 19.5 months after surgery. Conclusions. Extraforaminal stenosis at the lumbosacral junction is a rare but distinct pathological condition causing L-5 radiculopathy. Decompression surgery without fusion using a microendoscope or a surgical microscope/loupe is a feasible and less invasive surgical option for elderly patients with extraforaminal stenosis at the lumbosacral junction.

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Cordotomy for patients with thoracic malignant astrocytoma

Nakamura Masaya, Tsuji Osahiko, Fujiyoshi Kanehiro, Watanabe Kota, Tsuji Takashi, Ishii Ken, Matsumoto Morio, Toyama Yoshiaki, Chiba Kazuhiro

Journal of Neurosurgery: Spine 13 （ 4 ） 418 - 423 2010年

ISSN 1547-5654

Object. The optimal management of malignant astrocytomas remains controversial, and the prognosis of these lesions has been dismal regardless of the administered treatment. In this study the authors investigated the surgical outcomes of cordotomy in patients with thoracic malignant astrocytomas to determine the effectiveness of this procedure. Methods. Cordotomy was performed in 5 patients with glioblastoma multiforme (GBM) and 2 with anaplastic astrocytoma (AA). A Kaplan-Meier survival analysis was performed, and the associations of the resection level with survival and postoperative complications were retrospectively examined. Results. Cordotomy was performed in a single stage in 2 patients with GBM and in 2 stages in 3 patients with GBM and 2 patients with AA. In the 2 patients with GBM, cordotomy was performed 2 and 3 weeks after a partial tumor resection. In the 2 patients with AA, the initial treatment consisted of partial tumor resection and subtotal resection combined with radiotherapy, and rostral tumor growth and progressive paralysis necessitated cordotomy 2 and 28 months later. One patient with a secondary GBM underwent cordotomy; the GBM developed 1 year after subtotal resection and radiotherapy for a WHO Grade II astrocytoma. Four patients died 4, 5, 24, and 42 months after the initial operation due to CSF dissemination, and 3 patients (2 with GBM and 1 with AA) remain alive (16, 39, and 71 months). No metastasis to any other organs was noted. Conclusions. One-stage cordotomy should be indicated for patients with thoracic GBM or AA presenting with complete paraplegia preoperatively. In patients with thoracic GBM, even if paralysis is incomplete, cordotomy should be performed before the tumor disseminates through the CSF. Radical resection should be attempted in patients with AA and incomplete paralysis. If the tumor persists, radiotherapy and chemotherapy are indicated, and cordotomy should be reserved for lesions growing progressively after such second-line treatments.

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Sox10-Venus mice

Shibata Shinsuke, Yasuda Akimasa, Renault-Mihara Francois, Suyama Satoshi, Katoh Hiroyuki, Inoue Takayoshi, Inoue Yukiko U., Nagoshi Narihito, Sato Momoka, Nakamura Masaya, Akazawa Chihiro, Okano Hideyuki

Molecular Brain 3 （ 1 ） 2010年

Background. While several mouse strains have recently been developed for tracing neural crest or oligodendrocyte lineages, each strain has inherent limitations. The connection between human SOX10 mutations and neural crest cell pathogenesis led us to focus on the Sox10 gene, which is critical for neural crest development. We generated Sox10-Venus BAC transgenic mice to monitor Sox10 expression in both normal development and in pathological processes. Results. Tissue fluorescence distinguished neural crest progeny cells and oligodendrocytes in the Sox10-Venus mouse embryo. Immunohistochemical analysis confirmed that Venus expression was restricted to cells expressing endogenous Sox10. Time-lapse imaging of various tissues in Sox10-Venus mice demonstrated that Venus expression could be visualized at the single-cell level in vivo due to the intense, focused Venus fluorescence. In the adult Sox10-Venus mouse, several types of mature and immature oligodendrocytes along with Schwann cells were clearly labeled with Venus, both before and after spinal cord injury. Conclusions. In the newly-developed Sox10-Venus transgenic mouse, Venus fluorescence faithfully mirrors endogenous Sox10 expression and allows for in vivo imaging of live cells at the single-cell level. This Sox10-Venus mouse will thus be a useful tool for studying neural crest cells or oligodendrocytes, both in development and in pathological processes. © 2010 Shibata et al; licensee BioMed Central Ltd.

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Microendoscopic resection of lumbar discal cysts

Matsumoto M., Watanabe K., Tsuji T., Ishii K., Takaishi H., Nakamura M., Toyama Y., Chiba K.

Minimally Invasive Neurosurgery 53 （ 2 ） 69 - 73 2010年

ISSN 0946-7211

Introduction: A lumbar discal cyst is a relatively rare cystic lesion that communicates with lumbar intervertebral discs. Surgical resection of the cyst is the reported treatment of choice. In this study, the authors report the minimally invasive surgical resection of lumbar discal cysts using a microendoscopy. Patients and Methods: Seven male patients with lumbar discal cysts underwent microendoscopic resections (mean age: 25.1?3.2 years and the mean follow-up period: 27.9 months). During the surgeries, the cysts were subtotally resected in a piecemeal fashion, and the fistulas forming the communications between the cysts and the corresponding intervertebral discs were coagulated using a bipolar coagulator. Results: All the patients obtained relief from their pain after surgery, and no recurrences occurred during a mean follow-up period of 28 months. The mean operation time was 72.6?20.2min, and the mean blood loss was 44.4?13.7 grams. No intra- or peri-operative complications were noted in any of the patients. Conclusions: Microendoscopic resection appears to be a minimally invasive and feasible surgical option for the treatment of lumbar discal cysts. © Georg Thieme Verlag KG Stuttgart.

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Transplantation of dendritic cells promotes functional recovery from spinal cord injury in common marmoset

Yaguchi Masae, Tabuse Masanao, Ohta Shigeki, Ohkusu-Tsukada Kozo, Takeuchi Tamaki, Yamane Junichi, Katoh Hiroyuki, Nakamura Masaya, Matsuzaki Yumi, Yamada Masayuki, Itoh Toshio, Nomura Tatsuji, Toyama Yoshiaki, Okano Hideyuki, Toda Masahiro

Neuroscience Research 65 （ 4 ） 384 - 392 2009年12月

ISSN 0168-0102

We previously reported that implantation of dendritic cells (DCs) into the injured site activates neural stem/progenitor cells (NSPCs) and promotes functional recovery after spinal cord injury (SCI) in mice. Working toward clinical application of DC therapy for SCI, we analyzed whether DCs promote functional recovery after SCI in a non-human primate, the common marmoset (CM). CMs are usually born as dizygotic twins. They are thus natural bone marrow and peripheral blood chimeras due to sharing of the placental circulation between dizygotic twins, leading to functional immune tolerance. In this study, to identify adequate CM donor-and-host pairs, mixed leukocyte reaction (MLR) assays were performed. Then, CM-DCs were generated from the bone marrow of the twin selected to be donor and transplanted into the injured site of the spinal cord of the other twin selected to be host, 7 days after injury. Histological analyses revealed fewer areas of demyelination around the injured site in DC-treated CMs than in controls. Immunohistochemical analysis showed that more motor neurons and corticospinal tracts were preserved after SCI in DC-treated CMs. Motor functions were evaluated using three different behavior tests and earlier functional recovery was observed in DC-treated CMs. These results suggest DC therapy to possibly be beneficial in primates with SCI and that this treatment has potential for clinical application. © 2009 Elsevier Ireland Ltd and the Japan Neuroscience Society.

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Quantification of neurotrophins in skeletal muscle following nerve injury

Morisawa Yasushi, Takayama Shinichiro, Nakamura Masaya, Nakamura Toshiyasu, Ikegami Hiroyasu, Toyama Yoshiaki

Journal of Musculoskeletal Research 12 （ 4 ） 205 - 212 2009年12月

ISSN 0218-9577

Purpose: We investigated the kinematics of nerve growth factor (NGF)mRNA and brain-derived neurotrophic factor (BDNF)mRNA in a skeletal muscle following spinal cord and peripheral nerve injuries by utilizing the reverse-transcription polymerase chain reaction/high-performance liquid chromatography (RT-PCR/HPLC) method. Methods: We made mice models of spinal cord transection and sciatic nerve transection, plus sham and control groups. After RNA extraction from gastrocnemius muscle of mice, RT-PCR was done. We measured the levels of NGFmRNA and BDNFmRNA in a skeletal muscle following spinal cord and peripheral nerve injuries by utilizing the RT-PCR/HPLC method. All values are analyzed and graphed as means ±SED. Bonferroni test (Post-hoc test) was used when two values were compared. Differences were considered statistically significant when p < 0.05. Results: According to the wet muscle weight, at day 7, a significant difference was found between the peripheral lesion and control group, and at days 14 and 28, significant differences were found between the spinal and peripheral lesion and control group. According to the NGFmRNA, in the peripheral nerve injury group, the levels increased up to day 28 and when compared with the control group, the levels were significantly higher at days 14 and 28. According to the BDNFmRNA, levels at days 2, 7, 14, and 28 were significantly lower in the spinal cord injury group than in the control group. However, in peripheral nerve injury group, when compared with the control group, the levels significantly increased at days 7, 14, and 28. Conclusion: We clarified marked differences in chronological changes in neurotrophin kinetics in a skeletal muscle between spinal cord injury and peripheral nerve injury. © 2009 World Scientific Publishing Company.

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Progressive kyphoscoliosis associated with tethered cord treated by posterior vertebral column resection

Matsumoto Morio, Watanabe Kota, Tsuji Takashi, Ishii Ken, Takaishi Hironari, Nakamura Masaya, Toyama Yoshiaki, Chiba Kazuhiro

Spine 34 （ 26 ） 2009年12月

ISSN 0362-2436

Study Design: A case report. OBJECTIVES.: To report a case of progressive yphoscoliosis associated with a tethered cord that was corrected by posterior vertebral column resection after complicated untethering surgery. Summary of Background Data: There have been few clinical reports on posterior vertebral column resection conducted for severe deformity associated with a tethered cord. Methods: A patient with progressive kyphoscoliosis associated with a tethered cord first underwent untethering surgery, resulting in neurologic deterioration. Posterior vertebral column resection was performed to correct the kyphoscoliosis while shortening the spinal column to prevent the spinal cord from stretch injury. Results: Good correction of kyphoscoliosis was obtained without further neurologic deterioration. The Cobb angles of scoliosis was 103° before surgery and 25° after surgery (correction rate; 75.7%), and that of kyphosis was 90° and 36°, respectively (correction rate; 60.0%). Conclusion: Correction of progressive kyphoscoliosis associated with a tethered cord can be achieved successfully by posterior vertebral column resection even after complicated untethering surgery. © 2009, Lippincott Williams & Wilkins.

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Roles of ES cell-derived gliogenic neural stem/progenitor cells in functional recovery after spinal cord injury

Kumagai Gentaro, Okada Yohei, Yamane Junichi, Nagoshi Narihito, Kitamura Kazuya, Mukaino Masahiko, Tsuji Osahiko, Fujiyoshi Kanehiro, Katoh Hiroyuki, Okada Seiji, Shibata Shinsuke, Matsuzaki Yumi, Toh Satoshi, Toyama Yoshiaki, Nakamura Masaya, Okano Hideyuki

PLoS ONE 4 （ 11 ） 2009年11月

Transplantation of neural stem/progenitor cells (NS/PCs) following the sub-acute phase of spinal cord injury (SCI) has been shown to promote functional recovery in rodent models. However, the types of cells most effective for treating SCI have not been clarified. Taking advantage of our recently established neurosphere-based culture system of ES cell-derived NS/PCs, in which primary neurospheres (PNS) and passaged secondary neurospheres (SNS) exhibit neurogenic and gliogenic potentials, respectively, here we examined the distinct effects of transplanting neurogenic and gliogenic NS/PCs on the functional recovery of a mouse model of SCI. ES cell-derived PNS and SNS transplanted 9 days after contusive injury at the Th10 level exhibited neurogenic and gliogenic differentiation tendencies, respectively, similar to those seen in vitro. Interestingly, transplantation of the gliogenic SNS, but not the neurogenic PNS, promoted axonal growth, remyelination, and angiogenesis, and resulted in significant locomotor functional recovery after SCI. These findings suggest that gliogenic NS/PCs are effective for promoting the recovery from SCI, and provide essential insight into the mechanisms through which cellular transplantation leads to functional improvement after SCI. © 2009 Kumagai et al.

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Long-Term surgical outcomes for myxopapillary ependymomas of the Cauda equina

Nakamura Masaya, Ishii Ken, Watanabe Kota, Tsuji Takashi, Matsumoto Morio, Toyama Yoshiaki, Chiba Kazuhiro

Spine 34 （ 21 ） 2009年10月

ISSN 0362-2436

Study Design. Retrospective case series. Objective. To evaluate our treatment strategy for myxopapillary ependymomas of the cauda equina. Summary of Background Data. Some patients with myxopapillary ependymoma develop cerebrospinal fluid (CSF) dissemination leading to poor prognosis. Because of the rarity of this tumor, there is no consensus on its optimal treatment options and prognosis. Methods We reviewed 25 cases of myxopapillary ependymomas, treated surgically between 1972 and 2005. The mean postoperative follow-up period was 10.4 years. The effects of surgical margins at surgery and postoperative radiotherapy on tumor recurrence and prognosis were investigated. Results In 15 patients, total resection achieved (6 cases of en bloc resection without postoperative radiation, and in 9 cases piecemeal resection) was followed by whole brain and spinal cord radiation or local irradiation. Fourteen of these patients survived without tumor recurrence. In 1 case of total resection without radiotherapy, the tumor capsule was violated intraoperatively and local recurrence occurred 2 years after surgery. In 4 patients, the tumors were removed subtotally. Of these, 2 patients who received radiation (24 Gy) only to the whole brain and spinal cord developed recurrence, and 2 who received whole brain and spinal cord radiation (24 Gy) supplemented with local radiation (46 Gy) developed no recurrence. The remaining 6 patients received partial resection after local radiation (40-50 Gy) alone, and all 6 died of CSF dissemination. Conclusion. The results of the present study indicate that the surgical margin obtained at the initial surgery and the extent and amount of postoperative radiation can be crucial factors determining the prognosis of patients with myxopapillary ependymoma. Although this tumor is histologically benign, CSF dissemination can occur once tumor capsule is violated, before or during surgery. Therefore, early diagnosis is essential, and a therapeutic strategy including radiotherapy, on the assumption that this tumor is malignant, should be established. © 2009, Lippincott Williams & Wilkins.

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Neural crest-derived stem cells display a wide variety of characteristics

Nagoshi Narihito, Shibata Shinsuke, Nakamura Masaya, Matsuzaki Yumi, Toyama Yoshiaki, Okano Hideyuki

Journal of Cellular Biochemistry 107 （ 6 ） 1046 - 1052 2009年08月

ISSN 0730-2312

A recent burst of findings has shown that neural crest-derived stem cells (NCSCs) can be found in diverse mammalian tissues. In addition to their identification in tissues that are known to be derived from the neural crest, recent studies have revealed NCSCs in tissues that are not specifically derived from the neural crest, such as bone marrow. NCSCs can express a wide range of characteristics, and which properties are expressed mainly depends on their tissue sources and the ontogenic stage of the animal. The identification of NCSCs in various tissues opens an entirely new avenue of approach to developing autologous cell replacement therapies for use in regenerative medicine. In this review, we discuss the origin, migration, and lineage potential of NCSCs from various mammalian tissue sources. © 2009 Wiley-Liss, Inc.

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Intramedullary solitary fibrous tumor of the spinal cord

Ishii Ken, Nakamura Masaya, Matsumoto Morio, Mukai Makio, Toyama Yoshiaki, Chiba Kazuhiro

Journal of Orthopaedic Science 14 （ 4 ） 450 - 454 2009年07月

ISSN 0949-2658

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Clinical significance and prognosis of idiopathic syringomyelia

Nakamura Masaya, Ishii Ken, Watanabe Kota, Tsuji Takashi, Matsumoto Morio, Toyama Yoshiaki, Chiba Kazuhiro

Journal of Spinal Disorders and Techniques 22 （ 5 ） 372 - 375 2009年07月

ISSN 1536-0652

STUDY DESIGN: Retrospective case series. OBJECTIVE: To determine the clinical significance and prognosis of idiopathic syringomyelia. SUMMARY OF BACKGROUND DATA: With the widespread use of magnetic resonance imaging, cases of syringomyelia are found occasionally. However, the clinical significance and optimum treatment strategy for idiopathic syringomyelia remain unclear, because there are few reports on details of this condition. METHODS: The clinical records and magnetic resonance images of 15 patients with idiopathic syringomyelia were reviewed to determine the changes in patient's neurologic status assessed by the Japanese Orthopedic Association scores for cervical myelopathy and the distribution of the syringomyelia on magnetic resonance imaging. Twelve cases were treated conservatively (conservative group) and syringo-subarachnoid shunt was performed in the remaining 3 cases (surgical group). The follow-up period ranged from 7 to 20 years (mean: 10.5 y). RESULTS: The localized type of idiopathic syringomyelia, which extended under 3 vertebras (mean: 2.1 vertebras), was observed in the 12 patients of the conservative group. There were no significant changes in either the size of the syringomyelia or the severity of the neurologic deficits during the follow-up period (mean: 10 y). In contrast, the extended type, which distributed over 4 or more vertebras (mean: 10.2 vertebras), was observed in the 3 patients of the surgical group. Because of severe and progressive neurologic deficits, syringo-subarachnoid shunt was performed and the surgery successfully prevented further neurologic deterioration. The mean Japanese Orthopedic Association score of the surgical group was significantly lower than that of the conservative group, both at the time of the initial examination and at the final follow-up. CONCLUSIONS: There are 2 types of idiopathic syringomyelia. One is a "localized" type, which might represents congenital enlargement of the central canal of the spinal cord, and can be managed conservatively. The other is an "extended" type, which causes progressive neurologic dysfunction, and should be treated surgically to prevent further neurologic deterioration. Further study should be needed to clarify the mechanism of the extended type of idiopathic syringomyelia. © 2009 Lippincott Williams & Wilkins, Inc.

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Nocturnal leg cramps

Matsumoto Morio, Watanabe Kota, Tsuji Takashi, Ishii Ken, Takaishi Hironari, Nakamura Masaya, Toyama Yoshiaki, Chiba Kazuhiro, Michikawa Takehiro, Nishiwaki Yuji

Spine 34 （ 5 ） 2009年03月

ISSN 0362-2436

STUDY DESIGN.: Questionnaire survey on leg cramps for patients with lumbar spinal canal stenosis (LCS). OBJECTIVE.: To evaluate the prevalence of leg cramps in patients with LCS treated surgically and the relationship between leg cramps and the surgical outcomes. SUMMARY OF BACKGROUND DATA.: Although it has been anecdotally reported that LCS patients have suffered from leg cramps, the true prevalence remains unknown. METHODS.: One hundred twenty LCS patients who underwent decompression surgery (men 85, women 35, mean age 73.5) and 370 elderly subjects from the general population (men 162, women 208, mean age 75.6) were enrolled in the study. The participants filled in a questionnaire regarding: (all participants) (1) experience of leg cramps, (2) frequency and time of the day of the cramp attacks; (for LCS patients only), (3) changes in cramps before and after surgery, (4) activities of daily living disturbance because of leg cramps, (5) satisfaction with surgery and walking ability, (6) the Roland-Morris Disability Questionnaire, and (7) the Oswestry Disability Index. RESULTS.: Eighty-five (70.8%) patients with LCS and 137 (37.2%) of the control population experienced leg cramps (age and sex adjusted odds ratio; 4.6, P < 0.01). Leg cramps occurred once or twice a week in 34.9% of the LCS group and once in several months in 44.5% of the control group, and occurred nocturnally in 73.3% of the LCS patients and in 91.6% of the control group. In LCS patients, leg cramps improved after surgery in 18.2%, remained unchanged in 45.5%, and worsened in 26.1%, and activities of daily living were disturbed in 47.6%. There was no significant difference in satisfaction with surgery, the Oswestry Disability Index, the Roland-Morris Disability Questionnaire scores, or walking ability between the LCS patients with or without leg cramps. CONCLUSION.: LCS patients had significantly more frequent attacks of nocturnal leg cramps than the control population, and leg cramps disturbed the quality of the patients' life, and they rarely improved after decompression surgery. Leg cramps should be recognized as one of the symptoms of LCS, which disturb the patients' quality of life. © 2009, Lippincott Williams & Wilkins.

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Evaluation of human fetal neural stem/progenitor cells as a source for cell replacement therapy for neurological disorders

Ogawa Daisuke, Okada Yohei, Nakamura Masaya, Kanemura Yonehiro, Okano Hirotaka James, Matsuzaki Yumi, Shimazaki Takuya, Ito Mamoru, Ikeda Eiji, Tamiya Takashi, Nagao Seigo, Okano Hideyuki

Journal of Neuroscience Research 87 （ 2 ） 307 - 317 2009年02月

ISSN 0360-4012

It is expected that human neural stem/progenitor cells (hNS/PCs) will some day be used in cell replacement therapies. However, their availability is limited because of ethical issues, so they have to be expanded to obtain sufficient amounts for clinical application. Moreover, in-vitro-maintained hNS/PCs may have a potential for tumorigenicity that could be manifested after transplantation in vivo. In the present study, we demonstrate the in vitro and in vivo properties of long-term-expanded hNS/PCs, including a 6-month bioluminescence imaging (BLI) study of their in vivo tumorigenicity. hNS/PCs cultured for approximately 250 days in vitro (hNS/PCs-250) exhibited a higher growth rate and greater neurogenic potential than those cultured for approximately 500 days in vitro (hNS/PCs-500), which showed greater gliogenic potential. In vivo, both hNS/PCs-250 and -500 differentiated into neurons and astrocytes 4 weeks after being transplanted into the striatum of immunodeficient mice, and hNS/PCs-250 exhibited better survival than hNS/PCs-500 at this time point. We also found that the grafted hNS/PCs-250 survived stably and differentiated properly into neurons and astrocytes even 6 months after the surgery. Moreover, during the 6-month observation period by BLI, we did not detect any evidence of rapid tumorigenic growth of the grafted hNS/PCs, and neither PCNA/ Ki67-positive proliferating cells nor significant malignant invasive features were detected histologically. These findings support the idea that hNS/PCs may represent a nontumorigenic, safe, and appropriate cell source for regenerative therapies for neurological disorders. © 2008 Wiley-Liss, Inc.

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Visualization of peripheral nerve degeneration and regeneration

Takagi Takehiko, Nakamura Masaya, Yamada Masayuki, Hikishima Keigo, Momoshima Suketaka, Fujiyoshi Kanehiro, Shibata Shinsuke, Okano Hirotaka James, Toyama Yoshiaki, Okano Hideyuki

NeuroImage 44 （ 3 ） 884 - 892 2009年02月

ISSN 1053-8119

We applied diffusion tensor tractography (DTT), a recently developed MRI technique that reveals the microstructures of tissues based on its ability to monitor the random movements of water molecules, to the visualization of peripheral nerves after injury. The rat sciatic nerve was subjected to contusive injury, and the data obtained from diffusion tensor imaging (DTI) were used to determine the tracks of nerve fibers (DTT). The DTT images obtained using the fractional anisotropy (FA) threshold value of 0.4 clearly revealed the recovery process of the contused nerves. Immediately after the injury, fiber tracking from the designated proximal site could not be continued beyond the lesion epicenter, but the intensity improved thereafter, returning to its pre-injury level by 3 weeks later. We compared the FA value, a parameter computed from the DTT data, with the results of histological and functional examinations of the injured nerves, during recovery. The FA values of the peripheral nerves were more strongly correlated with axon-related (axon density and diameter) than with myelin-related (myelin density and thickness) parameters, supporting the theories that axonal membranes play a major role in anisotropic water diffusion and that myelination can modulate the degree of anisotropy. Moreover, restoration of the FA value at the lesion epicenter was strongly correlated with parameters of motor and sensory functional recovery. These correlations of the FA values with both the histological and functional changes demonstrate the potential usefulness of DTT for evaluating clinical events associated with Wallerian degeneration and the regeneration of peripheral nerves. © 2008 Elsevier Inc. All rights reserved.

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Diffusion-tensor neuronal fiber tractography and manganese- Enhanced MR imaging of primate visual pathway in the common marmoset

Yamada Masayuki, Momoshima Suketaka, Masutani Yoshitaka, Fujiyoshi Kanehiro, Abe Osamu, Nakamura Masaya, Aoki Shigeki, Tamaoki Norikazu, Okano Hideyuki

Radiology 249 （ 3 ） 855 - 864 2008年12月

ISSN 0033-8419

Purpose: To investigate whether diffusion-tensor tractography (DTT) of neuronal fibers is useful for delineating the configuration of the neuronal fiber trajectories in the primate visual pathway, including the well-developed optic chiasm, in comparison with tract tracing at manganese-enhanced magnetic resonance (MR) imaging. Materials and Methods: The handling methods used for all the animals in this study were approved by the institutional committee for animal experiments. Diffusion-tensor MR imaging was performed in four healthy common marmosets, and in two of these animals, manganese-enhanced MR imaging tract tracing was performed by using a 7.0-T MR imaging unit. The visual pathways were quantitatively investigated in terms of the manganese distribution observed on the manganese- enhanced MR images. The images obtained with DTT and manganese-enhanced MR imaging tract tracing were qualitatively compared, and the features of the visual pathway were verified through fusion of the reconstructed images obtained by using these two modalities. Results: DTT provided information regarding the neuroanatomic features of the marmoset visual pathway and revealed the bilateral branching patterns of the typical primate retino-geniculate pathways, although several incorrectly tracked fibers were noted. The distribution of manganese on the manganese-enhanced MR images revealed bilateral innervation of the retinal projections and depicted the layered internal structure of the lateral geniculate nuclei bilaterally, depending on the ocularity of each layer. These morphologic findings were consistent with those of previous histopathologic studies. Conclusion: The findings of this preliminary study raise the possibility that DTT is useful for visualizing the neuronal fiber trajectories in primate visual pathways. © RSNA, 2008.

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Risk factors for closure of lamina after open-door laminoplasty

Matsumoto Morio, Watanabe Kota, Tsuji Takashi, Ishii Ken, Takaishi Hironari, Nakamura Masaya, Toyama Yoshiaki, Chiba Kazuhiro

Journal of Neurosurgery: Spine 9 （ 6 ） 530 - 537 2008年12月

ISSN 1547-5654

Object. This retrospective study was conducted to evaluate the prevalence and clinical consequences of postoperative lamina closure after open-door laminoplasty and to identify the risk factors. Methods. Eighty-two consecutive patients with cervical myelopathy who underwent open-door laminoplasty without plates or spacers in the open side (Hirabayashi's original method) were included (62 men and 20 women with a mean age of 62 years and a mean follow-up of 1.8 years). In 67 patients the cause of cervical myelopathy was spondylotic myelopathy, and in 15 it was caused by ossification of posterior longitudinal ligament. Radiographic measurements were made of the anteroposterior diameters of the spinal canal and vertebral bodies from C3-6, and the presence of kyphosis were assessed. Lamina closure was defined as ≥ 10% decrease in the canal-to-body ratio at the final follow-up compared with that immediately after surgery at ≥ 1 vertebral level. The impact of lamina closure on neck pain, patient satisfaction, Japanese Orthopaedic Association scores, and recovery rates were also evaluated. Results. The mean canal-to-body ratio at C3-6 was 0.69-0.72 preoperatively, 1.25-1.28 immediately after surgery, and 1.18-1.24 at the final follow-up examination. Lamina closure was observed in 34% of patients and was not associated with sex, age, or cause of myelopathy, but was significantly associated with the presence of preoperative kyphosis (p = 0.014). Between patients with and without lamina closure, there was no significant difference in preoperative (9.7 ± 3.1 vs 10.6 ± 2.5) and postoperative (13.7 ± 2.4 vs 13.1 ± 2.7) Japanese Orthopaedic Association scores, recovery rates (53.9 ± 29.9% vs 44.3 ± 29.5%), neck pain scores (3.5 ± 0.7 vs 3.3 ± 1.0), or patient satisfaction level (4.0 ± 1.4 vs 4.8 ± 1.0). Conclusions. Lamina closure at ≥ 1 vertebral level occurred in 34% of patients. Although patients with lamina closure obtained equivalent recovery from myelopathy in a short-term follow-up, they tended to be less satisfied with surgery compared with those who did not have closure. The only significant risk factor identified was the presence of preoperative cervical kyphosis, and preventative methods for lamina closure, therefore, should be considered for patients with preoperative kyphosis.

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Radiographic predictors of residual low back pain after laminectomy for lumbar spinal canal stenosis

Xia Yingpeng, Ishii Ken, Matsumoto Morio, Nakamura Masaya, Toyama Yoshiaki, Chiba Kazuhiro

Journal of Spinal Disorders and Techniques 21 （ 3 ） 153 - 158 2008年05月

ISSN 1536-0652

STUDY DESIGN: Retrospective study of patients who underwent laminectomy for unification. OBJECTIVE: To identify radiographic predictors of residual low back pain (LBP) after laminectomy for lumbar spinal canal stenosis (LCS). SUMMARY OF BACKGROUND DATA: Residual LBP is a common complication of laminectomy and no radiographic predictors of its occurrence have been identified previously. METHODS: Clinical results and radiographic findings in 49 patients (21 males and 28 females, minimum 5-year follow-up) who underwent single level laminectomy for LCS were retrospectively reviewed. Patients who had an improvement in LBP scores in the Japanese Orthopedic Association (JOA) scoring system during the follow-up periods were classified as the recovery group, whereas those without improvements were classified as the nonrecovery group. Patients' clinical data (sex, duration of symptoms, age at surgery, JOA scores) and radiographic parameters (including lumbar lordotic angle, lumbar range of motion (ROM) and the intervertebral rotational angle) were analyzed to detect the factors significantly related with the occurrence of residual LBP. RESULTS: The average preoperative JOA score of 14.8±5.1 points improved to 21.6±5.5 points at the final follow-up providing an average recovery rate of 48.1±36.8%. Thirty-four and 15 patients were classified into the recovery and the nonrecovery groups, respectively. Binary logistic regression analysis revealed that significant predictors of residual LBP were preoperative lumbar lordosis angle and lumbar ROM. The mean preoperative lumbar lordosis and ROM in the nonrecovery group were significantly smaller than those in the recovery group (lordosis: 25.3±15.8 degrees vs. 37.8±13.6 degrees, P=0.006 and ROM: 22.1±10.6 degrees vs. 31.2±9.9 degrees, P=0.006). In addition, increase of the postoperative lumbar ROM was significantly larger in the nonrecovery than that in the recovery group (P=0.009). CONCLUSIONS: Our results indicate that preoperative lordosis angle and lumbar ROM were the significant radiographic predictors for residual LBP after laminectomy for LCS. Patient with flatback and limited lumbar mobility before surgery are prone to suffer residual LBP. It is suggested that these sagittal radiographic parameters should be taken into account when choosing laminectomy as the surgical option for LCS. © 2008 Lippincott Williams & Wilkins, Inc.

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Surgical treatment of intramedullary spinal cord tumors

Nakamura M., Ishii K., Watanabe K., Tsuji T., Takaishi H., Matsumoto M., Toyama Y., Chiba K.

Spinal Cord 46 （ 4 ） 282 - 286 2008年04月

ISSN 1362-4393

Study design: Retrospective case series. Objective: To evaluate our recent treatment strategy for intramedullary spinal cord tumors. Setting: Department of Orthopaedic Surgery, Keio University, Japan. Methods: We reviewed 68 cases of intramedullary tumors (ependymoma, 33; astrocytoma, 23; hemangioblastoma, 12), treated surgically between 1994 and 2003. There were 42 males and 26 females whose mean age at the time of surgery was 43 years. The mean follow-up period was 6.2 years. The tumor malignancy grade according to the WHO classification was astrocytoma grade I, 3; grade II, 8 (low-grade: 11 cases); grade III, 10; grade IV, 2 (high-grade: 12 cases). All ependymomas were grade II. Three of the 12 hemangioblastomas were associated with von Hippel-Lindau disease. Results: Total excision was achieved in 90% of the ependymomas and functional improvement was obtained when the preoperative neurological deficit was mild. Approximately 50% of low-grade astrocytomas could be totally excised with favorable survival outcomes, suggesting that total excision should be attempted for low-grade astrocytomas. However, total excision of high-grade tumors was difficult and the functional outcomes were poor. Cordotomy should be considered in patients with a thoracic high-grade astrocytoma. Total resection was possible in 92% of hemangioblastoma, and the functional outcomes were good, however, more attention should be paid for tumors with feeding arteries on the ventral side and for those associated with von Hippel-Lindau disease. Conclusions: Predictors of good surgical outcome for intramedullary spinal cord tumors were histological grades of the tumors, surgical margins, and neurological status of the patient before surgery. © 2008 International Spinal Cord Society All rights reserved.

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Ontogeny and Multipotency of Neural Crest-Derived Stem Cells in Mouse Bone Marrow, Dorsal Root Ganglia, and Whisker Pad

Nagoshi Narihito, Shibata Shinsuke, Kubota Yoshiaki, Nakamura Masaya, Nagai Yasuo, Satoh Etsuko, Morikawa Satoru, Okada Yohei, Mabuchi Yo, Katoh Hiroyuki, Okada Seiji, Fukuda Keiichi, Suda Toshio, Matsuzaki Yumi, Toyama Yoshiaki, Okano Hideyuki

Cell Stem Cell 2 （ 4 ） 392 - 403 2008年04月

ISSN 1934-5909

Although recent reports have described multipotent, self-renewing, neural crest-derived stem cells (NCSCs), the NCSCs in various adult rodent tissues have not been well characterized or compared. Here we identified NCSCs in the bone marrow (BM), dorsal root ganglia, and whisker pad and prospectively isolated them from adult transgenic mice encoding neural crest-specific P0-Cre/Floxed-EGFP and Wnt1-Cre/Floxed-EGFP. Cultured EGFP-positive cells formed neurosphere-like structures that expressed NCSC genes and could differentiate into neurons, glial cells, and myofibroblasts, but the frequency of the cell types was tissue source dependent. Interestingly, we observed NCSCs in the aorta-gonad-mesonephros region, circulating blood, and liver at the embryonic stage, suggesting that NCSCs migrate through the bloodstream to the BM and providing an explanation for how neural cells are generated from the BM. The identification of NCSCs in accessible adult tissue provides a new potential source for autologous cell therapy after nerve injury or disease. © 2008 Elsevier Inc. All rights reserved.

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Isolation and characterization of dendritic cells from common marmosets for preclinical cell therapy studies

Ohta Shigeki, Ueda Yoko, Yaguchi Masae, Matsuzaki Yumi, Nakamura Masaya, Toyama Yoshiaki, Tanioka Yoshikuni, Tamaoki Norikazu, Nomura Tatsuji, Okano Hideyuki, Kawakami Yutaka, Toda Masahiro

Immunology 123 （ 4 ） 566 - 574 2008年04月

ISSN 0019-2805

Dendritic cells (DCs) have important functions as modulators of immune responses, and their ability to activate T cells is of great value in cancer immunotherapy. The isolation of DCs from the peripheral blood of rhesus and African green monkeys has been reported, but the immune system in the common marmoset remains poorly characterized, although it offers many potential advantages for preclinical studies. In the present study, we devised methods, based on techniques developed for mouse and human DC preparation, for isolating DCs from three major tissue sources in the common marmoset: bone marrow (BM), spleen and peripheral blood. Each set of separated cells was analysed using the cell surface DC-associated markers CD11c, CD80, CD83, CD86 and human leucocyte antigen (HLA)-DR, all of which are antibodies against human antigens, and the cells were further characterized both functionally and morphologically as antigen-presenting cells. BM proved to be an excellent cell source for the isolation of DCs intended for preclinical studies on cell therapy, for which large quantities of cells are required. In the BM-derived CD11c⁺ cell population, cells exhibiting the characteristic features of DCs were enriched, with the typical DC morphology and the abilities to undergo endocytosis, to secrete interleukin (IL)-12, and to stimulate Xenogenic T cells. Moreover, BM-derived DCs produced the neurotrophic factor NT-3, which is also found in murine splenic DCs. These results suggest that BM-derived DCs from the common marmoset may be useful for biological analysis and for preclinical studies on cell therapy for central nervous system diseases and cancer. © 2007 Blackwell Publishing Ltd.

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Role of IL-6 in regulation of inflammation and stem cell differentiation in CNS trauma

Mukaino Masahiko, Nakamura Masaya, Okada Seiji, Toyama Yoshiaki, Liu Meigen, Okano Hideyuki

Nihon Rinshō Men'eki Gakkai kaishi = Japanese journal of clinical immunology 31 （ 2 ） 93 - 98 2008年04月

ISSN 0911-4300

Interleukin-6 (IL-6) has been demonstrated to play a pivotal role in CNS trauma as a proinflammatory cytokine which regulates inflammatory response. Not only being a mediator of inflammation, but IL-6 induces neural stem/progenitor cells to undergo astrocytic differentiation selectively in the injured CNS. These effects are considered to coordinate to prevent the CNS repair after traumatic injury. Consistently, we previously reported that the administration of anti-IL-6 receptor antibody (MR16-1) immediately after spinal cord injury in mice decreased the number of invading inflammatory cells and the severity of connective tissue scar formation, and led to improved functional recovery. These findings suggest that neutralization of IL-6 signaling in the acute phase of SCI will be beneficial for CNS repair. A critical merit of this anti-IL-6 receptor antibody is that humanized antibody to human IL-6 receptor (MRA; Atlizumab) has already been reshaped. However, there are several studies which show beneficial aspects of IL-6 signaling in the pathology of CNS trauma. Further investigation of the mechanisms how MR16-1 reduces tissue damage should be required for clinical application.

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[Strategies for axonal regeneration after spinal cord injury].

Kitamura Kazuya, Nakamura Masaya, Toyama Yoshiaki, Okano Hideyuki

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme 53 （ 4 Suppl ） 411 - 417 2008年03月

ISSN 0039-9450

Spinal cord injury

Renault-Mihara Francois, Okada Seiji, Shibata Shinsuke, Nakamura Masaya, Toyama Yoshiaki, Okano Hideyuki

International Journal of Biochemistry and Cell Biology 40 （ 9 ） 1649 - 1653 2008年

ISSN 1357-2725

Spinal cord injury (SCI), despite considerable progress in palliative care, has currently no satisfying therapeutic leading to functional recovery. Inability of central nervous system severed axons to regenerate after injury is considered to originate from both limited intrinsic capabilities of neurons and inhibitory effect of the local environment. Precisely, the so-called "glial scar" formed by reactive astrocytes in response to injury exerts a well-known axon-outgrowth inhibitory effect. However, recent studies revealed that role of reactive astrocytes after SCI is more complex. During the first weeks after injury, reactive astrocytes indeed protect the tissue and contribute to a spontaneous relative functional recovery. Compaction of the lesion center and seclusion of inflammatory cells by migrating reactive astrocytes seem to underlie this beneficial effect. Stimulation of reactive astrocytes migration in the sub-acute phase of SCI might thus represent a new approach to improve the functional outcome of patients. © 2008 Elsevier Ltd. All rights reserved.

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Microendoscopic discectomy for lumbar disc herniation with bony fragment due to apophyseal separation

Matsumoto M., Watanabe K., Tuji T., Ishii K., Takaishi H., Nakamura M., Chiba K., Toyama Y.

Minimally Invasive Neurosurgery 50 （ 6 ） 335 - 339 2007年12月

ISSN 0946-7211

The purpose of this study was to elucidate the feasibility of microendoscopic discectomy (MED) for the treatment of lumbar disc herniation with a bony fragment due to apophyseal separation. Eighteen patients with low back pain and unilateral sciatic pain due to lumbar disc herniation with a bony fragment were treated by MED using the unilateral approach (15 males and three females; mean age, of 28.9 years; mean follow-up period, 21.1 months); 18 age-and sex-matched patients with lumbar disc herniation without a bony fragment treated by MED served as the control group. The clinical outcomes were evaluated using the Japanese Orthopedic Association Score for Low Back Pain (JOA scores; maximum score, 29 points). Evaluation of the results revealed that good surgical outcomes equivalent to those in the control group were obtained in the subjects of LDH with a bony fragment (JOA scores; 14.1±3.5 in the patient group vs. 15.4±2.6 in the control group before surgery; 26.3±1.8 in the patient group vs. 26.9±1.3 at follow-up after the surgery). Although the mean surgical time was significantly longer in the patient group, there were no intra- or postoperative complications in either group. We conclude that MED using the unilateral approach is a feasible minimally invasive surgical option for patients of lumbar disc herniation with an apophyseal bony fragment. © Georg Thieme Verlag KG Stuttgart.

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In vivo tracing of neural tracts in the intact and injured spinal cord of marmosets by diffusion tensor tractography

Fujiyoshi Kanehiro, Yamada Masayuki, Nakamura Masaya, Yamane Junichi, Katoh Hiroyuki, Kitamura Kazuya, Kawai Kenji, Okada Seiji, Momoshima Suketaka, Toyama Yoshiaki, Okano Hideyuki

Journal of Neuroscience 27 （ 44 ） 11991 - 11998 2007年10月

ISSN 0270-6474

In spinal cord injury, axonal disruption results in motor and sensory function impairment. The evaluation of axonal fibers is essential to assess the severity of injury and efficacy of any treatment protocol, but conventional methods such as tracer injection in brain parenchyma are highly invasive and require histological evaluation, precluding clinical applications. Previous advances in magnetic resonance imaging technology have led to the development of diffusion tensor tractography (DTT) as a potential modality to perform in vivo tracing of axonal fibers. The properties and clinical applications of DTT in the brain have been reported, but technical difficulties have limited DTT studies of the spinal cord. In this study, we report the effective use of DTT to visualize both intact and surgically disrupted spinal long tracts in adult common marmosets. To verify the feasibility of spinal cord DTT, we first performed DTT of postmortem marmosets. DTT clearly illustrated spinal projections such as the corticospinal tract and afferent fibers in control animals, and depicted the severed long tracts in the injured animals. Histology of the spinal cords in both control and injured groups were consistent with DTT findings, verifying the accuracy of DTT. We also conducted DTT in live marmosets and demonstrated that DTT can be performed in live animals to reveal in vivo nerve fiber tracing images, providing an essential tool to evaluate axonal conditions in the injured spinal cord. Taken together, these findings demonstrate the feasibility of applying DTT to preclinical and clinical studies of spinal cord injury. Copyright © 2007 Society for Neuroscience.

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Hepatocyte growth factor promotes endogenous repair and functional recovery after spinal cord injury

Kitamura Kazuya, Iwanami Akio, Nakamura Masaya, Yamane Junichi, Watanabe Kota, Suzuki Yoshinori, Miyazawa Daisuke, Shibata Shinsuke, Funakoshi Hiroshi, Miyatake Shinichi, Coffin Robert S., Nakamura Toshikazu, Toyama Yoshiaki, Okano Hideyuki

Journal of Neuroscience Research 85 （ 11 ） 2332 - 2342 2007年08月

ISSN 0360-4012

Many therapeutic interventions using neurotrophic factors or pharmacological agents have focused on secondary degeneration after spinal cord injury (SCI) to reduce damaged areas and promote axonal regeneration and functional recovery. Hepatocyte growth factor (HGF), which was identified as a potent mitogen for mature hepatocytes and a mediator of inflammatory responses to tissue injury, has recently been highlighted as a potent neurotrophic and angiogenic factor in the central nervous system (CNS). In the present study, we revealed that the extent of endogenous HGF up-regulation was less than that of c-Met, an HGF receptor, during the acute phase of SCI and administered exogenous HGF into injured spinal cord using a replication-incompetent herpes simplex virous-1 (HSV-1) vector to determine whether HGF exerts beneficial effects and promotes functional recovery after SCI. This treatment resulted in the significant promotion of neuron and oligodendrocyte survival, angiogenesis, axonal regrowth, and functional recovery after SCI. These results suggest that HGF gene delivery to the injured spinal cord exerts multiple beneficial effects and enhances endogenous repair after SCI. This is the first study to demonstrate the efficacy of HGF for SCI. © 2007 Wiley-Liss, Inc.

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The validity of intraoperative angiography for the treatment of spinal arteriovenous fistula

Xia Yingpeng, Ishii Ken, Nakamura Masaya, Onozuka Satoshi, Ueda Ryo, Matsumoto Morio, Chiba Kazuhiro, Toyama Yoshiaki

Journal of Spinal Disorders and Techniques 20 （ 6 ） 442 - 448 2007年08月

ISSN 1536-0652

STUDY DESIGN: Retrospective study of patients with spinal arteriovenous fistula (AVF) who underwent surgical treatment. OBJECTIVE: To evaluate the validity of the intraoperative angiography (IA) for the surgical treatment of spinal AVF. SUMMARY OF BACKGROUND DATA: Owing to the development of interventional techniques, endovascular embolization has become the treatment of choice for AVF, but it is not applicable for every spinal AVF owing to anatomic complexity of the spinal cord vessels. To get effective occlusion of the AVF, IA has been routinely used in the management of cerebral vascular diseases, but report of its use for spinal AVF is rare. METHODS: Since 2004, 4 consecutive cases of spinal AVF (3 males and 1 female, 3 thoracic, and 1 thoracolumbar) were involved in this study. The mean age at the time of operation was 62.3 years (range from 48 to 76 y). Types of AVFs and surgical techniques were reviewed retrospectively and the outcomes were assessed using the Japanese Orthopedic Association scoring system. RESULTS: AVFs in 3 patients were diagnosed as the dural type and that in the remaining patient as the perimedullary type; all feeding arteries were derived from the ninth to 10th intercostal arteries. Preoperative angiography demonstrated that the feeding arteries in 2 patients with a dural AVF were the branches of Adamkiewicz artery and in another dural AVF case, the Adamkiewicz artery could not be determined, therefore, endovascular embolization was not feasible. Including a patient with perimedullary AVF, a microsurgical clipping combined with IA was selected as the treatment. Complete occlusion of the fistula was achieved in all cases, the mean preoperative Japanese Orthopedic Association score of 4.5 improved to 6 at the final follow-up, and no perioperative complications were observed during the follow-up period. CONCLUSIONS: The favorable clinical results in our spinal AVF cases confirmed that IA ensures safe and accurate occlusion of the fistula. This technique provides satisfactory surgical results for spinal AVFs. © 2007 Lippincott Williams & Wilkins, Inc.

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Regeneration-based therapies for spinal cord injuries

Okano Hideyuki, Kaneko Shinjiro, Okada Seiji, Iwanami Akio, Nakamura Masaya, Toyama Yoshiaki

Neurochemistry International 51 （ 2-4 SPEC. ISS. ） 68 - 73 2007年07月

ISSN 0197-0186

Although it has been long believed that the damaged central nervous system does not regenerate upon injury, there is an emerging hope for regeneration-based therapy of the damaged central nervous system (CNS) due to the progress of developmental biology and regenerative medicine including stem cell biology. In this review, we have summarized recent studies aimed at the development of regeneration-based therapeutic approaches for spinal cord injuries, including therapy with anti-inflammatory cytokines, transplantation of neural stem/precursor cells and induction of axonal regeneration. © 2007 Elsevier Ltd. All rights reserved.

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Extensive total spondylectomy for recurrent giant cell tumor in the thoracic spine. Case report

Matsumoto Morio, Ishii Ken, Takaishi Hironari, Nakamura Masaya, Morioka Hideo, Chiba Kazuhiro, Takahata Takeshi, Toyama Yoshiaki

Journal of Neurosurgery: Spine 6 （ 6 ） 600 - 605 2007年06月

ISSN 1547-5654

The authors report the case of a 47-year-old woman who harbored a giant cell tumor at the T-5 level. She had undergone curettage of the tumor via a combined anterior and posterior approach at a regional hospital and was later referred to the authors' institution for treatment after the tumor recurred. On examination she exhibited progressive paraparesis and was nonambulatory due to cord compression caused by the tumor, which had invaded the spinal canal and extended to the right paravertebral muscles and right thoracic cavity. A spondylectomy was performed through a single posterior approach. The tumor, together with a portion of the dura mater, pleura, and muscles, was resected en bloc from T-4 to T-6. After resection, spinal reconstruction was performed by placement of an anterior titanium mesh cage as well as posterior pedicle screw and rod instrumentation. The patient's postoperative course was uneventful, and she exhibited substantial neurological recovery and became ambulatory. Two and a half years after surgery, the patient was tumor free. En bloc resection of a recurrent giant cell tumor was successfully achieved through a single posterior approach. This surgical technique can be an effective option for this pathological condition, which is difficult to manage using other conventional treatment options including repeated curettage and radiotherapy.

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Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel

Steeves J. D., Lammertse D., Curt A., Fawcett J. W., Tuszynski M. H., Ditunno J. F., Ellaway P. H., Fehlings M. G., Guest J. D., Kleitman N., Bartlett P. F., Blight A. R., Dietz V., Dobkin B. H., Grossman R., Short D., Nakamura M., Coleman W. P., Gaviria M., Privat A.

Spinal Cord 45 （ 3 ） 206 - 221 2007年03月

ISSN 1362-4393

An international panel reviewed the methodology for clinical trials of spinal cord injury (SCI), and provided recommendations for the valid conduct of future trials. This is the second of four papers. It examines clinical trial end points that have been used previously, reviews alternative outcome tools and identifies unmet needs for demonstrating the efficacy of an experimental intervention after SCI. The panel focused on outcome measures that are relevant to clinical trials of experimental cell-based and pharmaceutical drug treatments. Outcome measures are of three main classes: (1) those that provide an anatomical or neurological assessment for the connectivity of the spinal cord, (2) those that categorize a subject's functional ability to engage in activities of daily living, and (3) those that measure an individual's quality of life (QoL). The American Spinal Injury Association impairment scale forms the standard basis for measuring neurologic outcomes. Various electrophysiological measures and imaging tools are in development, which may provide more precise information on functional changes following treatment and/or the therapeutic action of experimental agents. When compared to appropriate controls, an improved functional outcome, in response to an experimental treatment, is the necessary goal of a clinical trial program. Several new functional outcome tools are being developed for measuring an individual's ability to engage in activities of daily living. Such clinical end points will need to be incorporated into Phase 2 and Phase 3 trials. QoL measures often do not correlate tightly with the above outcome tools, but may need to form part of Phase 3 trial measures. © 2007 International Spinal Cord Society All rights reserved.

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Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel

Fawcett J. W., Curt A., Steeves J. D., Coleman W. P., Tuszynski M. H., Lammertse D., Bartlett P. F., Blight A. R., Dietz V., Ditunno J., Dobkin B. H., Havton L. A., Ellaway P. H., Fehlings M. G., Privat A., Grossman R., Guest J. D., Kleitman N., Nakamura M., Gaviria M., Short D.

Spinal Cord 45 （ 3 ） 190 - 205 2007年03月

ISSN 1362-4393

The International Campaign for Cures of Spinal Cord Injury Paralysis (ICCP) supported an international panel tasked with reviewing the methodology for clinical trials in spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the first of four papers. Here, we examine the spontaneous rate of recovery after SCI and resulting consequences for achieving statistically significant results in clinical trials. We have reanalysed data from the Sygen trial to provide some of this information. Almost all people living with SCI show some recovery of motor function below the initial spinal injury level. While the spontaneous recovery of motor function in patients with motor-complete SCI is fairly limited and predictable, recovery in incomplete SCI patients (American spinal injury Association impairment scale (AIS) C and AIS D) is both more substantial and highly variable. With motor complete lesions (AIS A/AIS B) the majority of functional return is within the zone of partial preservation, and may be sufficient to reclassify the injury level to a lower spinal level. The vast majority of recovery occurs in the first 3 months, but a small amount can persist for up to18 months or longer. Some sensory recovery occurs after SCI, on roughly the same time course as motor recovery. Based on previous data of the magnitude of spontaneous recovery after SCI, as measured by changes in ASIA motor scores, power calculations suggest that the number of subjects required to achieve a significant result from a trial declines considerably as the start of the study is delayed after SCI. Trials of treatments that are most efficacious when given soon after injury will therefore, require larger patient numbers than trials of treatments that are effective at later time points. As AIS B patients show greater spontaneous recovery than AIS A patients, the number of AIS A patients requiring to be enrolled into a trial is lower. This factor will have to be balanced against the possibility that some treatments will be more effective in incomplete patients. Trials involving motor incomplete SCI patients, or trials where an accurate assessment of AIS grade cannot be made before the start of the trial, will require large subject numbers and/or better objective assessment methods. © 2007 International Spinal Cord Society All rights reserved.

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Electrical stimulation modulates fate determination of differentiating embryonic stem cells

Yamada Masahisa, Tanemura Kentaro, Okada Seiji, Iwanami Akio, Nakamura Masaya, Mizuno Hideaki, Ozawa Michiru, Ohyama-Goto Ritsuko, Kitamura Naohito, Kawano Masako, Tan-Takeuchi Kyoko, Ohtsuka Chiho, Miyawaki Atsushi, Takashima Akihiko, Ogawa Masaharu, Toyama Yoshiaki, Okano Hideyuki, Kondo Takashi

Stem Cells 25 （ 3 ） 562 - 570 2007年03月

ISSN 1066-5099

A clear understanding of cell fate regulation during differentiation is key in successfully using stem cells for therapeutic applications. Here, we report that mild electrical stimulation strongly influences embryonic stem cells to assume a neuronal fate. Although the resulting neuronal cells showed no sign of specific terminal differentiation in culture, they showed potential to differentiate into various types of neurons in vivo, and, in adult mice, contributed to the injured spinal cord as neuronal cells. Induction of calcium ion influx is significant in this differentiation system. This phenomenon opens up possibilities for understanding novel mechanisms underlying cellular differentiation and early development, and, perhaps more importantly, suggests possibilities for treatments in medical contexts. ©AlphaMed Press.

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Plasma as a scaffold for regeneration of neural precursor cells after transplantation into rats with spinal cord injury

Takenaga Mitsuko, Ohta Yuki, Tokura Yukie, Hamaguchi Akemi, Suzuki Noboru, Nakamura Masaya, Okano Hideyuki, Igarashi Rie

Cell Transplantation 16 （ 1 ） 57 - 65 2007年

ISSN 0963-6897

The present study investigated whether plasma could be useful as a scaffold for cell transplantation in rats with spinal cord injury (SCI). Transplantation of cells with plasma promoted the recovery of SCI-induced motor dysfunction. Immunohistochemical analysis revealed that the grafted cells had differentiated into the neural lineage. When dissociated neural precursor cells were cultured with plasma, extensive neurite outgrowth was observed along with increased expression of p35 and NF68. Neural markers were also expressed by the cultured cells. Culture with plasma reduced thymidine incorporation, but promoted cell growth and increased the RNA contents. These findings suggest that the cells underwent differentiation into neurons in the presence of plasma. In conclusion, plasma could be a promising scaffold for cell transplantation therapy. Copyright © 2007 Cognizant Comm. Corp.

Establishment of three-dimensional culture of neural stem/progenitor cells in collagen Type-1 Gel

Watanabe Kota, Nakamura Masaya, Okano Hideyuki, Toyama Yoshiaki

Restorative Neurology and Neuroscience 25 （ 2 ） 109 - 117 2007年

ISSN 0922-6028

Purpose: Recent studies demonstrated that transplanting neural stem/precursor cells (NSPCs) into an injured spinal cord of adult rat promotes functional recovery. The functional recovery from spinal cord injury might be enhanced by transplanting NSPCs with a scaffold that fills the cavity, entraps the NSPCs in the cavity, and acts as an attachment for neurite extension. We recently focused on collagen type-1 as a scaffold for NSPC transplantation into the injured spinal cord. In the present study, we determined the optimal conditions for culturing NSPCs in 3D collagen type-1 gel with respect to cell survival and cell migration. We, then, evaluated the ability of NSPCs to differentiate under the optimal condition. Methods: NSPCs were derived from the striatum of rat embryos. To determine the optimal cell density and collagen concentration for 3D collagen gel culture for NSPC, we performed viability assay and migration assay. Then, we examined the proportion of phenotypes differentiated from NSPC in that optimal condition. Results: In viability assay, the viability rate increased as the NSPC density increased, and peaked at 1 × 10⁷ to 5 × 10⁷ cell/ml. For collagen concentration, the viability rate increased as the collagen concentration decreased. In migration assay, cell migration was most extensive at collagen concentrations between 0.3 and 0.75 mg/ml. Migration distances gradually declined as collagen concentrations increased. In the optimal condition, NSPCs differentiated into neurons (40.1%), astrocytes (53.1%), and oligodendrocytes (5.3%) in 3D collagen gel culture. Conclusion: The optimal conditions for NSPC culture in 3D collagen gel was a cell density between 1 × 10⁷ and 5 × 10⁷ cells/ml and a collagen concentration between 0.5 and 0.75 mg/ml. Under the condition, NSPCs could differentiate into neurons, astrocytes, and oligodendrocytes. © 2007 - IOS Press and the authors. All rights reserved.

Surgical outcomes of spinal cord astrocytomas

Nakamura M., Chiba K., Ishii K., Ogawa Y., Takaishi H., Matsumoto M., Toyama Y.

Spinal Cord 44 （ 12 ） 740 - 745 2006年12月

ISSN 1362-4393

Study design:Retrospective case series.Objectives:To analyze prognostic factors for patients with spinal cord astrocytomas.Setting:Department of Orthopaedic Surgery, Keio University, Japan.Methods:Seven patients received total excisions (group T), eight underwent partial excisions (group P), and 15 had excisional biopsies (group B). Impacts of the tumor histological grade, the level of the tumor, the types of surgical interventions, and the use of adjuvant radiotherapies on the survival and functional outcomes of 30 patients (18 in low-grade and 12 high-grade malignancy tumors) were analyzed.Results:The survival rate of the low-grade malignancy group was significantly higher than that of the high-grade group. The survival rate of the patients with thoracic astrocytomas was significantly higher than those with cervical astrocytomas. In both the low- and high-grade groups, the survival rates in groups P/T were significantly higher than those in group B. In the low-grade group, five patients, whose preoperative functional statuses were classified as 'fair' or better, remained 'fair' or better after surgery. In the high-grade group, the postoperative functional statuses were classified as 'no change' or 'aggravated' in all except two patients. No significant difference in the survival rates was detected between patients with and without adjuvant radiotherapy.Conclusions: The tumor grade and the extent of tumor resection were significant prognostic factors for survival rate. In low-grade malignancy group, good motor function was retained when surgeries were performed before substantial neurological deterioration. The efficacy of postoperative radiotherapy has yet to be determined and needs further study. © 2006 International Spinal Cord Society All rights reserved.

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Long-term results of expansive open-door laminoplasty for cervical myelopathy - Average 14-year follow-up study

Chiba Kazuhiro, Ogawa Yuto, Ishii Ken, Takaishi Hironari, Nakamura Masaya, Maruiwa Hirofumi, Matsumoto Morio, Toyama Yoshiaki

Spine 31 （ 26 ） 2998 - 3005 2006年12月

ISSN 0362-2436

STUDY DESIGN. Retrospective case series on long-term follow-up results of original expansive open-door laminoplasty for cervical myelopathy due to cervical spondylosis (CSM) and ossification of posterior longitudinal ligament (OPLL). OBJECTIVES. To elucidate efficacy and problems of original open-door laminoplasty to improve future surgical outcomes. SUMMARY OF BACKGROUND DATA. Little information is available on long-term outcomes of original open-door laminoplasty without grafts, implants, or instruments. METHOD. The study group included 80 patients who underwent original open-door laminoplasty and were followed for minimum 10 years. Clinical results, including Japanese Orthopedic Association scores, recovery rates, occurrences of complications, and long-term deterioration were investigated. Cervical alignments, type of OPLL, cervical range of motion, anteroposterior diameter of spinal canal, and progression of OPLL were assessed on plain radiographs. Spinal cord decompression was verified on magnetic resonance imaging. RESULTS. Average Japanese Orthopedic Association score and recovery rate improved significantly until 3 years after surgery and remained at an acceptable level in both cervical spondylosis and OPLL patients with slight deterioration after 5 years. Segmental motor palsy developed in 8 patients. Late deterioration, mainly lower extremity motor score decline, developed in 8 CSM and 16 OPLL patients. Overall cervical range of motion decreased by 36%. Patients with cervical lordosis decreased gradually in both patient groups. Such changes in alignments did not affect surgical results in CSM patients, while OPLL patients with preoperative kyphosis had lower recovery rates than those with straight and lordotic alignments. OPLL progression that was detected in 66% of patients did not affect clinical results. Although infrequent, magnetic resonance imaging revealed atrophy of spinal cord, spinal cord compression at adjacent segments due to degenerative changes and OPLL progression. CONCLUSIONS. Long-term results of open-door laminoplasty without bone graft, graft substitutes, or instruments were satisfactory. However, segmental motor paralysis, kyphosis, established before and after surgery, OPLL progression, and late deterioration due to age-related degeneration remain challenging problems. © 2006 Lippincott Williams & Wilkins, Inc.

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A selective Sema3A inhibitor enhances regenerative responses and functional recovery of the injured spinal cord

Kaneko Shinjiro, Iwanami Akio, Nakamura Masaya, Kishino Akiyoshi, Kikuchi Kaoru, Shibata Shinsuke, Okano Hirotaka J., Ikegami Takeshi, Moriya Ayako, Konishi Osamu, Nakayama Chikao, Kumagai Kazuo, Kimura Toru, Sato Yasufumi, Goshima Yoshio, Taniguchi Masahiko, Ito Mamoru, He Zhigang, Toyama Yoshiaki, Okano Hideyuki

Nature Medicine 12 （ 12 ） 1380 - 1389 2006年12月

ISSN 1078-8956

Axons in the adult mammalian central nervous system (CNS) exhibit little regeneration after injury. It has been suggested that several axonal growth inhibitors prevent CNS axonal regeneration. Recent research has demonstrated that semaphorin3A (Sema3A) is one of the major inhibitors of axonal regeneration. We identified a strong and selective inhibitor of Sema3A, SM-216289, from the fermentation broth of a fungal strain. To examine the effect of SM-216289 in vivo, we transected the spinal cord of adult rats and administered SM-216289 into the lesion site for 4 weeks. Rats treated with SM-216289 showed substantially enhanced regeneration and/or preservation of injured axons, robust Schwann cell-mediated myelination and axonal regeneration in the lesion site, appreciable decreases in apoptotic cell number and marked enhancement of angiogenesis, resulting in considerably better functional recovery. Thus, Sema3A is essential for the inhibition of axonal regeneration and other regenerative responses after spinal cord injury (SCI). These results support the possibility of using Sema3A inhibitors in the treatment of human SCI. © 2006 Nature Publishing Group.

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Neutralization of ciliary neurotrophic factor reduces astrocyte production from transplanted neural stem cells and promotes regeneration of corticospinal tract fibers in spinal cord injury

Ishii Ken, Nakamura Masaya, Dai HaiNing, Finn Tom P., Okano Hideyuki, Toyama Yoshiaki, Bregman Barbara S.

Journal of Neuroscience Research 84 （ 8 ） 1669 - 1681 2006年12月

ISSN 0360-4012

Transplantation of neural stem cells (NSC) into lesioned spinal cord offers the potential to increase regeneration by replacing lost neurons or oligodendrocytes. The majority of transplanted NSC, however, typically differentiate into astrocytes that may exacerbate glial scar formation. Here we show that blocking of ciliary neurotrophic factor (CNTF) with anti-CNTF antibodies after NSC transplant into spinal cord injury (SCI) resulted in a reduction of glial scar formation by 8 weeks. Treated animals had a wider distribution of transplanted NSC compared with the control animals. The NSC around the lesion coexpressed either nestin or markers for neurons, oligodendrocytes, or astrocytes. Approximately 20% fewer glial fibrillary acidic protein-positive/bromodeoxyuridine (BrdU)-positive cells were seen at 2, 4, and 8 weeks postgrafting, compared with the control animals. Furthermore, more CNPase⁺/BrdU⁺ cells were detected in the treated group at 4 and 8 weeks. These CNPase⁺ or Rip⁺ mature oligodendrocytes were seen in close proximity to host corticospinal tract (CST) and 5HT⁺ serotonergic axon. We also demonstrate that the number of regenerated CST fibers both at the lesion and at caudal sites in treated animals was significantly greater than that in the control animals at 8 weeks. We suggest that the blocking of CNTF at the beginning of SCI provides a more favorable environment for the differentiation of transplanted NSC and the regeneration of host axons. © 2006 Wiley-Liss, Inc.

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Postoperative factors affecting neurological recovery after surgery for cervical spondylotic myelopathy

Ogawa Yuto, Chiba Kazuhiro, Matsumoto Morio, Nakamura Masaya, Takaishi Hironari, Toyama Yoshiaki

Journal of Neurosurgery: Spine 5 （ 6 ） 483 - 487 2006年12月

ISSN 1547-5654

Object. Many prognostic factors associated with surgery for cervical spondylotic myelopathy (CSM) have been detailed in the literature. All of these factors, however, are defined preoperatively. If it is possible to clarify factors influencing surgical results that can be modulated after surgery, then the overall results of surgery may improve. The purpose of this study was to elucidate such postoperative factors affecting neurological recovery. Methods. The authors assessed the surgical outcomes obtained in 183 patients with CSM who underwent expansive open-door laminoplasty between 1993 and 2004 and who underwent follow up for a minimum of 1 year. They classified the cases into two groups according to the degree of neurological recovery: an excellent recovery group, comprising patients in whom the recovery rates were greater than 75%, and a poor recovery group, composed of patients in whom the recovery rates were lower than 30%. Comparisons of various clinical and imaging parameters revealed that the mean age at surgery was significantly lower in patients in the excellent recovery group than that in the poor recovery group. Therefore, the authors repeated the same analyses after adjustment for age. Postoperative cervical range of motion (ROM) was significantly more reduced in the excellent recovery group than in the poor recovery group. There was a significant positive correlation between reduced cervical ROM and recovery rate in the poor recovery group. Conclusions. Dynamic stress may deteriorate functional recovery of the degenerated spinal cord even after sufficient decompression. Postoperative preservation of cervical ROM may not always be beneficial for neurological recovery in patients with CSM.

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Pathognomonic radiological signs for predicting prognosis in patients with chronic atlantoaxial rotatory fixation

Ishii Ken, Chiba Kazuhiro, Maruiwa Hirofumi, Nakamura Masaya, Matsumoto Morio, Toyama Yoshiaki

Journal of Neurosurgery: Spine 5 （ 5 ） 385 - 391 2006年11月

ISSN 1547-5654

Object. The authors conducted a study to assess the correlation between radiological features and clinical courses in patients with chronic atlantoaxial rotatory fixation (AARF) and to determine diagnostic imaging signs for predicting prognosis. Methods. There were 24 patients (eight boys and 16 girls) whose mean age was 7.8 years (range 4-14 years) and in whom AARF was diagnosed. The mean follow-up duration was 3.7 years (range 5 weeks-12 years). There were two groups of patients: 15 patients who visited the hospital less than 8 weeks after symptom (torticollis) onset comprised the acute group, and nine patients in whom the diagnosis of AARF was established later than 3 months after symptom onset comprised the chronic group. The chronic group was divided into two subgroups: those in whom the closed reduction could be achieved and those in whom it could not. Clinical data and radiographic studies, including plain radiographs and plain and three-dimensional (3D) computed tomography (CT) reconstructions, were reviewed retrospectively. A deformity of the superior C-2 facet joint was frequently observed in the group of patients with chronic AARF (p < 0.0001). This sign represented a risk factor for recurrent dislocation (p = 0.0003, Fisher exact test). Prominent lateral inclination of C-1 was an impeding factor for reduction of chronic AARF (p < 0.0001, analysis of variance with Fisher post hoc test). Greater than 20° of lateral inclination of the atlas indicated an irreducible subluxation (p = 0.0023, Fisher exact test). Conclusions. Both facet joint deformity and lateral inclination observed on 3D CT reconstructions can be useful signs to predict the prognosis and the treatment of choice in patients with chronic AARFs.

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Posterior osteotomy and instrumentation for thoracolumbar kyphosis in patients with achondroplasia

Qi Xin, Matsumoto Morio, Ishii Ken, Nakamura Masaya, Chiba Kazuhiro, Toyama Yoshiaki

Spine 31 （ 17 ） 2006年08月

ISSN 0362-2436

STUDY DESIGN. A retrospective case series of surgically treated achondroplastic patients with severe thoracolumbar kyphosis. OBJECTIVE. To evaluate the outcome of surgical treatment for thoracolumbar kyphosis in patients associated with achondroplasia presenting with paraparesis. SUMMARY OF BACKGROUND DATA. Thoracolumbar kyphosis is one of the frequent skeletal manifestations in patients with achondroplasia. Few papers have been published on the surgical treatment of this condition, especially in skeletally mature patients. METHODS. Four patients with achondroplasia who developed neurologic deficit due to severe thoracolumbar kyphosis and underwent surgical treatment were evaluated (mean age, 32.5 years; mean follow-up, 3.0 years). Posterior osteotomy with segmental instrumentation was performed in all cases. The surgical procedures included pedicle subtraction osteotomy in 2 patients without a hypoplastic apical vertebra and spondylectomy with reconstruction of the anterior column in 2 patients with a hypoplastic apical vertebra. Neurologic outcomes (JOA scores), correction of kyphosis, and operative complications were assessed. RESULTS. All patients had gait disturbance, and 2 patients were unambulatory before surgery. The average preoperative JOA score was 5.8 points, which was improved to 9.3 points at the final follow-up (mean recovery rate, 75%). All patients obtained neurologic improvement and became ambulatory either with or without crutches after surgery. The mean preoperative kyphotic angle was 96.3° (range, 57°-117°). The postoperative angles averaged 55.3° (range, 30°-110°), yielding a mean correction rate of 43.6%. Neither loss of correction nor pseudarthrosis has been observed during the follow-up period. Partial nerve root laceration and dural tear resulting in transient postoperative muscle weakness were observed in 2 patients as complications. CONCLUSIONS. Posterior spinal osteotomy with segmental instrumentation is a reasonable surgical option for thoracolumbar kyphosis in patients with achondroplasia. Modification of the surgical procedures depending on the presence or absence of the dysplastic changes of the apical vertebra is necessary to obtain optimal results. ©2006, Lippincott Williams & Wilkins, Inc.

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Pleomorphic xanthoastrocytoma of the spinal cord

Nakamura Masaya, Chiba Kazuhiro, Matsumoto Morio, Ikeda Eiji, Toyama Yoshiaki

Journal of Neurosurgery: Spine 5 （ 1 ） 72 - 75 2006年07月

ISSN 1547-5654

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Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury

Okada Seiji, Nakamura Masaya, Katoh Hiroyuki, Miyao Tamaki, Shimazaki Takuya, Ishii Ken, Yamane Junichi, Yoshimura Akihiko, Iwamoto Yukihide, Toyama Yoshiaki, Okano Hideyuki

Nature Medicine 12 （ 7 ） 829 - 834 2006年07月

ISSN 1078-8956

In the injured central nervous system (CNS), reactive astrocytes form a glial scar and are considered to be detrimental for axonal regeneration, but their function remains elusive. Here we show that reactive astrocytes have a crucial role in wound healing and functional recovery by using mice with a selective deletion of the protein signal transducer and activator of transcription 3 (Stat3) or the protein suppressor of cytokine signaling 3 (Socs3) under the control of the Nes promoter-enhancer (Nes-Stat3^-/-, Nes-Socs3^-/-). Reactive astrocytes in Nes-Stat3^-/- mice showed limited migration and resulted in markedly widespread infiltration of inflammatory cells, neural disruption and demyelination with severe motor deficits after contusive spinal cord injury (SCI). On the contrary, we observed rapid migration of reactive astrocytes to seclude inflammatory cells, enhanced contraction of lesion area and notable improvement in functional recovery in Nes-Socs3^-/- mice. These results suggest that Stat3 is a key regulator of reactive astrocytes in the healing process after SCI, providing a potential target for intervention in the treatment of CNS injury. © 2006 Nature Publishing Group.

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Microendoscopic partial resection of the sacral ala to relieve extraforaminal entrapment of the L-5 spinal nerve at the lumbosacral tunnel

Matsumoto Morio, Chiba Kazuhiro, Ishii Ken, Watanabe Kota, Nakamura Masaya, Toyama Yoshiaki

Journal of Neurosurgery: Spine 4 （ 4 ） 342 - 346 2006年04月

ISSN 1547-5654

The authors report the cases of three patients with L-5 radiculopathy caused by extraforaminal entrapment of the L-5 spinal nerve at the lumbosacral tunnel; this structure comprises the lumbosacral ligament, the sacral ala, and the L-5 and S-1 vertebral bodies. All three patients suffered severe leg pain and neurological deficits compatible with L-5 radiculopathy. Decompressive surgery involved the microendoscopic partial resection of the sacral ala along the L-5 spinal nerve. All patients experienced immediate pain relief postoperatively. Microendoscopic partial resection of the sacral ala is an effective and minimally invasive surgical option for patients with extraforaminal entrapment of the L-5 spinal nerve.

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Lecithinized superoxide dismutase (PC-SOD) improved spinal cord injury-induced motor dysfunction through suppression of oxidative stress and enhancement of neurotrophic factor production

Takenaga Mitsuko, Ohta Yuki, Tokura Yukie, Hamaguchi Akemi, Nakamura Masaya, Okano Hideyuki, Igarashi Rie

Journal of Controlled Release 110 （ 2 ） 283 - 289 2006年01月

ISSN 0168-3659

PC-SOD (lecithinized superoxide dismutase) is a derivative of human Cu, Zn-SOD conjugated with 4 molecules of lecithin, yet having the enzyme activity of scavenging superoxide anion (O₂^-). Intravenous administration of PC-SOD promoted the recovery from spinal cord injury (SCI)-induced motor dysfunction in a dose-dependent manner in rat model, when evaluated by BBB (Basso Beattie Bresnahan) score. Even when given at 24 h after SCI, PC-SOD (1 mg/kg) significantly improved motor dysfunction. Distribution study demonstrated that PC-SOD gradually accumulated to the injured site. Enzyme-linked immunoassay revealed that PC-SOD prevented quantitative loss of neurons, astrocytes, and oligodendrocytes. PC-SOD inhibited SCI-induced oxidative stress, such as the decrease of free sulfhydryl residue, acetylcholine esterase activity, and the increase of lipid peroxidation. PC-SOD increased the production of neuroprotective factors. HIF-1α gene expression increased following SCI, and PC-SOD further increased it. In conclusion, PC-SOD gradually accumulated and retained at the damaged site to scavenge excessive O ₂^-, and suppressed neuronal death through reducing oxidative stress, increasing neuroprotective factor production and HIF-1α gene expression. © 2005 Elsevier B.V. All rights reserved.

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Disease progression of human SOD1 (G93A) transgenic ALS model rats

Matsumoto Arifumi, Okada Yohei, Nakamichi Masanori, Nakamura Masaya, Toyama Yoshiaki, Sobue Gen, Nagai Makiko, Aoki Masashi, Itoyama Yasuto, Okano Hideyuki

Journal of Neuroscience Research 83 （ 1 ） 119 - 133 2006年01月

ISSN 0360-4012

The recent development of a rat model of amyotrophic lateral sclerosis (ALS) in which the rats harbor a mutated human SOD1 (G93A) gene has greatly expanded the range of potential experiments, because the rats' large size permits biochemical analyses and therapeutic trials, such as the intrathecal injection of new drugs and stem cell transplantation. The precise nature of this disease model remains unclear. We described three disease phenotypes: the forelimb-, hindlimb-, and general-types. We also established a simple, non-invasive, and objective evaluation system using the body weight, inclined plane test, cage activity, automated motion analysis system (SCANET), and righting reflex. Moreover, we created a novel scale, the Motor score, which can be used with any phenotype and does not require special apparatuses. With these methods, we uniformly and quantitatively assessed the onset, progression, and disease duration, and clearly presented the variable clinical course of this model; disease progression after the onset was more aggressive in the forelimb-type than in the hindlimb-type. More importantly, the disease stages defined by our evaluation system correlated well with the loss of spinal motor neurons. In particular, the onset of muscle weakness coincided with the loss of approximately 50% of spinal motor neurons. This study should provide a valuable tool for future experiments to test potential ALS therapies. © 2005 Wiley-Liss, Inc.

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Ischemia-induced disturbance of neuronal network function in the rat spinal cord analyzed by voltage-imaging

Fukuda K., Okada Y., Yoshida H., Aoyama R., Nakamura M., Chiba K., Toyama Y.

Neuroscience 140 （ 4 ） 1453 - 1465 2006年

ISSN 0306-4522

Using a voltage-imaging technique, we analyzed the acute effect of ischemia, hypoxia and hypoglycemia on the neuronal network function of the rat spinal cord. Ischemic, hypoxic, or hypoglycemic stress was loaded to spinal cord slices with an oxygen- and glucose-free, oxygen-free, or glucose-free mock cerebrospinal fluid, respectively. Depolarizing signals in the dorsal horn, induced by dorsal root stimulation, consisted of fast (pre-synaptic) and slow (post-synaptic) components. The slow component was attenuated much more than the fast component under an ischemic condition (P<0.0002). Post-synaptic neuronal activities in lamina III-IV were suppressed earlier than those in lamina I-II. The nerve fiber was relatively resistant to ischemia. As long as the fast component was preserved in the dorsal horn, the suppression of the fast and slow components was reversible. There was a significant difference (P<0.05) in the recovered slow component sizes between the group in which the fast component was suppressed by more than 20% by ischemia and the group in which the suppression was less than 20%. Further prolonged stress irreversibly eliminated most of the slow component, and attenuated the fast component (to 59±8%) accompanied by cellular damage in histology. Suppression of neural activity by hypoxic or hypoglycemic stress was less prominent than that by ischemia. Prolonged ischemic stress suddenly and irreversibly eliminated depolarizing signals in the ventral horn accompanied by morphological damage of motoneurons. Immunohistochemical staining was negative for apoptosis. We have, for the first time, analyzed the processes of spinal cord disturbance induced by ischemia, hypoxia and hypoglycemia at the neuronal network level by directly observing the regional neuronal network activities within the spinal cord. We conclude that synaptic transmission in the dorsal horn, especially in deep regions, is vulnerable and first affected by these stresses. Severe ischemic stress induces irreversible dysfunction of neurons accompanied by eventual cell death in both dorsal and ventral horns. © 2006 IBRO.

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Chondroitinase ABC combined with neural stem/progenitor cell transplantation enhances graft cell migration and outgrowth of growth-associated protein-43-positive fibers after rat spinal cord injury

Ikegami Takeshi, Nakamura Masaya, Yamane Junichi, Katoh Hiroyuki, Okada Seiji, Iwanami Akio, Watanabe Kota, Ishii Ken, Kato Fumikazu, Fujita Hiroshi, Takahashi Toyomi, Okano Hirotaka James, Toyama Yoshiaki, Okano Hideyuki

European Journal of Neuroscience 22 （ 12 ） 3036 - 3046 2005年12月

ISSN 0953-816X

We previously reported that the transplantation of neural stem/progenitor cells (NSPCs) can contribute to the repair of injured spinal cord in adult rats and monkeys. In some cases, however, most of the transplanted cells adhered to the cavity wall and failed to migrate and integrate into the host spinal cord. In this study we focused on chondroitin sulfate proteoglycan (CSPG), a known constituent of glial scars that is strongly expressed after spinal cord injury (SCI), as a putative inhibitor of NSPC migration in vivo. We hypothesized that the digestion of CSPG by chondroitinase ABC (C-ABC) might promote the migration of transplanted cells and neurite outgrowth after SCI. An in vitro study revealed that the migration of NSPC-derived cells was inhibited by CSPG and that this inhibitory effect was attenuated by C-ABC pre-treatment. Consistently, an in vivo study of C-ABC treatment combined with NSPC transplantation into injured spinal cord revealed that C-ABC pre-treatment promoted the migration of the transplanted cells, whereas CSPG-immunopositive scar tissue around the lesion cavity prevented their migration into the host spinal cord in the absence of C-ABC pre-treatment. Furthermore, this combined treatment significantly induced the outgrowth of a greater number of growth-associated protein-43-positive fibers at the lesion epicentre, compared with NSPC transplantation alone. These findings suggested that the application of C-ABC enhanced the benefits of NSPC transplantation for SCI by reducing the inhibitory effects of the glial scar, indicating that this combined treatment may be a promising strategy for the regeneration of injured spinal cord. © Federation of European Neuroscience Societies.

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Spinal kyphosis causes demyelination and neuronal loss in the spinal cord

Shimizu Kentaro, Nakamura Masaya, Nishikawa Yuji, Hijikata Sadahisa, Chiba Kazuhiro, Toyama Yoshiaki

Spine 30 （ 21 ） 2388 - 2392 2005年11月

ISSN 0362-2436

Study Design. Histologic changes in the spinal cord caused by progressive spinal kyphosis were assessed using a new animal model. Objectives. To evaluate the effects of chronic compression associated with kyphotic deformity of the cervical spine on the spinal cord. Summary of Background Data. The spinal cord has remarkable ability to resist chronic compression, however, delayed paralysis is sometimes seen following the development of spinal kyphosis. In the past, no animal model to clarify the mechanism of spinal cord damage due to spinal kyphotic deformity has been available. Methods. Laminectomy and bilateral facetectomy at the C4-C5 level was performed in 52 Japanese small game fowls. Histologic changes in the spinal cord associated with progressive kyphotic deformity were examined at different time points after surgery in each animal. The degree of spinal cord flattening and the severity of demyelination in histologic sections were quantitatively evaluated using an image analyzer, and their association with the kyphotic angle was analyzed. Changes in the microvascular distribution in the spinal cord were also examined by microangiography. Results. In all operated animals, progressive kyphosis developed reproducibly. The kyphotic angle increased gradually until 3 weeks after surgery and stabilized thereafter. There was a significant correlation between the kyphotic angle and the degree of spinal cord flattening. The spinal cord was compressed most intensely at the apex of the kyphosis, where demyelination of the anterior funiculus as well as neuronal loss and atrophy of the anterior horn were observed. Demyelination progressed as the kyphotic deformity became more severe, initially affecting the anterior funiculus and later extending to the lateral and then the posterior funiculus. Angiography revealed a decrease of the vascular distribution at the ventral side of the compressed spinal cord. Conclusions. Progressive kyphosis of the cervical spine resulted in demyelination of nerve fibers in the funiculi and neuronal loss in the anterior horn due to chronic compression of the spinal cord. These histologic changes seem to be associated with both continuous mechanical compression and vascular changes in the spinal cord. ©2005, Lippincott Williams & Wilkins, Inc.

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In vivo imaging of engrafted neural stem cells

Okada Seiji, Ishii Ken, Yamane Jinichi, Iwanami Akio, Ikegami Takeshi, Katoh Hiroyuki, Iwamoto Yukihide, Nakamura Masaya, Miyoshi Hiroyuki, Okano Hirotaka James, Contag Christopher H., Toyama Yoshiaki, Okano Hideyuki

FASEB Journal 19 （ 13 ） 1839 - 1841 2005年11月

ISSN 0892-6638

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Neural stem cells and regeneration of injured spinal cord

Okano Hideyuki, Okada Seiji, Nakamura Masaya, Toyama Yoshiaki

Kidney International 68 （ 5 ） 1927 - 1931 2005年11月

ISSN 0085-2538

Recent progress in the stem cell biology has led much insight into new therapeutic interventions aiming for the regeneration of the damaged central nervous system. The major strategies can be classified into two subgroups: (1) activation of endogenous neural stem cells, and (2) cell transplantation therapies. In either of these strategies, it is crucial to understand the underlying mechanisms of maintenance, activation, and differentiation of neural stem cells and subsequent process, including the migration, survival, and functional maturation of differentiated cells. In this paper, we would like to summarize our recent findings on the therapeutic interventions of the injured spinal cord, especially focusing on the development of treatment for the acute phase of spinal cord injury with anti-interleukin (IL)-6 receptor blocking antibody. © 2005 by the International Society of Nephrology.

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Transplantation of neural stem cells for spinal cord injury

Nakamura Masaya, Toyama Yoshiaki, Okano Hideyuki

Clinical Neurology 45 （ 11 ） 874 - 876 2005年11月

ISSN 0009-918X

Neural progenitor cells, including neural stem cells (NSCs), are an important potential graft material for cell therapeutics of damaged spinal cord. Here we used as a source of graft material a NSC-enriched population derived from human fetal spinal cord (Embryonic week 8-9) and expanded in vitro by neurosphere formation. NSCs labeled with BrdU (TP) or culture medium (CON) were transplanted into the adult marmoset spinal cord after contusion injury at C5 level. Grafted NSCs survived and migrated up to 7 mm far from the lesion epicenter. Double-staining with TuJ1 for neuron, GFAP for astrocyte, or CNPase for oligodendrocyte and BrdU revealed that grafted NSCs differentiated into neurons and oligodendrocytes 8 weeks after transplantation. More neurofilaments were observed in TP than those of CON. Furthermore, behavioral assessment of forelimb muscle strength using bar grip test and amount of spontaneous motor activity using infrared-rays monitoring revealed that the grafted NSCs significantly increased both of them compared to those of CON. These results indicate that in vitro expanded NSCs derived from human fetal spinal cord are useful sources for the therapeutics of spinal cord injury in primates.

Long-term results after expansive open-door laminoplasty for the segmental-type of ossification of the posterior longitudinal ligament of the cervical spine

Ogawa Yuto, Chiba Kazuhiro, Matsumoto Morio, Nakamura Masaya, Takaishi Hironari, Hirabayashi Hisashi, Hirabayashi Kiyoshi, Nishiwaki Yuji, Toyama Yoshiaki

Journal of neurosurgery. Spine 3 （ 3 ） 198 - 204 2005年09月

ISSN 1547-5654

OBJECT: The segmental-type of ossification of the posterior longitudinal ligament (OPLL) of the cervical spine is distinct from other types in its morphological features. Whether the results of expansive open-door laminoplasty for the segmental-type are different from those for other types remains unclear. To clarify this issue, the long-term results after surgical treatment of segmental-type OPLL were compared with those of other types. METHODS: Clinical results were documented in 57 patients who underwent expansive open-door laminoplasty and were followed for a minimum of 7 years, results were quantified using the Japanese Orthopaedic Association (JOA) scoring system to determine function. Segmental-type OPLL was observed in 10 patients (Group 1) and other types in 47 patients (Group 2). Preoperative JOA scores were not significantly different between the two groups. As many as 5 years after surgery, clinical results were favorable and maintained in both groups, and no significant intergroup difference in postoperative JOA scores was observed; however, after 5 years postoperatively, JOA scores decreased in both groups. The decrease was greater in Group 1, and a significant intergroup difference in JOA scores was demonstrated when analyzing final follow-up data. In Group 1, the authors found that the degree of late-onset deterioration relating to cervical myelopathy positively correlated with the cervical range of motion. CONCLUSIONS: The long-term results of expansive open-door laminoplasty in the treatment of segmental-type OPLL were inferior to those for other types. Cervical mobility may contribute to the development of late deterioration of cervical myelopathy.

Targeted expression of anti-apoptotic protein p35 in oligodendrocytes reduces delayed demyelination and functional impairment after spinal cord injury

Tamura Mutsuhiro, Nakamura Masaya, Ogawa Yuto, Toyama Yoshiaki, Miura Masayuki, Okano Hideyuki

GLIA 51 （ 4 ） 312 - 321 2005年09月

ISSN 0894-1491

Functional impairment after spinal cord injury (SCI) is attributed to neuronal cell necrosis death and axonotmesis, with further worsening caused by the accompanying apoptosis of myelin-forming oligodendrocytes (OLGs). However, it is unclear as to how much OLG apoptosis contributes to functional impairment. To address this issue, we used transgenic mice characterized by the targeted expression of p35, a broad-spectrum caspase inhibitor, in OLGs using the cre/loxP system (referred to as cre/p35 transgenic mice). In this study, we examined the motor function and histopathologic changes after a contusive thoracic spinal cord injury in the cre/p35 transgenic mice. A larger number of OLGs and a lesser extent of demyelination were observed after SCI in the cre/p35 transgenic mice than in the control cre mice, which did not carry the p35 transgene. Furthermore, the motor function of the hindlimbs recovered to a significantly better degree in the cre/p35 transgenic mice than in the control ere mice. Thus, the inhibition of OLG apoptosis decreased the extent of functional impairment after SCI. These findings suggest that the inhibition of OLG apoptosis may be a potential treatment for SCI. ©2005 Wiley-Liss, Inc.

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Transplantation of embryonic spinal cord-derived neurospheres support growth of supraspinal projections and functional recovery after spinal cord injury in the neonatal rat

Nakamura M., Okano H., Toyama Y., Dai H. N., Finn T. P., Bregman Barbara S.

Journal of Neuroscience Research 81 （ 4 ） 457 - 468 2005年08月

ISSN 0360-4012

Great interest exists in using cell replacement strategies to repair the damaged central nervous system. Previous studies have shown that grafting rat fetal spinal cord into neonate or adult animals after spinal cord injury leads to improved anatomic growth/plasticity and functional recovery. It is clear that fetal tissue transplants serve as a scaffold for host axon growth. In addition, embryonic Day 14 (E14) spinal cord tissue transplants are also a rich source of neural-restricted and glial-restricted progenitors. To evaluate the potential of E14 spinal cord progenitor cells, we used in vitro-expanded neurospheres derived from embryonic rat spinal cord and showed that these cells grafted into lesioned neonatal rat spinal cord can survive, migrate, and differentiate into neurons and oligodendrocytes, but rarely into astrocytes. Synapses and partially myelinated axons were detected within the transplant lesion area. Transplanted progenitor cells resulted in increased plasticity or regeneration of corticospinal and brainstem-spinal fibers as determined by anterograde and retrograde labeling. Furthermore, transplantation of these cells promoted functional recovery of locomotion and reflex responses. These data demonstrate that progenitor cells when transplanted into neonates can function in a similar capacity as transplants of solid fetal spinal cord tissue. © 2005 Wiley-Liss, Inc.

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Endoscopic resection of cystic lesions in the lumbar spinal canal. A report of two cases

Ishii Ken, Matsumoto M., Watanabe K., Nakamura M., Chiba K., Toyama Y.

Minimally Invasive Neurosurgery 48 （ 4 ） 240 - 243 2005年08月

ISSN 0946-7211

We report excellent outcomes in two patients with cystic lesions in the lumbar spinal canal who underwent resection using the METRx™ microendoscopic discectomy (MED) system. Pathological examinations revealed the diagnoses of a synovial cyst and a discal cyst, respectively. Both of them were allowed to walk the next day after surgery with complete pain relief. Microendoscopic surgery provides excellent visualization of the spinal canal and allows minimally invasive removal of the pathological lesions. This technique can be an effective alternative to conventional open surgery for cystic lesions in the lumbar spine. © Georg Thieme Verlag KG Stuttgart.

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Role of IL-6 in spinal cord injury in a mouse model

Nakamura Masaya, Okada Seiji, Toyama Yoshiaki, Okano Hideyuki

Clinical Reviews in Allergy and Immunology 28 （ 3 ） 197 - 203 2005年06月

ISSN 1080-0549

In recent years, various studies have been conducted toward the goal of achieving regeneration of the central nervous system using neural stem cells. However, various complex factors are involved in the regulation of neural stem cell differentiation, and many unresolved questions remain. It has been reported that after spinal cord injury, the intrinsic neural stem cells do not differentiate into neurons but, rather, into astrocytes, resulting in the formation of glial scars. Based on reports that the expression of interleukin (IL)-6 and the IL-6 receptor (IL-6R) is sharply increased in the acute stages after spinal cord injury and that IL-6 may serve as a factor strongly inducing the differentiation of neural stem cells into astrocytes, we examined the effects of an antibody to IL-6R in cases of spinal cord injury and found that the antibody suppressed secondary injury (caused by inflammatory reactions) and glial scar formation, facilitating functional recovery. This article presents the data from this investigation and discusses the relationship between IL-6 signals and spinal cord injury. © Copyright 2005 by Humana Press Inc.

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Usefulness of neurological examination for diagnosis of the affected level in patients with cervical compressive myelopathy

Matsumoto Morio, Ishikawa Masayuki, Ishii Ken, Nishizawa Takashi, Maruiwa Hirofumi, Nakamura Masaya, Chiba Kazuhiro, Toyama Yoshiaki

Journal of neurosurgery. Spine 2 （ 5 ） 535 - 539 2005年05月

ISSN 1547-5654

OBJECT: Although neurological examination is the key step to reaching a correct diagnosis of cervical compressive myelopathy (CCM), the accuracy of diagnosis of the affected spinal level for CCM has not yet been tested. METHODS: The authors conducted a prospective study to elucidate how accurately the affected intervertebral level can be determined and decompressed based on neurological examination. Fifty patients who underwent successful decompressive surgery for cervical myelopathy caused by single-level disc herniation or spondylosis were included in this study (38 men and 12 women, mean age 60 years). Three board-certified spine surgeons participated in establishing the neurological diagnoses. One of the three surgeons made a diagnosis of CCM, and the other two conducted the neurological examination including deep tendon reflex, pinprick response, muscle weakness, and numbness in the hand only, knowing that the patient had CCM, and established the neurological-level diagnosis. A single intervertebral level responsible for patient's symptoms was determined concordantly based on magnetic resonance imaging and myelography findings by two spine surgeons, and this served as the standard. Agreement between neurological and neuroimaging/radiological level diagnoses was determined. The rate of agreement between neurological and neuroimaging diagnosis was 66%. Among the neurological tests, patient-perceived location of numbness in the hands was the most useful for establishing the affected level. For the other three tests the agreement rate was lower than 50% and thus each individual test may not be reliable for diagnosing the affected level. CONCLUSIONS: The results of this study suggested that neurological examination in patients with CCM is moderately accurate and reliable for determining the neurological level of disease.

Transplantation of human neural stem cells for spinal cord injury in primates

Iwanami A., Kaneko S., Nakamura M., Kanemura Y., Mori H., Kobayashi S., Yamasaki M., Momoshima S., Ishii H., Ando K., Tanioka Y., Tamaoki N., Nomura T., Toyama Y., Okano Hideyuki

Journal of Neuroscience Research 80 （ 2 ） 182 - 190 2005年04月

ISSN 0360-4012

Recent studies have shown that delayed transplantation of neural stem/progenitor cells (NSPCs) into the injured spinal cord can promote functional recovery in adult rats. Preclinical studies using nonhuman primates, however, are necessary before NSPCs can be used in clinical trials to treat human patients with spinal cord injury (SCI). Cervical contusion SCIs were induced in 10 adult common marmosets using a stereotaxic device. Nine days after injury, in vitro-expanded human NSPCs were transplanted into the spinal cord of five randomly selected animals, and the other sham-operated control animals received culture medium alone. Motor functions were evaluated through measurements of bar grip power and spontaneous motor activity, and temporal changes in the intramedullary signals were monitored by magnetic resonance imaging. Eight weeks after transplantation, all animals were sacrificed. Histologic analysis revealed that the grafted human NSPCs survived and differentiated into neurons, astrocytes, and oligodendrocytes, and that the cavities were smaller than those in sham-operated control animals. The bar grip power and the spontaneous motor activity of the transplanted animals were significantly higher than those of sham-operated control animals. These findings show that NSPC transplantation was effective for SCI in primates and suggest that human NSPC transplantation could be a feasible treatment for human SCI. © 2005 Wiley-Liss, Inc.

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Establishment of graded spinal cord injury model in a nonhuman primate

Iwanami A., Yamane J., Katoh H., Nakamura M., Momoshima S., Ishii H., Tanioka Y., Tamaoki N., Nomura T., Toyama Y., Okano Hideyuki

Journal of Neuroscience Research 80 （ 2 ） 172 - 181 2005年04月

ISSN 0360-4012

Most previous studies on spinal cord injury (SCI) have used rodent models. Direct extrapolation of the results obtained in rodents to clinical cases is difficult, however, because of neurofunctional and anatomic differences between rodents and primates. In the present study, the development of histopathologic changes and functional deficits were assessed quantitatively after mild, moderate, and severe spinal cord contusive injuries in common marmosets. Contusive SCI was induced by dropping one of three different weights (15, 17, or 20 g) at the C5 level from a height of 50 mm. Serial magnetic resonance images showed significant differences in the intramedullary T1 low signal and T2 high signal areas among the three groups. Quantitative histologic analyses revealed that the number of motor neurons, the myelinated areas, and the amounts of corticospinal tract fibers decreased significantly as the injury increased in severity. Motor functions were evaluated using the following tests: original behavioral scoring scale, measurements of spontaneous motor activity, bar grip test, and cage-climbing test. Significant differences in all test results were observed among the three groups. Spontaneous motor activities at 10 weeks after injury were closely correlated with the residual myelinated area at the lesion epicenter. The establishment of a reliable nonhuman primate model for SCI with objective functional evaluation methods should become an essential tool for future SCI treatment studies. Quantitative behavioral and histopathologic analyses enabled three distinct grades of injury severity (15-g, 17-g, and 20-g groups) to be characterized with heavier weights producing more serious injuries, and relatively constant behavioral and histopathologic outcomes. © 2005 Wiley-Liss, Inc.

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Regenerative medicine for the central nervous system - Transplantation of neural stem cells into the injured spinal cord -

Kaneko Shinjiro, Nakamura Masaya, Ogawa Yuto, Watanabe Kota, Iwanami Akio, Toyama Yoshiaki, Okano Hideyuki

Japan Medical Association Journal 48 （ 2 ） 68 - 80 2005年02月

ISSN 1346-8650

Advances in the stem cell biology of the central nervous system (CNS) and other studies enhance the possibility of regeneration of the damaged CNS, which has previously been considered to be almost impossible. The availability of signals to induce the appropriate differentiation of the transplanted and/or endogenous neural stem cells (NSCs) as well as the timing of the transplantation are vital factors for improving the functional recovery of the damaged CNS. Because the immediate post-traumatic microenvironment of the spinal cord is in an acute inflammatory stage, it does not favor the survival and differentiation of the transplants. Furthermore, in the chronic disease stage after injury, glial scars that inhibit the regeneration of neuronal axons form in the injured site. Thus, we consider that the optimal period of transplantation is 1-2 weeks after injury.

Impact of interlaminar graft materials on the fusion status in atlantoaxial transarticular screw fixation.

Matsumoto Morio, Chiba Kazuhiro, Nakamura Masaya, Ogawa Yuto, Toyama Yoshiaki, Ogawa Jun

Journal of neurosurgery. Spine 2 （ 1 ） 23 - 26 2005年01月

ISSN 1547-5654

OBJECT: Structural interlaminar graft materials were used for atlantoaxial transarticular screw fixation (TSF), and its impact on the fusion status was investigated. METHODS: Forty-two patients (10 men, 32 women, mean age 51 years, mean follow-up period 45 months; 30 with rheumatoid arthritis, and 12 with os odontoideum) underwent TSF and modified Brooks posterior wiring involving titanium cables. As interlaminar graft materials, autologous bone from posterior iliac crest alone was used in 20 patients (Group A), and a structural spacer (13 ceramic spacers, nine titanium mesh cages) in 22 (Group B). Lateral radiographs were evaluated to determine bone fusion, alignment of the cervical spine, and wire loosening. Solid osseous fusion was obtained in 95% of Group A and 96% of Group B patients. The mean atlantoaxial angle was 19.1+/-9.7 degrees and 16.7+/-10.4 degrees before surgery (p = 0.45), and 27.4+/-7.8 degrees and 22.1+/-5.5 degrees after surgery (p = 0.02) in Groups A and B, respectively. Atlantoaxial hyperlordosis (atlantoaxial angle > or = 30 degrees) was observed in 32% of Group A and 18% of Group B patients (p = 0.26). Postoperative kyphosis occurred in 40% of Group A and 23% of Group B patients (p = 0.28). Loosening of the cable was demonstrated in 50% of Group A and 36% of Group B patients(p = 0.37). In Group B patients maintenance of cervical lordosis was more likely than in those in Group A, although the differences did not reach statistical significance. CONCLUSIONS: These results indicate that structural interlaminar spacers can maintain proper cervical alignment without a decease in the fusion rate; the authors recommend their use in conjunction with TSF.

Long-term results of expansive open-door laminoplasty for ossification of the posterior longitudinal ligament of the cervical spine.

Ogawa Yuto, Toyama Yoshiaki, Chiba Kazuhiro, Matsumoto Morio, Nakamura Masaya, Takaishi Hironari, Hirabayashi Hisashi, Hirabayashi Kiyoshi

J Neurosurg Spine 1 （ 2 ） 168 - 174 2004年09月

ISSN 1547-5654

OBJECT: Numerous surgical procedures have been developed for treatment of ossification of the posterior longitudinal ligament (OPLL) of the cervical spine, and these can be performed via three approaches: anterior, posterior, or combined anterior-posterior. The optimal approach in cases involving OPLL-induced cervical myelopathy, however, remains controversial. To address this issue, the authors assessed the benefits and limitations of expansive open-door laminoplasty for OPLL-related myelopathy by evaluating mid- and long-term clinical results. METHODS: Clinical results obtained in 72 patients who underwent expansive open-door laminoplasty between 1983 and 1997 and who were followed for at least 5 years were assessed using the Japanese Orthopaedic Association (JOA) scoring system. The mean preoperative JOA score was 9.2 +/- 0.4; at 3 years postoperatively, the JOA score was 14.2 +/- 0.3 and the recovery rate (calculated using the Hirabayashi method) was 63.1 +/- 4.5%, both having reached their highest level. These favorable results were maintained up to 5 years after surgery. An increase in cervical myelopathy due to progression of the ossified ligament was observed in only two of 30 patients who could be followed for more than 10 years. Severe surgery-related complications were not observed. Preoperative JOA score, age at the time of surgery, and duration between onset of initial symptoms and surgery affected clinical results. CONCLUSIONS: Mid-term and long-term results of expansive open-door laminoplasty were satisfactory. Considering factors that affected surgical results, early surgery is recommended for OPLL of the cervical spine.

Postoperative changes of spinal curvature and range of motion in adult patients with cervical spinal cord tumors

Asazuma Takashi, Nakamura Masaya, Matsumoto Mario, Chibo Kazuhiro, Toyama Yoshiaki

Journal of Spinal Disorders and Techniques 17 （ 3 ） 178 - 182 2004年06月

ISSN 1536-0652

Objective: We sought to determine factors likely to influence postoperative changes in cervical spinal curvature and range of motion (ROM) in patients with cervical spinal cord tumors. Methods: Fifty-one patients who underwent tumor excision via a single posterior approach were examined. Surgical methods were classified as follows: group A, expansive open-door laminoplasty (ELAP); group B, conventional laminectomy; and group C, hemilaminectomy (HL). Pre- and postoperative cervical spinal curvature, cervical curvature type, and ROM were evaluated using lateral radiographs. Results: Worsening of cervical curvature type was statistically less frequent in group C than in group A or B (P < 0.05), although no significant difference was evident overall between pre- and postoperative cervical curvature indexes or ROM in any group. Cases of C2 surgery showed more frequent curvature worsening (80%) in group A than in other groups (P < 0.05). Postoperative changes of the cervical curvature in patients with cervical spinal cord tumors were greatly influenced by the surgical method; the cervical curvature was particularly unfavorable when patients had C2 decompression. Conclusions: Careful attention to postoperative changes in the spinal curvature is needed when ELAP is performed, especially if surgery involves C2. HL is the best posterior approach for resection of cervical spinal cord tumors from the viewpoint of postoperative spinal curvature and ROM.

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Implantation of Dendritic Cells in Injured Adult Spinal Cord Results in Activation of Endogenous Neural Stem/Progenitor Cells Leading to De Novo Neurogenesis and Functional Recovery

Mikami Yuji, Okano Hideyuki, Sakaguchi Masanori, Nakamura Masaya, Shimazaki Takuya, Okano Hirotaka James, Kawakami Yutaka, Toyama Yoshiaki, Toda Masahiro

Journal of Neuroscience Research 76 （ 4 ） 453 - 465 2004年05月

ISSN 0360-4012

We report a treatment for spinal cord injury involving implantation of dendritic cells (DCs), which act as antigen-presenting cells in the immune system. The novel mechanisms underlying this treatment produce functional recovery. Among the immune cells tested, DCs showed the strongest activity inducing proliferation and survival of neural stem/progenitor cells (NSPCs) in vitro. Furthermore, in DC-implanted adult mice, endogenous NSPCs in the injured spinal cord were activated for mitotic de novo neurogenesis. These DCs produced neurotrophin-3 and activated endogenous microglia in the injured spinal cord. Behavioral analysis revealed the locomotor functions of DC-implanted mice to have recovered significantly as compared to those of control mice. Our results suggest that DC-implantation exerts trophic effects, including activation of endogenous NSPCs, leading to repair of the injured adult spinal cord. © 2004 Wiley-Liss, Inc.

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Blockade of Interleukin-6 Receptor Suppresses Reactive Astrogliosis and Ameliorates Functional Recovery in Experimental Spinal Cord Injury

Okada S., Nakamura M., Mikami Y., Shimazaki T., Mihara M., Ohsugi Y., Iwamoto Y., Yoshizaki K., Kishimoto T., Toyama Y., Okano Hideyuki

Journal of Neuroscience Research 76 （ 2 ） 265 - 276 2004年04月

ISSN 0360-4012

Endogenous neural stem/progenitor cells (NSPCs) have recently been shown to differentiate exclusively into astrocytes, the cells that are involved in glial scar formation after spinal cord injury (SCI). The microenvironment of the spinal cord, especially the inflammatory cytokines that dramatically increase in the acute phase at the injury site, is considered to be an important cause of inhibitory mechanism of neuronal differentiation following SCI. Interleukin-6 (IL-6), which has been demonstrated to induce NSPCs to undergo astrocytic differentiation selectively through the JAK/STAT pathway in vitro, has also been demonstrated to play a critical role as a proinflammatory cytokine and to be associated with secondary tissue damage in SCI. In this study, we assessed the efficacy of rat anti-mouse IL-6 receptor monoclonal antibody (MR16-1) in the treatment of acute SCI in mice. Immediately after contusive SCI with a modified NYU impactor, mice were intraperitoneally injected with a single dose of MR16-1 (100 μg/g body weight), the lesions were assessed histologically, and the functional recovery was evaluated. MR16-1 not only suppressed the astrocytic diffentiation-promoting effect of IL-6 signaling in vitro but inhibited the development of astrogliosis after SCI in vivo. MR16-1 also decreased the number of invading inflammatory cells and the severity of connective tissue scar formation. In addition, we observed significant functional recovery in the mice treated with MR16-1 compared with control mice. These findings suggest that neutralization of IL-6 signaling in the acute phase of SCI represents an attractive option for the treatment of SCI. © 2004 Wiley-Liss, Inc.

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Retrospective study of surgery-related outcomes in patients with syringomyelia associated with Chiari I malformation

Nakamura Masaya, Chiba Kazuhiro, Nishizawa Takashi, Maruiwa Hirofumi, Matsumoto Morio, Toyama Yoshiaki

Journal of Neurosurgery 100 （ 3 SUPPL. ） 241 - 244 2004年03月

ISSN 0022-3085

Object. Pain is one of the major symptoms in patients with syringomyelia; however, its origin is not fully understood, and postoperative improvement of pain is difficult to predict. The objectives of this study were to assess the surgery-related results obtained in patients who underwent treatment for syringomyelia associated with Chiari I malformation, particularly related to pain status, and to identify factors that may influence improvement in postoperative pain by comparing pre- and postoperative magnetic resonance (MR) imaging findings. Methods. The correlation between pre- and postoperative changes in the size and the location of the syrinx and pain improvement was investigated in 25 patients. The shapes of the syringes were classified into three types: central, enlarged, and deviated. In most cases in which the syrinx deviated toward the posterolateral aspect of the spinal cord at the level corresponding to dermatomal distribution of preoperative pain, the lesion remained at the same position postoperatively, and improvement in pain was poor. On the other hand, enlarged-type syringes were the most frequently observed prior to surgery, exhibited diverse changes postoperatively, and improvement in pain status was difficult to predict. When postoperative MR imaging revealed a transformation to the deviated type, poor pain improvement was noted. Conclusions. Neurons in the dorsal horn were thought to be involved in the development of pain as a result of the deafferentiation mechanism in cases of syringomyelia.

Comparison between fetal spinal-cord- and forebrain-derived neural stem/progenitor cells as a source of transplantation for spinal cord injury

Watanabe Kota, Nakamura Masaya, Iwanami Akio, Fujita Yuko, Kanemura Yonehiro, Toyama Yoshiaki, Okano Hideyuki

Developmental Neuroscience 26 （ 2-4 ） 275 - 287 2004年

ISSN 0378-5866

Recently, we have shown that the transplantation of spinal-cord-derived neural stem/progenitor cells (NSPCs) can contribute to the repair of injured spinal cords in adult rats, which may correspond to a behavioral recovery. To apply these results to clinical practice, a system for supplying human NSPCs on a large scale must be established. However, human spinal-cord-derived NSPCs are known to have a low proliferation rate, compared with forebrain-derived NSPCs. This low proliferative potency limits the feasibility of large-scale spinal cord-derived NSPC use. Thus, forebrain-derived NSPCs should be examined as an alternative to spinal-cord-derived NSPCs for the treatment of spinal cord injuries. In this study, we compared spinal-cord- and forebrain-derived NSPCs transplanted into injured spinal cords with respect to their fates in vivo as well as the animals' functional recovery. Both spinal-cord- and forebrain-derived NSPCs promoted functional recovery in rats with spinal cord injuries. While both spinal-cord- and fore-brain-derived NSPCs survived, migrated and differentiated into neurons, astrocytes and oligodendrocytes in response to the microenvironment within the injured spinal cord after transplantation, forebrain-derived NSPCs differentiated into more neurons and fewer oligodendrocytes, compared to spinal-cord-derived NSPCs. Neurons that had differentiated from the transplanted forebrain-derived NSPCs were shown to be positive for neurotransmitters like GABA, glutamate and glycine, although authentic glycinergic neurons are not normally present within the forebrain. Thus, at least a subpopulation of the transplanted forebrain-derived NSPCs differentiated into spinal-cord-type neurons. In conclusion, forebrain-derived NSPCs could be used as an alternative to spinal-cord-derived NSPCs as a potential therapeutic agent for spinal cord injuries. Copyright © 2004 S. Karger AG.

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Synaptic Blockade Plays a Major Role in the Neural Disturbance of Experimental Spinal Cord Compression

Yoshida Hideaki, Okada Yasumasa, Maruiwa Hirofumi, Fukuda Kentaro, Nakamura Masaya, Chiba Kazuhiro, Toyama Yoshiaki

Journal of Neurotrauma 20 （ 12 ） 1365 - 1376 2003年12月

ISSN 0897-7151

We analyzed dynamic processes of neural excitation propagation in the experimentally compressed spinal cord using a high-speed optical recording system. Transverse slices of the juvenile rat cervical spinal cord were stained with a voltage-sensitive dye (di-4-ANEPPS). Two components were identified in the depolarizing optical responses to dorsal root electrical stimulation: a fast component of short duration corresponding to pre-synaptic excitation and a slow component of long duration corresponding to post-synaptic excitation. In the directly compressed dorsal horn, the slow component was attenuated more (attenuated to 37.4 ± 9.1% of the control) than the fast component (to 70.5 ± 14.9%) (p < 0.01) at 400 msec after stimulation. Depolarizing optical responses to compression and to chemical synaptic blockade were similar. There was a regional difference between white matter (attenuated to 86.2 ± 10.5%) and gray matter (to 72.6 ± 10.4%) (p < 0.03) in compression-induced changes of the fast components; neural activity in the white matter was resistant to compression, especially in the dorsal root entry zone. Depolarizing optical signals in the region adjacent to the directly compressed site were also attenuated; the fast component was attenuated to 77.6 ± 10.4% and the slow component to 31.8 ± 11.3% of the control signals (p < 0.01). Spinal cord dysfunction induced by purely mechanical compression without tissue destruction was virtually restored with early decompression. We suggest that a disturbance of synaptic transmission plays an important role in the pathophysiological mechanisms of spinal cord compression, at least under in vitro experimental conditions of juvenile rats.

Differences in cytokine gene expression profile between acute and secondary injury in adult rat spinal cord

Nakamura Masaya, Houghtling Richard A., MacArthur Linda, Bayer Barbara M., Bregman Barbara S.

Experimental Neurology 184 （ 1 ） 313 - 325 2003年11月

ISSN 0014-4886

It is likely that the environment within the injured spinal cord influences the capacity of fetal spinal cord transplants to support axonal growth. We have recently demonstrated that fetal spinal cord transplants and neurotrophin administration support axonal regeneration after spinal cord transection, and that the distance and amount of axonal growth is greater when these treatments are delayed by several weeks after injury (Coumans et al., 2001). In this study, we sought to determine whether differences in inflammatory mediators exist between the acutely injured spinal cord and the spinal cord after a second injury and re-section, which could provide a more favorable environment for the axonal re-growth. The results of this study show a more rapid induction of transforming growth factor (TGF) β1 mRNA expression in the re-injured spinal cord than the acutely injured spinal cord and an attenuation of proinflammatory cytokine mRNA expression. Furthermore, there was a rapid recruitment of activated microglia/macrophages in the degenerating white matter rostral and caudal to the injury but fewer within the lesion site itself. These findings suggest that the augmentation of TGFβ-1 gene expression and the attenuation of pro-inflammatory cytokine gene expression combined with an altered distribution of activated microglia/macrophages in the re-injured spinal cord might create a more favorable milieu for transplants and axonal regrowth as compared to the acutely injured spinal cord. © 2003 Elsevier Inc. All rights reserved.

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Relationship between alignment of upper and lower cervical spine in asymptomatic individuals

Nojiri Kenya, Matsumoto Morio, Chiba Kazuhiro, Maruiwa Hirofumi, Nakamura Masaya, Nishizawa Takashi, Toyama Yoshiaki

Journal of Neurosurgery 99 （ 1 SUPPL. ） 80 - 83 2003年07月

ISSN 0022-3085

Object. The aim of this study was to establish standard values for the normal alignment of the upper cervical spine and to clarify its relationship with the lower cervical spine in terms of alignment. Methods. Three hundred thirteen asymptomatic volunteers (155 men and 158 women) participated in this study. Lateral radiographs were obtained with the neck in neutral position, and the angles formed by the occiput (Oc) and the axis, the atlas and the axis, and C-2 to C-7 were measured. The mean Oc-C2 angle was 14.5 ± 8° in men and 16 ± 8.5° in women; the mean C1-2 angle was 26.5 ± 7° and 28.9 ± 6.7°, respectively; and the mean C2-7 angle was 16.2 ± 12.9° and 10.5 ± 10.3°, respectively. Although weak, statistically significant negative correlation was observed between Oc-C2 and C2-7 angles (r = -0.31 in men and -0.37 in women), and between C1-2 and C2-7 angles (r = -0.22 in men and -0.22 in women). The correlation coefficient between the Oc-C2 and C2-7 angles was greater than that between the C1-2 and C2-7 angles. Conclusions. Such relationships between alignment of the upper and lower cervical spines should be taken into consideration when performing occipitocervical fusion.

Transplantation of neural stem cells into the spinal cord after injury

Okano Hideyuki, Ogawa Yuto, Nakamura Masaya, Kaneko Shinjiro, Iwanami Akio, Toyama Yoshiaki

Seminars in Cell and Developmental Biology 14 （ 3 ） 191 - 198 2003年06月

ISSN 1084-9521

Thanks to advances in the stem cell biology of the central nervous system (CNS), the previously inconceivable regeneration of the damaged CNS is approaching reality. The availability of signals to induce the appropriate differentiation of the transplanted and/or endogenous neural stem cells (NSCs) as well as the timing of the transplantation are important for successful functional recovery of the damaged CNS. Because the immediately post-traumatic microenvironment of the spinal cord is in an acute inflammatory stage, it is not favorable for the survival and differentiation of NSC transplants. On the other hand, in the chronic stage after injury, glial scars form in the injured site that inhibit the regeneration of neuronal axons. Thus, we believe that the optimal timing of transplantation is 1-2 weeks after injury. © 2003 Elsevier Science Ltd. All rights reserved.

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腰椎変性すべり症に対する後方除圧術の成績—固定・非固定例の分析

松本守雄，西澤隆，中村雅也，丸岩博文，千葉一裕，戸山芳昭

臨床整形外科 38 （ 3 ） 271-277 2003年03月

研究論文（学術雑誌）, 共著

再生医療の現状と将来展望；＜臓器再生＞中枢神経系の再生医療

金子慎二郎，岩波明生，中村雅也，小川祐人，戸山芳昭，岡野栄之

日本医師会雑誌 129 （ 3 ） 355-359 2003年02月

研究論文（学術雑誌）, 共著

中枢神経系の再生医療

金子慎二郎，岩波明生，中村雅也，小川祐人，戸山芳昭，岡野栄之

日本医師会雑誌 129 （ 3 ） 355-359 2003年02月

研究論文（学術雑誌）, 共著

脊髄損傷に対する再生医療 / 神経幹細胞移植を中心として

金子慎二郎，中村雅也，岩波明生，小川祐人，戸山芳昭，岡野栄之

脊椎脊髄ジャーナル 16 （ 2 ） 123-129 2003年02月

研究論文（学術雑誌）, 共著

脊髄損傷に対する再生医療—神経幹細胞移植を中心として

金子慎二郎，中村雅也，岩波明生，小川祐人，岡野栄之，戸山芳昭

脊椎脊髄ジャーナル 16 （ 2 ） 123-129 2003年02月

研究論文（学術雑誌）, 共著

Transplantation of neural stem cells into the spinal cord after injury

Okano Hideyuki, Ogawa Yuto, Nakamura Masaya, Kaneko Shinjiro, Iwanami Akio, Toyama Yoshiaki

Seminars in cells & developmental biology 379 39455 2003年

研究論文（学術雑誌）, 共著

Transplantation of neural stem cells into spinal cord after injury

Nakamura Masaya, Toyama Yoshiaki

Nippon rinsho. Japanese journal of clinical medicine 61 （ 3 ） 463 - 468 2003年

ISSN 0047-1852

Recovery from central nervous system damage in adult mammals is hindered by their limited ability to replace lost cells and damaged myelin, and reestablish functional neural connections. However, recent progresses in stem cell biology are making it feasible to induce the regeneration of injured axons after spinal cord injury. Transplantation of in vitro expanded neural stem cells into rat spinal cord 9 days after contusion injury induced their differentiation into neurons and oligodendrocytes, and the functional recovery of skilled forelimb movement. It was partly because the microenvironment within the injured spinal cord at 9 days after injury was more favorable for grafted neural stem cells in terms of their survival and differentiation.

脊椎脊髄外科のすべて—この10年何が進歩したか—髄内腫瘍の診断と治療

中村雅也，千葉一裕，戸山芳昭

整形外科・災害外科 46 （ 5 ） 689-696 2003年

研究論文（学術雑誌）, 共著

脊椎脊髄外科のすべて- この10年何が進歩したか - 髄内腫瘍の診断と治療

中村雅也

整形外科・災害外科 46 （ 5 ） 689-696 2003年

研究論文（学術雑誌）, 単著

神経幹細胞と損傷脊髄の再生

岩波明生，小川祐人，中村雅也，金子慎二郎，戸山芳昭，岡野栄之

日本整形外科学会雑誌 76 （ 12 ） 579-589 2002年12月

研究論文（学術雑誌）, 共著

中枢神経系の再生医療

金子慎二郎，岩波明生，中村雅也，小川祐人，戸山芳昭，岡野栄之

日本小児科学会雑誌 106 （ 12 ） 1736-1743 2002年12月

研究論文（学術雑誌）, 共著

教育研修講座―神経幹細胞と損傷脊髄の再生

岩波明生，中村雅也，小川祐人，金子慎二郎，戸山芳昭，岡野栄之

日本整形外科学会誌 76 （ 12 ） 579-591 2002年12月

研究論文（学術雑誌）, 共著

小児科領域における最先端医療＜再生医療の最近の進歩＞―中枢神経系の再生医療

金子慎二郎，岩波明生，中村雅也，小川祐人，戸山芳昭，岡野栄之

日本小児科学会雑誌 106 （ 12 ） 1736-1743 2002年12月

研究論文（学術雑誌）, 共著

脊柱後弯による遅発性脊髄麻痺に関する実験的研究（第1報）―実験動物モデルの作成―

清水健太郎，西川雄司，土方貞久，中村雅也，千葉一裕，戸山芳昭

脊柱変形 17 （ 1 ） 7-13 2002年12月

研究論文（学術雑誌）, 共著

髄内外にわたるendodermal cyst 再発の1治験例

池上健，千葉一裕，西澤隆，中村雅也，丸岩博文，松本守雄，戸山芳昭，向井万起男

関東整形災害外科学会誌 33 （ 5 ） 311-315 2002年10月

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Transplantation of in vitro-expanded fetal neural progenitor cells results in neurogenesis and functional recovery after spinal cord contusion injury in adult rats

Ogawa Y., Sawamoto K., Miyata T., Miyao S., Watanabe M., Nakamura M., Bregman B. S., Koike M., Uchiyama Y., Toyama Y., Okano H.

Journal of Neuroscience Research 69 （ 6 ） 925 - 933 2002年09月

ISSN 0360-4012

Neural progenitor cells, including neural stem cells, are a potential expandable source of graft material for transplantation aimed at repairing the damaged CNS. Here we present the first evidence that in vitro-expanded fetus-derived neurosphere cells were able to generate neurons in vivo and improve motor function upon transplantation into an adult rat spinal-cord-contusion injury model. As the source of graft material, we used a neural stem cell-enriched population that was derived from rat embryonic spinal cord (E14.5) and expanded in vitro by neurosphere formation. Nine days after contusion injury, these neurosphere cells were transplanted into adult rat spinal cord at the injury site. Histological analysis 5 weeks after the transplantation showed that mitotic neurogenesis occurred from the transplanted donor progenitor cells within the adult rat spinal cord, a nonneurogenic region; that these donor-derived neurons extended their processes into the host tissues; and that the neurites formed synaptic structures. Furthermore, analysis of motor behavior using a skilled reaching task indicated that the treated rats showed functional recovery. These results indicate that in vitro-expanded neurosphere cells derived from the fetal spinal cord are a potential source for transplantable material for treatment of spinal cord injury. © 2002 Wiley-Liss, Inc.

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Transplantation of in vitro-expanded fetal neural progenitor cells results in neurogenisis and fuctional recovery after spinal cord contusion injury in adult rats

Ogawa Yuto, Sawamoto Kazunobu, T Miyata, S Miyano, Watanabe Masahiko, Nakamura Masaya, Brebman BS, M Koike, Uchiyama Y, Toyama Yoshiaki, Okano H

Journal of neuroscience research 69 （ 6 ） 925-933 2002年09月

研究論文（学術雑誌）, 共著

特集―脊椎・脊髄画像診断マニュアル；脊髄疾患―髄外腫瘍

中村雅也，千葉一裕，戸山芳昭

Monthly book orthopaedics 15 （ 9 ） 164-170 2002年09月

研究論文（学術雑誌）, 共著

Transplantation of in vitro-expanded fetal neural progenitor cells results in neurogenesis and functional recovery after spinal cord contusion injury in adult rats

Ogawa Yuto, Sawamoto Kazunobu, Miyata Takuki, Miyao Sachiyo, Watanabe M, Toyama Yoshiaki, Nakamura Masaya, Bregman BS, Koike M, Uchiyama Yasuo, Okano Hideyuki

Jounal of neuroscience research 69 （ 6 ） 925-933 2002年09月

研究論文（学術雑誌）, 共著

硬膜内に発生した傍神経節腫の1例

市原大輔，西澤隆，渡辺雅彦，中村雅也，丸岩博文，松本守雄，千葉一裕，戸山芳昭

臨床整形外科 37 （ 8 ） 971-974 2002年08月

研究論文（学術雑誌）, 共著

キアリ奇形に伴う脊髄空洞症の手術成績―特に疼痛の改善と空洞の局在に着目して

中村雅也，千葉一裕，田村睦弘，西澤隆，丸岩博文，松本守雄，戸山芳昭

臨床整形外科 37 （ 8 ） 911-916 2002年08月

研究論文（学術雑誌）, 共著

A simple and reliable behavioral analysis of locomotor function after spinal cord injury in mice

Mikami Yuji, Toda Masahiro, Watanabe Masahiko, Nakamura Masaya, Toyama Yoshiaki, Kawakami Yutaka

Journal of neurosurgery 97 （ 1Suppl ） 142-147 2002年07月

研究論文（学術雑誌）, 共著

A simple and reliable behavioral analysis of locomotor function after spinal cord injury in mice

Mikami Yuji, Toda Masahiro, Watanabe Masahiko, Nakamura Masaya, Toyama Yoshiaki, Kawakami Yutaka

Journal of neurosurg 97 （ 1Suppl ） 142-147 2002年07月

研究論文（学術雑誌）, 共著

頸椎症の手術療法；片開き式脊柱管拡大術

千葉一裕，丸岩博文，松本守雄，中村雅也，西澤隆，戸山芳昭

脊椎脊髄ジャーナル 15 （ 6 ） 663-667 2002年06月

研究論文（学術雑誌）, 共著

損傷脊髄への神経幹細胞移植

中村雅也，戸山芳昭，岡野栄之

実験医学 20 （ 9 ） 1301-1306 2002年06月

研究論文（学術雑誌）, 共著

腰椎変性すべり症に対する後方除圧術による腰痛治療成績の検討

西澤隆，千葉一裕，中村雅也，松本守雄，丸岩博文，戸山芳昭

臨床整形外科 37 （ 5 ） 601-605 2002年05月

研究論文（学術雑誌）, 共著

腰椎変性側弯症に対するinstrumentation surgery（広範囲固定例）の中・長期成績（5年以上）

戸山芳昭，松本守雄，丸岩博文，中村雅也，西澤隆，千葉一裕

臨床整形外科 37 （ 4 ） 467-473 2002年04月

研究論文（学術雑誌）, 共著

神経栄養因子による脊髄由来神経幹細胞の分化制御―特に内因性神経栄養因子に着目して

中村雅也，岡野栄之，戸山芳昭

臨床整形外科 37 （ 4 ） 475-480 2002年04月

研究論文（学術雑誌）, 共著

脊髄円錐高位の脊髄腫瘍

稲見州治，中村雅也，千葉一裕，戸山芳昭

脊椎脊髄ジャーナル 15 （ 4 ） 273-278 2002年04月

研究論文（学術雑誌）, 共著

神経栄養因子による脊髄由来神経幹細胞の分化制御

中村雅也，岡野栄之，戸山芳昭

臨床整形外科 37 475-480 2002年04月

研究論文（学術雑誌）, 共著

腰椎部に発生し硬膜内外および椎体内に進入した髄膜腫の1例

西脇徹，西澤隆，千葉一裕，渡辺雅彦，中村雅也，松本守雄，丸岩博文，戸山芳昭

関東整形災害外科学会誌 33 （ 2 ） 65-68 2002年04月

研究論文（学術雑誌）, 共著

腰椎部に発生した硬膜内外および椎体内に侵入した髄膜腫の1例

西脇徹，西澤隆，千葉一裕，渡辺雅彦，中村雅也，松本守雄，丸岩博文，戸山芳昭

関東整形災害外科学会雑誌 33 （ 2 ） 92-98 2002年04月

研究論文（学術雑誌）, 共著

L5-S1椎体骨棘による第5腰神経障害―解剖学的および臨床的検討―

松本守雄，野尻賢哉，石川雅之，西澤隆，中村雅也，丸岩博文，千葉一裕戸山芳昭，市原眞仁，西川雄司

臨床整形外科 37 （ 3 ） 257-267 2002年03月

研究論文（学術雑誌）, 共著

脊髄損傷と再生―神経幹細胞と神経栄養因子について―

中村雅也，戸山芳昭

関節外科 21 （ 3 ） 116-119 2002年03月

研究論文（学術雑誌）, 共著

新生ラット脊髄損傷に対する神経幹細胞移植

中村雅也，岡野栄之，小川祐人，岩波明生，金子慎二郎，Bergman Barbara S

Acta Anatomica Nipponica 77 （ Suppl ） 9 2002年03月

研究論文（学術雑誌）, 共著

損傷脊髄内サイトカイン・神経栄養因子mRNAの発現の変化

中村雅也，岡野栄之，千葉一裕，Bregman Barbara，戸山芳昭

日本パラプレジア医学会雑誌 15 （ 1 ） 126-127 2002年03月

研究論文（学術雑誌）, 共著

脊髄損傷と再生―神経幹細胞と神経栄養因子について―

中村雅也，戸山芳昭

関節外科 21 （ 3 ） 116-119 2002年03月

研究論文（学術雑誌）, 共著

男女間における腰椎変性すべり症の臨床像の違いについて―後方除圧術の分析

西澤隆，千葉一裕，中村雅也，松本守雄，丸岩博文，藤村祥一，戸山芳昭

臨床整形外科 37 （ 3 ） 257-262 2002年03月

研究論文（学術雑誌）, 共著

男女間における腰椎変性すべり症の臨床像の違いについて―後方除圧術例の分析―

西澤隆，千葉一裕，中村雅也，松本守雄，丸岩博文，藤村祥一，戸山芳昭

臨床整形外科 37 （ 3 ） 249-255 2002年03月

研究論文（学術雑誌）, 共著

L5 - S1椎体骨棘による第5腰神経障害―解剖学的および臨床的検討

松本守雄，野尻賢哉，石川雅之，西澤隆，中村雅也，丸岩博文，千葉一裕，戸山芳昭，市原眞人，西川雄司

臨床整形外科 37 （ 3 ） 257-262 2002年03月

研究論文（学術雑誌）, 共著

頚椎椎間板ヘルニアによる頚髄症に対する保存療法の有用性と限界―手術例との比較検討―

松本守雄，千葉一裕，西澤隆，中村雅也，丸岩博文，藤村祥一，戸山芳昭

臨床整形外科 37 （ 2 ） 129-133 2002年02月

研究論文（学術雑誌）, 共著

経静脈的patient controlled analgesiaによる脊椎術後疼痛管理

松本守雄，千葉一祐，西澤隆，中村雅也，丸岩博文，藤村祥一，戸山芳昭，橋口さおり

臨床整形外科 37 （ 2 ） 159-162 2002年02月

研究論文（学術雑誌）, 共著

頸椎椎間板ヘルニアによる頸髄症に対する保存療法の有用性と限界―手術例との比較検討

松本守雄，千葉一裕，西澤隆，中村雅也，丸岩博文，藤村祥一，戸山芳昭

臨床整形外科 37 （ 2 ） 129-133 2002年02月

研究論文（学術雑誌）, 共著

経静脈的patient controlled analgesiaによる脊椎術後疼痛管理

松本守雄，千葉一裕，西澤隆，中村雅也，丸岩博文，藤村祥一，戸山芳昭，橋口さおり

臨床整形外科 37 （ 2 ） 159-162 2002年02月

研究論文（学術雑誌）, 共著

A simple and reliable behavioral analysis of locomotor function after spinal cord injury in mice

Mikami Yuji, Toda Masahiro, Watanabe Masahiko, Nakamura Masaya, Toyama Yoshiaki, Kawakami Yutaka

Journal of Neurosurgery 97 （ 1 SUPPL. ） 142 - 147 2002年

ISSN 0022-3085

To establish a simple and reliable method to assess the behavioral function after spinal cord injury (SCI) in mice, the authors used an automated animal movement analysis system, SCANET. Two different SCI lesions were created in adult female BALB/c and C57BL/6 mice by transecting both the posterior columns and the left lateral and anterior funiculi or only the left lateral and anterior funiculi at T-8. Control mice underwent laminectomy only. The SCANET system consists of a cage equipped with two crossing sensor frames arranged at different heights, by which small (MI) and large (M2) horizontal movements and the vertical movement involved in rearing (RG) can be monitored. The authors assessed locomotor function by determining the M1, M2, and RG scores; to this end, they used the SCANET system and a previously established behavior test, the 21-point open-field Basso-Beattie-Bresnahan (BBB) Locomotor Rating Scale. The results indicated that the RG scores were significantly and consistently different between the spinal cord-injured and control mice, irrespective of the mouse strain or injury model, but that MI and M2 scores were not. Moreover, there was a statistically positive correlation between the RG score and the BBB Scale score. For the assessment of locomotor function after SCI, use of the SCANET sytem in behavioral analysis is simple and the method is highly reproducible. The analysis of vertical movement is useful for assessing the recovery of limb function in mice following thoracic hemisection.

特集―中枢神経系の再生に挑む；損傷脊髄への神経幹細胞移植

中村雅也，戸山芳昭，岡野栄之

実験医学 20 （ 9 ） 1301-1306 2002年

研究論文（学術雑誌）, 共著

損傷脊髄内サイトカイン・神経栄養因子mRNAの発現の変化

中村雅也，岡野栄之，千葉一裕，Bregman BS，戸山芳昭

日本パラプレジア医学会誌 15 （ 1 ） 126-127 2002年

研究論文（学術雑誌）, 共著

成功する胸椎手術―脊髄腫瘍（硬膜内髄外腫瘍）

中村雅也，千葉一裕，戸山芳昭

整形災害外科 45 651-657 2002年

研究論文（学術雑誌）, 共著

特集―再生医療：脊髄損傷に対する神経幹細胞移植

中村雅也，戸山芳昭

日本臨床 61 （ 3 ） 463-468 2002年

研究論文（学術雑誌）, 共著

脊髄円錐高位の椎間板ヘルニア

稲見州治，中村雅也，千葉一裕，戸山芳昭

脊椎脊髄ジャーナル 15 （ 4 ） 273-278 2002年

研究論文（学術雑誌）, 共著

仙骨全摘後2期的再建を行った脊索腫の2例

松本守雄，千葉一裕，丸岩博文，中村雅也，西澤隆，戸山芳昭

脊椎・脊髄神経手術手技 4 （ 1 ） 104-106 2002年

研究論文（学術雑誌）, 共著

L5椎体下縁の骨棘により生じたfar-out syndromeの1例

奥島雄一郎，千葉一裕，松本守雄，丸岩博文，中村雅也，西澤隆，戸山芳昭

関東整形災害外科学会雑誌 32 （ 5 ） 262-265 2001年10月

研究論文（学術雑誌）, 共著

Increase of oligodendrocyte progenitor cells after spinal cord injury

Ishii Ken, Toda Masahiro, Nakai Yoko, Asou Hiroaki, Watanabe Masahiko, Nakamura Masaya, Yato Yoshiyuki, Fujimura Yoshikazu, Kawakami Yutaka, Toyama Yoshiaki, Uyemura Keiichi

Journal of Neuroscience Research 65 （ 6 ） 500 - 507 2001年09月

ISSN 0360-4012

The reaction of oligodendrocyte progenitor cells (OPCs) after spinal cord injury (SCI) is poorly understood. In this study, we examined oligodendroglial reactions after contusion SCI in adult rats by immunohistochemistry. OPCs were identified by staining with monoclonal antibodies (mAbs) A2B5 and O4. Each of the A2B5-, O4-positive OPCs and galactocerebroside-positive oligodendrocytes dramatically increased in the lesion of the dorsal posterior funiculus. Bromodeoxyuridine (BrdU) incorporation studies showed that most O4-positive cells in the lesion were labeled with BrdU, suggesting that these OPCs were proliferative. In contrast, the expression of myelin basic protein was decreased in the lesion compared with controls that received laminectomy only. From the injured cord, OPCs were isolated by immunopanning with mAb A2B5. We observed an increased number of OPCs from the injured spinal cords compared with those isolated from controls and unoperated animals. After several days in culture, the OPCs from the lesion expressed galactocerebroside. These results suggest that OPCs are induced and can differentiate following SCI in the adult rat. © 2001 Wiley-Liss, Inc.

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Increase of oligodendrocyte progentior cells after spinal cord injury

Ishii Ken, Toda Masahiro, Nakai Yoko, Asou Hiroaki, Watanabe Masahiko, Nakamura Masaya, Yato Yoshiyuki, Fujimura Yoshikazu, Kawakami Yutaka, Toyama Yoshiaki, Uyemura Keiichi

Journal of Neuroscience Research 65 （ 6 ） 500-507 2001年09月

研究論文（学術雑誌）, 共著

脊柱管狭窄を伴う頚椎椎間板ヘルニアの手術療法―前後合併手術と後方除圧術との比較―

丸岩博文，千葉一裕，西澤隆，中村雅也，松本守雄，戸山芳昭

脊椎脊髄ジャーナル 14 （ 9 ） 799-803 2001年09月

研究論文（学術雑誌）, 共著

Increase of oligodendrocyte progenitor cells after spinal cord injury

Ishii Ken, Toda Masahiro, Nakai Yoko, Asou Hiroaki, Watanabe Masahiko, Nakamura Masaya, Yato Yoshiyuki, Fujimura Yoshikazu, Kawakami Yutaka, Toyama Yoshiaki, Uyemura Keiichi

Journal of Neuroscience Research 65 （ 6 ） 500-507 2001年09月

研究論文（学術雑誌）, 共著

第5腰椎椎体骨棘による第5腰神経根障害に対して腹腔鏡視下骨棘切除を行った1例

松本守雄，千葉一裕，西澤隆，中村雅也，丸岩博文，戸山芳昭

脊椎脊髄ジャーナル 14 （ 8 ） 112-115 2001年08月

研究論文（学術雑誌）, 共著

頚椎症性脊髄症（ヘルニアを含む）に対する腸骨inlay graftによる前方固定術

丸岩博文，千葉一裕，松本守雄，中村雅也，西澤隆，戸山芳昭

Monthly Book Orthopedics 14 （ 8 ） 1-8 2001年08月

研究論文（学術雑誌）, 共著

高齢者の歯突起骨折―その臨床像と治療成績について

松本守雄，千葉一裕，西澤隆，中村雅也，丸岩博文，藤村祥一，戸山芳昭，渡辺公三

臨床整形外科 36 （ 7 ） 881-884 2001年07月

研究論文（学術雑誌）, 共著

特集／腰椎椎間板ヘルニアの治療―最近の動向；ヘルニアの自然縮小―単純MRIによる観察

奥島雄一郎，千葉一裕，松本守雄，丸岩博文，中村雅也，西澤隆，西川雄司，戸山芳昭

骨・関節・靭帯 14 （ 7 ） 655-658 2001年07月

研究論文（学術雑誌）, 共著

Differences in neurotrophic factor gene expression profiles between neonate and adult rat spinal cord after injury

Nakamura Masaya, Bregaman Barbara

Experimental Neurology 169 （ 2 ） 407-415 2001年06月

研究論文（学術雑誌）, 共著

高齢者軸椎骨折の治療経験

松本守雄，千葉一裕，西澤隆，中村雅也，丸岩博文，戸山芳昭

日本パラプレジア医学会雑誌 14 （ 1 ） 116-117 2001年05月

研究論文（学術雑誌）, 共著

Differences in neurotrophic factor gene expression profiles between neonate and adult rat spinal cord after injury

Nakamura Masaya, Bregman Barbara S.

Experimental Neurology 169 （ 2 ） 407 - 415 2001年

ISSN 0014-4886

The capacity of the central nervous system for axonal growth decreases as the age of the animal at the time of injury increases. Changes in the expression of neurotrophic factors within embryonic and early postnatal spinal cord suggest that a lack of trophic support contributes to this restrictive growth environment. We examined neurotrophic factor gene profiles by ribonuclease protection assay in normal neonate and normal adult spinal cord and in neonate and adult spinal cord after injury. Our results show that in the normal developing spinal cord between postnatal days 3 (P3) and P10, compared to the normal adult spinal cord, there are higher levels of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and glial-derived neurotrophic factor (GDNF) mRNA expression and a lower level of ciliary neurotrophic factor (CNTF) mRNA expression. Between P10 and P17, there is a significant decrease in the expression of NGF, BDNF, NT-3, and GDNF mRNA and a contrasting steady and significant increase in the level of CNTF mRNA expression. These findings show that there is a critical shift in neurotrophic factor expression in normal developing spinal cord between P10 and P17. In neonate spinal cord after injury, there is a significantly higher level of BDNF mRNA expression and a significantly lower level of CNTF mRNA expression compared to those observed in the adult spinal cord after injury. These findings suggest that high levels of BDNF mRNA expression and low levels of CNTF mRNA expression play important roles in axonal regrowth in early postnatal spinal cord after injury. © 2001 Academic Press.

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Experimental study on MRI evaluation of the course of cervical spinal cord injury

Ohta Keiichi, Fujimura Yoshikazu, Nakamura Masaya, Watanabe Masahiko, Yato Yoshiyuki

Spinal Cord 37 （ 8 ） 580-584 1999年08月

研究論文（学術雑誌）, 共著

Experimental study on MRI evaluation of the course of cervical spinal cord injury

Ohta K., Fujimura Y., Nakamura M., Watanabe M., Yato Y.

Spinal Cord 37 （ 8 ） 580 - 584 1999年

ISSN 1362-4393

Study Design: An experimental study was conducted to evaluate MRI signal changes within the spinal cord after the injury in rats. Objectives: To clarify the significance of MRI signal changes in the injured cervical cord. Setting: Tokyo, Japan. Methods: Cervical spinal cord injury was produced in rats by placing a 20-g, or 35-g weight on exposed dura at the C6 level for 5 min (20 g- or 35 g-compression group). Motor function was evaluated by the inclined-plane method at 2, 7 and 28 days after the injury. T1- and T2-weighted images were produced by the spin-echo method with a static magnetic field strength of 2.0 tesla, at 2 and 28 days after the injury, and then the histopathological examinations were performed. Results: In the 20-g compression group which recovered from the paralysis at 28 days. MR images were T1 iso signal/T2 high signal 2 days after the injury and T1 iso signal/T2 high signal after 28 days. The changes in MRI signal 2 and 28 days represented edema and gliosis, respectively. In the 35-g compression group, which incompletely recovered from paralysis at 28 days. MR images were T1 iso-signal/T2 low signal surrounded by high signal 2 days after the injury and T1 low/T2 high signal at 28 days. The MRI signal changes 2 and 28 days reflected hemorrhage with edema and cavities, respectively. Conclusion: T2 low signal of the spinal cord observed early after injury reflects hemorrhage and may serve as an indicator of a poor prognosis. T1 low/T2 high signals from the subacute to chronic period indicated persistence of paralysis and limited recovery of function.

Multiple regression analysis of the factors influencing the results of expansive open-door laminoplasty for cervical myelopathy due to ossification of the posterior longitudinal ligament

Fujimura Y., Nishi Y., Chiba K., Nakamura M., Hirabayashi K.

Archives of Orthopaedic and Trauma Surgery 117 （ 8 ） 471 - 474 1998年10月

ISSN 0936-8051

We conducted a multiple regression analysis on the surgical results (minimum follow-up of 5 years) of 55 patients who underwent expansive open-door laminoplasty (open-door ELAP) for cervical myelopathy due to ossification of the posterior longitudinal ligament (OPLL) in order to determine statistically the impact of factors influencing the results. Duration of myelopathy was found to be a significant factor indicating poor results, while progression of ossification and age at the time of surgery were significant factors indicating deterioration. Three other factors (preoperative severity of myelopathy, degree of spinal canal expansion and changes of the curve indices before and after surgery did not have a significant influence on the results. To improve the surgical results, it is thus essential to operate on patients as soon as they develop symptoms of myelopathy. There exists a certain limitation in posterior decompression for OPLL including open-door ELAP until prevention of the progression of ossification becomes possible.

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Multiple regression analysis of the factors influencing the result of expansive open-door laminoplasty for cervical myelopathy due to the ossification of the posterior longitudinal ligament

Fujimura Yoshikazu, Nishi Yukimi, Chiba Kazuhiro, Nakamura Masaya, Hirabayashi Kiyoshi

Archives of Orthopaedic and Trauma Surgery 117 （ 8 ） 471-474 1998年10月

研究論文（学術雑誌）, 共著

MRI for cervical intervertebral discs in asymptomatic subjects

Matsumoto M, Fujimura Y, Suzuki N, Nishi Y, Nakamura M, Yabe Y, Shiga H

J Bone and Joint Surg 19-24 1998年08月

研究論文（学術雑誌）, 共著

Changes of amino acid levels and aspartate distribution in the cervical spinal cord after traumatic spinal cord injury

Watanabe Masahiko, Fujimura Yoshikazu, Nakamura Masaya, Yato Yoshiyuki, Ohta Keiichi, Okai Hiroki, Ogawa Yuto

Journal of Neurotrauma 15 （ 4 ） 285-293 1998年04月

研究論文（学術雑誌）, 共著

Influence of minor trauma on surgical results in patients with cervical OPLL

Fujimura Yoshikazu, Nakamura Masaya, Toyama Yoshiaki

J Spinal Disord 11 （ 1 ） 16-20 1998年02月

研究論文（学術雑誌）, 共著

Magnetic resonance imaging of the spinal cord in cervical ossification of the posterior longitudinal ligament

Nakamura Masaya, Fujimura Yoshikazu

Spine 23 （ 1 ） 38 - 40 1998年01月

ISSN 0362-2436

Study Design. Magnetic resonance imaging findings of an increased signal in the cervical cord in patients undergoing surgery for ossification of the posterior longitudinal ligament were analyzed to determined whether an increased signal on T2-weighted images correlated with a poorer outcome. Objectives. To clarify whether preoperative magnetic resonance imaging findings of a high signal in the cord constitute a poor prognostic factor. Summary of Background Data. The importance of a high, T2-weighted, intramedullary signal on preoperative magnetic resonance studies in patients undergoing surgery for ossification of the posterior longitudinal ligament requires further clarification. Methods. Of 91 patients having cervical surgery for ossification of the posterior longitudinal ligament, 26 had a history of minor trauma. High, T2-weighted signals in the cord were note din 23 patients who had sustained trauma and in 39 patients who had no history of trauma. Patients were divided into four groups according to the presence or absence of a high cord signal and/or a trauma history. Pre- and postoperative Japanese Orthopaedic Association scores and recovery ratios then were evaluated. Results. The pre-and postoperative Japanese Orthopaedic Association scores and recovery ratios of the patients with a high signal and a trauma history were significantly less than those with no high signal but with a trauma history. Among the patients with no history of trauma, however, there were no significant differences in the pre- and postoperative JOA scores and recovery ratios between the patients with a high signal and those with no high signal. Conclusion. A high preoperative cord signal on T2- weighted magnetic resonance images for patients undergoing surgery for ossification of the posterior longitudinal ligament constitutes a poor prognostic factor, when trauma has placed a role.

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MRI of cervical intervertebral discs in asymptomatic subjects

Matsumoto Morio, Fujimura Yoshikazu, Suzuki Nobumasa, Nishi Yukimi, Nakamura Masaya, Yabe Yutaka, Shiga Hayao

Journal of Bone and Joint Surgery - Series B 80 （ 1 ） 19 - 24 1998年01月

ISSN 0301-620X

We studied degenerative changes in the cervical intervertebral discs of 497 asymptomatic subjects by MRI and evaluated disc degeneration by loss of signal intensity, posterior and anterior disc protrusion, narrowing of the disc space and foraminal stenosis. In each subject, five disc levels from C2-C3 to C6-C7 were evaluated. The frequency of all degenerative findings increased linearly with age. Disc degeneration was the most common observation, being present in 17% of discs of men and 12% of those of women in their twenties, and 86% and 89% of discs of both men and women over 60 years of age. We found significant differences in frequency between genders for posterior disc protrusion and foraminal stenosis. The former, with demonstrable compression of the spinal cord, was observed in 7.6% of subjects, mostly over 50 years of age. Our results should be taken into account when interpreting the MRI findings in patients with symptomatic disorders of the cervical spine.

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Magnetic resonance imaging of the spinal cord in cervical ossification of the posterior longitudinal ligament; can it predict surgical outcome?

Nakamura M, Fujimura Yoshikazu

Spine 23 （ 1 ） 38-40 1998年01月

研究論文（学術雑誌）, 共著

MRI of cervical intervertebral discs in asymptomatic subjects

Matsumoto Morio, Fujimura Yoshikazu, Suzuki Nobuyuki, Nishi Yukimi, Nakamura Masaya, Yabe Yutaka, Shiga Hayao

J Bone Joint Surg 80-B （ 1 ） 19-24 1998年01月

研究論文（学術雑誌）, 共著

Influence of minor trauma on surgical results in patients with cervical OPLL

Fujimura Yoshikazu, Nakamura Masaya, Toyama Yoshiaki

Journal of Spinal Disorders 11 （ 1 ） 16 - 20 1998年

ISSN 0895-0385

This study was designed to evaluate the relationship between minor trauma and surgical results of cervical ossification of the posterior longitudinal ligament (OPLL), focusing on static compressive and dynamic factors contributing to cord compression plus the type of attendant OPLL. Of the 91 patients treated surgically, 26 had sustained minor trauma (injury group), and the other 65 had no trauma (noninjury group). The pre- /postoperative JOA scores and recovery ratio for the injury group were significantly lower than those for the noninjury group. In the segmental, localized, and mixed types, which had good ranges of motion of the cervical spine, the recovery ratios of the injury group were significantly lower than those of the noninjury group. In the continuous type, which had a poor range of motion and severe spinal cord compression, there was no significant difference in the recovery ratio between the injury and noninjury groups. Thus, dynamic factors may play an important role in neurologic deterioration after minor trauma in patients with segmental, mixed, and localized cervical OPLL.

Anterior Decompression and Fusion via the Extrapleural Approach for Thoracic Disc Herniation Causing Myelopathy

Fujimura Yoshikazu, Nakamura Masaya, Matsumoto Mono

Keio Journal of Medicine 46 （ 4 ） 173 - 176 1997年12月

ISSN 0022-9717

Anterior decompression and fusion via an extrapleural approach was performed for 33 patients with myelopathy arising from thoracic disc herniation and the clinical usefulness and problems related to this procedure were assessed on the basis of surgical results and complications. The severity of the myelopathy was evaluated by the Japanese Orthopaedic Association score, and the surgical results were based on the recovery rate. The upper-level limit of decompression and fusion via the extrapleural approach was T4-5. The recovery rate for the mean postoperative follow-up period of 41 months was 66.7%. An age of 60 years or more, long duration of illness and severe preoperative myelopathy were indicators of a poor prognosis. Two patients suffered from a postoperative transient pulmonary complication due to hemothorax. X-ray examinations revealed good bone union in all the patients. The present study indicates that anterior decompression and fusion via the extrapleural approach is a useful technique which can be used to achieve a high success rate in the surgical treatment of thoracic disc herniation, if intervention is early.

Anterior decompression and fusion via extrapleural approach for thoracic disc herniation causing myelopathy

Fujimura Yoshikazu, Nakamura Masaya, Matsumoto Morio

Keio J Med 46 （ 4 ） 173-176 1997年12月

研究論文（学術雑誌）, 共著

Decreased choline acetyltransferase activity in the murine spinal cord motoneurons under chronic mechanical compression

Yato Yoshiyuki, Fujimura Yoshikazu, Nakamura Masaya, Watanabe Masahiko, Yabe Yutaka

Spinal Cord 35 （ 11 ） 729-734 1997年11月

研究論文（学術雑誌）, 共著

Myelopathy secondary to ossification of the posterior longitudinal ligament of the thoracic spine treated by anterior decompression and bony fusion

Fujimura Yoshikazu, Nishi Yukimi, Nakamura Masaya, Watanabe Masahiko, Matsumoto Morio

Spinal Cord 35 （ 11 ） 777-784 1997年11月

研究論文（学術雑誌）, 共著

Muscle reorganization following incomplete spinal cord injury the rats

Nakamura Masaya, Fujimura Yoshikazu, Ogawa Yuto, Okai Hiroki,Ohta Keiichi, Yato Yoshiyuki, Watanabe Masahiko

Spinal Cord 35 （ 11 ） 752-756 1997年11月

研究論文（学術雑誌）, 共著

Dorsal shift and expansion of the spinal cord after expansive open-door laminoplasty

Fujimura Yoshikazu, Nishi Yukimi, Nakamura Masaya

J Spinal Disord 10 （ 4 ） 282-287 1997年08月

研究論文（学術雑誌）, 共著

胸部椎間板ヘルニアの症候学

藤村祥一，中村雅也，松本守雄，千葉一裕

脊椎脊髄ジャーナル 10 （ 5 ） 455-460 1997年05月

研究論文（学術雑誌）, 共著

MRIによる頚髄不全損傷の経時的評価に関する実験的研究

太田圭一，藤村祥一，中村雅也，渡辺雅彦，谷戸祥之

日パラプレジア医会誌 10 （ 1 ） 62-63 1997年04月

研究論文（学術雑誌）, 共著

頸椎後縦靭帯骨化症における髄内高信号の臨床的意義

中村雅也，藤村祥一，松本守雄，鎌田修博，戸山芳昭，鈴木信正

日パラプレジア医会誌 10 （ 1 ） 72-73 1997年04月

研究論文（学術雑誌）, 共著

頸椎後縦靭帯骨化症の治療成績と外傷の関連--MRI髄内高信号の臨床的意嚢--

中村雅也，藤村祥一，松本守雄，鎌田修博，戸山芳昭，鈴木信正

臨整外 32 （ 4 ） 321-325 1997年04月

研究論文（学術雑誌）, 共著

Long-term follow-up study of anterior decompression and fusion for thoracic myelopathy resulting from ossification of the posterior longitudinal ligament

Fujimura Yoshikazu, Nishi Yukimi, Nakamura Masaya, Toyama Yoshiaki, Suzuki Nobumasa

Spine 22 （ 3 ） 305 - 311 1997年02月

ISSN 0362-2436

Study Design. This was a retrospective study of the results of anterior decompression and fusion in patients with thoracic myelopathy secondary to ossification of the posterior longitudinal ligament with a minimum follow-up time of 5 years. Objectives. To clarify the effectiveness and limits of anterior decompression and fusion for thoracic ossification of the posterior longitudinal ligament. Summary of Background Data. Posterior decompression for the surgical management of thoracic ossification of the posterior longitudinal ligament has had an uncertain success record. Anterior decompression and fusion have been considered the treatment of choice; however, there are few reports describing the long-term results. Methods. The participants in this investigation were 33 patients whose cases were followed for an average period of 8 years and 2 months. The factors that were investigated included changes in the Japanese Orthopedic Association score and in recovery rates, postoperative complications, and radiographic findings of bone union and progression of ossification of the posterior longitudinal ligament within the area of anterior decompression. Results. Although the recovery rates were relatively stable from 1-5 years after surgery, the rates declined thereafter. The average recovery rate at the final follow-up visit was 53.2%. Postoperative complications included three cases of deterioration of thoracic myelopathy and four cases of extrapleural cerebrospinal fluid leakage. Except for the one case of deterioration of thoracic myelopathy, the remainder of the complications were transient. Conclusions. Anterior decompression and fusion is an effective surgical procedure for thoracic ossification of the posterior longitudinal ligament with good, stable, long- term results; when thoracic ossification of the posterior longitudinal ligament was extensive or coincident with ossification of the intraspinal ligament, however, the results were not as predictable.

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Long-term follow-up study of anterior decompression and fusion for thoracic myelopathy resulting from ossification of the posterior longitudinal ligament

Fujimura Yoshikazu, Nishi Yukimi, Nakamura Masaya, Toyama Yoshikazu, Suzuki Nobumasa

Spine 22 （ 3 ） 305-311 1997年

研究論文（学術雑誌）, 共著

Decreased choline acetyltransferase activity in the marine spinal cord motoneurons under chronic mechanical compression

Yato Y., Fujimura Y., Nakamura M., Watanabe M., Yabe Y.

Spinal Cord 35 （ 11 ） 729 - 734 1997年

ISSN 1362-4393

The tiptoe-walking Yoshimura (twy) mouse is a model of chronic spinal cord compression caused by ossification of intraspinal ligaments. Choline acetyltransferase (CAT), which is known to be a specific marker of cholinergic neurons, best reflects spinal motoneuron function. Changes in CAT immunoreactivity following chronic spinal cord compression in twy mice were investigated quantitatively in order to elucidate spinal motoneuron functional changes according to the degree and direction of compression. Thirty 24-week-old twy mice were used in this study. They were divided into three groups according to the direction of spinal cord compression (anterior, posterior, and lateral) and the CAT immunoreactivities in whole sections of their upper cervical spinal cords were investigated quantitatively using a fluorescence microphotometry system. The lateral compression group showed histological spinal motoneuron atrophy and loss on the compressed, but not the non-compressed, side. Spinal motoneuron atrophy and loss were observed when the severity of spinal canal stenosis due to the ossified lesion, expressed as the occupation rate, was 30% or more, but the spinal motoneurons appeared normal when it was below 30%. The CAT immunofluorescence intensity of the anterior horn showed a linear negative correlation with the degree of canal stenosis. When the occupation rate was below 20%, the CAT immunofluorescence intensities in the anterior horns of the compression and control groups did not differ significantly. The CAT immunofluorescence intensity of twy mice with occupation rates of 20% or more were significantly lower than that of those with occupation rates below 20%. Furthermore, the CAT immunofluorescence intensity was significantly lower on the compressed than the noncompressed side of the lateral compression group. Thus, our findings indicate that an occupation rate of about 20% may be the critical level for functional changes in the spinal motoneurons.

Muscle reorganization following incomplete cervical spinal cord injury in rats

Nakamura M., Fujimura Y., Yato Y., Watanabe M.

Spinal Cord 35 （ 11 ） 752 - 756 1997年

ISSN 1362-4393

This study on rats was designed to evaluate the change of biceps muscle fibers by enzyme histochemical examination and the change of distribution of motoneurons innervating biceps muscle fibers by retrograde tracer examination after incomplete spinal cord injury. Incomplete spinal cord injury was produced by placing a 20 g weight on exposed dura at the C6 level. The number of the labeled motoneurons of C6 segment significantly decreased compared with that in the control, but there were no significant changes in the other segments at 4 weeks after the injury. Moreover, there was type grouping of biceps muscle fibers at 4 weeks after the injury. These findings indicated that the incomplete cervical spinal cord injury at C6 level in rats caused the partial denervation and then reinnervation of biceps muscle fibers by the collateral sprouting of the remaining motoneurons which belonged to the same motoneuron pool of the injured motoneurons.

Myelopathy secondary to ossification of the posterior longitudinal ligament of the thoracic spine treated by anterior decompression and bony fusion

Fujimura Y., Nishi Y., Nakamura M., Watanabe M., Matsumoto M.

Spinal Cord 35 （ 11 ） 777 - 784 1997年

ISSN 1362-4393

We examined the utility of anterior decompression and bony fusion via the extrapleural approach in the treatment of thoracic myelopathy secondary to ossification of the posterior longitudinal ligament (OPLL). Patient outcome and complications were analyzed in 48 patients treated with this procedure, with a follow-up of at least 2 years. The Japanese Orthopaedic Association score was used to evaluate the severity of the thoracic myelopathy, and the recovery rate was used to evaluate the surgical outcome. The outcome, postoperative complications, radiographic evaluations of bony union, and progression of OPLL within the area of anterior decompression were examined. The T3 vertebral body was the highest level to which anterior decompression was applied. The average follow-up period was 57 months with a recovery rate of 56.7% which stabilized 1 year after operation. However, the surgical outcome was less favorable in patients with long-standing myelopathy, extensive OPLL, or thoracic OPLL with coexisting intraspinal ligament ossification. Four patients experienced deterioration of their myelopathy, and seven patients had the postoperative complication of extraspinal leakage of cerebrospinal fluid. The myelopathy was transient in all but one patient. Radiographic studies showed that bony union was achieved and restenosis of the spinal canal due to progression of OPLL within the area of decompression did not occur. We conclude that anterior decompression and bony fusion using the extrapleural approach provides a good outcome and is useful in treating mid- and lower thoracic OPLL when performed carefully at an early stage of disease.

Dorsal shift and expansion of the spinal cord after expansive open-door laminoplasty

Fujimura Yoshikazu, Nishi Yukimi, Nakamura Masaya

Journal of Spinal Disorders 10 （ 4 ） 282 - 287 1997年

ISSN 0895-0385

We investigated dorsal shift and anteroposterior spinal cord diameter after expansive open-door laminoplasty, comparing pre- and postoperative computed tomographic myelographic images to clarify the relationships between surgical outcome and these changes. Dorsal shift occurred at the midcervical spine in cervical spondylotic myelopathy (CSM) but was less extensive in ossification of the posterior longitudinal ligament (OPLL). Spinal cord anteroposterior diameter expanded for OPLL but did not for CSM. Correlation of outcome and dorsal shift was not significant for OPLL or CSM. Correlation of outcome and expansion was significant for OPLL, but not for CSM.

Changes in choline acetyltransferase activity and distribution following incomplete cervical spinal cord injury in the rat

Nakamura M., Fujimura Y., Yato Y., Watanabe M., Yabe Y.

Neuroscience 75 （ 2 ） 481 - 494 1996年10月

ISSN 0306-4522

Incomplete cervical spinal cord injuries were produced in rats by placing 10 g or 20 g weight on exposed dura at the C6 level for 5 min (Mild or Moderate injury). These two degrees of the injury resulted in initial motor functional deficits, followed by recoveries. In this study, changes in choline acetyltransferase activity and distribution following the incomplete cervical cord injuries were investigated using radioenzyme assay, and fluorescence microphotometry. We demonstrated that mild injury led to a transient decrease of choline acetyltransferase activity in the compressed spinal cord segment, but showed almost no histologic change at two days after injury. Although a low level of choline acetyltransferase immunofluorescence was found in the ventrolateral anterior horn at two days after injury, it recovered completely by one week after injury. These findings suggest that there was a strong correlation between the transient motor functional deficit and the decrease in choline acetyltransferase activity following mild injury. Moderate injury resulted in a persistent low level of choline acetyltransferase activity in the compressed spinal cord segment accompanied by a striking loss of gray matter. On the other hand, at seven, 14 and 28 days after injury, over-expression of choline acetyltransferase activity was found in the neighboring spinal cord segments located both rostral and caudal to the injury, which showed no histologic change. In addition, excessively high levels of choline acetyltransferase immunofluorescence were found in the ventrolateral anterior horn of these segments. A strong correlation was found between the motor functional recovery and the late, e high levels of choline acetyltransferase activity in the neighboring regions. These results suggest that cholinergic neurons, especially spinal motor neurons may play an important role in the motor functional recovery following incomplete cervical spinal cord injury.

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Metastases to the upper cervical spine

Nakamura Masaya, Toyama Yoshiaki, Suzuki Nobumasa, Fujimura Yoshikazu

Journal of Spinal Disorders 9 （ 3 ） 195 - 201 1996年

ISSN 0895-0385

A retrospective study of 13 patients with metastases to the upper cervical spine was designed to examine the clinical efficacy of surgical treatment. All patients had severe neck pain and two had quadriplegia. Eleven patients underwent operative posterior stabilization, and two patients were treated with a brace and radiotherapy. Pain relief after surgery was significant so that 10 of the 11 patients could leave bed and resume their normal activities. The other two patients who were treated nonoperatively had severe dementia and sudden death from a respiratory arrest after a fall, despite temporary relief from pain. Surgery may be very successful in improving the quality of life of patients who have pain and/or paralysis caused by metastases to the upper cervical spine.

Anterior decompression and fusion for ossification of the posterior longitudinal ligament of the upper thoracic spine causing myelopathy ; using the manubrium splitting approach

Fujimura Yoshikazu, Nishi Yukimi, Nakamura Masaya, Toyama Yoshiaki, Suzuki Nobumasa

Spinal Cord 34 （ 7 ） 387-393 1996年

研究論文（学術雑誌）, 共著

Metastases to the upper cervical spine

Nakamura Masaya, Fujimura Yoshikazu, Toyama Yoshiaki, Suzuki Nobumasa

J Spinal Disord 9 （ 4 ） 195-201 1996年

研究論文（学術雑誌）, 共著

Changes in choline acetyltransferase activity and distribution following incomplete cervical spinal cord injury in the rat

Nakamura Masaya, Fujimura Yoshikazu, Yato Yoshiyuki, Watanabe Masahiko, Yabe Yutaka

Neuroscience 75 （ 2 ） 481-494 1996年

研究論文（学術雑誌）, 共著

頚椎後縦靭帯骨化症の手術治療成績と外傷の関連について

中村雅也，藤村祥一，松本守雄，鎌田修博，戸山芳昭，鈴木信正

臨整外 31 （ 12 ） 1339-1342 1996年

研究論文（学術雑誌）, 共著

慢性脊髄圧迫による前角細胞の機能的変化

谷戸祥之，藤村祥一，中村雅也，渡辺雅彦

日パラ医誌 9 （ 1 ） 62-63 1996年

研究論文（学術雑誌）, 共著

Anterior decompression and fusion for ossification of the posterior longitudinal ligament of the upper thoracic spine causing myelopathy

Fujimura Y., Nishi Y., Nakamura M., Toyama Y., Suzuki N.

Spinal Cord 34 （ 7 ） 387 - 393 1996年

ISSN 1362-4393

The effectiveness and problems associated with the operation of anterior decompression and fusion using the manubrium splitting approach for thoracic myelopathy due to ossification of the posterior longitudinal ligament (OPLL) of the upper thoracic spine carried out in nine patients was investigated. They were followed up for 1 year or more following the operation. The severity of the thoracic myelopathy was evaluated using the Japanese Orthopaedic Association score, and the surgical outcome was evaluated using recovery rates. This study includes investigation of the surgical outcome and of any postoperative complications, and radiographic observation of bony union and the progression of OPLL within the area of the anterior decompression. The caudal limit of the anterior decompression achieved by splitting the manubrium was the T3 vertebral body. A recovery rate of 71% was achieved during an average follow-up period of 35 months. Only one transient recurrent nerve palsy, and in another patient cerebrospinal fluid leakage occurred as postoperative complications. Radiographic examinations confirmed bony union in all of the patients, and there was no instance of spinal canal stenosis caused by progression of the OPLL within the area of the anterior decompression. Anterior decompression and fusion by splitting the manubrium was an effective surgical procedure for OPLL of the upper thoracic spine, to achieve a good outcome, however, the extent of anterior decompression was limited.

後弯変形による頚椎症性筋萎縮症の2例

中村雅也，戸山芳昭，河野亨，平石英一，木原未知也，赤坂勁二郎

整形外科 46 （ 7 ） 841-845 1995年07月

研究論文（学術雑誌）, 共著

頚椎後縦靭帯骨化症に対する片開き式脊柱管拡大術の成績

西幸美，藤村祥一，中村雅也，朝妻孝仁，戸山芳昭，鈴木信正，平林洌

脊髄外科 9 11-16 1995年06月

研究論文（学術雑誌）, 共著

損傷脊髄内における興奮性アミノ酸の経時的変化

渡辺雅彦，藤村祥一，中村雅也，谷戸祥之，太田圭一

日パラ医誌 8 （ 1 ） 64-65 1995年04月

研究論文（学術雑誌）, 共著

不全損傷頸髄内コリン・アセチル基転移酵素の活性および分布の変化

中村雅也，藤村祥一，渡辺雅彦，谷戸祥之

日パラ医誌 8 （ 1 ） 66-67 1995年04月

研究論文（学術雑誌）, 共著

頚椎後縦靭帯骨化症に対する片開き式脊柱管拡大術の成績

西幸美，藤村祥一，中村雅也，朝妻孝仁，戸山芳昭，鈴木信正，平林洌

Spinal Surg 9 （ 1 ） 11-16 1995年04月

研究論文（学術雑誌）, 共著

Changes in choline acetyltranferase distribution in the cervical spinal cord after reversible cervical spinal cord injury

Nakamura M., Fujimura Y., Yato Y., Watanabe M., Iwamoto Y.

Paraplegia 32 （ 11 ） 752 - 758 1994年

ISSN 0031-1758

Reversible spinal cord injury (SCI) at C6 level in rats, produced by the weight-placed method, resulted in a severe motor functional deficit initially, followed by a gradual recovery. During the recovery, choline acetyltransferase (CAT) distribution in the cervical spinal cord was investigated at 2, 4, 7, 14 and 28 days after the injury by quantitative immunohistochemistry with a fluorescence microphotometry system. At C6 level, the flourescence intensity of the ventrolateral anterior horn (VLAH), which reflected the concentration of CAT, decreased to approximately 50% of that of the sham-operated group at 2 days. It then recovered to 60% at 4 days after the injury, and remained unchanged thereafter. Fluorescence intensities in VLAH at C4-5 and C7-8 levels decreased to approximately 60-70% at 2 days after the injury, but it recovered and increased to 110-130% thereafter.

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