Details of a Researcher - Nakamura, Masaya

Papers - Nakamura, Masaya

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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 2012.08

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 2012.07

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 2012.07

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 2012.07

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 2012.06

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 2012.06

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 ) 2012.05

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 2012.04

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 2012.03

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 2012.03

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 ) 2012.03

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 2012.02

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 2012.02

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 2012.01

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

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

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 2011.12

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 ) 2011.11

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 2011.11

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 2011.11

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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