Details of a Researcher - Nakamura, Masaya

Papers - Nakamura, Masaya

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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 2009.02

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 2009.02

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 2008.12

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 2008.12

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 2008.05

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 2008.04

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 2008.04

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 2008.04

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 2008.04

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 2008.03

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

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 2007.12

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 2007.10

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 2007.08

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 2007.08

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 2007.07

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 2007.06

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 2007.03

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 2007.03

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 2007.03

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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