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Dive into the research topics where Kenyu Ito is active.

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Featured researches published by Kenyu Ito.


Human Molecular Genetics | 2014

LRP4 third β-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated MuSK signaling in a position-specific manner

Bisei Ohkawara; Macarena Cabrera-Serrano; Tomohiko Nakata; Margherita Milone; Nobuyuki Asai; Kenyu Ito; Mikako Ito; Akio Masuda; Yasutomo Ito; Andrew G. Engel; Kinji Ohno

Congenital myasthenic syndromes (CMS) are heterogeneous disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanisms. Using Sanger and exome sequencing in a CMS patient, we identified two heteroallelic mutations, p.Glu1233Lys and p.Arg1277His, in LRP4 coding for the postsynaptic low-density lipoprotein receptor-related protein 4. LRP4, expressed on the surface of the postsynaptic membrane of the neuromuscular junction, is a receptor for neurally secreted agrin, and LRP4 bound by agrin activates MuSK. Activated MuSK in concert with Dok-7 stimulates rapsyn to concentrate and anchor AChR on the postsynaptic membrane and interacts with other proteins implicated in the assembly and maintenance of the neuromuscular junction. LRP4 also functions as an inhibitor of Wnt/beta-catenin signaling. The identified mutations in LRP4 are located at the edge of its 3rd beta-propeller domain and decrease binding affinity of LRP4 for both MuSK and agrin. Mutations in the LRP4 3rd beta-propeller domain were previously reported to impair Wnt signaling and cause bone diseases including Cenani-Lenz syndactyly syndrome and sclerosteosis-2. By analyzing naturally occurring and artificially introduced mutations in the LRP4 3rd beta-propeller domain, we show that the edge of the domain regulates the MuSK signaling whereas its central cavity governs Wnt signaling. We conclude that LRP4 is a new CMS disease gene and that the 3rd beta propeller domain of LRP4 mediates the two signaling pathways in a position-specific manner.


Asian Spine Journal | 2015

Neuropathic Pain in Elderly Patients with Chronic Low Back Painand Effects of Pregabalin: A Preliminary Study

Yoshihito Sakai; Kenyu Ito; Tetsuro Hida; Sadayuki Ito; Atsushi Harada

Study Design Preliminary study. Purpose To assess the association of neuropathic pain with chronic low back pain (LBP) and the effect of pregabalin on neuropathic pain in the elderly. Overview of Literature Of those with chronic LBP, 37% were predominantly presenting with neuropathic pain in young adults. Pregabalin is effective for pain in patients with diabetic neuropathy and peripheral neuralgia. No study has reported on the effects of pregabalin for chronic LBP in elderly patients yet. Methods Pregabalin was administered to 32 patients (age, ≥65 years) with chronic LBP for 4 weeks. Pain and activities of daily living were assessed using the Neuropathic Pain Screening Questionnaire (NePSQ), the pain DETECT questionnaire, visual analog scale, the Japanese Orthopedic Association score, the short form of the McGill Pain Questionnaire and the Roland Morris Disability Questionnaire. Modic change and spinal canal stenosis were investigated using magnetic resonance imaging. Results Altogether, 43.3% of patients had neuropathic pain according to the NePSQ and 15.6% patients had pain according to the pain DETECT. The efficacy rate of pregabalin was 73.3%. A significant effect was observed in patients with neuropathic pain after 4 weeks of administration. Conclusions Neuropathic pain was slightly less frequently associated with chronic LBP in the elderly. Pregabalin was effective in reducing pain in patients with chronic LBP accompanied with neuropathic pain. Lumbar spinal stenosis and lower limb symptoms were observed in patients with neuropathic pain. We recommend the use of pregabalin for patients after evaluating a screening score, clinical symptoms and magnetic resonance imaging studies.


PLOS ONE | 2015

Zonisamide Enhances Neurite Elongation of Primary Motor Neurons and Facilitates Peripheral Nerve Regeneration In Vitro and in a Mouse Model.

Hideki Yagi; Bisei Ohkawara; Hiroaki Nakashima; Kenyu Ito; Mikito Tsushima; Hisao Ishii; Kimitoshi Noto; Kyotaro Ohta; Akio Masuda; Shiro Imagama; Naoki Ishiguro; Kinji Ohno

No clinically applicable drug is currently available to enhance neurite elongation after nerve injury. To identify a clinically applicable drug, we screened pre-approved drugs for neurite elongation in the motor neuron-like NSC34 cells. We found that zonisamide, an anti-epileptic and anti-Parkinson’s disease drug, promoted neurite elongation in cultured primary motor neurons and NSC34 cells in a concentration-dependent manner. The neurite-scratch assay revealed that zonisamide enhanced neurite regeneration. Zonisamide was also protective against oxidative stress-induced cell death of primary motor neurons. Zonisamide induced mRNA expression of nerve growth factors (BDNF, NGF, and neurotrophin-4/5), and their receptors (tropomyosin receptor kinase A and B). In a mouse model of sciatic nerve autograft, intragastric administration of zonisamide for 1 week increased the size of axons distal to the transected site 3.9-fold. Zonisamide also improved the sciatic function index, a marker for motor function of hindlimbs after sciatic nerve autograft, from 6 weeks after surgery. At 8 weeks after surgery, zonisamide was protective against denervation-induced muscle degeneration in tibialis anterior, and increased gene expression of Chrne, Colq, and Rapsn, which are specifically expressed at the neuromuscular junction. We propose that zonisamide is a potential therapeutic agent for peripheral nerve injuries as well as for neuropathies due to other etiologies.


Modern Rheumatology | 2017

Staged decrease of physical ability on the locomotive syndrome risk test is related to neuropathic pain, nociceptive pain, shoulder complaints, and quality of life in middle-aged and elderly people – The utility of the locomotive syndrome risk test

Shiro Imagama; Yukiharu Hasegawa; Kei Ando; Kazuyoshi Kobayashi; Tetsuro Hida; Kenyu Ito; Mikito Tsushima; Yoshihiro Nishida; Naoki Ishiguro

Abstract Objectives: A locomotive syndrome (LS) risk test for evaluation of physical ability is recently proposed. The objective of this study is to evaluate the utility of this test by examining physical ability, neuropathic pain, nociceptive pain, shoulder complaints, and quality of life (QOL). Methods: A prospective cohort study was conducted in 523 subjects (240 males, 283 females; mean age: 63.3 years) at a health checkup. Data collected using visual analog scales (VAS) for shoulder pain, low back pain, sciatica, and knee pain, neuropathic pain, shoulder complaint, body mass index (BMI), osteoporosis, and SF-36 were compared among three LS risk stages. Results: Subjects in LS risk stage 1 (24%) had significantly more osteoporosis, slower gait speed, weaker muscle strength and higher VAS, with no difference in age and BMI compared to those with no LS risk (50%). Subjects in stage 2 (26%) had significantly poorer results for all items. Shoulder complaint, neuropathic pain and QOL differed significantly among all three groups and worsened with decline in mobility on the LS risk test. Conclusions: LS risk test is easy and useful screening tool for evaluation of mobility and for screening for pain and complaint associated with activity of daily living and QOL.


Journal of Neurosurgery | 2017

Transcranial motor evoked potential waveform changes in corrective fusion for adolescent idiopathic scoliosis

Kazuyoshi Kobayashi; Shiro Imagama; Zenya Ito; Kei Ando; Tetsuro Hida; Kenyu Ito; Mikito Tsushima; Yoshimoto Ishikawa; Akiyuki Matsumoto; Yoshihiro Nishida; Naoki Ishiguro

OBJECTIVE Corrective surgery for spinal deformities can lead to neurological complications. Several reports have described spinal cord monitoring in surgery for spinal deformity, but only a few have included patients younger than 20 years with adolescent idiopathic scoliosis (AIS). The goal of this study was to evaluate the characteristics of cases with intraoperative transcranial motor evoked potential (Tc-MEP) waveform deterioration during posterior corrective fusion for AIS. METHODS A prospective database was reviewed, comprising 68 patients with AIS who were treated with posterior corrective fusion in a prospective database. A total of 864 muscles in the lower extremities were chosen for monitoring, and acceptable baseline responses were obtained from 819 muscles (95%). Intraoperative Tc-MEP waveform deterioration was defined as a decrease in intraoperative amplitude of ≥ 70% of the control waveform. Age, Cobb angle, flexibility, operative time, estimated blood loss (EBL), intraoperative body temperature, blood pressure, number of levels fused, and correction rate were examined in patients with and without waveform deterioration. RESULTS The patients (3 males and 65 females) had an average age of 14.4 years (range 11-19 years). The mean Cobb angles before and after surgery were 52.9° and 11.9°, respectively, giving a correction rate of 77.4%. Fourteen patients (20%) exhibited an intraoperative waveform change, and these occurred during incision (14%), after screw fixation (7%), during the rotation maneuver (64%), during placement of the second rod after the rotation maneuver (7%), and after intervertebral compression (7%). Most waveform changes recovered after decreased correction or rest. No patient had a motor deficit postoperatively. In multivariate analysis, EBL (OR 1.001, p = 0.085) and number of levels fused (OR 1.535, p = 0.045) were associated with waveform deterioration. CONCLUSIONS Waveform deterioration commonly occurred during rotation maneuvers and more frequently in patients with a larger preoperative Cobb angle. The significant relationships of EBL and number of levels fused with waveform deterioration suggest that these surgical invasions may be involved in waveform deterioration.


Scientific Reports | 2016

R-spondin 2 promotes acetylcholine receptor clustering at the neuromuscular junction via Lgr5

Hiroaki Nakashima; Bisei Ohkawara; Shinsuke Ishigaki; Takayasu Fukudome; Kenyu Ito; Mikito Tsushima; Hiroyuki Konishi; Tatsuya Okuno; Toshiro Yoshimura; Mikako Ito; Akio Masuda; Gen Sobue; Hiroshi Kiyama; Naoki Ishiguro; Kinji Ohno

At the neuromuscular junction (NMJ), acetylcholine receptor (AChR) clustering is mediated by spinal motor neuron (SMN)-derived agrin and its receptors on the muscle, the low-density lipoprotein receptor-related protein 4 (LRP4) and muscle-specific receptor tyrosine kinase (MuSK). Additionally, AChR clustering is mediated by the components of the Wnt pathway. Laser capture microdissection of SMNs revealed that a secreted activator of Wnt signaling, R-spondin 2 (Rspo2), is highly expressed in SMNs. We found that Rspo2 is enriched at the NMJ, and that Rspo2 induces MuSK phosphorylation and AChR clustering. Rspo2 requires Wnt ligands, but not agrin, for promoting AChR clustering in cultured myotubes. Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5), an Rspo2 receptor, is also accumulated at the NMJ, and is associated with MuSK via LRP4. Lgr5 is required for Rspo2-mediated AChR clustering in myotubes. In Rspo2-knockout mice, the number and density of AChRs at the NMJ are reduced. The Rspo2-knockout diaphragm has an altered ultrastructure with widened synaptic clefts and sparse synaptic vesicles. Frequency of miniature endplate currents is markedly reduced in Rspo2-knockout mice. To conclude, we demonstrate that Rspo2 and its receptor Lgr5 are Wnt-dependent and agrin-independent regulators of AChR clustering at the NMJ.


The Spine Journal | 2015

Dynamic changes in the spinal cord cross-sectional area in patients with myelopathy due to cervical ossification of posterior longitudinal ligament

Kenyu Ito; Yasutsugu Yukawa; Keigo Ito; Masaaki Machino; Shunske Kanbara; Hiroaki Nakashima; Tetsuro Hida; Naoki Ishiguro; Shiro Imagama; Fumihiko Kato

BACKGROUND CONTEXT Dynamic changes in the spinal cord cross-sectional area due to cervical ossification of the posterior longitudinal ligament (C-OPLL) are unknown, but dynamic multidetector-row computed tomography (MDCT) may be a useful tool. PURPOSE The purpose of this study was to evaluate the influence of dynamic factors on the spinal cord in patients with C-OPLL using MDCT during flexion and extension after myelography. STUDY DESIGN/SETTING This was a prospective cohort study. PATIENT SAMPLE Participants included 107 prospectively enrolled consecutive patients with C-OPLL and myelopathy. OUTCOME MEASURE The outcome measure was the extension/flexion ratio at the spinal cord cross-sectional area at the most stenotic cervical level (SCASL). METHODS Dynamic MDCT was performed, and the SCASL was measured. Patients were divided into the kyphosis group or lordosis group according to C2-C7 alignment. They were divided further into the K-line (-) group or K-line (+) group. The Japanese Orthopedic Association (JOA) score was used to determine myelopathy severity. RESULTS All patients with C-OPLL had myelopathy, with a mean JOA score of 10.7 and mean disease duration of 16.7 months. The average extension/flexion ratio at all disc levels was less than 100%, suggesting that the spinal cord was compressed more during extension. In the kyphosis group, the spinal cord was compressed slightly more during flexion than during extension. In the K-line (-) group, the spinal cord was compressed more during flexion, although C2-C7 alignment was slightly lordotic on average. Large changes in the spinal cord cross-sectional area during extension-flexion and disease duration significantly influenced the severity of myelopathy. CONCLUSIONS Dynamic MDCT was useful for evaluating dynamic changes in the spinal cord. At the most stenotic level, the spinal cord became narrower during extension at all disc levels. In the kyphosis group and K-line (-) group, it became narrower during flexion. Cervical flexion may induce greater spinal cord compression in patients with kyphosis and K-line (-).


Global Spine Journal | 2016

Resection of Beak-Type Thoracic Ossification of the Posterior Longitudinal Ligament from a Posterior Approach under Intraoperative Neurophysiological Monitoring for Paralysis after Posterior Decompression and Fusion Surgery

Shiro Imagama; Kei Ando; Zenya Ito; Kazuyoshi Kobayashi; Tetsuro Hida; Kenyu Ito; Yoshimoto Ishikawa; Mikito Tsushima; Akiyuki Matsumoto; Satoshi Tanaka; Masayoshi Morozumi; Masaaki Machino; Kyotaro Ota; Hiroaki Nakashima; Norimitsu Wakao; Yoshihiro Nishida; Yukihiro Matsuyama; Naoki Ishiguro

Study Design Prospective clinical study. Objective Posterior decompression and fusion surgery for beak-type thoracic ossification of the posterior longitudinal ligament (T-OPLL) generally has a favorable outcome. However, some patients require additional surgery for postoperative severe paralysis, a condition that is inadequately discussed in the literature. The objective of this study was to describe the efficacy of a procedure we refer to as “resection at an anterior site of the spinal cord from a posterior approach” (RASPA) for severely paralyzed patients after posterior decompression and fusion surgery for beak-type T-OPLL. Methods Among 58 consecutive patients who underwent posterior decompression and fusion surgery for beak-type T-OPLL since 1999, 3 with postoperative paralysis (5%) underwent RASPA in our institute. Clinical records, the Japanese Orthopaedic Association score, gait status, intraoperative neurophysiological monitoring (IONM) findings, and complications were evaluated in these cases. Results All three patients experienced a postoperative decline in Manual Muscle Test (MMT) scores of 0 to 2 after the first surgery. RASPA was performed 3 weeks after the first surgery. All patients showed gradual improvements in MMT scores for the lower extremity and in ambulatory status; all could walk with a cane at an average of 4 months following RASPA surgery. There were no postoperative complications. Conclusions RASPA surgery for beak-type T-OPLL after posterior decompression and fusion surgery resulted in good functional outcomes as a salvage surgery for patients with severe paralysis. Advantages of RASPA include a wide working space, no spinal cord retraction, and additional decompression at levels without T-OPLL resection and spinal cord shortening after additional dekyphosis and compression maneuvers. When used with IONM, this procedure may help avoid permanent postoperative paralysis.


Global Spine Journal | 2017

Rapid Worsening of Symptoms and High Cell Proliferative Activity in Intra- and Extramedullary Spinal Hemangioblastoma: A Need for Earlier Surgery

Shiro Imagama; Zenya Ito; Kei Ando; Kazuyoshi Kobayashi; Tetsuro Hida; Kenyu Ito; Yoshimoto Ishikawa; Mikito Tsushima; Akiyuki Matsumoto; Hiroaki Nakashima; Norimitsu Wakao; Yoshihito Sakai; Yukihiro Matsuyama; Naoki Ishiguro

Study Design A retrospective analysis of a prospective database. Objective To compare preoperative symptoms, ambulatory ability, intraoperative spinal cord monitoring, and pathologic cell proliferation activity between intramedullary only and intramedullary plus extramedullary hemangioblastomas, with the goal of determining the optimal timing for surgery. Methods The subjects were 28 patients (intramedullary only in 23 cases [group I] and intramedullary plus extramedullary in 5 cases [group IE]) who underwent surgery for spinal hemangioblastoma. Preoperative symptoms, ambulatory ability on the McCormick scale, intraoperative spinal cord monitoring, and pathologic findings using Ki67 were compared between the groups. Results In group IE, preoperative motor paralysis was significantly higher (100 versus 26%, p < 0.005), the mean period from initial symptoms to motor paralysis was significantly shorter (3.5 versus 11.9 months, p < 0.05), and intraoperative spinal cord monitoring aggravation was higher (65 versus 6%, p < 0.05). All 5 patients without total resection in group I underwent reoperation. Ki67 activity was higher in group IE (15% versus 1%, p < 0.05). Preoperative ambulatory ability was significantly poorer in group IE (p < 0.05), but all cases in this group improved after surgery, and postoperative ambulatory ability did not differ significantly between the two groups. Conclusions Intramedullary plus extramedullary spinal hemangioblastoma is characterized by rapid preoperative progression of symptoms over a short period, severe spinal cord damage including preoperative motor paralysis, and poor gait ability compared with an intramedullary tumor only. Earlier surgery with intraoperative spinal cord monitoring is recommended for total resection and good surgical outcome especially for an IE tumor compared with an intramedullary tumor.


Journal of Neurosurgery | 2016

How do spinal schwannomas progress? The natural progression of spinal schwannomas on MRI

Kei Ando; Shiro Imagama; Zenya Ito; Kazuyoshi Kobayashi; Hideki Yagi; Tetsuro Hida; Kenyu Ito; Mikito Tsushima; Yoshimoto Ishikawa; Naoki Ishiguro

OBJECTIVE Little is known about the progression of spinal schwannomas. The aim of this study was to determine the natural progression of spinal schwannomas and establish the risk of tumor growth. METHODS This study retrospectively analyzed data from 23 patients (12 men and 11 women, 40-89 years old) with schwannomas detected by MRI. The mean follow-up period was 5 years (range 2-10 years). The absolute and relative growth rates of the tumors were calculated. RESULTS The average tumor size was 1495 mm(3) at the initial visit and 2224 mm(3) at the final follow-up. The average absolute growth rate was 139 mm(3) per year, and the average relative growth rate was 5.3% per year. Tumors were classified into 3 groups based on enhancement patterns: isointense/hyperintense (iso/high; 11 cases), rim enhancement when enhancement was peripheral (high/rim; 5 cases), and heterogeneous/heterogeneous (hetero/hetero; 7 cases) based on Gd-enhanced T2-weighted MRI. The average absolute growth rates of the 3 lesion groups were 588 mm(3), 957 mm(3), and 3379 mm(3), respectively (p < 0.01). CONCLUSIONS Although the tumors classified as iso/high and high/rim on T2-weighted Gd-enhanced MR images were small and grew very little, most tumors with hetero/hetero classification increased in size. Hetero/hetero-type tumors should be followed closely and may require surgery.

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