Sakae Tanaka

The University of Tokyo, Edo, Tōkyō, Japan

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Publications (170)589.23 Total impact

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    ABSTRACT: We have previously reported that transforming growth factor β (TGF-β) plays an essential role in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. However, the detailed underlying molecular mechanisms still remain unclear. Formaldehyde-assisted isolation of regulatory elements and chromatin immunoprecipitation followed by sequencing (FAIRE-seq and ChIP-seq) analyses indicated the cooperation of Smad2/3 with c-Fos during osteoclastogenesis. Biochemical analysis and immunocytochemical analysis revealed that physical interaction between Smad2/3 and c-Fos is required for their nuclear translocation. The gene expression of Nfatc1, a key regulator of osteoclastogenesis, was regulated by RANKL and TGF-β, and c-Fos binding to open chromatin sites was suppressed by inhibition of TGF-β signaling by SB431542. Conversely, Smad2/3 binding to Nfatc1 was impaired by c-Fos deficiency. These results suggest that TGF-β regulates RANKL-induced osteoclastogenesis through reciprocal cooperation between Smad2/3 and c-Fos. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 11/2014; · 6.04 Impact Factor
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    ABSTRACT: Disc degeneration (DD) reportedly causes low back pain (LBP) and is often observed concomitantly with endplate signal change (ESC) and/or Schmorl's node (SN) on magnetic resonance imaging (MRI). To examine the association between DD and LBP, considering ESC and/or SN presence, in a large population study. Cross-sectional, population-based study in 2 regions of Japan PARTICIPANT SAMPLE: Of 1011 possible participants, data from 975 participants (324 men, 651 women; mean age, 66.4 years; range, 21-97 years) were included. Prevalence of DD, ESC, and SN alone and in combination in the lumbar region, and the association of these prevalence levels with LBP. This study was funded by Japanese Grant-in-Aid for Scientific Research. There is no conflict of interest. Sagittal T2-weighted images were used to assess the intervertebral spaces between L1/2 and L5/S1. DD was classified using the Pfirrmann classification system (grade 4 and 5 indicated degeneration); ESC was defined as a diffuse high-signal change along either area of the endplate, and SN was defined as a small well-defined herniation pit with a surrounding wall of hypointense signal. Logistic regression analysis was used to determine the odds ratios (OR) and confidence intervals (CI) for LBP in the presence of radiographic changes in the lumbar region and at each lumbar intervertebral level, compared to patients without radiographic change, after adjusting for age, body mass index, and sex. The prevalence of lumbar structural findings was as follows: DD alone, 30.4%; ESC alone, 0.8%; SN alone, 1.5%; DD and ESC, 26.6%; DD and SN, 12.3%; and DD, ESC, and SN, 19.1%. These lumbar structural findings were significantly associated with LBP in the lumbar region overall, as follows: DD, ESC, and SN, OR 2.17, 95% CI 1.2-3.9; L1/2, OR 6.00, 95% CI 1.9-26.6; L4/5, OR 2.56, 95% CI 1.4-4.9; and L5/S1, OR 2.81, 95% CI, 1.1-2.3. The combination of DD and ESC was significantly associated with LBP as follows: L3/4, OR 2.43, 95% CI 1.5-4.0; L4/5, OR 1.82, 95% CI 1.2-2.8; L5/S1, OR 1.60, 95% CI 1.1-2.3. Our data suggest that DD alone is not associated with LBP. By contrast, the combination of DD and ESC was highly associated with LBP. Copyright © 2014 Elsevier Inc. All rights reserved.
    The spine journal: official journal of the North American Spine Society 11/2014; · 2.90 Impact Factor
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    ABSTRACT: Objective. This study aimed to assess the mutual associations between musculoskeletal diseases (knee osteoarthritis [KOA], lumbar spondylosis [LS], osteoporosis [OP]) and metabolic syndrome components (obesity [OB], hypertension [HT], dyslipidemia [DL], impaired glucose tolerance [IGT]). Methods. Of the 1,690 participants (596 men, 1,094 women) at baseline, 1,384 individuals (81.9%; 466 men, 918 women) had complete data at the first follow-up in 2008. Logistic regression analysis included the occurrence or nonoccurrence of the musculoskeletal diseases or metabolic components as the outcome variable and the remaining musculoskeletal diseases and metabolic components at baseline as explanatory variables, adjusted for age, sex, residential region, smoking, and alcohol consumption. Results. The risk of KOA occurring increased significantly with HT (odds ratio [OR], 2.57; 95% confidence interval [CI], 1.22–5.42; p = 0.013) and IGT (OR, 1.99; 95%CI, 1.07–3.70; p = 0.029). The risk of OP occurring at the lumbar spine increased with OP at the femoral neck (OR, 4.21; 95%CI 1.46–12.1; p = 0.008), and vice versa (OR, 2.19; 95%CI, 1.01–479; p = 0.047). KOA increased the risk of HT (Kellgren–Lawrence [KL] grade = 0, 1 vs. KL = 2: OR, 1.84; 95%CI, 1.09–3.12; p = 0.024) and DL (KL = 0, 1 vs. KL ≥ 3: OR, 1.66; 95%CI, 1.05–2.61; p = 0.029) occurring. Reciprocal relationships existed between the presence of metabolic components and the occurrence of the other metabolic components. Conclusion. Mutual relationships existed between the occurrence and presence of musculoskeletal diseases, particularly KOA, and metabolic syndrome components.
    Modern Rheumatology. 11/2014;
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    ABSTRACT: Gene expression is dependent not only on genomic sequences, but also epigenetic control, in which the regulation of chromatin by histone modification plays a crucial role. Histone H3 lysine 4 trimethylation (H3K4me3) and histone H3 lysine 27 trimethylation (H3K27me3) are related to transcriptionally activated and silenced sequences, respectively. Osteoclasts, the multinucleated cells that resorb bone, are generated by the fusion of precursor cells of monocyte/macrophage lineage. To elucidate the molecular and epigenetic regulation of osteoclast differentiation, we performed a chromatin immunoprecipitation sequencing (ChIP-seq) analysis for H3K4me3 and H3K27me3 in combination with RNA sequencing. We focused on the histone modification change from H3K4me3(+)H3K27me3(+) to H3K4me3(+)H3K27me3(–) and identified the protocadherin-7 gene (Pcdh7) to be among the genes epigenetically regulated during osteoclastogenesis. Pcdh7 was induced by RANKL stimulation in an NFAT-dependent manner. The knockdown of Pcdh7 inhibited RANKL-induced osteoclast differentiation due to the impairment of cell–cell fusion, accompanied by a decreased expression of the fusion-related genes Dcstamp, Ocstamp and Atp6v0d2. This study demonstrates that Pcdh7 plays a key role in osteoclastogenesis by promoting cell–cell fusion.
    Biochemical and Biophysical Research Communications 11/2014; · 2.28 Impact Factor
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    ABSTRACT: Spinal cord injury (SCI) is a serious clinical problem that suddenly deprives patients of neurologic function and drastically diminishes their quality of life. Gene introduction has the potential to be effective for various pathological states of SCI because various proteins can be produced just by modifying nucleic acid sequences. In addition, the sustainable protein expression allows to maintain its concentration at an effective level at the target site in the spinal cord. Here we propose an approach using a polyplex system composed of plasmid DNA (pDNA) and a cationic polymer, poly{N′-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} [PAsp(DET)], that has high capacity to promote endosome escape and the long-term safety by self-catalytically degrading within a few days. We applied brain-derived neurotrophic factor (BDNF)-expressing pDNA for SCI treatment by intrathecal injection of PAsp(DET)/pDNA polyplex. A single administration of polyplex for experimental SCI provided sufficient therapeutic effects including prevention of neural cell death and enhancement of motor function recovery. This lasted for a few weeks after SCI, demonstrating the capability of this system to express BDNF in a safe and responsible manner for treatment of various pathological states in SCI.
    Journal of Controlled Release 11/2014; · 7.63 Impact Factor
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    ABSTRACT: Surgical site infection is a serious and significant complication after spinal surgery and is associated with high morbidity rates, high healthcare costs and poor patient outcomes. Accurate identification of risk factors is essential for developing strategies to prevent devastating infections. The purpose of this study was to identify independent risk factors for surgical site infection among posterior thoracic and/or lumbar spinal surgery in adult patients using a prospective multicenter surveillance research method.
    Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association. 11/2014;
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    ABSTRACT: A 45-year-old man sustained an Achilles tendon rupture while playing futsal. A concomitant medial malleolar fracture was not diagnosed until the patient underwent an operation for Achilles tendon repair. A routine postoperative radiograph showed a minimally displaced medial malleolar fracture. Conservative treatment was chosen for the fracture. The function of the Achilles tendon recovered well, and the fracture was united. A medial malleolar fracture can be missed when an Achilles tendon rupture occurs simultaneously. Thus, surgeons should consider the possibility of medial malleolar fracture associated with an Achilles tendon rupture. Copyright © 2015 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.
    The Journal of foot and ankle surgery: official publication of the American College of Foot and Ankle Surgeons 11/2014;
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    ABSTRACT: Patient satisfaction with posterior laminoplasty for cervical compression myelopathy is not yet established. Moreover, postoperative patient-reported outcomes (PROs) associated with patient satisfaction remain unclear. This study aimed to investigate patient satisfaction after double-door laminoplasty for cervical compression myelopathy, and to identify the postoperative patient-reported outcomes associated with patient satisfaction.
    Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association. 10/2014;
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    ABSTRACT: Modifying the surface and substrate of a crosslinked polyethylene (CLPE) liner may be beneficial for high wear resistance as well as high oxidative stability and excellent mechanical properties, which would be useful in contributing to the long-term performance of orthopaedic bearings. A grafted poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) layer on a vitamin E-blended crosslinked PE (HD-CLPE[VE]) surface may provide hydrophilicity and lubricity without compromising the oxidative stability or mechanical properties.
    Clinical Orthopaedics and Related Research 10/2014; · 2.79 Impact Factor
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    ABSTRACT: In this study, we aimed to determine whether the outcomes of total hip arthroplasty (THA) after rotational acetabular osteotomy (RAO) are equal to those of primary THA, and to elucidate the characteristics of THA after RAO. The clinical and radiographic findings of THA after RAO (44 hips), with minimum 24 months follow-up, were compared with a matched control group of 58 hips without prior RAO. We found that the outcomes in terms of functional scores and complication rates did not differ between THA after RAO and THA without previous pelvic osteotomy, indicating that the results of THA after RAO are equivalent to those of primary THA. Although THA after RAO requires technical considerations, similar clinical outcomes to primary THA can be expected.
    The Journal of Arthroplasty. 10/2014;
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    ABSTRACT: Recently, remnant-preserving anterior cruciate ligament (ACL) reconstruction has been increasingly performed to achieve revascularization, cell proliferation, and recovery of high-quality proprioception. However, poor arthroscopic visualization makes accurate socket placement during remnant-preserving ACL reconstruction difficult. This study describes a surgical technique used to create an anatomical femoral socket with a three-dimensional (3D) fluoroscopy based navigation system during technically demanding remnant-preserving ACL reconstruction.
    Knee surgery & related research. 09/2014; 26(3):168-76.
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    ABSTRACT: Necrotising soft-tissue infections (NSTIs) of the upper limb are uncommon, but potentially life-threatening. We used a national database to investigate the risk factors for amputation of the limb and death. We extracted data from the Japanese Diagnosis Procedure Combination database on 116 patients (79 men and 37 women) who had a NSTI of the upper extremity between 2007 and 2010. The overall in-hospital mortality was 15.5%. Univariate analysis of in-hospital mortality showed that the significant variables were age (p = 0.015), liver dysfunction (p = 0.005), renal dysfunction (P < 0.001), altered consciousness (p = 0.049), and sepsis (p = 0.021). Logistic regression analysis showed that the factors associated with death in hospital were age over 70 years (Odds Ratio (OR) 6.6; 95% confidence interval (CI) 1.5 to 28.2; p = 0.011) and renal dysfunction (OR 15.4; 95% CI 3.8 to 62.8; p < 0.001). Univariate analysis of limb amputation showed that the significant variables were diabetes (p = 0.017) mellitus and sepsis (p = 0.001). Multivariable logistic regression analysis showed that the factors related to limb amputation were sepsis (OR 1.8; 95% CI 1.5 to 24.0; p = 0.013) and diabetes mellitus (OR 1.6; 95% CI 1.1 to 21.1; p = 0.038). For NSTIs of the upper extremity, advanced age and renal dysfunction are both associated with a higher rate of in-hospital mortality. Sepsis and diabetes mellitus are both associated with a higher rate of amputation.
    Journal of Bone and Joint Surgery - British Volume 08/2014; 96-B:1530-4. · 2.69 Impact Factor
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    ABSTRACT: Object Despite its potential clinical impact, information regarding progression of thoracic ossification of the posterior longitudinal ligament (OPLL) is scarce. Posterior decompression with stabilization is currently the primary surgical treatment for symptomatic thoracic OPLL; however, it remains unclear whether thoracic OPLL increases in size following spinal stabilization. It is also unknown whether patients' clinical symptoms worsen as OPLL size increases. In this retrospective case series study, the authors examined the postoperative progression of thoracic OPLL. Methods Nine consecutive patients with thoracic OPLL who underwent posterior decompression and fixation with a minimum follow-up of 3 years were included in this study. Thin-slice CT scans of the thoracic spine obtained at the time of surgery and the most recent follow-up were analyzed. The level of the most obvious protrusion of ossification was determined using the sagittal reconstructions, and the ossified area was measured on the axial reconstructed scan at the level of the most obvious protrusion of ossification using the DICOM (digital imaging and communications in medicine) software program. Myelopathy severity was assessed according to the Japanese Orthopaedic Association (JOA) scale score for lower-limb motor function on admission, at postoperative discharge, and at the last follow-up visit. Results The OPLL area was increased in all patients. The mean area of ossification increased from 83.6 ± 25.3 mm (2) at the time of surgery to 114.8 ± 32.4 mm (2) at the last follow-up visit. No patients exhibited any neurological deterioration due to OPLL progression. Conclusions The present study demonstrated that the size of the thoracic OPLL increased after spinal stabilization. Despite diminished local spinal motion, OPLL progression did not decrease or stop. Physicians should pay attention to ossification progression in patients with thoracic OPLL.
    Journal of neurosurgery. Spine. 08/2014;
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    ABSTRACT: Objectives. This study aimed to evaluate the clinical safety and wear-resistance of the novel highly cross-linked polyethylene (HXLPE) acetabular liner with surface grafting of poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) at 3 years after total hip replacement (THR). Methods. Eighty consecutive patients underwent cementless THR using a 26-mm diameter cobalt-chromium-molybdenum alloy femoral head and a PMPC-grafted HXLPE liner for the bearing couplings. We evaluated the clinical and radiographic outcomes of 76 patients at 3 years after the index surgery. Results. The clinical results at 3 years were equivalent to a Harris hip score of 95.6 points. No adverse events were associated with the implanted PMPC-grafted HXLPE liner, and no periprosthetic osteolysis was detected. The mean femoral head penetration rate was 0.002 mm/year, representing marked reduction compared with other HXLPE liners. Conclusions. A PMPC-grafted HXLPE liner is a safe option in THR and probably reduces the generation of wear particles.
    Modern rheumatology / the Japan Rheumatism Association. 08/2014;
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    ABSTRACT: Pulmonary embolism (PE) is recognized as an important complication in patients undergoing hip fracture surgery. However, clinical evidence demonstrating the effectiveness of pharmacological thromboprophylaxis, including fondaparinux, is limited because the occurrence of postoperative PE after hemiarthroplasty is very low. The goal of this study was to analyze the effect of fondaparinux in reducing PE following hemiarthroplasty for femoral neck fracture using large-scale retrospective data.
    Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association. 07/2014;
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    ABSTRACT: The inflammatory response following spinal cord injury (SCI) has both harmful and beneficial effects; however, it can be modulated for therapeutic benefit. Endotoxin/lipopolysaccharide (LPS) preconditioning, a well-established method for modifying the immune reaction, has been shown to attenuate damage induced by stroke and brain trauma in rodent models. Although such effects likely are conveyed by tissue-repairing functions of the inflammatory response, the mechanisms that control the effects have not yet been elucidated. The present study preconditioned C57BL6/J mice with 0.05 mg/kg of LPS 48 hr before inducing contusion SCI to investigate the effect of LPS preconditioning on the activation of macrophages/microglia. We found that LPS preconditioning promotes the polarization of M1/M2 macrophages/microglia toward an M2 phenotype in the injured spinal cord on quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemical analyses. Flow cytometric analyses reveal that LPS preconditioning facilitates M2 activation in resident microglia but not in infiltrating macrophages. Augmented M2 activation was accompanied by vascularization around the injured lesion, resulting in improvement in both tissue reorganization and functional recovery. Furthermore, we found that M2 activation induced by LPS preconditioning is regulated by interleukin-10 gene expression, which was preceded by the transcriptional activation of interferon regulatory factor (IRF)−3, as demonstrated by Western blotting and an IRF-3 binding assay. Altogether, our findings demonstrate that LPS preconditioning has a therapeutic effect on SCI through the modulation of M1/M2 polarization of resident microglia. The present study suggests that controlling M1/M2 polarization through endotoxin signal transduction could become a promising therapeutic strategy for various central nervous system diseases. © 2014 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 07/2014; · 2.97 Impact Factor
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    ABSTRACT: The aim of this study was to examine the clinical characteristics of rheumatoid arthritis (RA) patients who underwent cervical spine surgery using a multicenter observational database.
    BMC Musculoskeletal Disorders 06/2014; 15(1):203. · 1.88 Impact Factor
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    ABSTRACT: The objective of the present longitudinal study was to clarify whether osteophytosis and joint space narrowing predict quality of life (QOL) decline using a longitudinal population-based cohort of the Research on Osteoarthritis/osteoporosis Against Disability (ROAD) study. The present study analyzed 1,525 participants who completed the radiographic examination at baseline and questionnaires regarding QOL at a 3-year follow-up (546 men and 979 women; mean age, 67.0 ± 11.0 years). This study examined the associations of osteophyte area (OPA) and minimum joint space width (mJSW) in the medial compartment of the knee at baseline with pain and physical functional disability measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). OPA and mJSW in the medial compartment of the knee were measured using a knee osteoarthritis (OA) computer-aided diagnosis system. Overall, OPA independently predicted physical functional disability after 3 years of follow-up. When analyzed in men and women separately, OPA, rather than mJSW, was an independent predictor for pain and physical functional disability after 3 years of follow-up in men. OPA, rather than mJSW, also predicted worsening of pain in men during the 3-year follow-up, whereas in women, mJSW, rather than OPA, predicted worsening of pain. In conclusion, the present longitudinal study using a large-scale population from the ROAD study found gender differences in the association of osteophytosis and joint space narrowing with pain and physical functional disability.
    Annals of the Rheumatic Diseases 05/2014; · 9.11 Impact Factor
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    ABSTRACT: The ultimate goal in manipulating the surface and substrate of a cross-linked polyethylene (CLPE) liner is to obtain not only high wear resistance but also high oxidative stability and high-mechanical properties for life-long orthopedic bearings. We have demonstrated the fabrication of highly hydrophilic and lubricious poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) grafting layer onto the antioxidant vitamin E-blended CLPE (HD-CLPE(VE)) surface. The PMPC grafting layer with a thickness of 100 nm was successfully fabricated on the vitamin E-blended CLPE surface by using photoinduced-radical graft polymerization. Since PMPC has a highly hydrophilic nature, the water wettability and lubricity of the PMPC-grafted CLPE and HD-CLPE(VE) surfaces were greater than that of the untreated CLPE surface. The PMPC grafting contributed significantly to wear reduction in a hip-joint simulator wear test. Despite high-dose gamma-ray irradiation for cross-linking and further UV irradiation for PMPC grafting, the substrate modified by vitamin E blending maintained high-oxidative stability because vitamin E is an extremely efficient radical scavenger. Furthermore, the mechanical properties of the substrate remained almost unchanged even after PMPC grafting or vitamin E blending, or both PMPC grafting and vitamin E blending. In conclusion, the PMPC-grafted HD-CLPE(VE) provided simultaneously high-wear resistance, oxidative stability, and mechanical properties.
    Biomaterials 05/2014; · 8.31 Impact Factor
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    ABSTRACT: Introduction Microendoscopic techniques through a unilateral paramedian approach or muscle-preserving techniques using a microscope have been reported as minimally invasive spinal decompression procedures for the cervical spine. In this study, we developed a novel technique, cervical microendoscopic interlaminar decompression (CMID) through a midline approach, for treating cervical compression myelopathy. Methods A total of 29 consecutive patients with single- or two-level cervical compression myelopathy were reviewed. For the single-level cases (e.g., C5-C6), a midline skin incision, ∼ 2 cm in length, was made at the spinal level to be decompressed (C5-C6) under fluoroscopic guidance. The nuchal ligament was longitudinally cut, and tips of the spinous processes (C5 and C6) were exposed. A 16-mm tubular retractor was inserted between the tips of the C5 and C6 spinous processes. A dome-like laminectomy of C5, partial laminectomy of the upper part of C6, and flavectomy were performed. For the two-level cases (e.g., C4-C5 and C5-C6), the decompression procedure was completed by splitting the spinous process (C5). Pre- and postoperative neurologic status was evaluated using the Japanese Orthopedic Association (JOA) score. Neck and arm pain was also evaluated using a numerical rating scale (NRS). Results Overall, 10 patients underwent single-level decompression, and 19 patients underwent two-level decompression. The average age was 67 years (range: 40-83 years), and the mean follow-up period was 11 months (range: 4-14 months). The average pre- and postoperative JOA scores were 10.2 and 13.5, with a mean recovery rate of 49%. The mean preoperative and postoperative NRS scores were 3.5 and 1.5 for neck pain and 4.6 and 2.9 for arm pain, respectively. One patient showed transient mild weakness of the leg that recovered neurologically within a few weeks. No other postoperative complications were observed. Conclusion This procedure revealed good short-term surgical results. This technique has advantages including (1) a symmetrical orientation of the surgical field, (2) an intermuscular incision that minimizes blood loss and muscle trauma, and (3) the ability to safely complete the decompression procedure without retracting the cervical spinal cord compared with the unilateral approach. Although long-term surgical results are required, this technique is not only safe but also minimally invasive as a treatment for cervical compression myelopathy.
    Journal of neurological surgery. Part A, Central European neurosurgery. 05/2014;

Publication Stats

4k Citations
589.23 Total Impact Points

Institutions

  • 1997–2014
    • The University of Tokyo
      • • Department of Orthopaedic Surgery and Spinal Surgery
      • • Department of Surgical Sciences
      • • Division of Sensory and Motor System Medicine
      Edo, Tōkyō, Japan
  • 2013
    • Kanto Rosai Hospital
      Kawasaki Si, Kanagawa, Japan
  • 2011–2012
    • Jichi Medical University
      • Department of Orthopaedic Surgery
      Totigi, Tochigi, Japan
  • 2010–2012
    • Tokyo Metropolitan Institute of Gerontology
      Edo, Tōkyō, Japan
  • 2009–2012
    • Tokyo Medical University
      • • Division of Rheumatology
      • • Department of Orthopedic Surgery
      Edo, Tōkyō, Japan
  • 2006–2012
    • Tokyo Medical and Dental University
      • Department of Cell Signaling
      Edo, Tōkyō, Japan
    • Tokyo Metropolitan Komagome Hospital
      Edo, Tōkyō, Japan
  • 2005
    • National Hospital Organization Sagamihara Hospital
      Sagamihara, Kanagawa, Japan
  • 2004
    • Sagamihara National Hospital
      Йокосука, Kanagawa, Japan
  • 2003–2004
    • Yale University
      • Department of Cell Biology
      New Haven, CT, United States
    • Matsumoto Dental University
      • Institute for Oral Science
      Matsumoto, Nagano-ken, Japan
  • 1993
    • Showa University
      • Department of Biochemistry
      Shinagawa, Tōkyō, Japan